Memorandum

Close Concerns' Reflections 2019 + 2020 - December 31, 2019

Executive Highlights

  • Diabetes Therapy: While 2018 was another foundational year of CVOTs for diabetes drugs, 2019 opened exciting new doors for the therapeutic field as a whole.

    • For SGLT-2 inhibitors, landmark DAPA-HF results (for AstraZeneca’s Farxiga) drew roaring cheers at ESC 2019 for robust positive effects in proven heart failure with reduced ejection fraction benefit in patients both with and without type 2 diabetes. In addition, J&J’s Invokana nabbed the first renal indication for the SGLT-2 inhibitor class in patients with type 2 diabetes and CKD based off of landmark CREDENCE results.
    • On the GLP-1 front, FDA approval of Novo Nordisk’s Rybelsus marked the first ever approval for an oral GLP-1-, ushering in a new formulation that will hopefully bring many more patients to this highly efficacious drug class.
    • As for DPP-4 inhibitors, results from CAROLINA (for BI/Lilly’s Tradjenta) confirmed neutrality on three-point MACE vs. sulfonylurea glimepiride, with significantly elevated rates of hypoglycemia for the SU, and VERIFY (for Novartis’ Galvus) displayed the first long-term clinical trial evidence for early combination therapy of a DPP-4 inhibitor and metformin – both of these trials should help boost commercial performance for the class and solidify their utility earlier on in combination therapies.
    • It was also a momental year for glucagon, headlined by the long-waited approvals of Lilly’s nasal glucagon Baqsimi and Xeris’ Gvoke HypoPen and pre-filled syringe. Every patient taking insulin, at minimum, should have one of these. We assume we will see investment only in truly best-in-class therapies as well as more greater relative investment on diabetes technology, drug delivery, and areas in which these two converge.
    • Finally, we saw renewed excitement for cures to type 1 diabetes, following anti-CD3 teplizumab becoming the first drug to show delay in type 1 diagnosis. Vertex Pharmaceuticals additionally made quite a splash in both the diabetes and investment communities with its $950 million acquisition of stem cell-based cure company Semma Pharmaceuticals. The T1D Fund, JDRF, and the Helmsley Charitable Trust all saw successes and we await their decisions in the year ahead and the influence of all three organizations continues to grow. Read our 11 detailed themes on diabetes therapy below, including more on combination therapies, novel therapies, and the emerging fields of NASH/NAFLD.
  • Diabetes Technology: In 2019, the biggest successes in diabetes technology went beyond CGM. Automated insulin delivery (AID) was the “here and now” that excited patients and providers. We’ve rarely, if ever, heard as much enthusiasm from patients about any therapy or technology and we’ve never seen such improvement in outcomes achieved so quickly for those that had access.
    • In 2020, we expect CGM and AID (see CGM and AID competitive landscapes) to propel patients toward better choices around medicine, food, and behavior, and to help patients live safer lives with less hypoglycemia. Less hyperglycemia is also happening due to “softer landings,” fewer overcorrections, and better decisions around food stemming from algorithm-enabled education. We estimate there are now 2.5 million people globally on CGM, and at least 250,000 on automated insulin delivery (including Tandem’s Control-IQ and Basal-IQ, Medtronic’s 670G and 640G, and all DIY), and far more growth is ahead than behind us, especially as better outcomes are validated.
    • The major problem today? Too many untrained, undertrained, and overworked HCPs. While the best technology is still available primarily to those with good access, the tide is turning as payers and employers see the power of far less hypoglcyemia and hyperglycemia as patients and HCPs get better at using TIR and tools like Ambulatory Glucose Profiles (AGPs). With AGP and CGM targets making their way into the ADA Standards of Care, momentum is strong on this front.
    • Coaching came into the mainstream in 2019, and much of the broader world learned about behavior change from the very successful $350 million IPO for Livongo. Better advice to patients should result in more prescriptions being given to the right people at the right time in the right doses – we’re staying very tuned in.
    • Problems around insulin affordability were tragic, and the one bright associated light was greater visibility of diabetes and the need to contain and address it. Juxtaposed against AID successes were stories of patients lacking access who rationed insulin regularly, and we see policies ahead that will advocate for AID and next-gen glucagon for anyone on insulin at risk of hypoglycemia.
    • Our most widely read report was once again our Automated Insulin Delivery competitive landscape. Propelling AID was intense consumer demand as well as creation of the ACE pump pathway and iController pathway by Tandem’s t:slim X2 and Control-IQ, respectively. The latter happened following the FDA’s articulation of, and vision for, fully interoperable, component-ized AID systems, which emerged in less than two years. The iCGM and iController classifications created lower-risk class II 510(k) pathways for their respective components (insulin pumps were already class II devices), and we look forward to continuing to watch how interoperability approaches emerge, given that the field is moving so this quickly, including at FDA. All eyes will be on these new pathways, with as many as four new major AID systems launching in 2020 (Tandem’s Control-IQ, Medtronic’s MiniMed 780G, Insulet’s Omnipod Horizon, and Tidepool’s Loop) and some exciting systems are not far behind.
    • Funding continues to move into digital health and deal sizes continue to grow. There were multiple high-profile companies that raised a total of $7.3 billion in 2019 digital health funding, according to Rock Health, ahead of nearly $6.0 billion in 2017 though down slightly from just over $8.0 billion in 2018. Notably, the funds raised in 2019 included two $100+ million deals - Beta Bionics and the next-gen pharmacy called Capsule – as well as Omada’s $75 million Series D and One Drop’s $40 million Series B. The field awaits proof in scalability and we await payers and employer seeing the long-term light - there’s been so much discussion about the power of prevention and the ecosystem is now looking for serious investment on this front.
  • Big Picture: In 2019, diabetes prevalence continued its unrelenting rise, as documented in the IDF’s ninth edition of its biannual Diabetes Atlas. According to these new statistics, there are now an estimated 463 million people with diabetes globally, up 9% from the last estimate in 2017. Of course, insulin pricing continues to be a topic of great importance, represented by each of the three major insulin manufacturers stepping up with landmark measures meant to combat the complex pricing situation. In March, Lilly announced its plans to introduce an authorized generic version of Humalog in the US at half the normal list price. Following the initial launch of its VALyou Savings Program in early 2018, Sanofi further expanded the program in April to provide access to all of its insulins at a flat rate of $99/month. In September, Novo Nordisk announced two major new offerings aimed at addressing insulin affordability in the US: (i) a new “Cash Card” program for analog insulins, allowing customers to purchase up to three vials or two packs of pens for $99; and (ii) the launch of follow-on-brands (authorized generics) of NovoLog and NovoLog Mix, to be priced at 50% of the list price of the branded versions.

  • Obesity: The obesity landscape continues to evolve at an increasing pace, though long-term commercial and epidemiological success for the field remains somewhat elusive. Without a doubt, however, there were a number of triumphs, including a diverse array of innovative partnerships and successful clinical trials. BI and Gubra penned their second obesity collaboration in May 2019, focusing on next-generation, peptide poly-agonists to treat the condition. Novo Nordisk and Noom partnered to bring Noom’s digital health solutions to Novo Nordisk’s portfolio of obesity treatments. Denmark-based Saniona released positive phase 3 results for its triple monoamine reuptake inhibitor tesofensine. In obesity devices, the FDA approved Gelesis’ prescription hydrogel capsule Plenity. Despite exciting movement on the development side, obesity prevalence data is still quite sobering – a December NEJM study predicted that obesity prevalence will spike to 49% by 2030, with no state at less than 35%. Already, the CDC’s 2018 state-by-state obesity data showed prevalence exceeding 20% in all US states and territories.

Table of Contents 

Diabetes Therapy

Themes

1. SGLT-2 Inhibitors Continue to Shine Across the Cardiorenal Axis, With Potential to Move Outside of Diabetes and Cardiology

2019 was a watershed year for the SGLT-2 inhibitor class, headlined by landmark data readouts from DAPA-HF for AZ’s Farxiga (dapagliflozin) in heart failure with reduced ejection fraction (HFrEF) and full results for CREDENCE for J&J’s Invokana (canagliflozin) in chronic kidney disease. With these results, the SGLT-2’s role in reducing risk of diabetes complications has been cemented, and there is great potential in even broader patient populations. Commercially, SGLT-2 revenue is increasing at double digit pace (+29% YOY in 3Q19), driving 24% of overall diabetes drug and device market growth, and we see no reason this will not continue in coming quarters.

  • Results from DAPA-HF signaled the potential of this class to address a broader patient population beyond diabetes. Cardiologists are already prescribing these agents for patients with and without type 2 diabetes (see the 2018 Journal of the American College of Cardiology paper The Changing Landscape of Diabetes Therapy for Cardiovascular Risk Reduction for the evolving role of SGLT-2 inhibitors and GLP-1s). In DAPA-HF, dapagliflozin (10 mg) conferred a 26% relative risk reduction vs. placebo on the primary composite outcome of CV death/HF hospitalization/urgent HF visit in HFrEF patients with and without type 2 diabetes. At EASD 2019, Dr. Subodh Verma (Cardiologist, University of Toronto, CAN) posited that dapagliflozin will become a “foundational therapy” for heart failure, regardless of diabetes status, and will “help cardiologists overcome inertia in patients with ASCVD.” Furthermore, he added that the results solidify that CV benefits associated with SGLT-2 inhibitors are independent of glucose lowering effects. Because SGLT-2s introduce a new mechanism of action,  dapagliflozin may show additive (and potentially synergistic) effects in current standards of care for heart failure, e.g. with Novartis’ highly effective blockbuster HF therapy Entresto (sacubitril/valsartan). In September, dapagliflozin was granted FDA Fast Track designation for development in CV death risk reduction or the worsening of HF, in adults with ejection fraction (HFpEF) or HF.

    • Dapagliflozin also received a first-in-class indication for reduced hospitalization from heart failure in October 2019, following a more comprehensive EU label expansion in August. The updated US label now includes the reduction of hospitalization for heart failure (hHF) in patients with type 2 diabetes and established CVD or with multiple CV risk factors, based on results from the DECLARE-TIMI 58 trial released in November 2018. The potential for SGLT-2 inhibitors to reduce heart failure readmission rates (>20% within 30 days) is a huge win for hospitals.

  • J&J’s Invokana obtained the first renal indication for SGLT-2 inhibitors, also including hospitalization reduction, backed by outstanding results from CREDENCE in patients with type 2 diabetes and CKD. Invokana is the first drug in nearly two decades to receive a CKD indication, the result of a 30% relative risk reduction in the primary renal endpoint of ESKD, doubling of serum creatinine, and renal or CV death compared to placebo without an increased amputation signal. In November, J&J partnered with Swiss-based Vifor Pharmaceuticals to commercialize the drug in the US for the treatment of diabetic kidney disease. Vifor brings a nephrology salesforce, while J&J’s will cover internists, endocrinologists, and cardiologists. Considering the drug’s struggling sales (-5% YOY; +2% sequentially in 3Q19), we hope this new indication brings much needed tailwind to a highly beneficial drug.

  • Pharma continues to invest in the cardio and renal benefits of SGLT-2 inhibitors. In November, Lilly and BI updated the companies’ partnership to prioritize Jardiance’s role in the risk prevention of HF and CKD. In Lilly’s press release, Carine Brouillon (Head of Global Therapeutic Areas for BI) noted that “As the versatility of the SGLT-2 inhibitor class continues to be realized, focusing our combined expertise and investment to support this important treatment will not only result in greater value for both companies but better enable us to help more people with and without type 2 diabetes." Simultaneously,  Lilly/BI launched the sixth HF trial, EMPULSE, in acute heart failure hospitalization, after receiving Fast Track designation from the FDA in June. In renal, the company’s outcomes trial EMPA-KIDNEY (n=5,000, with or without type 2 diabetes; including type 1) is scheduled to complete in June 2022. 

    • AZ also has a slew of ongoing trials --  featuring the much-anticipated DAPA-CKD renal outcomes trial (expected completion November 2020). This trial is of special interest because of Fast Track designation for CKD. For heart failure, the DELIVER HFpEF trial is slated for June 2021 completion, and two smaller walk-test trials in both HFrEF and HFpEF are scheduled for January and February 2020, respectively. Farxiga is also currently under regulatory review in China with a decision expected 1H20.

    • In addition, SGLT-1/2 inhibitor Zynquista (sotagliflozin) has several ongoing trials, including CVOTs SOLOIST-WHF in patients with worsening HF and SCORED in patients with moderate renal impairment and CV risk – though the fate of the drug is at best uncertain following Sanofi’s July decision to terminate its collaboration with Lexicon. Lexicon stated that it is seeking a new partner to carry sotagliflozin through the aforementioned phase 3 trials, as settlements with Sanofi are only expected to cover the drug’s six remaining core phase 3 programs.

Ongoing Major Trials of SGLT-2 inhibitors on Cardio and Renal Outcomes

Drug

Sponsor

Trial Name

Population

Completion Date/Latest Update

Farxiga (dapagliflozin)

AZ

Dapa-CKD

n=4,000 with CKD (eGFR ≥25 to <75 ml/min/1.73 m2), with or without diabetes. UACR ≥200 and ≤5000 mg/g. Type 1 patients excluded

Expected completion November 2020. Fast Track designation received from FDA in August 2019.

Jardiance (empagliflozin)

Lilly/BI

EMPA-KIDNEY

n=5,000 with CKD (eGFR ≥20 to <45 mL/min/1.73m² or eGFR ≥45 to <90 mL/min/1.73m² with UACR ≥200 mg/g) with or without diabetes. Type 1 patients included.

Expected completion June 2022.

Jardiance (empagliflozin)

Lilly/BI

EMPEROR HF-Preserved

Heart failure with preserved ejection fraction (n=5,250)

 

October 2020

Jardiance (empagliflozin)

Lilly/BI

EMPEROR HF-Reduced

Heart failure with reduced ejection fraction (n=3,600)

 

June 2020

Farxiga (dapagliflozin)

AZ

DELIVER

Heart failure with preserved ejection fraction (n=4,700)

June 2021

Zynquista (sotagliflozin)

Sanofi/Lexicon

SOLOIST-WHF

Type 2 diabetes and heart failure (n=4,000), with prespecified subpopulation examination of those with type 2 and heart failure with LVEF <50% after admission for worsening heart failure

January 2021

Steglatro (ertugliflozin)

Merck/Pfizer

VERTIS CV

Type 2 diabetes and established CVD (n=8,000)

December 2019

Jardiance (empagliflozin)

Lilly/BI

EMPULSE

In hospital administration in acute heart failure events in patients with and without type 2 (n=500)

July 2021

2. GLP-1s Innovate Throughout 2019 with Oral Semaglutide Approval and Positive CVOT Results

The GLP-1 class has exhibited steady growth throughout 2019 (~20% YOY growth each quarter compared to average growth per quarter in 2018 of ~25%), buoyed by continued innovation within the field and numerous exciting clinical trial results. This is a class that continues to push the frontier for safe and efficacious diabetes treatments —from excellent glucose-lowering and weight loss benefits (without risk of hypoglycemia) to novel delivery methods, in addition to solid cardio and renal protective effects. We look forward to what should be a key year in 2020 for GLP-1s.

  • Novo Nordisk’s Rybelsus (once-daily oral semaglutide, 7 mg and 14 mg)  approval following the expansive  phase 3 PIONEER program, with all 10 PIONEER studies demonstrating efficacy and tolerability with superior glucose-lowering and weight loss compared to other therapies (even SGLT-2 inhibitors). The KOL response to the drug’s approval was overwhelmingly positive, and we look forward to seeing patients’ response. Novo Nordisk disclosed that Rybelsus will be priced similarly to Ozempic ($6,520/year), and has mentioned that further access and affordability parameters are still being developed. As of December 2019, Rybelsus’ “specialist launch” is officially complete, and NN management expects a 1Q20 full commercial launch. A CV risk reduction indication based on pooled data from SUSTAIN 6 and PIONEER 6 is expected in January 2020.

    • At Novo Nordisk’s 2019 Capital Markets Day, management announced its goal to expand the GLP-1 market by promoting Rybelsus as the norm for treatment of renal, CV, and body weight comorbidities. Oral delivery will be key here, as many patients, and thus providers,  resist injections . We do believe that many, perhaps most, patients who already take once-weekly injections – Ozempic or Trulicity or Bydureon – will not change; however,  we also believe that oral formulations will be attractive to those who have considered GLP-1 in the past but not tried it – and to those who haven’t considered it but learn about this new application. We believe education by HCPs will be phenomenally important and hope that there is more focus on awareness and education with oral GLP-1 than there has been with injectable GLP-1. We also hope that HCPs who think GLP-1 only in terms of the original twice-daily version will also see that it is now much easier to prescribe and take, given so many options. We also hope HCPs won’t be too confused by so many options (this is easy to educate on, as long as doctors can take a little time)! As UCSD’s Dr. Nathan Painter said in August at AADE in Houston – “… just get them on ANY GLP-1 possible!” We look forward to learning more about patient preferences (in order to avoid nausea Rybelsus is taken on an empty stomach followed by 30 minutes before eating or drinking for best results – we’re staying tuned on this one). Regardless, we are very excited to see new GLP-1 applications that offer genuine improvement and more choice, albeit for those for whom reimbursement is not a problem.

      • As a sidenote on reimbursement, Kelly has been lucky to have been given two Ozempic pens previously by her doctor, and she loved the drug and felt it really “worked” and had a stabilizing influence on her glucose overall. However, Aetna did not cover it, even though they have covered Victoza in the past. She was thrilled to find that Aetna covers Rybellus with a $0 co-pay (and without any “cards” necessary, which would’ve been what she tried next). It is quite striking from our view that such positive reimbursement is available from such a big company, and it is particularly notable given they did not cover Ozempic (the bill for that would have been $900).  

  • By our count, there are five other oral GLP-1 candidates in development. The next push in the oral GLP-1 field appears to be towards small molecules (instead of larger peptide drugs), which might allow for cheaper manufacturing costs, better bioavailability, enhanced patient experience (eliminating fasting requirements for optimal absorption), and ultimately lower costs for patients. More speculatively, we’re interested in what the potential could be for combo pills of small molecule oral GLP-1s and SGLT-2 inhibitors. Lilly and AZ both have a GLP-1 and SGLT-2 in their portfolios. Moreover, both companies have sponsored studies showing superior benefits with GLP-1 + SGLT-2 co-administration vs. either monotherapy alone (DURATION-8 and AWARD 10). In 3Q19, Novo Nordisk discontinued development of their second oral GLP-1 “OG2023SC” in favor of a next-gen enhanced semaglutide formulation, leaving the four remaining candidates below:

    • Lilly has its own oral GLP-1 candidate (licensed from Chugai Pharmaceuticals in September 2018) that was recently moved into phase 1. Lilly’s philosophy with oral GLP-1 has been a bit different, as the company has emphasized two key points at how it’s looked at the development of such therapies: (i) improved bioavailability compared to current treatments – important for a more convenient patient experience (this could be interpreted as contrast to Novo Nordisk’s oral semaglutide, which involves a fasting requirement before administration that may be an additional burden to patients); and (ii) offering greater efficacy in oral products than currently available once weekly GLP-1s. Notably, on the first point, Lilly believes the way forward is by pursuing small molecule oral GLP-1s (rather than large peptides that get degraded in the gut, leading to low bioavailability), which was the driving motivation behind its deal with Chugai

    • vTv has an oral GLP-1 candidate (TTP273) which already has had promising phase 2 data readout at EASD 2017. TTP273 is a small molecule oral GLP-1, and phase 2 data showed particular intrigue at a low dose.

    • Pfizer is quite enthusiastic about its oral GLP-1 set to soon enter phase 2 trials. The candidate has had “very encouraging” phase 1 PK/PD results, with management noting that the candidate “is the only true small molecule that has come this far and shown this level of promise in favorable PK/PD effects.”

    • Rounding out the landscape, AZ recently confirmed that it also has a phase 1 oral GLP-1 candidateThe candidate was first added to the pipeline in 1Q18, but it’s identity had been unclear until AZ’s 2Q19 update. The candidate (MEDI7219) is currently in a phase 1 trial (n=118) expected to complete in April 2020.

  • After a breakout year for GLP-1 based dual agonists in 2018 (due to extremely positive results for Lilly’s GLP-1/GIP dual agonist tirzepatide and AZ’s GLP-1/glucagon dual agonist), dual agonists that incorporate GLP-1 continue to have forward momentum and will likely form an important part of next-gen treatments in diabetes, obesity, and NASH. GLP-1/glucagon dual agonists are plentiful in the landscape, with further development seen in 2019: In August, Innovent Biologics licensed Lilly’s GLP-1/glucagon dual agonist OXM3 for development and commercialization in China, where there is of course an enormous and growing need for more efficacious diabetes therapies. Zealand and BI’s GLP-1/glucagon candidate also advanced to phase 2 this year. Adocia plans to initiate the first-in-human study for BC glucagon GLP-1 in late 2020 as well. Further, a new type of GLP-1 combination therapy may be on the horizon, as BI partners with Yuhan Corporation to develop a first-in-class GLP-1/FRF-21 dual agonist for NASH. GLP-1 continues to be the bedrock of further pipeline development with dual and multi-agonist therapies.

  • Commercially, the GLP-1 class posted another strong year in 2019; in 3Q19, sales grew 19% YOY to $2.4 billion. Even from a high base, the class continues along a striking growth trajectory, consistently posting high double-digit YOY growth marks. Growth in 2019 reflected the strong ongoing launch of Novo Nordisk’s once-weekly injectable semaglutide (Ozempic), along with continued growth of Lilly’s blockbuster GLP-1 Trulicity. Novo Nordisk continues to flesh out the clinical profile of semaglutide, and in 2Q19 announced the initiation of four new clinical trials (FOCUS retinopathy trial, SUSTAIN FORTE of 2.0 mg higher dose, FLOW renal outcomes trial, and the SOUL CVOT) for the molecule that should further expand its indications and bolster growth. Moreover, Lilly scored a major win for Trulicity in the form of positive REWIND CVOT results for the therapy (see next paragraph). For a deeper dive on the commercial dynamics of the GLP-1 market, see our 3Q19 pooled analysis of the class.

  • Trulicity REWIND results were a major breakthrough and credibly support GLP-1’s ability to prevent MACE events in people with type 2 diabetes and without established CVD. REWIND provided the first solid evidence that GLP-1-mediated cardioprotection extends to those without established CVD, with strong consistency on the primary outcome between the trial’s primary (69% of participants) and secondary (31%) prevention cohorts (HR=0.87 on 3-point MACE for both cohorts). Importantly, many consider REWIND to be more applicable to the general type 2 population than any other previously conducted CVOT, bolstered by a long duration of follow-up (median 5.4 years), as well as a low baseline A1c (median 7.2%) and large enrollment of women (46%). This is further supported by the study’s low annual placebo MACE rate (2.7 events/100 patient-years), demonstrating a low-risk population. KOLs interpreted REWIND results as solidifying a class effect for cardioprotection. Consequently, there’s hope that these results may spur clinicians to adopt GLP-1 therapy earlier on in the treatment of type 2 diabetes, along with influencing future guidelines.

3. SGLT-2 Inhibitors Gain Approval for Type 1 Diabetes in Europe and Japan, and Meet Safety Requirements There Easily But Still Struggle to Address FDA Safety Concerns

In Europe, both AZ’s Forxiga and Lexicon’s Zynquista gained approval for patients with a BMI ≥27 kg/m2. In Japan, both Forxiga and Astellas’ Suglat were approved. The BMI cutoff in Europe was a surprise, given the relative absence of discussion around this potential mitigating factor to DKA risk beforehand. Following approval, pooled data from the DEPICT trial of dapagliflozin in type 1 showed a lower risk of DKA in those with a BMI above the 27 cutpoint.

  • In the US, Sanofi/Lexicon, AZ, and Lilly have all sought approval for SGLT-2 inhibitors in type 1, but thus far, none has been able to meet the FDA’s safety standards. Sanofi/Lexicon’s Zynquista and AZ’s Farxiga received CRLs in March and July, respectively, primarily due to DKA concerns. The prevalence of euglycemic DKA in patients with both type 1 and type 2 diabetes taking SGLT-2 inhibitors is likely grossly underreported.  Zynquista’s denial was hardly a big surprise following a deadlocked 8-8 FDA Advisory Committee ruling, one of the more tension-filled Ad Comms in our memory. DKA risk dominated the discussion, with the AC noting that there is no evidence-based or currently validated approach to reducing risk. Furthermore, a Sentinel analysis presented by FDA suggested higher-than-expected DKA rates in the real world compared to the rate seen in sotagliflozin’s clinical program. Despite the safety concerns, half of the panelists found the benefits of sotagliflozin worth the risks, and multiple members cited the need to address current off-label use. There is a lot of discussion on diabetes professional organizations listservs about when to stop SGLT-2 inhibitors prior to surgery to lower risk of DKA. One KOL recommends up to five days prior to any NPO procedure/surgery – we’re happy to see some closure on this group and would like to see formal consensus for this smaller but important group.

  • Lilly/BI also went before the FDA Advisory Committee with a specialized 2.5 mg dose of Jardiance (empagliflozin) in type 1. Although panelists overwhelmingly agreed that there was an unmet need in type 1 and emphasized that they saw promise for the therapy, critique over inadequate study size (this was surprising it would not have been earlier discussed) and length from the sole phase 3 trial EASE-3 dominated the conversation. In contrast to the deadlocked vote for Zynquista, surprisingly, only two of 16 committee members voted in favor of approval, which seemed odd since the DKA seemed far less a concern at this dose. However, there did seem to be general optimism that a low dose SGLT inhibitor (at the “sweet spot” of efficacy and safety) could one day be approved given more expansive data to better understand its entire risk/benefit profile. Disappointingly, we found some advisory committee members very blithe about what they would approve, with seemingly very little commercial understanding that the trials were very unlikely to be pursued. Although there appears to be growing interest in the potential renal and cardiovascular benefits of SGLT-2 inhibitors for patients with type 1, and while we sincerely hope to see outcomes trials to answer these questions in coming years, we believe it is very unlikely these will be easy investments for industry to make on their own, or collectively, given the small population and lack of consensus on DKA. The renowned Dr. John Buse of UNC expressed earlier this year that he felt very strongly that those with type 1 and chronic kidney disease would have a very strong likelihood of seeing reduction of risk. Specifically, he said: “…. there is a 95% chance that SGLT-2 inhibitor use in people with type 1 diabetes with CKD or heart failure would reduce heart failutre hospitalizations and CKD profession in patients. He and other researchers would like to see this studied – and people with type 1 diabetes would also like to see this investment.”

  • A growing number of KOLs have addressed this topic at recent conferences, including ADA and EASD. Germany’s Dr. Thomas Danne has had a particularly strong presence in the field, again petitioning for a dedicated type 1 CVOT and presenting a post-hoc analysis from sotagliflozin’s inTandem program at EASD.

  • Indeed, DKA risk mitigation strategies became much more specific in 2019.  At EASD, Dr. Danne highlighted several new interventions aimed at improving risk mitigation explained in detail below:

    • The EASD released two, no-cost e-learning modules for healthcare providers on adjunct type 1 therapy, with informational videos narrated by Drs. Danne and Mathieu. The Rationale for Adjunct Therapies module began with a comparison of total mortality between type 1 and type 2 diabetes from the Swedish Registry study to contextualize the importance of type 1 adjunct therapy. This was further emphasized with a focus on unmet needs in glycemic control (mean US A1c of 8.3% in type 1), severe hypoglycemia (7% surveyed reported severe hypoglycemia in the last year), and DKA (8% reported DKA in the last year) from T1D Exchange data. As higher A1c is linked with higher mortality, new adjunctive, non-insulin therapies like metformin, amylin analogues, GLP-1 agonists, DPP-4 inhibitors, and SGLT inhibitors can improve type 1 outcomes. The module states that SGLT inhibitors sotagliflozin and dapagliflozin are pertinent treatment options for adults with type 1, but do come with the risk of DKA. Dr. Danne concluded with a reminder that attaining glycemic control in type 1 is difficult, and that new treatments are needed to complement intensive insulin therapy or CGM. SGLT inhibitors are of promise given that they promote more TIR, promote weight loss, as well as potentially promote beta cell preservation, renal protection, and CV risk reduction. These modules provide a holistic view of the type 1 diabetes drug landscape, with information on the less often discussed risk of DKA. Resources like these, which include many short and informative videos with relevant data, are ideal for physicians who may not have the time to sift through years of clinical trial data.

    • ATTD also provides similar free, educational resources for those in industry with their education portal. The SGLT-2 Inhibitor Use in Type 1 resource provides a plethora of information for both endocrinologists and healthcare educators. Information is available via PowerPoint, and topics include (i) disease burden in those with uncontrolled type 1; (ii) the DEPICT trial; (iii) dapagliflozin’s EU approval for type 1; (iv) dapagliflozin’s vascular and renal outcomes in type 1; and (v) managing DKA for patients with type 1 on SGLT inhibitors. The DKA management presentation provided clarity on what DKA is, risk factors for DKA specific to those on SGLTs, and required patient education before use. The presentation also highlighted the STITCH and STOP DKA protocols, which are integral for providers to know when prescribing SGLTs to those with type 1. Materials for facilitating a peer-to-peer education program on SGLT use were also available for download in ten languages, with an option to request more translations. This slide deck led HCPs through expected, normal insulin physiology, insulin’s role as a type 1 therapy, the roles of different adjunct therapies, and the mechanism, evidence, and safety of SGLT-2 inhibitors.

    • Combined, these resources made up ~300 slides of material, definitely ample for learning more about what can lead to DKA and how to mitigate it. We hope other large diabetes organizations as well as patient nonprofits join both ATTD and EASD in providing free, downloadable materials for individuals to learn about advancements in diabetes clinical practice online. It is with resources like these that the field is able to learn altogether, allowing HCPs to practice in unison when prescribing newer medications, as well as preparing for and treating emergencies that may be linked to novel therapies.

    • The KetoAWARE Program is a free, downloadable educational program for structured DKA education in type 1 diabetes, all the way from the biological mechanisms of DKA to creating personal treatment plans for people at higher risk of DKA. The program uses the metaphor of a factory to describe glucose metabolism, making it suitable for HCPs like diabetes educators and community health workers who do not have extensive experience in medicine and biomedical science. The program also heavily emphasizes euglycemic DKA, stressing the importance of regular blood and urine ketone monitoring for those on SGLT inhibitors whenever they feel slightly ill or “off.” While the danger of DKA is underscored, the program provides information on the physical signs of DKA to look out for, guidance on when to perform ketone measurements, and ways to treat early stages of DKA with insulin and carbs. KetoAWARE also goes great lengths to outline why one may be at increased risk for DKA (i.e. if they omit insulin, participate in intense physical activity, or fast), along with using SGLT inhibitors. The program stresses that when in doubt, patients should discontinue SGLT use until DKA or symptoms subside. If increasing bolus insulin does not help symptoms subside, the program suggests finding caretaker support and getting medical help to treat DKA properly. KetoAWARE importantly takes a holistic approach to explain DKA, and we hope to see the resource translated for use by patients in the future, as well as in languages beyond English and German. 

    • Beyond online educational programs, JDRF announced a call-in request for research grant proposals investigating safe use of SGLTs in type 1 diabetes. The full announcement requested letters of intent from researchers to study safe and effective use of SGLT inhibitors for people with type 1. JDRF highlighted DKA risk as the biggest hurdle for SGLT use, with special focus on euglycemic DKA. Letters of intent were due by October 28, 2019, and full applications are due on January 8, 2020 with awardees receiving notification starting May 31, 2020. Projects are set to begin on August 31, 2020.

    • Also, at Keystone 2019, renowned endocrinologist Dr. Anne Peters revealed her personal DKA risk mitigation protocol, notably without any initial changes to insulin dosing or BMI requirements, and with the added patient selection criterion of an A1c <9.0%. This protocol was inspired by an impactful story with one of her patients. An “ideal” patient with diabetes on an SGLT inhibitor underwent DKA and would have continued to if not for Dr. Peters’ informing doctors on call to increase insulin dosage instead of decreasing it as they had been since the patient was hospitalized. Dr. Peters underscored that patient and provider education is a crucial first step, and “even with the best job that I can do, I can’t prevent DKA unless the rest of the world understands this as well.” She will be teaching her DKA risk mitigation protocol at this year’s upcoming Emergency Department Physicians meeting to inform this group about what to do when low glucose levels are seen in tandem with high ketone levels. Patients who follow her protocol need to be adherent with A1c <9.0% and an understanding of the risks of DKA and hypoglycemia from SGLT use. Ketones should be tested in the morning for two weeks to establish a baseline, only after this should low doses of SGLTs be initiated. Dosage should increase every 2 weeks based on ketone levels, and insulin does should not be altered. Ketone monitoring should persist until a patient is stable on their maximum dose but can be stopped two weeks after SGLT use has stabilized. Even after daily ketone monitoring has stopped, patients should have ketone testing supplies readily available. Patients should be advised to avoid a low-carb diet, hold SGLT use if sick, dehydrated, planning for intense exercise, or during insulin pump failure. Practitioners should also teach patients to increase carb and fluid intake and insulin dosage while holding SGLTs until ketones fall to baseline. It is integral for HCPs to be on the same page for DKA treatment protocols, and we hope the effort that doctors like Anne Peters take to share and distribute their successful protocols does not go unnoticed. Actions like these support standard, effective protocols, and individual changes can be made based on solid foundational approaches to provide the best care to patients.

4. Major Year for DPP-4s, with Data Readouts for CAROLINA and VERIFY That May Critically Influence Clinical Practice in Regard to Sulfonylureas

With the advent of SGLT-2s and GLP-1s and their increased prominence in recent years, DPP-4 inhibitors have been receding in treatment paradigms. Certainly, they do not offer the cardiovascular risk reduction and weight loss that the other two classes of medications do. Nevertheless, 2019 centered these therapies in an important way with major clinical trial results of the class.

  • Full results from the CAROLINA CVOT of DPP-4 inhibitor Tradjenta (linagliptin) vs. sulfonylurea glimepiride were presented at ADA 2019, revealing robust neutrality on three-point MACE but significantly elevated rates of hypoglycemia with sulfonylurea. As a reminder, linagliptin conferred a hazard ratio of 0.98 (95% CI: 0.84-1.14, p<0.0001 for non-inferiority, p=0.76 for superiority) – a very neutral finding indeed, and one that brings clarity to decades of concern and confusion over the cardiovascular safety of glimepiride specifically though not necessarily to the class. On body weight, linagliptin was associated with a significant reduction of 1.5 kg (95% CI: 1.8 kg to 1.3 kg weight loss) when compared to glimepiride at the end of the trial, although it is notable that the glimepiride group also achieved weight loss when compared to baseline (~0.7 kg). These results were highly anticipated and helped to shed light on a major lingering concern with sulfonylureas especially in the elderly and potential associated elevated cardiovascular risk. In his commentary of results at ADA 2019, cardiologist Dr. Darren McGuire argued that cardiologists should be reassured by the CV safety of glimepiride in the study’s population and even asserted that FDA should revisit the product-label warning for increased CV mortality for glimepiride (currently, all sulfonylureas have a black box warning for increased CV mortality). Also at ADA 2019, Dr. Julio Rosenstock summarized three main takeaway points from the trial as well:

    • CAROLINA supports the use of linagliptin before glimepiride, other than in relation to cost considerations;

    • CV safety should no longer be a consideration in the decision-making process for selecting between these two agents; and

    • CAROLINA reaffirms current clinical recommendations to choose an agent after metformin based on proven cardiovascular benefit, which neither linagliptin or glimepiride provide. It will be key moving forward to see how CAROLINA results impact clinical prescribing practices of these two classes. While it is certainly reassuring that millions of patients can be confident that the sulfonylureas they are taking do not harbor an increased CV mortality risk (assuming “real-life” weight gain associated with many SFUs is ignored), the significantly higher rates of hypoglycemia with SFUs cannot be ignored (hypoglycemia is not a risk with DPP-4 inhibitors), especially in light of more efficacious and available therapies such as SGLT-2s and GLP-1s that do not bring about such risks and offer weight loss along with important cardio and renal protection for many in each class. Sulfonylureas have certainly been deemphasized in current clinical guidelines; however, their low cost and ease of accessibility means that they are still used by millions of patients and still stand as the most prescribed second-line therapy after metformin in type 2 diabetes. When prescribing diabetes therapies, affordability often trumps efficacy although we know that many patients often do not even hear about the benefits of GLP-1 or SGLT-2 inhibitors, as demonstrated in an ADA 2019 abstract by Jimmy McDermott and Brian Levine and Eric Shogur, and we know that multiple patients may well be able to get benefit from Patient Access Programs but don’t know about them because (understandably), HCPs sometimes do not have time to deal with the hassle of PAPs (or don’t want to). We’d love to see further cost analysis that incorporate elevated hypoglycemia and weight gain risks into the costs associated with sulfonylureas compared to newer therapies. In our view, sulfonylureas should be a very last choice for patients – although SFUs may not cause overt heart disease as once feared, surely the weight gain associated with them (especially in “real life”) must indirectly be negative for patient physicial and emotional well-being.

    • The study was also well-received from the KOL community because of its active comparator design (compared to most CVOTs and large placebo-controlled trials). At EASD 2019, for example, Prof. Philip Home noted that he loved CAROLINA from the moment I heard of its conception, because it was an active comparator study pitting linagliptin against an active comparator.” Indeed, while we were excited to see the results of this much-anticipated trial, and while we hope that the important learnings that it has stimulated for the community further spurs sponsors and other stakeholders to engage in such active comparator trial designs, we also would love to continue to see real-world data on this class to better understand challenges of the class. We’d also be very interested in seeing future trials with lower-dose SFUs and we’d love to see active comparator trials using SGLT-2s and GLP-1s in the future as well.

  • Results from the VERIFY study, investigating early combination therapy of DPP-4 Galvus (vildagliptin) and metformin, brought forward the first pieces of evidence from long-term clinical trials of the benefits of such combination therapy. Presented at EASD 2019, VERIFY showed that initial combination therapy conferred a significant, 26-month delay in the primary outcome of treatment failure (A1c > 7%; HR: 0.51; 95% CI: 0.45-0.58; p<0.0001). Those on early combination surpassed 7% A1c at 62 months versus 36 months on monotherapy and also showcased a delay in insulin initiation over the course of the 60-month study (p<0.0001). Interestingly, initial combination therapy was associated with fewer CV events – sparking deep interest for future exploration of CV outcomes, particularly associated with prevention of type 2. We see immense potential for VERIFY results to positively combat therapeutic inertia in the field. In The Lancet publication of VERIFY results, the study’s authors Matthews et al., note that “The findings of VERIFY support and emphasize the importance of achieving and maintaining early glycemic control… However, durable A1c values below 6.5% are unlikely to be achieved with monotherapy alone…Real-world evidence has shown how delayed treatment intensification after monotherapy failure results in increasing time spent with avoidable hyperglycaemia, raising a crucial barrier to optimized care. The durable effect we observed with an early combination strategy therefore provides initial support for such an approach as an effective way to combat clinical inertia.” Many KOLs have similarly reacted to VERIFY results: Prof. Stefano Del Prato was optimistic in his independent commentary that these results could help overcome therapeutic inertia in treatment practice, Dr. Daniel Drucker interpreted results as a reason to “think like an oncologist” and adopt combination treatments earlier on in disease in order to successfully treat the complex disease that is type 2 diabetes, and Dr. Kamlesh Khunti similarly emphasized the implications of VERIFY in addressing inertia. We’re glad to see this push for earlier combination therapies to take the place of sequential treat-to-failure paradigms.

  • Commercially, the sum of these two trials should serve as a boost to DPP-4 sales. While CAROLINA results were not necessarily resoundingly positive for the class (a clear win would have been Tradjenta showing superiority on reducing CV events vs. glimepiride), we believe the resounding benefits seen in regard to hypoglycemia will further shift the field away from sulfonylureas and toward other therapies, including DPP-4s. VERIFY results should amplify this trend, as we hope to see patients and providers move toward earlier adoption and more aggressive use of DPP-4s in treatment paradigms. We’re curious as to whether future guidelines may even promote combos of generic DPP-4/metformin as first-line therapy. Looking even further ahead, we’re highly optimistic about the potential of triple therapy generics of SGLT-2s/DPP-4s/metformin – these could be low-cost, potent polypills that should streamline ease-of-use for patients early on in disease progression with a lower pill burden. We do note that one drawback of these combination pills may be their rigidity when it comes to flexible dose adjustments, although we maintain that the many benefits patients experience with these pills far outweigh this concern.

5. Landmark Year for Next-Gen Glucagon with Approval of Lilly’s Nasal Glucagon Baqsimi and Xeris’ Gvoke HypoPen and Pre-Filled Syringe

A landmark year for next-gen glucagon was highlighted by the long-awaited approval of two new treatment options for patients: Lilly’s nasal glucagon Baqsimi and Xeris’ Gvoke HypoPen and pre-filled syringe. In a very popular win for patients and the entire diabetes community, Lilly’s nasal glucagon Baqsimi gained FDA approval in July 2019 as the first-ever severe hypoglycemia emergency treatment that does not require an injection. Baqsimi comes in a single-use dispenser that passively administers nasal powder glucagon without the need for preparation, injection or active inhalation and is available at the same price as current glucagon injections at $280/pack. The price did receive a fair degree of negativity on social media, and we believe the pricing for “traditional” glucagon had been fairly under the radar screen. Following approval, we’ve noted significant enthusiasm for Baqsimi at major diabetes conferences though we aren’t yet positive about access overall, particularly for Medicare and Medicaid. For example, at AADE 2019, a mannikin study of Baqsimi drew considerable interest: To mimic a real-world situation in which emergency glucagon would be needed, site staff first formally instructed a person with diabetes on how to use either nasal glucagon (NG) or injectable glucagon (IG). An hour later, the person with diabetes instructed a caregiver on how to use the same technology. After a week, the caregiver returned to the testing site, where they were challenged with using the assigned technology in a simulated hypoglycemic emergency on a high-fidelity manikin. Of the trained users in this small study (n=32), 90.3% of NG users were able to administer medication successfully, while only 15.6% of IG users were able to do so. Impressively, in a follow-up study, even 90% of untrained users (n=33) were able to successfully administer nasal glucagon, while none were able to use the IG successfully. As expected, participants overwhelmingly favored NG, finding it easier to prepare and use. Notably, Lilly has also widely promoted Baqsimi at product theaters and in exhibit halls, and we expect “modern” applications of glucagon will make a huge difference in filling the large unmet need for easier to use glucagon in emergency situations in multiple community settings formerly unable to administer injectable remedies. We can even envision a future where Baqsimi in particularly is available side by side with AEDs in public places; an aligned advocacy effort would need to be put together to make this happen, which we see as a very possible area of exploration (admittedly, we have not thought through costs and logistics in detail).

  • In addition, and just as importantly, Xeris’ Gvoke HypoPen and pre-filled syringe were approved by the FDA in September 2019. This breakthrough for the field had been a long time coming, especially considering Xeris expected an NDA filing for the franchise in late 2013 (which then got delayed to October 2018). Designed to be easier for patients and caregivers, both forms of GVOKE will greatly reduce the steps to prepare and administer glucagon during severe hypoglycemia. Along with not requiring reconstitution or manual dosing, the HypoPen auto-injects and auto-retracts with a needle guard. Xeris’ usability studies have shown a 99% success rate in giving the full dose of glucagon in only two steps, compared to 6%-31% for traditional glucagon emergency kits. This, combined with positive results from Xeris’ phase 3 data (ADA 2018) from efficacy, safety, and utility studies, reaffirmed GVOKE’s ability to lessen the stress of emergency hypoglycemia management. The availability of an injectable glucagon also remedies any theoretical concerns on dosing or nasal/respiratory irritation for the nasal glucagon Baqsimi. The pre-filled syringe officially launched in November, and is now available by prescription for home delivery (via Amazon’s PillPack) and at local pharmacies. Looking ahead, the HypoPen’s launch is expected in 2020.

    • A variety of trials have supported the GVOKE franchise up to its launch. Positive phase 3 results in the European HypoPen trial supported its non-inferiority to Novo Nordisk’s GlucaGen HypoKit on achieving primary endpoints of primary endpoint of achieving (i) plasma glucose >70 mg/dl; or (ii) a ≥20 mg/dl increase in plasma glucose concentration within 30 minutes of glucagon administration during severe hypoglycemia (BG <54 mg/dl). Results from a cost study in March 2019 suggested 8% cost savings with HypoPen over traditional glucagon kits. Mini-dose glucagon has recently shown positive results in patients having undergone bariatric surgery, and is currently being studied in the prevention of exercise-induced hypoglycemia.

  • Looking ahead, Zealand appears to have its next-gen glucagon (HypoPal dasiglucagon rescue pen) on the cusp of market entry. As of their 3Q19 update, HypoPal is still slated for an “early 2020” submission to the FDA. In September 2019, the company shared positive phase 3 results supporting HypoPal’s use in pediatric populations. Both primary and secondary endpoints were met with a median time to blood glucose recovery of 20 minutes – matching the time to recovery seen in adults. Efforts are currently in place to prepare US commercial operations for an anticipated upcoming product launch, which we assume will be sometime in 2020. Our understanding is that all of the necessary trials for HypoPal’s submission have been completed except for an ongoing technical study to expand the room temperature shelf life of dasiglucagon, which appears to be underway. A longer room temperature shelf life is important to patients who are often resistant to keeping hypoglycemia emergency kits on hand that wind up unused and discarded when expired.

  • In terms of market potential, we see broad opportunity for Baqsimi and other next-gen glucagon products to experience commercial success. Lilly’s glucagon grossed $150 million in 2018, and we estimate Novo Nordisk’s GlucaGen sales to be in a similar range, although they do not officially release these results (Novo Nordisk posted $712 million in “other diabetes care” sales in 2018, though breakdown between oral products, needles, and GlucaGen was not provided). In the past, Xeris has officially estimated US market potential for its Gvoke HypoPen at $2 billion annually based on current glucagon emergency kit prices and a patient population of 3.5 million – this would assume the patient population is buying 2-3 glucagon kits/year, and that Xeris is able to reach half of all insulin users, which seems quite ambitious though the number of people going on insulin will certainly continue to grow. On the other hand, Zealand estimates a >$700 million market by 2025, a less ambitious estimate that still represents more than doubling from the 2016 base of $300 million/year (a number Zealand provided at its 2018 Capital Markets Day). Regardless, it’s clear that there’s major demand for this innovation in diabetes care, and that numerous patients could benefit from nasal glucagon, along with broader education on glucagon use as an effective and now simpler hypoglycemia treatment. Looking ahead, we hope to see manufacturers and other stakeholders leverage these innovations within the class to promote broader uptake and education within insulin users in the diabetes community – certainly anyone on rapid-acting insulin in our view should have access and there is definitely an argument for anyone on insulin at all. There are still costs that are far too high for severe hypoglcyemia that culminate in the emergency room or calling an ambulance. Both of these should be 100% preventable with the right easy-to-prescribe and easy-to-use tools, which now exist.

  • We continue to view glucagon as an especially underutilized therapy, and hope to see the emergence of these more innovative treatment options help to fill this important gap in treatment. Following GVOKE’s approval, Xeris’ CEO Paul Edick emphasized this point, highlighting that there are only ~660,000 annual glucagon prescriptions filled (many go un-filled) for what he estimated as ~5.6 million insulin users in the US. While the implication here is that every insulin user in the US should have a glucagon prescription, which seems a bit intractable, it’s clear that the market is underpenetrated and has ample room for further growth and improvement.

6. Updated European Society of Cardiology (ESC) Guidelines Make a Splash with Highly Debated Recommendation for First-Line SGLT-2/GLP-1 Usage Above Metformin in Select Patients – ADA Guidelines Also Gain Major Attention, as Does Greater Focus on Risk Stratification

  • ESC made a major splash this year by updating its diabetes, prediabetes, and CVD guidelines for the first time since 2013 – most notably, this update contained a recommendation of using SGLT-2 inhibitors and GLP-1 agonists as first line therapies ahead of metformin in patients with established ASCVD or at very high CV risk. This update, which lowered the ranking of metformin as first line therapy for overweight patients with type 2 diabetes without CVD at moderate CV risk, received much discussion in the diabetes community. KOL reaction was mixed but generally positive. Dr. Silvio Inzucchi commented that the decision was “forward-thinking but may push the envelope a bit too much”; Dr. Sanjay Kaul noted that “this recommendation was a long time coming and is faithful to the evidence”; Dr. John Buse was a bit more reserved, saying that “The ESC group has clearly thought carefully about their recommendations. Though I think they are acceptable, they do go a bit beyond the available data with best intentions.” Further, Dr. Mikhail Kosiborod explained that this decision was a “huge step in the right direction”, while Dr. Dan Drucker commented more cautiously that “it is worth noting that the majority of people studied in these trials were already on metformin-our database for robust cardioprotection with these two classes of drugs as first-line therapy alone in the absence of metformin is much less scientifically compelling.” We applaud ESC for progressively incorporating breakthroughs from recent CVOTs into its guidelines and working to combat therapeutic inertia by recommending cardioprotective agents even earlier on during treatment. With newer glucose-powering agents offering CV benefits, diabetes medications for those with type 2 should be less “glucose-centric” or selected based on the ability to reduce A1c or time-in-range, but selected on their ability to positively affect the many multimorbidities associated with the disease that lead to costly care in the later stages of disease progression.

  • New ESC guidelines also brought focus to risk stratification when diagnosing patients and tailoring treatment options. ESC provided new risk categories for CV, replacing the binary distinction of “primary vs. secondary” prevention patients with a wider spectrum (very high risk, high risk, moderate risk, and low risk). Accompanying this finer distinction of CV risk was the introduction of new assessments of patient risk. At ESC 2019, for example, a newly developed TIMI Risk Score for Heart Failure in Diabetes was presented for use as a clinical tool in predicting HHF. The Risk Score is a composite of five clinical variables: 

    • prior heart failure (two points);

    • atrial fibrillation (one point);

    • coronary artery disease (one point);

    • eGFR below 60 (one point); and

    • two points for an UACR >300 or one point for UACR between 30-300.

  • Notably, at AHA 2019, a biomarker analysis of DECLARE found that integrating NT-proBNP and hsTnT levels may yield important information regarding risk stratification and SGLT-2 treatment.

  • ADA just published its 2020 Standards of Care as well, highlighted by the recommendation that the decision to use GLP-1s and SGLT-2 inhibitors for CV/renal benefit should be considered independently of baseline or target A1c. This is a crucial distinction and underscores the glucose-independent effects of both of these classes and emphasizes the shift away from glucose-centric diabetes management approaches. Importantly, however, metformin remains the first-line treatment in these guidelines, differing from the abovementioned ESC guidelines. That said, from our view, GLP-1 and SGLT-2 are also really considered “first-line” if someone with diabetes is diagnosed and at that time is at high risk of CVD, heart failure in particular, or CKD.

  • 2019 also marked the second year of ADA’s Living Standards of Care that integrates recent research in the constantly evolving diabetes ecosystem. ADA published its 2019 Standards of Care in December 2018, and then proceeded to issue several updates over the course of the following year to reflect important new information generated. In March, updates were issued include data from DECLARE (CVOT for Farxiga) and REDUCE-IT (CVOT for Vascepa). In April, ADA released its nutrition therapy consensus report, with accompanying updates to its living standards as well. In June, A-level recommendations were made recommending SGLT-2 inhibitors in people with type 2 and CKD, based on CREDENCE data (CKD trial of Invokana). In August, updates were made to include (i) time in range goals and standardized CGM metrics; (ii) REWIND results (CVOT for Trulicity); and (iii) a recommendation for Victoza in pediatric populations. We are thrilled to see ADA’s commitment to ongoing updates to its Standards of Care as new findings emerge.

7. Renewed Excitement in Cures to Type 1 Diabetes: Anti-CD3 Teplizumab as First Drug to Show Diagnosis Delay, Semma Therapeutics’ $950 Million Acquisition, First Clinical Trials Show Early Success

It was a breakout year for type 1 intervention therapies, headlined by anti-CD3 teplizumab’s breakthrough results demonstrating it to be the first drug shown to delay type 1 diagnosis. The phase 2 study (n=76), presented at ADA 2019, demonstrated marked reductions on cumulative diabetes onset (72% vs. 43%, HR=0.41, p=0.006) and time to diagnosis (48 months vs. 24 months) with just a single 14-day course of the anti-CD3 treatment compared to placebo. Participants were identified by TrialNet’s Pathway to Prevention screening program and in “Stage 2” of type 1 disease progression, meaning that they had two or more type 1 autoantibodies and abnormal blood glucose levels (nearly 100% of those in Stage 2 progress to a clinical diagnosis of type 1 in their lifetime). The results were also simultaneously published in NEJM and accompanied by an editorial penned by Drs. Clifford Rosen and Julie Ingelfinger, indicating the importance of this landmark finding. Anti-CD3 drugs have a very challenging history, with failed phase 3 trials in 2010 (MacroGenics and Lilly) and 2011 (Tolerx and GSK); will larger studies replicate teplizumab’s promising early results?

  • Also in phase 2, Novo Nordisk unveiled promising topline results for its anti-IL-21 and GLP-1 liraglutide combination therapy in people with newly-diagnosed type 1 diabetes during its 2Q19 update. The study (n=308) found statistically significant improvements in beta cell function (measured in AUC for stimulated C-peptide) for the combination of anti-IL-21 (administered through IV every six weeks) and liraglutide (daily injections) after 54 weeks vs. placebo. Importantly, neither anti-IL-21 or liraglutide monotherapy conferred any of these benefits, indicating the synergistic effect of the therapies may be the key to success. A full presentation of the data is expected at a future medical conference, and management is currently “engaging with regulatory authorities to evaluate next steps” – no further updates were given in the company’s 3Q19 update. Excitingly, Novo Nordisk additionally expressed reignited commitment to curative therapies during its 2019 Capital Markets Day, where CSO Dr. Mads Thomsen shared the company’s goal to have a “curative, cell-replacement therapy to alleviate and eliminate the need for insulin therapy in type 1” within the next ten years.

  • Vertex Pharmaceuticals made a big splash in both the diabetes and investment communities following its whopping $950 million acquisition of Semma Pharmaceuticals. Semma was a pre-clinical stage company; Vertex is planning to initiate the first clinical trial in patients with “difficult to treat diabetes” and hypoglycemia unawareness in 1H20, following positive pre-clinical data, in collaboration with Defymed (encapsulation system), announced in July 2019. Looking to others in the field, Sernova announced positive preliminary results for its phase 1/2 Cell Pouch microencapsulation system, also designed to provide a vascularized environment for donor islet cells or stem cells; study completion is slated for February 2022. ViaCyte also released news of the first demonstrated C-peptide production in participants from its phase 1/2 PEC-Direct trial (n=7) in October 2019. A European PEC-Direct clinical program was similarly initiated in January 2019. Of note, ViaCyte’s PEC-Direct is the first and only stem-cell derived therapy currently in human clinical trials, using PEC-01 cells derived from ViaCyte’s proprietary CyT49 pluripotent stem cell line.

  • In research, JDRF announced a new partnership with Stanford and UCSF to create a type 1 “Cure Accelerator”. The type 1 “Center of Excellence” will build upon two key advancements pioneered by Stanford and UCSF: (i) Stanford’s protocol for kidney transplantation without immunosuppression; and (ii) UCSF’s method for deriving insulin-producing beta cells from stem cells. Leadership for the Center will include Drs. Matthias Hebrok (UCSF), Seung Kim (Stanford), Aaron Kowalski (JDRF President and CEO), Andrew Rakeman (JDRF AVP of Research), and Jeffrey Bluestone (UCSF). JDRF is currently spearheading funding efforts for the Center and is committed to providing annual funding for the first five years of operation with funding beyond year three confirmed after a review and evaluation. In addition to the new leadership role, Dr. Matthias Hebrok also published a February 2019 report in Nature Cell Biology on his lab’s novel procedure for transforming human stem cells into mature insulin-producing “enriched beta-clusters” using islet-like clustering.

  • To learn more, check out our type 1 diabetes cure and prevention competitive landscape.

8. Phase 3 Successes and Flops in NASH as Field Moves Toward First Approved Therapies Indicated for the Disease

This past year saw great movement within the NASH landscape, with several candidates having phase 3 results reported and the first potential approval for NASH being submitted to FDA. We saw tremendous investment in the field from multiple major stakeholders looking to capitalize on the large unmet need in NASH and the lack of any currently approved therapies for the disease.

  • Intercept Pharmaceuticals’ obeticholic acid (OCA) has the potential to become the first drug to be officially FDA approved for the treatment of NASH. In February, the company announced positive interim results from its phase 3 REGENERATE trial (n=2,370) of OCA in NASH, with additional details presented at EASL 2019. Notably, OCA 25 mg (once-daily) achieved superiority on one of its two co-primary endpoints in the 72-week interim analysis: OCA 25 mg met significance on the primary endpoint of fibrosis improvement of at least one stage with no worsening of NASH (p=0.0002 vs. placebo), while trending toward improvement without reaching significance on the endpoint of NASH resolution with no worsening of liver fibrosis. Then, in December, FDA officially accepted the company’s NDA for OCA in NASH and also granted it priority review, with a PDUFA date set for March 26 and an Advisory Committee to be convened sometime before then.

    • On December 16, Intercept management held a Commercial Day to review OCA data and preview commercial plans. The company’s commercial focus will be “advanced fibrosis due to NASH”, which is the last, most serious stage before cirrhosis. While only 10% of NASH patients have cirrhosis, cirrhosis accounts for over 80% of annual direct medical costs of the disease, according to data cited by the company. Of the approximately 20 million people estimated to have NASH, 500,000 fall within the definition of “advanced fibrosis due to NASH”. Intercept believes that with a sales force of 5000 reps covering hepatologists and another 10,000 covering gastroenterologists, 250,000 patients within this category can be reached. Payer coverage is approximately 60% private and 40% public (Medicare). As a reminder, Intercept currently sells OCA for use in primary biliary cirrhosis (“PBC”) and has annualized sales of $250 million globally in that market. Intercept has already had significant success in hepatology marketing a first-in-class drug.

    • Intercept has also been tracking critical biomarkers throughout the REGENERATE trial and presented data during Commercial Day, arguing that biomarkers can be used in place of (highly) invasive and expensive liver biopsies to measure disease regression or progression. In addition to individual biomarkers, the company also referenced algorithms that have been developed by researchers in the field, and imaging technologies that are gaining acceptance in the management of NASH. Data generated by Intercept and others increasingly suggest that algorithms combining blood serum markers (FIB-4, NFS, APRI) confirmed by imaging (FibroSURE, ELF, FibroScan) have accuracy comparable to liver biopsies. To the extent that the practitioners and payors accept algorithms, or their components, Intercept’s targeted patient population potentially expands dramatically. As it stands now, patients with advanced fibrosis due to NASH routinely have liver biopsies. There is of course strong interest in what OCA pricing will be, and during the meeting the company deflected questions on this topic by reasonably responding that it will need to see the FDA label before making final pricing decisions. Once the FDA approves a drug for the treatment of NASH, a required liver biopsy could be a potential barrier for some patients.

  • Once a leader in the field, Gilead also announced negative phase 3 results for its NASH candidate selonsertib. Disappointingly, the candidate did not meet its primary endpoint in either of its phase 3 trials (STELLAR 3 or STELLAR 4). As a result, the company is no longer investigating selonsertib as a monotherapy, but continues to have hope for it in combination therapies for the treatment of NASH. The phase 2 ATLAS trial, testing combinations of selonsertib, cilofexor (FXR agonist), and firsocostat (ACC inhibitor) in F3-F4 patients also failed to reach primary endpoints in December.  There is increasing investor pressure on Gilead to reduce its research commitment to NASH.

  • There are at least 40 companies, public and private, active in developing therapies for NASH, including diabetes giants Novo Nordisk and Lilly. Novo Nordisk has a research collaboration in place with Gilead, exploring potential combinations of GLP-1 with anti-fibrotic agents. We imagine Lilly has similar interest in finding an anti-fibrotic to combine with terzepatide (GLP-1/GIP).

  • In June, FDA released a draft guidance for the development of drugs for the treatment of NASH with compensated cirrhosis (F4 fibrosis due to NASH). This is a particularly high-risk and high-need population within the subset of patients with NASH, and came six months after FDA put forward a similar guidance for clinical and early drug development of noncirrhotic NASH (F1-F3 fibrosis) drugs. The draft guidance primarily focuses on considerations industry sponsors should make in designing phase 3 trials for compensated NASH cirrhosis drugs. The document contained three dedicated sections for (i) patient population/enrollment criteria; (ii) trial design/efficacy endpoints; and (iii) safety considerations. It’s clear that FDA is paying close attention to the landscape, with multiple industry stakeholders on the verge of submission for potential approval.

  • 2019 saw a number of novel partnerships and collaborations between various industry stakeholders interested in the NASH landscape. See table below for a recap of the partnerships that were announced this year in NASH and let us know if we’ve missed any!

NAFLD/NASH Partnerships in 2019

Companies Involved and Date of Partnership Announcement

Implications

Gilead and Insitro (April 2019)

Three-year collaboration between Gilead and Insitro to use machine learning and genomics to discover and develop NASH therapies

Novo Nordisk and Gilead (April 2019)

Novo Nordisk and Gilead announced they will conduct a proof-of-concept study combining GLP-1 agonist Ozempic (semaglutide), FXR agonist cilofexor (GS-9674), and ACC inhibitor firsocostat (GS-0976) in NASH.

Gilead and Renown Institute (October 2019)

Gilead and Renown will collect and analyze genetic and electronic health data to enhance the understanding of NASH and potentially inform development of treatment options for the disease

Novo Nordisk and Dicerna (November 2019)

Novo Nordisk and Dicerna Pharmaceuticals announced  a partnership  to develop RNAi therapies for the treatment of liver-related cardio-metabolic diseases, utilizing Dicerna’s proprietary GalXC (pronounced “galaxy”) RNAi platform technology.

9. Hope for GLP-1/Basal Insulin Fixed-Ratio Combinations? Growth Bounces Back Following First-Line Injectable Indications

It was another tepid year for Sanofi’s Soliqua (insulin glargine/lixisenatide) and Novo Nordisk’s Xultophy (insulin degludec/liraglutide), including the market’s first sequential decline of -3% in 1Q19. Notably, growth does seem to have bounced back following US label expansions for both Xultophy and Soliqua to first-line injectable status in February 2019, with the class rising +33% YOY to $122 million from $92 million in 3Q18. On top of the first-line indication, the FDA also approved adding CV safety from both LEADER and DEVOTE, the CVOTs for Victoza (liraglutide) and Tresiba (insulin degludec), to Tresiba’s label in 2019. Interestingly, despite the added CV safety bonus for Tresiba, Soliqua has actually demonstrated more robust sales than Tresiba in the last quarter (+19% sequential growth vs. -2%). Coverage remains a significant access barrier for these fixed ratio combination therapies, with the choice often made by the payer, not the prescriber. We also wonder if Sanofi’s growth is in part aided by the company’s commitment to putting Soliqua front-and-center at recent conference exhibit halls, where we’ve heard many eager sales representatives share the drug’s impressive range of benefits. Putting the exact product aside, we continue to hope for greater uptake of this therapy. In our view, fixed ratio combination therapy is a simpler alternative to basal/bolus insulin therapy for patients with type 2 diabetes that would benefit from a reduction in both pre and post prandial blood glucose levels. They both come with an added bonus of weight loss, single daily injection and less need for pre-prandial glucose monitoring and insulin dose calculations. When both product’s initially launched, there was significant excitement from the KOL community – Dr. John Buse called Xultophy “the most effective anti-hyperglycemic agent on the planet” – but we’ve yet to see real-world results reflect these opinions. Considering the plethora of positives backing up these agents and that US labels now allow direct initiation of these combinations prior to GLP-1 or basal therapy, it’s likely that (i) reimbursement/affordability; and (ii) HCP familiarity remain the two greatest barriers to further expansion. Of course, the shift to first-line injectable will need more time to disseminate fully, but we’d be surprised if sales were to jump without serious changes to drug accessibility and marketing.  

10. Rhetoric and Pressure Continues to Build on Insulin Pricing, with Manufacturers Taking Dramatic Steps to Address Issue + Potential Action for Legislative Bodies in US

Following a year of intense rhetoric surrounding insulin pricing, 2019 saw important action from manufacturers in addressing this large and growing problem. Like never before, each of the three major insulin manufacturers introduced prominent measures meant to address the failures of complex insulin pricing regimes: In March, Lilly announced its plans to introduce an authorized generic version of Humalog in the US at half the Humalog list price. The new brand, to be called Insulin Lispro, is the same molecule as Humalog – meaning it will be interchangeable at the pharmacy counter (key for patient and provider convenience) – and will be made available through Lilly subsidiary ImClone Systems. Following the initial launch of its VALyou Savings Program in early 2018, Sanofi further expanded the program in April to provide access to all of its insulins at a flat rate of $99/month. Sanofi promised that uninsured patients with a valid prescription would pay $99 total for up to 10 boxes of pens or 10 vials per month, instead of the previous $99 per vial and $149 per five pack of pens. This was a fantastic move to address the “dosing tax” associated with insulin – additive costs for those who use more than one pack of pens or vial per month. Lastly, in September, Novo Nordisk announced two major new offerings addressing insulin affordability in the US: (i) a new “Cash Card” program for analog insulins, allowing customers to purchase up to three vials or two packs of pens for $99; and (ii) the launch of follow-on-brands (authorized generics) of NovoLog and NovoLog Mix, to be priced at 50% of the list price of the branded versions. Novo Nordisk’s program blends features offered by Lilly (authorized generic) and Sanofi (flat rate savings). Although steps in the right direction, the key test will be patient accessibility, which is often dependent not only on company marketing but also on the interest of HCPs and their time needed to help submit required paperwork.

  • Action followed several high-profile congressional hearings centering on insulin and drug pricing. To recap: In late January, the Senate Committee on Finance and House Committee on Oversight and Reform held simultaneous hearings on rising drug costs, with a notable focus on insulin pricing. A few weeks later, the Senate Finance Committee held a second highly-anticipated hearing on drug pricing, featuring testimony from AbbVie, AZ, BMS, J&J, Merck, Pfizer, and Sanofi execs.  Each executive emphasized similar points of action to address rising drug costs: (i) eliminate the current rebate system that promotes high list prices (for both public and private contracts) for chronic-use drugs; (ii) initiate value-based contracts that link drug prices to patient outcomes; and (iii) encourage biosimilar and generic competition. There was no specific focus on insulin pricing at this hearing, although the Committee had announced an inquiry into insulin pricing the previous week. Next, in April, leadership from five pharmacy benefit managers (PBMs) testified before the Senate Finance Committee in part three of its “Drug Pricing in America” series, with a specific emphasis on insulin pricing. Finally, on April 15, the House Committee on Energy & Commerce held a hearing – “Priced Out of a Lifesaving Drug: Getting Answers on the Rising Cost of Insulin” – where members engaged execs from Novo Nordisk, Sanofi, Lilly, Express Scripts, CVS Health, and OptumRx on insulin affordability. The day ended without any concrete policy recommendations, and without many answers, but with assertions that “something” will be done.

    • While we won’t attempt to address the complexities of drug pricing here, a major question is whether insulin should be a special case within current drug pricing regimes due to the size of the affected population and the enormous health system benefits potentially to be achieved by better control of diabetes. The prominence of rebates within current pricing systems leads to egregious pricing of insulin for many patients, a fact that literally no one disputes or defends. However, whether rebates in general be retained is hotly disputed; manufacturers would love to see them go away while PBMs see them as a key feature to moderating overall drug prices for payors. The Trump administration, led by HHS Secretary Azar, initially strongly supported rebate ‘reform’ (essentially elimination), only to reverse itself following publication of analyses showing dramatic 10 years costs if rebate reform were enacted. Needless to say, lobbying on this issue has been intense and the financial forecasts are highly controversial.

  • Following these congressional hearings, several legislative measures have been proposed to address insulin pricing specifically. Most notably, Colorado passed a law in May to cap the cost a person on private insurance is required to pay for insulin at $100/month regardless of number of vials needed. In July, several US Senators introduced a bipartisan bill that would create a new insulin pricing model where the use of rebates would be restricted for any insulin product for which the manufacturer reduces the list price back to a level no higher than the price of the product in 2006. This bill was endorsed by both ADA and JDRF. Finally, the US House of Representatives passed its much anticipated drug pricing legislation earlier in December. The bill, if passed by the Senate and signed by the President, would have big implications for the diabetes drug pricing, as it would allow Medicare to directly negotiate prices for all insulin products, along with 250 other commonly used drugs. President Trump has already indicated he will veto the bill, making its ultimate passage unlikely. A more moderate drug pricing package is under consideration in the Senate currently. 

  • These initiatives from manufacturers followed immense pressure from multiple constituents of the diabetes community. Social media posts detailing the enormous human costs and struggle of dealing with expensive insulin were very common in 2019, and reflected the growing anger, disillusionment, and frustration of patients, loved ones and the health care providers. Many stories were told by patients who could have benefited from Patient Access Programs but did not pursue them, highlighting additional problems – it was never clear throughout the year that there was consensus on how many patients needed help, what help was open to whom (particularly those on Medicare), and whether the funding would be sustainable (beyond “emergency measures” to help, which were very welcome). Major media continued to shine a light on insulin pricing, and the issue became a lens in which larger frustrations with the American healthcare system and the pharmaceutical industry in general were voiced. It was perhaps unsurprising under this spotlight to see Sanofi decide to end investment in R&D in diabetes altogether. Although politics is not our expertise, we would be very surprised if drug pricing, especially for insulin, were not a major US campaign issue in 2020, driven by needs of patients who still cannot access the insulin they need.  We believe in addition to further help for patients on Medicare, much more work could be done on marketing patient access programs and educating people with diabetes on various opportunities. To boot, we are dismayed often to learn that HCPs simply do not have the time to help people with diabetes with these and we are uncertain how this could be better addressed.

11. Medicine Company’s siRNA Compound, Inclisiran, Successful Phase 3 Trial Portends Big Jump in Clinical Relevance for PCSK9i Class with Improved Efficacy and Dosing

Novartis’ November acquisition of MDCO for $9.7 billion implies peak market sales of at least ~$2 billion, while Street consensus is $7 billion by 2025: “it could become one of the largest products by sales in Novartis’ portfolio” (Narasimhan, Novartis CEO). The Company expects to close the acquisition in 1Q 2020, file EMA in 1Q 2020 and NDA in late 2020, and launch inclisiran in 2021. Sales would be constrained (particularly in Europe) until CVOT results in 2025 confirm expected benefits.  In its analyst presentation following the acquisition announcement, management contrasted the significant unmet needs in Atherosclerotic Cardiovascular Disease with the acknowledged disappointment of approved PCSK9 mAbs treatments (Amgen’s Repatha and Regeneron/Sanofi’s Praluent). While 60% of patients taking statins/ezetimibe do not meet goal, approved PCSK9 have had difficulty establishing value (cost vs benefit), leading to major problems with reimbursement (80% of initial claims rejected) and affordability (50% abandonment rate after 90 days in commercial accounts and higher in Medicare). 

  • Inclisiran’s (siRNA) MoA is highly differentiated from mAbs Repatha and Praluent. Whereas current therapies reduce circulating PCSK9, inclisiran degrades PCSK9 mRNA inside the cell, preventing production. Furthermore, while statins up-regulate LDL receptors in the liver, decreasing LDL, they tend to raise PCSK9, increasingly at higher statin doses. By inhibiting (“interfering”) with PCSK9 at the source, inclisiran up-regulates LDL receptors while simultaneously down-regulating PCSK9, leading to more effective LDL lowering. Importantly, this MoA has implications for dosing; inclisiran is given by injection twice a year while current mAb therapy is bi-weekly. Furthermore, statin compliance is notoriously poor. In two Phase 3 trials (ORION-11 and ORION-10), inclisiran lowered LDL by more than 50% (54% and 58%, respectively) in patients on maximum statin regimes.

  • Payor acceptance will be critical to product success. Not surprisingly given the pricing and reimbursement problems that have plagued Repatha and Praluent, Street analysts have focused on these issues in their commentary. One challenge is that inclisiran CVOT data is not expected to be available until 2024-2025. However, most analysts are deriving peak sales estimates based on current market pricing for mAbs and are using $4500-$5000 for the annual cost of inclisiran. On its investor call, Novartis steered launch expectations towards steady-but-not-too-slow, although it cautioned that European acceptance was likely to lag US sales growth (despite the earlier European filing date). Current annualized revenue of PCSK9 products is approximately $1 billion; it would be great to see this product class overcome the difficulties of the past few years and establish itself as a major treatment.

Top Ten Most Highly Read Closer Look Reports in Therapy

Most Highly Read diaTribe Learn Reports in Therapy

Most Unexpected News/Things We Got Wrong

  • SGLT inhibitors in type 1 face tough regulatory hurdles in the US: FDA’s Advisory Committee for Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin ends in an 8-8 deadlock, followed by a CRL in March. Concerns over DKA risk dominated much of the discussion at the Ad Comm, and the final vote ending in a tie was perhaps less surprising than it should have been considering the robust arguments on both sides of the potential approval but the lack of information on risk management and the lack of acceptance, to date, in Time in Range as a validated endpoint by FDA. We do believe that TIR is an endpoint where there is interest at FDA. Jardiance’s Ad Comm in type 1 faced a similar situation, with a 14-2 vote against approval – in that case, we were very surprised that the manufacturers did not appear to have the information that the trial size was far too small, which is what virtually every advisor voting against said.
  • Sanofi terminates its collaboration with Lexicon to develop, manufacture, and commercialize SGLT-1/2 dual inhibitor Zynquista (sotagliflozin). The news accompanied the release of topline results from three of sotagliflozin’s phase 3 trials (SOTA-METSOTA-CKD3, and SOTA-CKD4) that did not meet Sanofi’s internal expectations – we imagine regulatory action also had something to do with this. Sotagliflozin had been previously touted as a potential best-in-class SGLT inhibitor, with unique effects in the CKD population due to its SGLT-1 inhibition but the trial results did not show this to be the case. Given this, Sanofi’s termination was not ultimately surprising.
  • Sanofi announces that it is discontinuing R&D in diabetes/CV. The news, while not unexpected, came at the company’s Capital Markets Day and follows the constant dwindling of pipeline assets for Sanofi in diabetes/CV after several discontinuations. This discontinuation includes its phase 3 GLP-1 efpeglenatide.
  • Results from DAPA-HF of Farxiga in HFrEF are overwhelmingly positive, beginning to pave the way for SGLT-2 inhibitors being used across the cardio-renal axis irrespective of type 2 diabetes status.
  • Positive results from the teplizumab trial: after many years of tumultuous development of the anti-CD3 class, it broke through in 2019 and gave the first evidence that the onset of type 1 can be delayed with a drug.
  • Lilly announces that the CVOT for its GLP-1/GIP dual agonist tirzepatide will be a head-to-head trial with Trulicity. This is the first CVOT to use an active comparator that is known to be cardioprotective.
  • Novo Nordisk announces that Rybelsus will be priced at the same level as Ozempic. Previously, there had been speculation that Rybelsus may be priced lower than Ozempic as a way to compete with other oral diabetes drugs such as SGLT-2s and DPP-4s. Of course, there are unique manufacturing costs to be considered with the oral semaglutide formulation that certainly contribute to cost considerations here.
  • Amgen announces massive, four-trial of PCSK9 inhibitor Repatha in primary prevention. VESALIUS-CV, set to begin in 2Q19 and complete May 2024, will enroll ≥13,000 participants at high CV risk (type 2 diabetes or atherosclerotic CVD) receiving lipid-lowering treatment but without prior heart attack or stroke.
  • Novartis acquires The Medicines Company for $9.7 billion, primarily to add the novel therapy inclisiran, a twice-yearly injectable (by provider) PCSK9 inhibitor. Inclisiran is currently in the midst of its phase 3 program, with regulatory submissions for to FDA expected in 4Q19 and to EMA in 1Q20.
  • FDA Advisory Committee for Amarin’s Vascepa votes unanimously 16-0 to approve CV indication. There was intense debate before the Ad Comm regarding the breadth of the potential label for Vascepa.

Key Questions for 2020

  • How will FDA rule on a potential CV indication for Rybelsus/Ozempic? A decision is expected in mid-January.

  • Will Invokana sales rebound following its new, first-in-class renal indication? How will patients and providers reconsider Invokana’s risk/ benefit profile now, additionally in light of more reassuring amputation safety data seen in CREDENCE?

  • What effects will FDA’s official shift in March 2020 to classifying insulin as a biologic have?

  • What will next steps look like for Novo Nordisk’s anti-IL-21 + liraglutide combo therapy in type 1 diabetes, following positive results announced in phase 2? How will regulatory agencies approach potential trial design and approval considerations?

  • How will Rybelsus’ commercial launch fare? How much revenue will the therapy earn in its first year on the market, how many patients will swirch from a GLP-1 injectable and how many new patients might it bring to the GLP-1 class?

  • Will BI/Lilly pursue additional studies to support another submission of empagliflozin in type 1 diabetes following FDA’s recent recommendations at its Advisory Committee meeting?

  • What will uptake of next-gen glucagons Baqsimi and Gvoke look like? Will health care institutions switch to newer formulations, especially in outpatient settings?

  • Will REWIND results for Trulicity support a primary prevention indication from FDA?

  • Will any external partner seek to pick up Sanofi’s now-discontinued once-weekly GLP-1 efpeglenatide?

  • Will Intercept’s obeticholic acid become the first approved therapy in NASH?

  • Will Merck/Pfizer more highly prioritize SGLT-2 inhibitor Steglatro in 2020? Both companies have been near-silent on the new SGLT-2 franchise so far, perhaps given a lack of payer coverage since the therapy’s launch.

  • What progress can we expect on patient-reported and psychosocial outcomes? We would love to see greater incorporation of patient-centered and mental health measures into clinical trials.

  • Will FDA do anything following its October 2018 Advisory Committee meeting on the 2008 draft guidance and CVOT requirements? The meeting saw near unanimity on lowering the barriers to demonstrating CV safety for new diabetes drugs; how will FDA respond?

  • Will reimbursement for fixed ratio combination basal insulin/GLP-1 improve, thus increasing adoption?

  • How will programs for affordable insulin change insulin usage patterns? Will at-risk patients be able to access programs?

  • Now that CGM metrics are available to guide therapy decisions, will we see a rise in patients/providers downloading devices and utilizing the data? Will download capability be a factor when choosing devices?

  • Will Lexicon find a partner for SGLT-1/2 inhibitor sotagliflozin? Will its launch in Europe for type 1 be carried out?

What’s Coming in 2020

The list below covers expected 2020 milestones for phase 3 and approved products - 2019 – notably, this list is far shorter than it has been in previous years, and perhaps this is unsurprising with Sanofi exiting diabetes and CVD and obesity R&D and with J&J and Merck effectively out of investment in both diabetes and obesity R&D investment as well.. We acknowledge that this list may not be 100% complete, though we’ve tried to be as comprehensive as possible based on the most recent public updates. If you notice anything missing, please write us.

Insulin

  • Lilly’s basal insulin-FC (LY3209590): Management announced the candidate’s movement in phase 2 during 2019 Investor Day, and topline phase 1 data is expected in 2020.

  • Mylan biosimilar insulin aspart: The European submission for insulin aspart was accepted at the end of October 2019, and the FDA submission remains slated for mid-2020. The product is still in phase 3, but is expected to launch in 2H21.

GLP-1 Agonists

  • AZ’s Bydureon BCise (exenatide once-weekly): Despite production constraints of the Bydureon BCise auto-injector plaguing earnings throughout 2019, management expects revenue to be on the increase in late 2019 and beyond. AZ also expected to see the BCise autoinjector approved in China by 2020 at the earliest.

  • Novo Nordisk’s Rybelsus (oral semaglutide): After a first-in-class oral GLP-1 FDA approval in September, the franchise is expecting a cardiovascular indication decision from the FDA in 1Q20. The company has already submitted two NDAs to the FDA in March 2019 with a priority review voucher requesting approval for (i) treatment of type 2 diabetes; and (ii) CV risk reduction in adults with type 2 diabetes. The latter decision will be based off of pooled data from SUSTAIN 6 and PIONEER 6. It remains a possibility that an FDA Ad Comm will be held to discuss this decision, although Novo Nordisk has not yet heard from FDA regarding such a meeting. Regulatory approvals for Rybelsus in Europe and Japan are also expected in 2020, with submissions in both regions already completed. In the EU, Novo Nordisk submitted oral semaglutide in April 2019, with an EMA decision expected in early 2Q20. Submission in Japan occurred in July 2019, with a decision expected in mid-2020.

  • Lilly’s oral GLP-1/GIP pre-clinical once-daily oral dual agonist: In 3Q19, Lilly announced its first-of-its-kind once-daily oral formulation of dual GLP-1/GIP agonists. Preclinical experiments are currently underway and appear to be progressing nicely, with an expectation of phase 1 trial initiation in 2020. 

  • Lilly’s GLP-1/GIP/glucagon tri-agonist: In 3Q19, Lilly shared an internal readout of phase 1 results to inform a potential movement into phase 2 in 2020.

  • AZ’s oral GLP-1 (MEDI7219): In 2Q19, AZ confirmed its phase 1 candidate MEDI7219 to be an oral GLP-1. It is currently in phase 1 with completion expected in April 2020.

  • Novo Nordisk’s injectable semaglutide: A phase 2 study in biopsy-confirmed NASH is expected to complete by April 2020.

  • Novo Nordisk’s injectable semaglutide + cilofexor + firsocostat: A phase 2 proof-of-concept study was initiated in July 2019 and is expected to complete by June 2020. The combination therapy is part of a partnership Novo Nordisk has with Gilead in NASH.

  • Novo Nordisk’s Ozempic (semaglutide): Novo Nordisk has requested a CV indication for Ozempic that will be bolstered by the SOUL CVOT. Positive CV outcomes from SOUL will support a CV indication for both oral semaglutide and Ozempic, and positive renal outcomes from FLOW will support a renal indication for both, assuming the data are consistent. A decision is expected by the end of January 2020.

  • AZ’s phase 2 GLP-1/glucagon candidate (cotadutide): AZ announced the initiation of a phase 2 trial of the GLP-1/glucagon dual agonist cotadutide in NASH, and completion is slated for September 2020. We are also still waiting for readouts from cotadutide’s type 2 diabetes/overweight obesity phase 2b dose-ranging study (three doses vs. liraglutide). The study completed in June with results expected by the end of 2019, but there have been no updates so far.

SGLT-2 Inhibitors

  • Merck/Pfizer’s Steglatro (ertugliflozin) in type 2: Results on the Steglatro VERTIS CVOT, for the newest member of the SGLT-2 inhibitor class, were slated to complete December 2019, and topline results should be available within the year.

  • AZ’s Farxiga (dapagliflozin) in HF:  Two smaller walk-test trials in both HFrEF and HFpEF are scheduled to complete in January and February 2020, respectively.

  • AZ’s Farxiga (dapagliflozin) in CKD: Topline results from the DAPA-CKD renal outcomes trial in patients with chronic kidney disease are expected in 2020, following November 2020 study completion. FDA Fast Track designation for the compound in CKD was granted in 3Q19

  • Lilly/BI’s Jardiance (empagliflozin) in HF: Emperor HF-Reduced assessing Jardiance in HFrEF is now expected to complete at the end of 2020, pushed back from its original June 2020 date. 

  • Lexicon’s Zynquista (sotagliflozin) in type 2: We expect to see results from SOTA-GLIM, sotagliflozin’s head-to-head study vs. sulfonylurea glimepiride, which completed in August 2019. SOTA-BONE, a bone safety study, is also set to complete in December 2020. 

Glucagon

  • Zealand’s dasiglucagon: Zealand announced the start of a phase 2 dose-finding and clinical proof-of-concept trial for dasiglucagon post-bariatric surgery in October. results are expected in 2020, and if positive, may expand treatment possibilities from the HypoPal rescue pen and in treating or preventing non-severe hypoglycemia.

  • Zealand’s HypoPal (dasiglucagon rescue pen): Zealand confirmed that its HypoPal remains on track for FDA submission in “early 2020.” As a reminder, results from Phase 3 pediatrics study support the use of the same dose of dasiglucagon in both adults and children. 

PCSK9 Inhibitors

  • Regeneron/Sanofi’s Praluent (alirocumab): During Capital Markets Day 2019, Sanofi stated that Regeneron will own Praluent in the US, while Sanofi will own it internationally but with notice of resources. This comes after Sanofi’s announcement of discontinuing diabetes R&D.

Top Therapy KOL Quotes of 2019

From "FDA approves novel renal indication for J&J’s SGLT-2 inhibitor Invokana (and CREDENCE commentary)"

  • Dr. Yehuda Handelsman (Metabolic Institute of America): “This new indication celebrates the 1st drug in nearly 20 years to reduce the decline of CKD. This indication highlights a paradigm shift in the future use of the SGLT-2 inhibitor class. Moving forward the class will surely continue to be an important tool for the diabetologist/endocrinologist in reducing glucose level. However, it is now also a medication for the nephrologists to manage patients with advanced DKD (and without worrying about glucose level), and soon it will become a drug for the cardiologists to manage CHF, specifically with reduced EF (HFrEF, and time will tell whether HFpEF patients would also benefit) regardless of their glycemic status.”
  • Dr. Darren McGuire (UT Southwestern Medical Center): “The CREDENCE results are impressive and impactful, providing direct support for previously reported secondary observations of the cardiovascular outcomes trials completed to date across the class, moving the needle substantially toward supporting the use of SGLT2i’s in patients with type 2 diabetes with compromised kidney function.”
  • Dr. David Harlan (UMass Memorial Health Care): “My view is that the CREDENCE study simply adds to the already strong and consistent data showing that SGLT2 inhibitors improve outcomes for those with diabetes and associated complications. I view the new data important for five particular reasons:
    • The previously reported increased risk for amputation conferred by canagliflozin was not seen in this study;
    • The agent improved outcomes for those with pre-existing kidney disease with GFRs as low as 30 mL/min/1.73 m2;
    • The early decline in glomerular filtration is more than made up over time (akin to the worsening retinopathy that can be observed when glycemia control is implemented);
    • The overall profound improvement in the most relevant endpoints- including all-cause mortality; and
    • While it is risky to say with certainty, the profound benefit for those with T2D included in the CREDENCE study (since individuals with T1D were excluded) may well apply to those with T1D and I believe the question must be squarely addressed considering the profound effect on the most important endpoints.”
  • Dr. Daniel Drucker (University of Toronto): “These results are transformative for the field, and further enable personalized diabetes medicine in the clinic to prevent kidney complications, improve cardiovascular outcomes, and save lives, for people with type 2 diabetes.”

From "FDA approves Novo Nordisk’s oral semaglutide under brand name Rybelsus"

  • Dr. James Gavin: “This is inspiring news for the diabetes community. This astonishing breakthrough treatment can now be made available to a broader segment of patients with type 2 diabetes. Importantly, this does not replace anything, but rather provides another option for providers and patients who have limitations or reservations in the use of the injectable form of this important new drug that offers so many benefits for vast numbers of patients with type 2 diabetes. This is a true breakthrough that changes the face of oral therapy in diabetes.” 
  • Dr. Daniel Einhorn (Scripps Health): "On the positive side, a pill has a lower barrier to entry in primary care and in the mind of people and their families compared with an injectable. The concept that a pill can give you 10 plus lbs of weight loss is huge, especially if it’s covered by insurance for your diabetes and produces other benefits for your heart and kidneys without risk of hypoglycemia. Fewer GI side effects is only good. On the negative side: It’s a daily ritual vs a weekly anytime 1 minute injectable (for experienced patients) and PCPs. Let’s see the cost. 14 mg vs 1 mg has to cost Novo a lot. They appear to have geared up for that. Many will prefer once a week."
  • Dr. Timothy Bailey (AMCR Clinic): “GLP-1 agonists are currently underutilized and associated with suboptimal persistence. The availability of a new oral dosing option for a potent GLP-1 agonist will both help clinicians to recommend and people with type 2 diabetes to start and continue taking a medication in this important class. On a scientific level, the technology that allows successful absorption of semaglutide is a promising platform that will be used for the delivery of other therapeutic entities.” 

Diabetes Technology

Themes

1. CGM Milestones Continue to Mount: Another Blowout Year for CGM, with 2+ Million Users, ~$4.2 Billion in Sales (+45% YOY); Drive by Open and Closed Loop, Regulated and DIY; Drive Into Pharmacy Channel Bodes Well for 2020

Twenty-nineteen has been a banner year for both personal and professional CGMs, as devices became smaller, simpler and far more accurate. The latest products have taken a giant step toward an industry standard of no calibration and the ability to dose insulin based on the sensor BG. Patients who are on the fence about wearing a personal CGM now have the opportunity to test drive a professional one that requires little effort, instruction or cost. When choosing a personal CGM, considerations also include alerts and alarms vs. intermittent scanning and an implantable option. Having a variety of choices and the ability to download and interpret the data using standardized metrics will promote greater CGM adoption in patients with type 1 and type 2 diabetes and the clinicians that care for them.

The global CGM user base is now fast approaching 2.5 million, compared to ~1.5 million a year ago and just over 700,000 two years ago. This report includes short summaries of the major CGM and glucose monitoring players, where we get a snapshot of where each company is and what it achieved during 2019. We look to this technology to drive more therapy overall (GLP-1, SGLT-2, and basal and rapid acting insulin) as well as more pumps.

  • The last decade in CGM has been exciting – better, faster, cheaper - and the changes in care that have been enabled by CGM are monumental. Kelly’s first conference she attended for Close Concerns took place in 2003, and focused on CGM, led by Dr. David Gough in San Diego. CGM data was not considered accurate or reliable yet, the algorithms were very basic, and many considered the early models quite painful – but full of potential. Dexcom’s first sensor, the Dexcom STS, came out in 2006 – see “Test Driving Dexcom's Short-Term Sensor (STS): A Look at Continuous Glucose Monitoring” for a look back at the earliest CGM (excluding Glucowatch). That was exactly 13 years ago, and while it’s taken the field some time to get to a user base of 2.5 million, this is now far bigger than the pump market.

  • While we see BGM continue as an important device market, we’d like to see far more connected to the cloud. While virtually all meters made today are set up to share data in the cloud, very few actually do that – this is still under 10% globally, according to dQ&A estimates. While the potential to use data connected to the cloud (we love “Results in Range” becoming more common to discuss) is high, the number of patients using data in this way (or HCPs requesting it) remains low from what we can tell.

  • The upside to more people using CGM to enable better diabetes management is very high. Given that there are over 225 million people diagnosed with diabetes and 463 million now estimated to have diabetes overall, we believe potential for considerably better outcomes (particularly given poor outcomes now) is high if patients have an incentive to use the data (high for CGM, low for BGM). CGM is best suited to drive therapeutic changes, and with “professional” CGM at the ready, we anticipate many more conversions. Indeed, to date, CGM has been justified to ensure safety and no hypoglycemia, and we think the field is ready to demand CGM to measure and avoid hyperglycemia.

  • Companies are continuing to make the CGM acquisition more attractive with more accurate, reliable, easier-to-use, less complicated systems. The pain associated with CGM from some years ago disappeared with the advent of Abbott’s Libre and Dexcom’s G6, and the systems have continued to advance with use of RileyLink, the unapproved devices enabling closed loop delivery. For those on closed loop, the Time in Range numbers driven by algorithms show many improvements – for those on “open loop” or “closed loop,” CGM is a far easier way to track glucose with easier-to-monitor data leading to improved glycemic control. 
  • CGM has enabled far better management with easier-to-interpret data that drives both open and closed loop, regulated and DIY. Read Dr. Anne Peters “Better Glycemic Control Than I’ve Ever Seen” for more input on patient improvements on the closed loop. As a reminder, Dexcom’s G6, which now drives closed loop systems from Tandem and Insulet (through RileyLink), was approved in mid-2018, just after Medtronic’s first standalone sensor, the Guardian Connect, was approved. Dexcom’s G6 has flown off the shelves, with frequent supply constraints, and it is particularly in demand by Tandem users, which have risen in installed base from ~25,000 in late 2015 to ~150,000 in late 2019, as well as Insulet users of an estimated well-over-200,000 (last confirmed numbers were 175,000 in 4Q18). While the Guardian Connect sales have been slow going due to the need for a better sensor, it was important for Medtronic to demonstrate that it could separate CGM from its pumps. The US market continues to await Abbott’s Libre 2 in the US– presumably the requirements for interoperability are slowing approval, though that is speculation.
  • CGM is far easier to prescribe and use than several years ago due to better, easier-to-obtain, lower-hassle systems – with Medicare as a huge area of frustration and opportunity. CGM companies have made the process to get CGM easier, in part by moving toward pharmacy distribution. Abbott’s FreeStyle Libre has been available in major US pharmacies since late 2017, while most of Dexcom’s business still runs through the DME channel. However, Dexcom is continuing to make progress in the pharmacy channel, which will become Dexcom’s “primary distribution channel” over time. Walgreens announced in November that, through a “new billing solution” for CGM, it will bring CGM for Medicare patients into its pharmacy locations, beginning with Dexcom G6. Pharmacy distribution has benefits for CGM manufacturers, reducing their work effort, and also for patients and providers as the prescribing, processing, and prescription filling process becomes easier. We would like to see prescriptions optional for CGM, given the number of people that may benefit from using CGM as a behavioral tool. On the implantable CGM front, Senseonics secured a major win by getting Eversense reimbursed by Medicare as a physician service. This will enable physicians and patients to insert Eversense directly in the clinic (or in a nearby surgeons’ office) once they decide Eversense is the right choice (it is especially popular with many teen girls, as it is more discreet), and physicians will bill for the insertion/removal procedure and the Eversense device together using existing CPT codes.

Total CGM Market, 2014 - 2019


Chart assumptions: includes 4Q19 estimated sales for Abbott, Dexcom, Medtronic, and Senseonics based on either 3Q19 guidance or conservative growth projections.


Where are the opportunities in CGM? Where will CGM go?

  • Finding the “must-have” features vs. “nice to have” features is key to showing value in CGM. No fingersticks, for example, is a “nice to have” feature that is popular with patients, but improved Time in Range enabled by CGM that results in far lower hypoglycemia is what is important for the system and what is most meaningful to payers. At the same time, not needing fingersticks has been essential to uptake. When we think about what will prompt uptake of other devices like smart pens, we believe it will take some time to gain popularity without a popular driver like “no fingersticks”.
  • CGM data integration with insulin delivery devices (pumps and smart pens) is essential to enable patients to achieve better outcomes. AGP is becoming more standardized, along with the 11 essential metrics and the Time in Range variables, as decided at ATTD in 2019. Ultimately, there seems to be widespread agreement that the closed loop enables many patients to have far greater Time in Range, reflecting better and higher-quality A1cs.
  • Multiple apps related to CGM and insulin dosing and food management are gaining in popularity and are becoming more user-friendly. Apps like UnderMyFork enable patients to see two-hour post-meal glucose levels easily and automatically, as those using Dexcom and Senseonics have their two-day data “pulled in” by Apple Health – this is not the case for Abbott or Medtronic. Apps LibreLink app for Abbott and the Clarity app for Dexcom have become better and easier to use, although dQ&A estimates that there are still a significant number of CGM users that are not yet using apps.
  • Interoperability evolution (this relates to use of iCGM 510(k) pathway) and an ecosystem of CGM-driven automated insulin delivery products will continue to be closely watched. Best case scenario, this will mean less regulatory time required, though in some cases, reaching the interoperability requirements may result in delays, ostensibly the case with the Libre 2 in the US.
  • Positive CGM evidence for improved outcomes has expanded significantly, particularly in populations that have not historically been represented in trials, such as children and older people with diabetes. At ADA 2019, we saw three (!) large CGM trials showing benefit in broad age groups: WISDM (type 1s ≥ 60 years), CITY (type 1 young adults), SENCE (2-8-year-old patients). Atboth ADA 2019 as well as EASD 2019, we also saw COMISAIR (type 1s). To increase uptake, addressing barriers including education on the differences among various CGMs, expectations about how the product can help, and issues with reimbursement are all paramount to future success.
    • While CGM update is slower in Medicare populations than it should be, we believe this will become a bigger advocacy issue in 2020. See DT&T commentary from key opinion leaders Dr. John Anderson, Dr. James Gavin, and Ms. Davida Kruger on “clinically irresponsible” insurance requirements for CGM coverage. This now needs better marketing and visibility – this is still a weak spot for the field.

  • Managing the newer consumer-facing sides of CGM – Responsibilities have never been so great for CGM manufacturers as the business grows exponentially and becomes more complex. In the early days of CGM devices, manufacturers were responsible for issues related to sensors and receivers, such as accuracy and reliability. Today, manufacturers must also address issues related to the hardware, smartphones, browsers, connectivity, smartphone and smartwatch apps, cloud infrastructure, social media and Bluetooth issues. 

What we are looking for in the future:

  • More standardization and translation around Advanced Glucose Profiles, more instruction on clinical decision support (how to interpret AGP), more seamless workflow integration, and improved communication showing successful remote monitoring for HCPs.

  • Electronic medical record (EMR) integration of CGM data could have a huge upside.

  • We are interested to see how the most successful HCPs will work with patients on behavior design/ behavior change related to CGM, and we look to see how the most successful phone apps evolve – will business models develop around apps?

  • We are interested to learn more about the most successful coaching and where using human/automated coaching is used to create behavior change. Ultimately, what is adoption of CGM like in digital health? Of connected BGM? What are new models like for type 2? Helmsley/Cecilia’s “Geek Squad” pilot?

  • We’d like to see more real-world CGM data on the “state of diabetes,” similar to T1D Exchange data on A1c – with consensus goals for CGM metrics, where is the population? Average Time in Range? Time above and below range? How do these metrics correlate with long-term outcomes?

2. Time in Range Conversation Accelerates: Goals, Guidelines, and Move to Validation

As shown below from a PubMed Search, the Time in Range discussion really accelerated in 2019 – more studies, more scientific questions, and more alignment. Developed at a February 2019 meeting at ATTD, consensus goals around Time in Range (and other CGM metrics) were published as an ADA Poster and in Diabetes Care, and added into ADA Standards of Care in August. With consensus targets now developed, many have asked how the field can further validate Time in Range as a meaningful endpoint for drugs, devices, regulations, payers, physicians, and patients – though preferably without having to invest in expensive, time-consuming trials that will be challenging to conduct, just because there are so many changes happening now. As a side note, many are asking who “invented” the more widely used term, Time in Range. The first result for “Time in Range” in 1998 points to a paper by Dr. Satish Garg and colleagues at Barbara Davis, “Slicing the Pie: Correlating HbA1c values with average blood glucose values in a pie chart form.

PubMed Results by Year for “Time in Range”

  • One of Close Concerns’ most widely read pieces of 2019 was on IQVIA’s white paper on Time in Range, estimating that improving the US diabetes population’s Time in Range to 70% could save at least $2-$4 billion over ten years. With a population average Time in Range of 80% (type 1s and type 2s) and 40% reduction in hypoglycemic events (type 1s), up to $9.7 billion in cost savings could be generated. Perhaps more impressively, we think the $2-$4 billion in cost savings estimate is conservative, given that the authors assumed the current population’s average Time in Range is 58%. See our report for some speculation on what the actual population Time in Range could be.
  • We saw a big CGM dataset from about half a million FreeStyle Libre users at ATTD 2019 and subsequently ADA 2019. The data gives insight into how the typical FreeStyle Libre, and CGM user more generally, is doing: the ATTD data showed a median of 56% Time in Range. For median users, 2% (34 minutes/day) of time was spent below 54 mg/dl and 17% (4 hours/day) above 240 mg/dl. We wonder how many users had Time in Range >70%, the consensus goal, and how realistic it is for the population to reach a Time in Range of 70% - there will no doubt be more consensus on this in 2020 once Time in Range has been used a longer time. The data also showed that higher glucose levels do not protect against hypoglycemia. Time <54 mg/dl was higher in groups with the highest estimated A1c and lowest in those with the lowest estimated A1c. In other words, running high all the time is not a strategy to avoid lows. 
  • Limitations of A1C Support Use of TIR. Dr. Rich Bergenstal (International Diabetes Center) gave an exciting oral presentation at ADA, using “individualized A1c,” which accounts for variations in red blood cell turnover among individuals. Seventy percent of individualized A1c values differed from their lab A1c by >0.5%. At Keystone 2019, Dr. Roy Beck (Jaeb Center) expressed particular concern for clinical guidelines that call for particular actions (e.g., medication changes) when individuals do or do not reach a specified A1c level. Later in the year at ISPAD, Dr. Beck said, “The only value of HbA1c if CGM is available is for historical purposes.” He displayed an ambulatory glucose profile and asked, “Would you rather have this or would you rather have one number that reflects someone’s average over the last three months, and may not even be an accurate average?” Dr. Anne Peters (Keck School of Medicine) expressed similar sentiments at CMHC, saying “[A1c] is an average. Does it tell you how to manage a patient? No. It doesn’t tell you whether they’re going low, whether they’re going high, whether to inject, add medications.” The beyond A1c discussion was even evident internationally, with Diabetes Australia’s Ms. Renza Scibilia and other international patients discussing the limitations of A1c and benefits of Time in Range and patient-reported outcomes on a panel at IDF 2019.
  • On the validation front, Dr. Roy Beck published a paper in DT&T  in January, showing that biochemical hypoglycemia (time <70 mg/dl, <54 mg/dl) predicts severe hypoglycemia. The post-hoc analysis was done using the seven-point BGM profiles collected from the DCCT study, similar to the Time in Range validation analysis published in October 2018. Earlier this month, Medtronic’s Dr. Robert Vigersky published a notable “first step” paper linking Time in Range with the CVD biomarker, carotid intima-media thickness (CIMT).
  • Time in Range and A1c Correlations: UVA’s Dr. Boris Kovatchev presented data at DTM 2019 showing Time in Range and A1c correlations could achieve coefficients >0.9 using a differential equation model and one individualized parameter (i.e., one “calibration” point is needed to personalize the model to each individual). The model is based on the premise that both Time in Range and A1c reflect the same underlying phenomenon (i.e., blood glucose). These tight correlations would suggest that Time in Range and diabetes-related complications are associated.
  • Also, at DTM 2019, we heard others more skeptical of Time in Range and CGM metrics. Dr. Lutz Heinemann (Science and Co.) called Time in Range a valuable addition to A1c in clinical care settings, but not a replacement in clinical practice. There is now less confusion about the differences – not everyone can get CGM, but those who can should use it to drive better outcomes. FDA’s Dr. Courtney Lias expressed concerns about different performance levels of different CGMs at various glucose concentrations. Dr. Lias also highlighted the need for studies demonstrating the validity of the definitions of what glucose ranges and differences are meaningful.

3. Pumps and Automated Insulin Delivery: Tandem Drives Fully Interoperable AID Components into Reality; 2020 Promises to be a Big Year: Tandem Control-IQ, MiniMed 780G, Insulet Horizon, Tidepool Loop

Insulin pumps have finally gotten into the HOV lane and are racing toward commercialization of a true artificial pancreas (AP). We started 2019 with automated insulin delivery (AID) and a streamlined pathway for integrated CGM (iCGM) and ended on a high note with an alternate controller enabled (ACE) system. What does this all mean in the real world? We now have the capacity to offer people with diabetes a far superior option for insulin delivery than ever before. Advanced hybrid closed loop means that patients are no longer burdened with self-calculations to determine basal rates and correction doses, as the pump will take over these tasks. All that is left is calculating meal-time insulin doses, which is well on its way to automation with food photo and hand gesture software to guide us. Patients who are already on pump therapy and those that have been sitting on the fence and considering it are suddenly excited by these new advances. So are the clinicians that care for them. Automated calculations and increased Time in Range are pushing clinicians and patients towards pump therapy. We look forward to what 2020 will bring with more and more products in development racing to the finish line.

  • For the second consecutive year, Automated Insulin Delivery (AID) competitive landscape was the #1 read and shared Closer Look report – by nearly 50%. Though we didn’t see any new product launches in 2019, we will see a lot of the groundwork realized in 2020. Tandem Control-IQ received FDA clearance earlier in December and is expected to launch by “the end of January 2020.” (A limited clinician-user launch actually began in December 2019.) Medtronic says the MiniMed 780G is “on track” for a potential launch by April 2020, and Insulet has maintained the same 2H20 launch timing Horizon for over a year. Launch timelines for Tidepool Loop are harder to predict, but it could become the fourth (!) new major AID system available on the US market by the end of 2020. Of course, the hassle of ordering supplies and maintaining both hardware (see Medtronic field notification for 630G/670G) and software (see Tandem’s Control-IQ pivotal trial patch) will be ongoing challenges for the field – ordering supplies from different companies may be a hassle.
  • In 2019, the FDA realized its vision for fully interoperable, componentized AID systems with the creation of iCGM (March 2018), ACE pump (February 2019), and iController (December 2019) categories. The iCGM and iController classifications created lower-risk class II 510(k) pathways for their respective components (insulin pumps were already class II devices). Altogether, the new pathways will be interesting to watch in innovation, patient choice, and timing regarding getting AID systems to market. Given the advantages for quicker iteration for some, it should only be a matter of time for other players to bring their own interoperable components to market (e.g., Abbott, Senseonics, Medtronic, Tidepool). Of course, we have yet to see commercial multi-company interoperable AID systems in action, and there are some open questions – one of the most critical is how will customer service be handled? The same question is true for supply ordering. Some patients may prefer single-company systems (e.g., MiniMed 670G), but the existence of both options may be a major win for patient choice and competition – or it may be a hassle.
  • Will 2020 be another “breakthrough year” for AID? We could see four new major AID systems available on the US market one year from now, but as Tidepool CEO Howard Look said at DiabetesMine’s Innovation Summit 2019, “The diabetes community has been burned before.” When MiniMed 670G was approved by the FDA in an impressive 3-month review, we declared 2016 a “pivotal year” for AID; instead, the race to become the second commercial AID system will extend into 2020, presumably ending in January 2020 when Control-IQ is launched. Still, we have seen the entire field come a long way since the FDA first published its guidance on the artificial pancreas back in 2012, particularly around interoperability and regulation. We have been praising the FDA’s device division for its progressive thinking around AID and interoperability since 2015 and are (cautiously) optimistic for 2020. Here is a summary of where major AID systems stand today, moving into 2020

Tandem

  • Tandem began 2019 with Control-IQ in pivotal trial and will end the year with FDA clearance, creating two new regulatory pathways in between! Tandem’s t:slim X2 became the first ACE pump in February. At ADA 2019, strong pivotal trial data for Control-IQ was read-out and later published in the New England Journal of Medicine. Similar, confirmatory data from Project Nightlight was presented at DTM 2019. Control-IQ was submitted to the FDA in July and received clearance as the first “Interoperable Automated Glycemic Controller” in December. When the system launches (by “end of January 2020”), it will become the first hybrid closed loop that does not require fingersticks (Dexcom G6), has automated correction boluses, and at-home software updates. Control-IQ will be offered as a free, at-home software update for in-warranty t:slim X2 users. As of 3Q19, Tandem was planning on launching a smartphone app for secondary display and data upload simultaneously with Control-IQ; that app will help Tandem capture real-world data (first no-cable data uploads for a pump in the US) and serve as an interim step before full-on smartphone control of the pump. We’ll hear updates on pediatric submission and international launches of Control-IQ on Tandem’s 4Q19 call early next year; pediatric submission (6+ years) is expected to come in 1Q20. Very strong real-world data on Basal-IQ was shared this year in pediatrics (n=2,696; 0.9% <70 mg/dl) and adults (n=2,712; 1.2% <70 mg/dl). Basal-IQ has also begun rollout into OUS countries, which should help Tandem compete well in any of the remaining Animas conversion opportunities. Looking forward (aside from Control-IQ), 2020 may see more details on Tandem’s plans to work with Abbott’s FreeStyle Libre and potential submission of the patch-like t:sport pump (expected “summer 2020”).

Medtronic

  • Medtronic’s 2019 saw strong growth of MiniMed 670G, driven by OUS launches. MiniMed 670G’s user base grew by nearly 100,000, from “>135,000” in November 2018 to “~224,000” in November 2019. In that time span, Medtronic also secured nationwide reimbursement for 670G in Germany for 7+ years. Throughout 2019, Medtronic showed off 670G real-world data; data from ~120,000 users shared in May showed 71% Time in Range when in Auto Mode. Non-adjunctive indication for Guardian Sensor 3 was filed in July, which would enable Medicare coverage for 670G. Pediatric (2-6 years old) pivotal data for 670G was presented at ATTD 2019, though the launch for this is unclear. Also at ATTD, Medtronic showed impressive data from MiniMed 640G demonstrating 84% reduction in severe hypoglycemia in hypoglycemia-unaware patients (8.1% vs. 2.8% time <70 mg/dl). Looking ahead, the hardware for MiniMed 780G has already been submitted to the FDA, and “some data” will be shared at ATTD 2020. The pivotal trial for MiniMed 780G had begun as of ADA 2019. Looking at the next-gen Personalized Closed Loop (PCL) system, Medtronic secured Breakthrough Device designation in February and acquired gesture-based food tracking startup Klue in December, to strengthen PCL’s meal prediction capabilities.

Insulet

  • Insulet launched Omnipod Dash in the spring, becoming the only no-upfront-cost and no four-year-warranty pump offering in the US. Dash sales also primarily run through the pharmacy channel, improving patient and provider experience and improving profitability for Insulet. As of 3Q19, “over 20%” of Insulet’s total sales volume was running through the pharmacy channel. By eliminating the upfront cost barrier to starting pump therapy, Insulet is particularly well-positioned to expand the pump market by converting MDI users and type 2 patients with Omnipod Dash. In September, Insulet also quietly announced ACE pump clearance for Omnipod, making ACE pump the first interoperable regulatory classification with two commercially available products (Tandem’s t:slim X2 is the other). Insulet’s hybrid closed loop offering Omnipod Horizon was expected to begin a pivotal trial this month with launch in 2H20. Horizon will bring smartphone control (see final user interface demo at DiabetesMine Innovation Summit), be designed for simplicity, and have adjustable glucose targets.

Tidepool

  • The ~14-month old Tidepool Loop project gained momentum in 2019, adding Dexcom and Medtronic as partners, joining Insulet. Tidepool is continuing to work on enlisting more partners, and as of November, two more were at the “term sheet” stage. Also as of November, the Jaeb Center and Tidepool-driven Loop observational study has already enrolled 874 people after beginning recruitment in January. Helping to drive the rapid enrollment, RileyLink inventor Pete Schwamb posted code bringing Omnipod into the DIY Loop ecosystem in April. Tidepool CEO Howard Look has been careful not to overset expectations or give submission or launch dates, but with the creation of an iController pathway earlier this month by Control-IQ, many of the critical pieces are falling into place.
    • For some insight into how the FDA may be thinking about DIY systems, several key events occurred this year: (i) the agency issued a safety communication in May warning against use of “unauthorized diabetes management devices”; (ii) the FDA and Medtronic both sent warnings in July about cybersecurity risks in certain Medtronic pumps (the same communication loophole that enables DIY Loop, OpenAPS, and AndroidAPS); and (iii) the FDA Patient Engagement Advisory Committee hosted a meeting on cybersecurity in medical devices.

Beta Bionics

  • Massachusetts public benefit corporation Beta Bionics had a strong year in fundraising, bringing in over $126 million in Series B funding including investment from Dexcom. The Gen 4 iLet design was shown off at Friends for Life 2019, with cartridge slots for pre-filled Humalog, Novolog, or Fiasp insulins and Zealand’s dasiglucagon. Data from the first human study of Gen 3 iLet was read out at ADA 2019, which included users of both Dexcom G5 and Senseonics Eversense CGMs. Compared to usual care, Time in Range (70-180 mg/dl) improved by 1.9 hours per day on the iLet (70% vs. 62%; p=0.01). Beta Bionics’ iLet received Breakthrough Device designation in December and the insulin-only pivotal trial is expected to begin in 1Q20. The bi-hormonal pivotal trial, using insulin and dasiglucagon, is expected to begin in late 2020, assuming that Zealand’s dasiglucagon is ready for the pivotal trial.

Bigfoot Biomedical

  • The year 2019 saw a pivot for Bigfoot to focus on its smart pen efforts (Unity) over its AID efforts (Autonomy). We had a chance to interview Bigfoot CEO Jeffrey Brewer in June, where he told us conversations with payers, HCPs, and competitive dynamics had pushed Unity ahead of its Autonomy. At DiabetesMine Innovation Summit, we learned that Bigfoot’s smart pen launch is now expected “2021” with Autonomy hybrid closed loop coming in “~2023.”

Lilly

  • Lilly was quiet about its “Personalized Diabetes Management System” (smart pen and AID projects) this year. In December, Lilly and Dexcom formalized a non-exclusive agreement to use Dexcom CGM as part of Lilly’s AID system, though this came as no surprise as Dexcom CGM has been used throughout Lilly’s design process and early clinical trials.

Diabeloop

  • Diabeloop’s DBLG1 hybrid closed loop algorithm (CE-Marked 13 months ago) is still awaiting European launch. Still, depending on competitors’ launches, DBLG1 could be the second commercial AID system to come to market in Europe (following MiniMed 670G). In April, Diabeloop found a new pump partner, Kaleido (formerly known as ViCentra), after Cellnovo went out of business. Diabeloop has also been working on reimbursement discussions; the company is in the process of obtaining national reimbursement in France, and “advanced discussions” are ongoing with “notable German health plans.” A €31 million (~$34 million) Series B funding round closed in December – those funds will enable a study for FDA submission.

Cellnovo

  • In April, France-based Cellnovo announced it would stop commercial operations and manufacturing, effective immediately. The announcement served as a reminder of the ultra-competitive insulin pump market – how many pump companies can the market actually support? How does each component capture value and build a sustainable business in the world of interoperable automated insulin delivery? At this point in the pump market’s development, how long will investors give a novel pump company to reach profitability?

Open Questions for AID

  • How much will interoperable components speed up innovation cycles? How will companies handle customer service and other responsibilities? Will this be scalable into hundreds of thousands of patients?
  • How will patients view interoperable systems vs. single-manufacturer systems? How will payers view interoperable vs. single-manufacturer?
  • Will new payment models help lower upfront cost for patients/payers? Will subscription-based models (e.g., Omnipod) help expand the pump/AID market? As more data comes in, could manufacturers shift to value-based payment models?
  • When will we see more AID studies in new populations, e.g., pregnancy, elderly, newly diagnosed, etc.?
  • Is there an upper bound on percent time spent in closed loop? How will manufacturers prepare for when systems inevitably fail? How can AID systems “fail gracefully”?
  • Who will have the first smartphone-control pump/AID system?
  • How much adaptation will be implemented into next-gen algorithms? How much can these reduce user hassle and the initial learning curve, e.g., meal entry, prefilled insulin, etc.?
  • How much higher might Time in Range go with insulin and glucagon? Is there interest and investment potential for sub-cu insulin for those at massive risk of hypoglycemia?

4. Digital Health Momentum Continues

Momentum in diabetes coaching, remote care, and digital health carried in 2019 as numerous companies continue to offer services in areas beyond their original domains of expertise. Livongo had a July IPO on the NASDAQ, posted strong quarters (sales of $47 million in 3Q19, rising 149% YOY and 14% sequentially), and announced partnerships with telehealth companies MDLive and Doctor on Demand; Omada added Telcare BGM (with unlimited strips) and a cellular blood pressure monitor in addition to mental health care; Virta published positive two-year data; and One Drop secured retail distribution wins with Walmart and Apple. Both Omada and One Drop have also seen dramatic increases in funding; Omada raised $73 million in Series D funding to scale its programs for type 2 diabetes, hypertension, and anxiety while One Drop raised $40 million in Series B funding.

We also have seen moves from major tech companies like Google with Alphabet’s acquisition of Fitbit and Verily’s commitment to Onduo. The access Google will gain to billions of data points from users on activity, sleep, weight loss, and nutrition will help the company compete against Apple in the wearable tracking space. The focus on big data also resonates with efforts Glooko is taking; as January, the company had 2.2 million patients, 9,000 clinical locations, and over 12 billion data points in its database, making it one of the largest diabetes repositories.

Furthermore, payers are increasingly seeking services that enable patients to manage diabetes and its associated comorbidities, including hypertension and obesity. Likewise, both patients and clinicians certainly would prefer obtaining all healthcare management tools from one entity as opposed to disconnected apps and services.

  • We also saw this year increased diabetes technology integration with remote care. Much of this has been spearheaded by the growing uptake of CGM. A new review article published in Diabetes Technology & Therapeutics by Dr. Bob Gabbay and Brian Levine provides a snapshot of 12 connected care players, including Canary Health, Livongo, mySugr, Noom, Onduo, Vida Health, and Welldoc. Omada partnered with Abbott to bring FreeStyle Libre (real-time) to its members with type 2 diabetes, both those taking insulin and those on non-insulin therapies. Onduo has also worked with select type 2 enrollees through real-time intermittent CGM “sprints” since 2018 to help them learn how certain behaviors impact blood glucose levels. Six-month data from the company’s “virtual diabetes clinic” (connected Telcare BGM/Dexcom CGM + telemedicine coaching + app) has shown A1c reductions of 2% for those with a baseline >9.0%; a 0.7% reduction from a baseline of 8.0%-9.0%; and a 0.2% reduction from a baseline of 7.0-8.0%.
  • The article asserts that the future of connected care lies in the following: (i) horizontal expansion; (ii) limiting fragmentation through establishing stronger relationships among connected care companies, employers, and clinics; (iii) integrating electronic health records (EHRs) between traditional healthcare providers and connected care companies; (iv) finding the appropriate balance between human vs. automated coaching; and (v) greater use of randomized controlled trials.

5. Smart Pens: Latest Updates and New Partnerships Pave the Way for an Exciting 2020

The smart insulin pen/pen cap landscape saw increased R&D and commercial movement in 2019: the estimated number of people with diabetes (~two-thirds of type 1s and >90% of type 2s in the US and more in the EU) are on MDI. Especially if combined with CGM, connected pens have the potential to be transformative for patients, providers, and caregivers in their understanding of diabetes, providing both positive (“Bright Spot”) and negative (“Landmine”) behavioral insights. Having insulin-on-board guidance can also be helpful for patients to prevent lows. Connected pens can also enable more personalized and improved titration and may provide valuable real-world data for insulin manufacturers on how their products are used. As an emerging technology, a lot of open questions also remain on smart pens. In the US, patients’ insulin choices are limited by the payer – will smart pen users have to switch pens if their insurance changes or if their insurance changes its preferred insulin brand? Similar to CGM, it will also take years for connected pens to demonstrate their ability to drive improved outcomes across different populations in order to gain reimbursement and patient and provider adoption.

Novo Nordisk’s NovoPen 6 and NovoPen Echo Plus pens may launch in 2020, eventually in the US. Data from the pens can be downloaded with NFC, and the pens are compatible with any Novo Nordisk insulin cartridge. Promising data from a 12-site Swedish pilot study (n=94) with CGM (Dexcom G4 or Abbott FreeStyle Libre) and NovoPen 6 were first shown at two ADA 2019 posters: (i) two weeks of CGM metrics at follow-up (14 days after the initial clinic visit) were compared to two-week baseline metrics (14 days following obtaining the pen); (ii) compared to baseline mean Time in Range improved 38% to 46% (+1.9 hours/day); and (iii) 43% fewer missed meal boluses.

It was also a strong year for Companion, with its Bluetooth-enabled InPen now available in retail pharmacies and a co-pay assistance program to ensure that all commercial copays remain ≤$99 per year. Pharmacy availability will enable HCPs to directly e-prescribe InPen from the EMR, reducing inconveniences and boosting access.

Lilly also announced a non-exclusive agreement to use Dexcom CGMs in its smart pen and hybrid closed loop pump projects. Lilly’s smart pen was submitted to the FDA in 1Q19, but we haven’t heard updates beyond this since. Additionally, France-based Biocorp also announced a distribution partnership with Sanofi to incorporate its connected pen attachment “Mallya” with Sanofi’s insulin pens. This partnership could be an easy way for the company to operate in the connected pen landscape without having to invest in internal R&D.

2019 also had its share of new partnerships in the smart pen field, setting the stage for an exciting 2020.

  • Abbott and Novo Nordisk announced a non-exclusive partnership in February to integrate insulin dosing data form Novo Nordisk’s connected pens directly into the FreeStyle LibreLink app and LibreView diabetes management system. The partnership made Abbott Novo Nordisk’s fourth publicly-announced smart pen data partner, joining Dexcom, Glooko, and Roche. It also made Novo Nordisk as Abbott’s second smart pen partner, after Bigfoot. Abbott has not disclosed how it intends to utilize the data.
  • Sanofi became Abbott’s third smart pen partner in a September announcement stating that data from Abbott’s FreeStyle Libre and FreeStyle Libre 2 CGMs will be combined with insulin dosing information from Sanofi’s future connected care products. The partnership gives Sanofi’s first CGM partner in insulin injection titration and access to data from the world’s most widely used CGM.
  • Medtronic and Novo Nordisk’s partnership, announced in September, will share data from Novo Nordisk’s smart pens (NovoPen 6, NovoPen Echo Plus, and a disposable pen attachment) with Medtronic CGMs. Medtronic will likewise update its Guardian Connect CGM application to incorporate insulin data. The partnership made Novo Nordisk as Medtronic’s first smart pen partner.
  • Companion partnered with Dexcom to incorporate CGM data and insulin injection data into both companies’ software applications - that integration was live as of September 2019. Companion also announced a separate collaboration to integrate injection data into Rimidi’s and Glooko’s platforms.

6. Emerging Role for Tech in Type 2s: Professional and Real-Time CGM, Smart Pens, and Pumps?

As technology use has greatly increased over the past decade in type 1s, particularly CGM (CGM was used in 7% of type 1s in 2010-2012 vs. 30% in 2016-2018, per the T1D Exchange), we saw some developments in 2019 that could help crack open the type 2 market for diabetes technology. October saw FDA clearance for Dexcom’s G6 Pro, which includes a real-time mode that effectively allows users to “try” CGM before committing to a personal system – this seems like a valuable way for some new users to use CGM with provider help and lower upfront cost (clinic-owned reader and fully disposable transmitter) as long as the economics work for them. Helmsley, Jaeb Center, and Cecelia Health shared positive results from the pilot “Geek Squad” study (n=36), which onboarded type 1 and type 2 patients onto Dexcom G6 and Abbott FreeStyle Libre. A remarkable 80% of people who received a letter from Geek Squad registered for the study without any follow-up, demonstrating the demand for a service like Geek Squad and interest in CGM. There may well be a place for device-agnostic groups like Geek Squad to help drive CGM adoption – while there are questions (e.g., would the group be non-profit? Company-supported? Insurer-supported?), patients of all kinds clearly want help, and the positive early results show a clear demand for CGM across geographies and type of diabetes. Partnerships between CGM companies and digital health companies (e.g., Abbott and Omada) also present another potential way to drive CGM into type 2 diabetes. The data from these CGM + coaching programs could also encourage payers and providers to cover and prescribe CGM for type 2s. Of course, there are also open questions on the business and wear models for CGM in type 2 diabetes (e.g., real-time CGM, intermittent CGM, quarterly wear, etc.) and how to pair CGM data with education, behavior change, etc., as well as with weight, blood pressure, and other biometric data.

  • Connected BGMs remain low-hanging fruit, especially for people with type 2 diabetes. According to a Rock Health and Stanford report, just 29% of people are tracking their blood sugar digitally, while 36% use pen & paper and another 35% are not tracking at all. Accurate and consistent glucose recordings are critical for education and behavior changes. Physicians, CDEs, and coaches can also make much more informed suggestions to patients with better data. In encouraging signs, we’ve seen bundled connected BGM and digital health coaching programs start to access the retail distribution channel, a channel that could reach a much wider swath of the type 2 population (see One Drop in Walmart and Apple Stores; DarioHealth in Best Buy).
  • For the sizeable type 2 population on MDI, there has been much excitement around smart pens for a few years now (see Reflections 2018 and 2017), but 2019 will end with Companion Medical’s InPen as the only product on the market. Novo Nordisk’s connected pen and Biocorp’s Mallya pen attachment were expected to launch this year, but both were hit with delays. We’re glad to see companies taking the time to make sure products are ready for launch, but accurate injection logs have the potential to drive helpful tools, like dose calculators, and behavior changes. The power of injection data can be amplified when partnered with glucose data, and 2019 has been a strong year on that front: Companion integrated InPen data into Dexcom Clarity, Sanofi added Abbott as a CGM partner for its smart pen, while Lilly announced a partnership with Dexcom, and Novo Nordisk now has partnerships with Abbott, Dexcom, and Medtronic CGMs.
  • The insulin pump market in type 2s remains largely untapped, though Insulet’s Omnipod Dash has seen strong early signs. Insulet’s no-upfront-cost, pay-as-you-go Omnipod Dash model has obvious appeal for the type 2 market, and in 3Q19, CEO Shacey Petrovic cited a “significant increase” in type 2 diabetes users for Dash. Valeritas’ patch pump V-Go also saw continued growth, albeit from a low base (revenue in 3Q19 totaled $8.5 million). Elsewhere, however, it has been another year of delays for the patch pump market. BD’s Swatch patch pump was withdrawn from FDA submission, though it remains in the pipeline. CeQur’s bolus-only PAQ Meal was pushed back to a launch in 1Q20, while Roche’s Accu-Chek Solo pump was being expanded from pilot to markets in Europe and the Middle East as of EASD 2019. Altogether, the delays serve as a reminder of the quality and cost difficulties for patch pumps (a 3-day wear patch pump translates to 487 devices over the four-year warranty period for a traditional pump).

7. Enabling Data-Driven Diabetes Care: More Connected Devices, Easier Data Downloading, Data Aggregators (Tidepool Uploader and Glooko Population Tracker), Automated Patient and Physician Decision Support

Data-generating devices (e.g., CGM, pumps, smart pens) are driving better, more personalized care for many patients with diabetes. However, as these technologies become more widespread, how will the existing healthcare system adapt to incorporate the influx of data? How can device and software manufacturers make the data integration process more seamless, especially getting data to HCPs and patients, while maintaining security and flexibility for various devices and types of users? Perhaps most importantly, how can we make sure that these transformative technologies become accessible for everyone?

  • Simply getting more connectivity built into devices and making data downloads easier may be the best places to begin for improving access to data-driven care. We are uncertain at this stage who is using this data the most and where are improvements being seen. As mentioned above (theme 6), just 29% of people are tracking their blood sugar digitally, while 36% use pen & paper, and another 35% are not tracking at all. Even for those on SMBG, capturing some data is better than no data, and given the size of the SMBG population, connected BGMs may help millions improve their outcomes. More broadly, digital health companies like Livongo, mySugr, and One Drop, have been integrating other sources of data, e.g., exercise trackers, blood pressure monitors, etc. It’s unclear which of these data sources and how much of the data will be meaningful for patients and providers, but seeing companies work together to integrate data from different devices bodes well for the future of interoperability. Getting data from the patient to the provider is also getting easier, as remote monitoring for CGMs and BGMs becomes more widely used. On the pump side, Tandem will become the first company to have fully no-cable data uploads when it launches the t:slim X2 smartphone app (expected to launch concurrently with Control-IQ). 
  • With the influx of data, the need for centralized data management software, such as Glooko’s Population Tracker and Tidepool Uploader, has become more obvious. These software offerings may also be the most natural place for physician-facing decision support – for example, DreaMed’s Advisor Pro is built into Glooko’s Population Tracker. While complete standardization of data display is lacking, the one-page Ambulatory Glucose Profile (AGP) made its way into the ADA’s Standards of Care update in August 2019 and is a very big deal. So far, device manufacturers have largely built out their own data management platforms, e.g., Dexcom Clarity, Abbott LibreView, but are also integrated with second and third-party partners, e.g., Glooko and Tidepool.
  • Making sure healthcare teams, including primary care and endocrinology practices alike, are prepared to efficiently incorporate data into care may be one of the most important public health projects of this decade. In 2019, DreaMed’s Advisor Pro received FDA clearance to provide optimal pump settings for SMBG-only users. Positive physician acceptance data (cost unknown) on Advisor Pro was shared at ISPAD 2019, and we are eagerly awaiting glycemic outcomes data from the Advice4U study, expected to read out at ATTD 2020. Medtronic’s Pattern Snapshot for professional CGM, Glytec’s Glucommander insulin titration software, and Rimidi’s Diabetes+Me software are also players to watch in this area. Taking a different approach, some groups have begun to rethink the traditional clinic workflow. The Helmsley-funded, Jaeb and Cecelia Health “Geek Squad” is piloting an effort to remotely prescribe and onboard new CGM users. At AADE 2019, we learned about Texas Children’s Hospital’s rearranged clinical model to accommodate increasing CGM interpretation visits without getting overloaded, and we learned about Nationwide Children Hospital’s automation of the CGM acquisition process, which reduced the time for patients to get access to CGM from two weeks to a few days and reduced the paperwork burden for providers and staff.

8. Big Tech Companies Continue Diabetes Push: Major Moves from Google/Verily, Fitbit, and Amazon

Large technology companies, formerly deemed “non-traditional healthcare players,” spent the year solidifying their positions in the diabetes field. With the rising rates of chronic illnesses like diabetes, investments from big companies represent a large financial opportunity, especially given their almost inexhaustible resources and valuable expertise. As an example of the impact these “Big Tech” companies can have, when Samsung incorporated the CDC’s prediabetes risk assessment (validated from the ADA) into the Samsung Health application, which has a ~70 million monthly active users globally, over half a million people (!) had completed the assessment in a month. Over 30% of those who took the test were at risk for prediabetes. In a similar effort, Google began highlighting the same risk-assessment in searches for “prediabetes” and “type 2 diabetes” in July. Though we haven’t heard any numbers on how many people have accessed the risk assessment through Google, we wouldn’t be surprised if the number is in the hundreds of thousands or even millions.

  • Google/Alphabet/Verily: Alphabet made headlines in early November, with its $2.1 billion acquisition of Fitbit that is expected to close in 2020. The move directly puts Google on a rapid path to compete against the highly successful Apple Watch in the wearable fitness tracking space. Alphabet also made two big-time hires, adding former FDA Commissioner Dr. Robert Califf as Verily and Google Health’s Head of Strategy and Policy and former US Assistant Secretary for Health Dr. Karen DeSalvo as the company’s first Chief Health Officer. The wealth of experience these individuals bring in regulatory affairs, clinical trials, and digital health offers boundless opportunity to create impact in diabetes and obesity.

  • Few updates were provided on Verily’s diabetes-related partnerships with Dexcom and Onduo among others. Dexcom expects an initial launch of the G7 by late 2020, featuring 14-15-day wear, a fully disposable design, factory calibration, and Bluetooth to app communication. We also wonder what Verily’s involvement in Onduo will resemble given Sanofi’s exit from the diabetes and cardiovascular research fields and the success the initiative has seen. Could we see an RCT in 2020? Other initiatives, such as expanding AI diabetes retinopathy screening efforts in Thailand to partnering with Walgreens to make Onduo’s “virtual diabetes clinic” available to employees and family members, are expected to charge ahead in 2020.

  • Amazon made waves last year with its plans of partnering with JP Morgan and Berkshire Hathaway for an independent healthcare venture (now called “Haven”) led by Dr. Atul Gawande. According to CNBC, the company intends to build a “risk-based clinically integrated network”: (i) building a curated network of physicians based on performance data; (ii) build trust with employees; (iii) and use such a network to direct employees to the appropriate type of care for a specific condition. The company has also made some big-time hires, including Dr. Sandhya Rao, a former senior medical director at healthcare system Partners Population Health, to run clinical strategy. We hope to hear more about the latest updates at JPM 2020 (see here for our preview). Last year, the company acquired online pharmacy PillPack and launched a line of medical devices under the “Choice” brand name (beginning with BGM and blood-pressure monitor products).

  • Fitbit closed 3Q19 with $347 million in sales in what appeared to be a choppy financial year. Its acquisition by Alphabet could not only increase financial stability but also provide access to Alphabet’s R&D prowess to scale products faster, transition away from consumer wellness to healthcare, and combine chronic disease management tools with Verily’s diabetes partnerships. The combination of Google and Fitbit has enormous potential in diabetes and obesity through the fusion of wearable hardware, data collection, and motivating technology to improve nutrition, physical activity, weight loss, and higher Time in Range. Beyond the acquisition by Google, Fitbit had also planned on launching one-on-one coaching in 2020 to assist with “diabetes” or “weight loss” management” and a pilot for the program in late 2019. In August 2019, Fitbit launched three new products: (i) a Premium Service ($9.99 per month); (ii) Bluetooth-enabled Aria Smart Scale ($49.95); (iii) and Versa 2 smartwatch. The Aria Smart Scale was selected as Solera Health’s “preferred scale” to be offered for free to participants in a diabetes prevention, heart disease, and chronic disease program. Updates on this along with the company’s work with the FDA’s PreCert Program, $6 million investment in CGM startup Sano, and partnerships with companies like Dexcom and Medtronic are all things to look for in 2020. We are curious to see how these initiatives will be restructured and evaluated pending the acquisition’s closing in 2020.

  • Apple is the only major player on this list with a significant retail footprint; One Drop secured a win by making its BGM+app bundle available at Apple Stores across the US (the bundle comes with one year of one-on-one CDE coaching). Apple’s very successful Apple Watch also has potential in the diabetes space. Livongo also announced that it would integrate data from Apple and Samsung’s wearable trackers (presumably starting with steps, heart rate, and sleep). Dexcom’s direct-to-Apple-Watch (no smartphone required) was expected to launch this year but may now be slated for an early 2020 launch. For a few years, the idea of glucose sensing in the Apple Watch has been floated, but this front has been largely quiet.
  • Samsung has a variety of multi-year partnerships with Medtronic, Welldoc, and Insulet to bring CGM, digital health, and insulin pump control into its popular line of Galaxy smartphones. At IDF 2019, Samsung’s Dr. Ricky Choi mentioned that Samsung’s vision is “better health for billions,” an ambitious, but achievable goal given the company’s reach (Samsung is in 70% of American homes in the form of TVs and appliances).

9. Inpatients and Diabetes – So Much Potential, Not Much Change

Overall, the use of diabetes technology devices by inpatient clinicians is still in the dark ages. As we reflect on the year behind us and the year ahead, we believe there are several improvements that leaders in this area would like to see. 

  • As a reminder, use of any technology in the hospital setting is subject to a wide variety of legal and regulatory rules and restrictions. This has resulted in great variability from system to system and virtually no standardization of approach. With the advent of more patients using CGM and various insulin delivery devices at home, hospitals have been more widely encouraged to create insulin pump and continuous glucose monitoring policies that guide when patients should and should not use their personal devices as well as safety considerations. We are impressed by policies that include guidance to patients with adjusting insulin pump settings (insulin to carb ratios, correction factors and basal rates that work at home rarely work during acute illness) and using the hospital blood glucose monitoring equipment for dosing insulin (which is subject to daily quality control testing to ensure accuracy).  Another area of debate is hospital meal plans which may offer menu items that patients tend to avoid at home such as muffins, pancakes and high fat foods in general.  Some hospitals have moved to more plant-based offerings, lower carb options such as Greek yogurt and the elimination of sugar-containing beverages from both meal trays and employee cafeterias.

  • Although a number of electronic glycemic management systems for hospital use are commercially available, market penetration is low, perhaps due to the cost and plethora of homegrown hospital protocols. Further studies are needed to compare the efficacy and cost-savings of computer-generated dosing algorithms to well-validated hospital insulin protocols. Some inpatient management leaders would like to see a re-do of the NICE-SUGAR trial, using standardized insulin drip and glucose monitoring methods, to gain evidence-based guidance on optimal glycemic targets in critically ill patients.
  • CGM has the potential to be a perfect fit in the inpatient setting by warning clinicians of impending hypo and hyperglycemia, thus enabling preventive action rather than being reactive. Indeed, the efficacy and safety of insulin drips, common in the ICU versus traditional subcutaneous insulin therapy, could be revolutionized with CGM as an early warning system. In a 2017 Consensus Statement on the Use of Continuous Glucose Monitoring in the Hospital, barriers to CGM adoption in hospitals included: lack of accuracy and outcomes research of CGM devices in acutely ill patients comparing CGM results to the current standard of care (point-of-care blood glucose meters); need to identify impact of vasoconstriction, dehydration, edema and some inpatient medications on CGM accuracy; and secure data storage/cybersecurity concerns. CGM use in the hospital setting has the potential to guide insulin therapy during hospitalization, and reduce both poor glycemic control and length of stay. With the use of diabetes devices exploding in the outpatient setting, we would like to see hospitals step up and offer patients the same level of diabetes care during their inpatient stay. Unfortunately, this has not been a major focus of advocacy groups, and because the same patients are not in the hospital frequently, we haven’t seen much patient input on this side.

     

Top Ten Most Highly Read Closer Look Reports in Technology

  1. Automated Insulin Delivery (AID) Competitive Landscape
  2. IQVIA White Paper on Time in Range: Improving US Diabetes Population TIR to 70% Could Save At Least $2-$4 Billion Over Ten Years
  3. Interview with Senseonics CEO Dr. Tim Goodnow and new CMO Dr. Fran Kaufman: opportunities and challenges for implantable CGM
  4. CGM Competitive Landscape
  5. Dexcom 1Q19 – Sales of $281 million rise 52%, driven by 45% US growth; G7 in late 2020-early 2021 (“spectacular”); FY19 Guidance raised by $75 million; Cigna pharmacy coverage
  6. FDA clears Tandem t:slim X2 as first interoperable insulin pump: “alternate controller enabled (ACE) infusion pump” (aka iPump)
  7. Abbott 1Q19 – FreeStyle Libre 2 under FDA review as iCGM; Sales of $566 million up 42% YOY, driven by $379 million in FreeStyle Libre sales; almost 1.5 million FreeStyle Libre users
  8. Medtronic Names Sean Salmon New Group President of Diabetes
  9. FDA safety communication warns against use of unauthorized diabetes management devices in wake of serious adverse event with DIY AID
  10. Abbott 2Q19 – Record FreeStyle Libre sales of $433 million rise 64% YOY, 14% sequentially; Libre 2 iCGM remains under FDA review, with clearance expected “relatively soon”

(Higher total page views will generally be skewed towards reports published earlier in the year.)

Most Highly Read diaTribe Learn Reports in Therapy

  1. Tandem’s Control-IQ Hybrid Closed Loop Algorithm Submitted to FDA
  2. Taking the Sting Out of Fingersticks: Lancets, Life Hacks and More
  3. Tandem’s Control-IQ System: Launch Now Expected in Second Half of 2019
  4. News from Medtronic: Hypoglycemia Prediction (IQcast) with Sugar.IQ and Timing on the Next-Gen MiniMed 780G Closed Loop
  5. Tech on The Horizon: Automated Insulin Delivery Systems Coming In 2020

Most Unexpected News/Things We Got Wrong

Glucose Monitoring

Insulin Delivery (AID, Pumps, Smart Pens, Devices)

Data, Digital Health, Connected Care

Key Questions for 2020

  • What are all the ways in which data integration surrounding CGM and insulin delivery can be leveraged together to produce real-time decision support and better outcomes? For now, patients appear to be doing far better on CGM when they are using arrows actively or when they are using systems that automate delivery in some way.
  • What is the best role for CGM, particularly in type 2s, and what are the best payment models? From our view, the companies that are best able to demonstrate improved outcomes and cost will be best-positioned to thrive in the fast-paced ecosystem where there continues to be pricing pressure.
  • What is the future of BGM as CGMs continue to become lower cost and better reimbursed?
  • Which companies will be able to hit their expected hybrid closed loop launch targets over the next 1-2 years?
  • What is the future of the four-year pump warranty cycle? Will patients, providers, and payers favor the subscription/pay-as-you-go model?
  • Is it possible to “close the loop” by combining CGM with smart pens?
  • How much will adoption will see around smart pens? Which companies will take the lead here?
  • Will we see more studies of MDI/CGM based decision support?
  • Will clinical decision support finally gain traction? How much will physicians accept recommendations? How will these tools be reimbursed?

Glucose Monitoring

  • Will we see FDA clearance of FreeStyle Libre 2 as an iCGM? Will the US features look different?
  • Will we see more progress on use of CGM: (i) in type 2 diabetes (especially non-insulin users)? (ii) in pregnancy? and (iii) in the hospital?
  • Will Dexcom get G7 launched as expected in late 2020/early 2021?
  • Will Senseonics get 180-day labeling in 2020? Will it obtain iCGM labeling and integrate with more AID systems?
  • How much can we see Time in Range further validated?
  • What are the biggest barriers in CGM adoption? To what extent would adoption accelerate with: (i) better payer coverage; (ii) more awareness; (iii) more HCP willingness to prescribe? (iv) different products?
  • Where will CGM adoption go in type 1 diabetes in 2020? What about type 2 diabetes in 2020? When will CGM eclipse pump penetration in the US in people with type 1 diabetes? What about in Europe?
  • How will CGM be deployed in different populations and use cases, especially in type 2 diabetes? – e.g., professional vs real-time, 24/7 vs. quarterly, coaching vs. no coaching, remote monitoring, etc. Will we see more CGM studies/pilots in type 2 diabetes in 2020?
  • What is the future of BGM with no-calibration and lower-cost CGM? Can Ascensia, LifeScan, Roche, and others continue to innovate in BGM software/apps/coaching? Will their various CGM partnerships pan out?

Insulin Delivery (AID, Pumps, Smart Pens, Devices)

  • Could we see five strong closed-loop systems on the US market by the end of 2020 – Tandem Control-IQ, MiniMed 780G, Insulet Horizon, Tidepool Loop? Will Diabeloop and Cambridge (CamDiab) successfully launch in Europe?
  • Will these next-gen AID systems accelerate uptake of insulin pumps?
  • How will Medtronic’s MiniMed 780G compare to Tandem’s Control-IQ? Will 780G hit the goal for >80% Time in Range?
  • As Novo Nordisk and Lilly seem poised to launch their smart pens in 2020: what will uptake look like in this category? Will we see novel business models – e.g., subscription models? Will innovation move faster in this area? 
  • Will Beta Bionics finally start its iLet insulin-only pivotal study?
  • Will Bigfoot submit its Unity smart pen platform to FDA, ahead of its planned 2021 launch?
  • Will we finally see the launch of CeQur’s PAQ Meal, following the acquisition from J&J (formerly Calibra Finesse)? (March)

Data, Digital Health, Connected Care

  • Will we see more progress on insulin-dosing decision support in 2020? Which players will lead this – the CGM companies, smart pen companies, connected care/digital health companies? What business models will best fit the market?
  • How much can digital health help drive CGM into new markets (e.g., type 2s)?
  • Will we see more studies in MDI/CGM decision support?
  • How much traction can clinical decision (e.g., DreaMed Advisor Pro, Dexcom Clarity) support gather in 2020? What will be the business model for these systems?
  • How intensive does a digital health intervention need to be to achieve outcomes?
  • What sorts of business models around digital health will win out? Which payers will favor subscription-based models (e.g., Livongo) vs. value-based payments (e.g., Virta Health)?
  • What sorts of SMBG-based features (e.g., glucose prediction, A1c prediction, lifestyle modification suggestions) will actually drive better outcomes?
  • How can AI drive help identify higher-risk patients for more timely and appropriate interventions?
  • How can fitness, sleep, and other trackers become integrated with CGM (or BGM) data to provide insights?

What’s Coming in 2020?

Below we include the pipeline products we are aware of, though we acknowledge this list is likely not 100% complete. We have done our best to be as comprehensive as possible based on the most recent public updates we’ve heard.

Glucose Monitoring

Abbott

  • FreeStyle Libre 2 iCGM FDA Approval. Working through “handful of open items” with the FDA as of October 2019
  • Continued expansion of FreeStyle Libre 2 in Europe. Currently available in France and Germany. Possible FDA submission and US launch?

Waveform/AgaMatrix

  • Cascade CGM CE marked with initial launch forthcoming in “select countries” driven by distribution partner A. Menarini - 14-day wear-time, one calibration/day, Blouetooth-toapp, rechargeable transmitter (up to 2 years), no acetaminophen interference, readings transmitted every minute
  • Clinical trials to support PMA submission to FDA to begin 1Q20, FDA submission as iCGM in “2020”

Ascensia

  • Coaching & BGM bundle expected to launch in 2020, currently in pilot stage
  • Partnership with POCTech to co-develop a CGM? Previously expected sales of “Ascensia branded and boxed” CGMs by the end of 2019

DarioHealth

  • Continued scaling of “hypertension solution” integrating connected blood glucose and blood pressure monitors in the same application
  • Continued expansion of B2B2C channel with clients like Walmart, Best Buy, and Giant Eagle
  • Expansion of BGM, strips, and digital coaching “membership-in-a-box” bundle to brick and mortar retail stores.

Dexcom

  • G6 Professional CGM Launch – FDA clearance in October 2019
  • G7 launch
  • Direct-to-Apple Watch transmission
  • Novo Nordisk-G6 CGM data integration
  • AID launches in the US for Insulet (Horizon Hybrid Closed Loop) and Tandem (Control-IQ Hybrid Closed Loop); and in Europe for Diabeloop (DBLG1 Hybrid Closed Loop)
  • Tidepool Loop Integration?
  • Integration with Lilly’s Hybrid Closed Loop and smart pens?

EyeSense

  • Fibersense 29-day wear, 1 cal/day potential launch in late 2020

Glysens

  • The Gen 3 Eclipse fully implantable CGM system was supposed to enter clinical trials in 2019. Possible updates in 2020?

Intuity Medical

  • Raised $70 million in January 2018 to support commercialization of all-in-one POGO Automatic BGM and secured FDA clearance about three years ago – will this launch in 2020?

Lifescan

  • OneTouch Verio Reflect continued expansion in the EU and Canada, possible launch in the US?

Medtronic

  • Non-adjunctive labeling for Guardian Sensor 3
  • Zeus iCGM pivotal trial completion and FDA submission

PercuSense

  • Multi-analyte sensor with 14-day wear, 30-min warm-up potential launch in ~late 2020?

Pops! Diabetes Care

  • Continued commercialization of all-in-one BGM and digital platform

Roche

  • Launch of Accu-Chek SugarView “meter-free BGM” in Europe and the Middle East
  • Updates on the pivotal trial for the Roche-Senseonics-TypeZero hybrid closed loop system?

Senseonics

  • Completion of the 180-day PROMISE study for Eversense XL
  • Securing iCGM indication for 90-day Eversense
  • Rollout of Medicare coverage for Eversense payment starting in 2020 as a “Physician Service”
  • Expanding controlled launch of Eversense in the Middle East
  • Obtaining 250 million US lives covered under Eversense
  • Automated insulin delivery progress: (i) 1Q20 pivotal rial start for insulin-only iLet with Beta Bionics; (ii) Roche-Senseonics-Type Zero hybrid closed loop system pivotal trial currently “on hold”

Insulin Delivery (AID, Pumps, Smart Pens, Devices)

BD

  • Continued progress with “third party R&D partner” to advance type 2 patch pump

Beta Bionics

  • Insulin-only AID pivotal study to begin in 1Q20 (pediatrics and adults), finish by 2020
  • Bihormonal pivotal study to start in ~2H20 with Zealand dasiglucagon

Biocorp

  • Launch and distribution of reusable smart pen cap Mallya (formerly “Easylog”) with Sanofi

Capillary Biomedical

  • 2020 launch of a seven-day wear version of SteadiSet – extended wear, no-kink (wire reinforced), multi-ported (3 side holes) insulin catheter that provides “consistent absorption of insulin from day to day and dose to dose.”
  • NIH-funded crossover trial comparing use of the SteadiSet for seven days vs. use of a commercial Teflon set for seven days in type 1s

Cellnovo

  • Pilot study assessing Gocap, Bluetooth-enabled cap that captures doses from disposable insulin pens, with Sanofi and Innovation Health

Companion Medical

  • Continued expansion Smart pen/CGM data integration between InPen and Dexcom’s Clarity

Convatec

  • Partnership with iLet to make “portions” of Unomedical’s infusion portfolio available for use with the Beta Bionics’ iLet
  • US launch of MiniMed Mio Advance?

CeQur

  • US launch of Calibra Finesse (OneTouch Via) bolus patch insulin delivery device in 1Q20

Diabeloop

  • Broader European launch of DBLG1 hybrid closed loop system amid new ~$34 million in Series B funding

Insulet

  • US launch of Omnipod Horizon hybrid closed loop system in 2H20 following pivotal trial
  • Continued European rollout of Omnipod Dash
  • Increased US volume of sales through the pharmacy channel
  • Expansion of the pump market by converting MDI users and increased US uptake of Dash in the type 2 market
  • Potential 2020 launch of Lilly-partnered U500 Omnipod?

Lilly

  • Connected care products are expected to launch in stages of 2019-2021, presumably starting with the smart pen that was under FDA review as of April

Medtronic

  • MiniMed 780G pivotal data readout expected at ATTD 2020 – possible April launch?
  •  “Smart Guide” system launch for Sugar.IQ?

Novo Nordisk

  • Connected NovoPen 6 and Echo Plus to launch in 2Q20

Roche

  • Broader EU commercialization phase of Solo tubeless patch pump. FDA submission?

Tidepool

  • Compilation data from Tidepool observational study of DIY Loop – n=874 as of November. FDA submission?
  • More pump and CGM partners for Tidepool Loop?

Tandem

  • US launch of Control-IQ hybrid closed loop with Dexcom CGM and TypeZero algorithm integrated into t:slim x2 ACE pump expected by end of January 2020 for 14+ years
  • FDA ACE pump submission by summer 2020 – targeting clearance by end of 2020

Valeritas

  • FDA 510(k) clearance filing in 1Q20 for the V-Go SIM (Simple Insulin Management), the company’s Bluetooth connected V-Go dose capture accessory
  • Increased patient enrollment in the V-Go Cares Program for reimbursement support

Ypsomed

  • FDA submission by the end of 2020 (calendar) for closed loop system with YpsoPump, CGM (partner not named), and myLife Control smartphone app
  • Distribution of i-SENS’s myLife Aveo (BGM system) in Spring 2020

Data, Digital Health, Connected Care

Amalgam

  • News on collaboration with Hygieia?
  • Continued collaboration with Novo Nordisk to launch white-labeled version of iSage Rx basal titration app (“DoseCheck”) in Brazil

DreaMed

  • Commencement of pilot for Advisor Pro in MDI patients likely already occurred with support for type 1 MDI users targeted for 2020

Glooko

  • Data integration for Yposymed’s myLife YpsoPump – dosing data can be uploaded to Glooko through the myLife smartphone app via Bluetooth

Glytec

  • Conversations with the FDA in the 510(k) process for the Therapy Advisor clinical decision support software
  • Ongoing partnerships with Livongo and Onduo?

Hygieia

  • More reimbursement traction following positive arrangement with BCBS Michigan

Livongo

  • Telehealth integrations for behavioral health with MDLive and Doctor on Demand
  • Data integrations from wearable trackers through Apple, Fitbit, and Samsung
  • Continued horizontal expansion into other chronic conditions and behavioral health
  • Increased client wins from Fortune 500 companies and major health plans (e.g. Blue Cross Blue Shield)
  • Data from the Voluntis partnership?

mySugr (Roche)

  • Adding Novo Nordisk smart pen-derived insulin dose data into application?
  • Adding scale for bundled coaching/unlimited strips?
  • Surpassing 2 million users by end of 2020?

Omada

  • Omada Health/Abbott Type 2 Diabetes Connected Care Program progress

Onduo

  • Restructuring of Sanofi’s involvement in the company given the recent discontinuation of cardiovascular and diabetes research
  • Pursuing a randomized controlled trial and intermittent use of real-time CGM initiatives in addition to engagement and lifestyle interventions
  • News on the partnership with John Hancock to offer life insurance to people with diabetes through Onduo

One Drop

  • Expansion of starter kit (Bluetooth-enabled BGM, strips, lancing supplies) into brick-and-mortal retail stores (e.g. Walmart, Apple)

Virta

  • Additional results from pilot study with the US Department of Veterans Affairs and future partnership updates with the VA

Verily

  • Greater involvement in Onduo given Sanofi’s discontinuing of cardiovascular and diabetes research
  • Collaborations with Fitbit given Alphabet’s acquisition of the company
  • Updates on partnerships with Palo Alto Veterans Affairs and Atrius Health
  • Expansion of AI retinopathy screenings in Thailand and India

Voluntis

  • FDA review of Insulia’s (basal insulin titration app) NPH module
  • Updates on partnerships (Onduo, Livongo, Sanofi, Ascensia, Welldoc)?

Welldoc

  • Launch of BlueStar app that adds retrospective CGM data and support

Appendix 1: Company-by-Company CGM Comparison to late 2018

 

Progress & Momentum

Challenges

Abbott

Added 600,000+ FreeStyle Libre users globally in 2019

Impressive sales growth +67% (estimated YOY) to ~$1.9 billion

Reimbursement wins: US pharmacy, Canada

Partnerships: Novo Nordisk, Omada, Tandem, Sanofi

Lengthy FDA review for FreeStyle Libre 2 iCGM

No US pediatric approval for FreeStyle Libre

No near-term hybrid closed loop

Bigfoot focus on the pen, which prompted some strategic delays

Dexcom

Impressive Sales Growth: estimated ~$1.4 billion (+39% YOY) in 2019 on G6 uptake globally; record profitability

Keeping G7 on track with eye on supply

G6 Professional CGM cleared, fully disposable transmitter

Launch of G6 into Medicare

Pharmacy building blocks: Walgreen’s partnership

Time in Range goals in Clarity mobile app

Customer service transition to Philippines

Meeting CGM demand for G6

Dexcom Follow outage

Majority of US business is still in headache-inducing DME channel

Medtronic

670G International launch and uptake

Starts iCGM US pivotal trial

Launches Envision Pro No-Calibration professional CGM

Slow progress on real-time CGM calibration reduction, on-body form factor

Very tough competition in standalone CGM

Leadership transitions

Senseonics

Non-Adjunctive labeling: submitted, approved, launched

Medicare coverage in bundled model (starting 2020)

Over 150 million US covered lives

180-Day US trial ahead of schedule

Eversense bridge program

Win in attracting Chief Medical Officer Dr. Fran Kaufman

Modest uptake in US thus far

Source: Reflections 2018

Big Picture

Themes

1. IDF Atlas 9th Edition Shows Rise in Global Diabetes Burden

IDF published the ninth edition of its Diabetes Atlas (download here) – once again, the global diabetes burden continues its apparently unstoppable, unrelenting rise. There are now an estimated 463 million people with diabetes globally, a 9% rise from the last estimate in 2017. The latest increase estimates +38 million more with diabetes compared to 2017, which had reflected a much lower +10 million rise from 2015 – although we think this is largely due to shifting methodologies by country that resulted in an underestimate in the 2017 figure, the 2019 figure is certainly worse than we might have expected. IDF estimates that 578 million people will be living with diabetes by 2030 (25% growth), expected to grow to 700 million by 2045 (52% growth). Since 2009, the estimated global diabetes population has risen 62%. While some of this reflects advances in methodology at the country level, clearly by population, the mixed approaches to diabetes are not working as favorably as possible. Certain factors, like country of residence, income level, and age, have been linked to different levels of diabetes. China and India account for ~42% of the world diabetes population, slightly higher than the 39% of the world’s population they are estimated to have. The diabetes population in these two countries is expected to grow 27% and 74%, respectively, by 2045 – adding an additional 88 million people with diabetes alone. Low- and middle-income countries account for 79% of the world’s diabetes population (compared to 85% of the world’s population), a reminder that addressing the global diabetes burden will require truly accessible, global, low-cost, culturally sensitive screening tools, patient and professional education, and innovative care models. Two out of three people with diabetes live in urban areas, which is both an opportunity (concentrated access) and a thorny problem (hard to change the built environment though some cities like Copenhagen serve as shining examples). About one in five people with diabetes (136 million) are over age 65, and the global diabetes burden is 20% for those between 75 and 79 years old, further complicating the issue. The Atlas also shared mortality statistics, and four million people ages 20-79 are expected to die from diabetes in 2019 – one death every eight seconds. This statistic is in line with 2017 and accounts for ~11% of all-cause mortality for this age group. Almost half (~46%) of deaths associated with diabetes among 20-79 age group are in people under the age of 60 years, which IDF notes is the working age group, and which can negatively impact the economy as an “indirect cost” of a shrinking work force. There are also disparities across regions in terms of diabetes mortality. In Africa, the region with the highest mortality, 73% of deaths before the age of 60 are due to diabetes, while in Europe, the region with lowest mortality, the proportion drops to 31%.

  • Over 50% of global cases of diabetes (232 million) are undiagnosed, highlighting the need for global screening, education about symptoms, and appropriate, early care that will result in greater prevention of pre-diabetes. Longer periods of undiagnosed diabetes lead to higher risk of complications, increased healthcare use, and increased healthcare costs – improving this stat will be critical to improving the global burden of diabetes. Lower-income countries exhibit the highest proportions of undiagnosed type 1 and 2 diabetes (69%) due to limited access to healthcare. Specifically, the African region has the highest rates of undiagnosed diabetes (60%) due to vast rural areas that make clinical visits harder, limited resources, and prioritization of other health issues. Though this number has declined from an undiagnosed rate of 69% in 2017, there is clearly still a very long way to go. The lowest proportion of undiagnosed cases (38%) exist in North America and the Caribbean.

    • The Atlas again puts a very conservative estimate on global type 1 diabetes prevalence, only covering it for people under age 20 (we’d love to see this changed): “over 1.1 million children and adolescents” have type 1 diabetes globally”. Of course, we know from the US that most people with type 1 diabetes are adults, so this stat is not terribly helpful for understanding the global prevalence of type 1 diabetes. It is expected that incidence of type 1 diabetes increases 3% annually, but likely with differences between different areas of the world that have not yet been studied extensively. Type 1 diabetes is life-threatening in areas with limited access to insulin, glucose monitoring supplies and other health services, along with the risk of developing serious complications.

  • Diabetes continues to present a massive and worsening, financial burden: one in ten healthcare dollars globally are now spent on diabetes – $760 billion in 2019 (+2.5% from $727 billion in 2017 compared to the 9% increase in diagnoses) – and results and outcomes are not improving at a population level nearly as much as we’d like to see, given improvement in therapies and tools to manage diabetes. While in 2017, one in eight global healthcare dollars was estimated to go toward diabetes, we don’t think the overall costs are lower now though methodologies to estimate these figures do continue to fluctuate – and not make sense in certain respects. By 2030, the Atlas projects that expenditure will be $825 billion, reaching $845 billion by 2045 – the 2014 estimate is, as one example, certainly an underestimate considering currently prevalence trends. Right now, US expenditures account for 39% (!) of diabetes spending globally, down from 48% in 2017, but still reflecting huge regional disparities in spending. With this, there are huge disparities in healthcare spending based on geographic region: 87% of diabetes-related deaths occur in low- and middle-income countries, but only 35% of spending occurs in these countries.

2. Nearly a Dozen Notable Leadership Changes in Diabetes in 2019

Here are some of the most significant leadership changes that happened in diabetes in 2019.

Big Picture

Company/Organization

Leadership Change

EASD

Prof. David Matthews voted 2019 President (January 2019)

Diabetes Research Institute Foundation

Ms. Alice Rodd O’Rourke appointed as CEO (March 2019)

FDA

Dr. Ned Sharpless replaces Dr. Scott Gottlieb as Acting FDA Commissioner (April 2019)

JDRF

Dr. Aaron Kowalski promoted to CEO & President from Chief Mission Officer (April 2019)

T1D Exchange

Mr. David Walton named as CEO (November 2019)

IDF

Prof. Andrew Boulton appointed 2020-2021 President (December 2019)

Joslin Diabetes Center

Dr. Roberta Herman appointed President and CEO (December 2019)

Diabetes Therapy

Company/Organization

Leadership Change

Sanofi

Mr. Paul Hudson chosen to succeed Mr. Olivier Brandicourt as CEO; Brandicourt to retire (June 2019)

Mylan/Upjohn

Current president of Upjohn Mr. Michael Goettler appointed as future CEO of Mylan/Upjohn merger company (July 2019)

Zealand

Dr. Emmanuel Dulac hired as new CEO (April 2019)

Lilly

Mr. Enrique Conterno retires as SVP and Head of Diabetes/President Lilly USA; Replaced by former SVP of Connected Care and Insulin Commercial Development Mr. Mike Mason (October 2019)

Top Five Most Highly Read Closer Look Reports in Big Picture

Top Five Most Highly Read diaTribe.org Articles in Big Picture

Most Unexpected News/Things We Got Wrong

  • A major and disturbing study published in JAMA found that the rate of adults with diabetes achieving A1c, blood pressure, and cholesterol targets has not improved significantly since 2005. We would have assumed with so much better understanding of what is needed in diabetes that at least some improvement would’ve been seen at the population level.

  • The T1D Exchange published updated Registry data, underscoring that only 17% of youth and 21% of adults are meeting A1c goals (<7.5% for youth, <7% for adults). Mean A1c has also risen to 8.4% in the T1D Exchange in this new dataset, up from 7.8% in 2010-2012! This meaningful increase was predominately seen in adolescents and young adults. “There is no indication,” note the authors, “that A1c levels in the registry as a whole have improved over this 5-year period despite an increase in the use of insulin pumps and CGM.”  

  • The Trump Administration rolled out an executive order aimed at improving care for Americans with kidney disease. Broadly, the initiative will focus on improved education on prevention, better access to kidney transplants, and a shift toward in-home dialysis treatment. More specifically, the executive order will strongly encourage incentive structures that lead to greater use of in-home dialysis and kidney transplants. 

  • The CDC published an analysis of NHIS data suggesting that US adult diabetes incidence has significantly decreased since 2007 (from 7.8 new cases per 1,000 adults to 6.0 in 2017). Indeed, the CDC’s 2017 Diabetes Report Card asserted that diabetes incidence ­has been on the decline since 2008. However, according to this new analysis, prevalence has leveled out since 2009 (from 8.2 cases per 100 adults to 8.0 in 2017).

  • Amidst immense public pressure, Lilly releases a generic version of its Humalog. Novo Nordisk soon follows suit with a similar measure for its NovoLog, as manufacturers seek to circumvent a complicated insulin pricing environment with their own generic versions.  

  • The ADA’s 2019 Nutrition Therapy Consensus Report adopts a much more positive stance on low-carb approaches.

Key Questions for 2020

  • What will happen at an ecosystem level to better address prevention of complications, particularly given new therapies that show so much better outcomes?

  • How will healthcare reform rhetoric in the 2020 US election cycle impact the diabetes ecosystem? Will any substantial drug pricing reform legislation pass the US Congress in 2020, following the introduction and discussion of multiple such proposals in 2019?

  • What will happen with ecosystem initiatives like soda/junk food tax movements?

  • Can the National DPP scale by orders of magnitude?

Title

Journal

Date

 

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

 

 

NEJM

 

January 2019

 

State of Type 1 Diabetes Management and Outcomes from the T1D Exchange in 2016–2018

 

 

DT&T

 

February 2019

 

Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up

 

 

NEJM

 

June 2019

 

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

 

 

NEJM

 

June 2019

 

Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial

 

 

 

The Lancet

 

 

July 2019

 

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial

 

 

 

The Lancet

 

 

 July 2019

 

Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial

 

 

 

The Lancet

 

 

July 2019

 

An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes

 

 

NEJM

 

August 2019

 

Evaluation of the Cascade of Diabetes Care in the United States, 2005-2016

 

 

JAMA

 

August 2019

 

Vitamin D Supplementation and Prevention of Type 2 Diabetes

 

 

NEJM

 

August 2019

 

Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

 

 

NEJM

 

August 2019

 

Liraglutide in Children and Adolescents with Type 2 Diabetes

 

 

NEJM

 

August 2019

 

Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes

 

 

NEJM

 

October 2019

 

Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction

 

 

NEJM

 

October 2019

 

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction

 

 

NEJM

 

November 2019

 

Effects of Intermittent Fasting on Health, Aging, and Disease

 

 

NEJM

 

December 2019

Top Big Picture KOL Quotes of 2019

From "ADA 2020 Standards of Care"

  • Dr. Anne Peters (USC): “The key to the success of any guidelines is helping implementation with our primary care colleagues. Which is why we tried to make it clearer, even though it is not possible to make it simple.”
  •  Dr. Silvio E. Inzucchi (Yale):While the new Standards of Care don’t go so far to advise these meds over metformin as first line therapy, they do recommend that they be used regardless of HbA1c.  Although I tend to agree with this approach, I would point out one flaw. This strategy has never been actually proven to be effective in a dedicated clinical trial. Instead, we are inferring this to be the correct approach from relatively small subgroups in these trials.  On the other hand, properly powered studies are unlikely to ever be conducted to specifically prove that this approach is valid. Accordingly, as in many areas of medicine, we are forced to interpret the data we have, often suboptimal, and then contextualize this for the patients we see in our practices.”

From "KOLs React to ESC 2019 Guidelines: Mixed Opinions on First-Line Use of SGLT-2/GLP-1"

  • Dr. Mikhail Kosiborod (Saint Luke’s): "I think that recommending SGLT-2 inhibitors  and GLP-1 receptor agonists  as first line therapy in patients with type 2 diabetes and ASCVD (or high CV risk) is a huge step in the right direction – and is based on consistent evidence from multiple large clinical trials. It’s great to see that the guidelines continue to emphasize the selection of agents with proven cardiovascular benefit for high-risk patients with type 2 diabetes. Since cardiovascular disease remains the main cause or morbidity and mortality in this patient group, prevention of these common and morbid complications should be the key goal of management." 

  • Dr. Lawrence Leiter (University of Toronto): “It is certainly noteworthy that the new guidelines have made this change. In the past guidelines have said that SGLT2 inhibitors or GLP1RAs should be add-ons to metformin in order to be consistent with the design of the trials. Importantly, however, subgroup analyses from all of the trials have shown similar benefits in the smaller groups of patients not on background metformin. Since the cardiologist may not continue to follow the patient on a long term basis, omitting the requirement that patients already be on metformin will hopefully get more patients on evidence based therapies. In addition, industry has been reluctant to do head-to-head trials vs. metformin as initial therapy fearing that even positive results might not supplant metformin’s role as the foundational therapy. Hopefully these new guidelines may encourage proper comparative trials to now be initiated.” 

  • Dr. Sanjay Kaul (Cedars-Sinai Medical Center): “This recommendation was a long time coming and is faithful to the evidence. There is little to no evidence supporting the use of metformin in mitigating cardiovascular risk in patients with diabetes. On the other hand, there is clinically compelling and statistically persuasive evidence for CV risk reduction with SGLT2 inhibitors and GLP1-RA in T2DM patients with underlying ASCVD. The fact that metformin continues to enjoy status as first-line therapy in current guidelines is an example of old habits die hard! While metformin is affordable and safe and physicians are facile with its use, the evidentiary basis for its recommendations rest on a shaky foundation. In the EMPA-REG OUTCOME trial, about a quarter of the patients were not on metformin at baseline, and this subgroup experienced a greater risk reduction in the primary endpoint (28% vs 8%) or CV death (54% vs 29%) than the subgroup on metformin at baseline. These data support the use of empagliflozin as monotherapy in patients with established ASCVD. I will not be surprised to see other guidelines following the lead of ESC recommendations.”

Obesity

Themes

1. Tech/Drug Partnerships, Novel Compounds, and Prescription Devices Underscore Evolving Nature of Obesity Landscape

2019 marked a fruitful year in obesity partnerships and compound development, especially considering a rather challenging period for the field in 2018. Without a doubt there were a number of positives, including a diverse array of innovative partnerships and successful clinical trials; on the negative side, of course, as the recent NEJM article showed (“US Adult Obesity Prevalence Expected to Rise to 50% by 2030; Severe Obesity to Rise to 24%”), outcomes in obesity have never been worse and this area continues to be a moving target for researchers and industry alike. Given that there is still so much of the pathophysiology to be understood, the question of how to even approach preventing and treating obesity – pharmacotherapy vs. behavioral treatment? which biological mechanisms? etc. – remains. In our view, it’s still too early to put together any concrete predictions for the field. Still, that means there is still ample room for new players, compounds, and devices to join the field, and we anticipate watching the landscape evolve rapidly in the next five to ten years.

  • BI and Gubra penned their second obesity collaboration in May 2019, focusing on next-generation, peptide poly-agonists to treat the condition, with Gubra standing to receive up to ~$267 million in upfront, milestone, and royalty payments. As the impetus for this new deal, BI cited the success thus far from the companies’ first ~$300 million partnership, which is targeting therapies to reduce food intake and has “already achieved important milestones.” It’s highly encouraging to see BI doubling down on investments with Gubra, and we look forward to seeing new data and a clear sign of continued investment in 2020.

  • In one of the more innovative collaborations of the year, Novo Nordisk and Noom partnered to bring Noom’s digital health solutions to Novo Nordisk’s portfolio of obesity treatments. Even before the deal, Noom, which provides weight management services, education, and human coaches through an app, had an impressive 10+ million downloads on Google Play. We’ve seen an overall increased commitment to tackling issues of obesity from Novo Nordisk this year, including remarks on the company’s plans to double current obesity sales by 2025 at Capital Markets Day 2019 and a three-year partnership with UNICEF to address childhood obesity. Novo Nordisk’s Saxenda (liraglutide 3.0 mg) is certainly the front runner in obesity medications, jumping +46% YOY to $213 million in 3Q19 sales, and we’re glad to see at least one compound doing fairly well commercially given the difficulty the field has had overall.   We’d like to continue to see more news on improving payer coverage and patient access here.   

  • A number of GLP-1/glucagon dual agonists are in consideration for obesity treatment despite Sanofi dropping its phase 3 candidate in 2018. In August 2019, Innovent licensed Lilly’s OXM3 for development and commercialization in China as a potential therapy for obesity, but more broadly, also diabetes and NASH. Lilly first announced this candidate in its May 2016 R&D update and moved the candidate into phase 1 in 4Q16, but updates beyond this have been scarce. Preclinical data highlighted by Lilly during its 4Q16 update suggested superior efficacy to Novo Nordisk’s semaglutide in mouse models for NASH. Nonetheless, we’ve been unable to find clinical results for OXM3, although Innovent’s press release notes that early stage clinical trials for the candidate have demonstrated “potential for potent weight loss and evidence of improved glycemic control.” OPKO Health’s OPK88003 also remains in phase 2, though no mention of the candidate was made during the company’s 3Q19 update, following topline phase 2b dose-escalation results announced in 2Q19.

  • In a win for late stage development, Denmark-based Saniona released positive phase 3 results (n=372) for its triple monoamine reuptake inhibitor tesofensine (a daily oral). Participants on tesofensine lost an average 10% of body weight at 24 weeks compared to placebo (p<0.001), and more than half of the participants on tesofensine lost >10% of body weight in 24 weeks. The only noted safety signal was a significant increase in heart rate with tesofensine, however, some have emphasized that cardiovascular safety may be an issue with the drug due to its sympathomimetic mechanism and observed increases in heart rate and blood pressure. Importantly, partner Medix conducted this study in Mexico, and these results will only support regulatory filings for tesofensine in Mexico and Argentina, where Medix owns commercial rights. The compound was just submitted to Mexico’s regulatory agency in December, though no news of broader studies or filings have been announced.

    • Rhythm Pharmaceuticals announced positive phase 3 results for its trials evaluating MC4R agonist setmelanotide in POMC and LEPR deficiency obesity. Eight of the ten study participants achieved the primary endpoint of >10% weight loss over one year (p<0.0001) vs. placebo, with a mean reduction of -25.4% from baseline (p<0.0001). The company is slated to complete NDA submission to the FDA in 4Q19 or 1Q120.

    • Intriguingly, Novartis also presented positive phase 2 results (n=75) for activin receptor agonist bimagrumab at Obesity Week 2019. This candidate has been flying under the radar thus far, but we were impressed with the -7.5 kg fat reduction from a baseline of 90.1 kg (-21%) vs. -0.2 kg from 96.9 kg on placebo (p<0.0001) seen at week 48, with intravenous administration every four weeks. Bimagrumab also demonstrated an 0.9% drop in A1c from 8% at baseline, compared to an 0.1% decrease from 7.7% in the placebo arm. Of note, the majority of patients were on metformin, with a small proportion also taking a DPP-4 inhibitor. Gastrointestinal adverse events were significantly higher in the bimagrumab group (~40% experienced diarrhea vs. 10% on placebo), though the frequency of adverse events seemed to taper off after the first dose was administered. Given these results, we’ll be curious to see how Novartis moves forward with the candidate, as the drug has gone unmentioned during previous quarterly updates.

  • In obesity devices, the FDA approved Gelesis’ prescription hydrogel capsule Plenity in April 2019. Of note, the capsules are approved as an adjunct to diet and exercise for weight management in adults with BMIs of 25-40 kg/m2. Plenity is taken orally with lunch and dinner and rapidly absorbs water in the stomach and mixes with food, expanding ~100x to give a feeling of satiety. Approval for the device follows positive phase 3 GLOW trial results presented at Obesity Week 2018.

    • GI Dynamics also received a $10 million investment from Crystal Amber in August 2019 to further finance its clinical trials for the EndoBarrier gastric device to treat type 2 diabetes and obesity. Funding will be used to work on (i) STEP-1 trial enrollment in the US; (ii) I-STEP (India) trial enrollment; and (iii) CE mark commercialization in the EU and Middle East. Enrollment for STEP-1 was expected to complete in 1H19, however, updates have not been shared by the company as of yet. As a reminder, FDA approved the pivotal STEP-1 trial last year in August 2018 after early termination of the original US pivotal ENDO Trial  based on high incidence of hepatic abscesses and missed primary efficacy and safety endpoints.

  • In interesting (very) early-stage development, Germany-based Velabs, a biotech company focused on rapid antibody screening, partnered with Alytas to develop an immune therapy for diabetes. Notably, Alytas has already identified and validated gene targets for a potential immune therapy that acts upon excessive amounts of adipocytes, both in vitro and in vivo. Although any candidate emerging from this partnership is surely a long way from entering clinical studies, we’re still glad to see more potential pharmacotherapies enter the obesity competitive landscape,

2. Obesity Prevalence Continues to Rise, Highlighting Need for More Aggressive and Comprehensive Interventions

  • The CDC released its annual state-by-state obesity data for 2018 in September, with prevalence exceeding 20% in all US states and territories. As we’ve come to expect, the trends continue to be quite worrisome and sobering. Prevalence of obesity ranges from a low of 23% in Colorado to a high of 39.5% in Mississippi and West Virginia. Nine states showed prevalence of adult obesity over 35%, up from seven in 2017 and five in 2016. Again, only two states (Colorado and Hawaii) and DC show prevalence of obesity between 20% and 25%. From 2013 to 2018, prevalence has increased over 15% relatively in Utah, New Mexico, Nebraska, Minnesota, Missouri, and Florida, and 33 states showed significant increases in obesity prevalence. Compared to 2017 alone, only Alaska exhibited a statistically significant decrease in obesity, while Florida, Kansas, Minnesota, Missouri, New Mexico, New York, and Utah showed statistically significant increases. Obesity rates have been growing at an alarming rate since the late 1980s: back in 1985, no state had an adult obesity prevalence over 15%. Now, the lowest prevalence in the entire country is 23%. What’s more, these statistics are based on BRFSS data (Behavioral Risk Factor Surveillance System), a self-report survey than systematically underestimates obesity rates compared to NHANES (National Health and Nutrition Examination Survey). Obesity incurs exorbitant costs for the healthcare systems, with an estimated $147 billion spent annually in the US for obesity alone. Community-based, comprehensive programs are necessary to lower the prevalence of obesity, especially due to obesity’s tight relationship with neighborhood design, access to healthy and affordable foods, and safe, convenient and affordable places for being physically active.

  • Racial/ethnic minorities and Americans with lower levels of education continue to be disproportionally affected by obesity. From 2016-2018, the prevalence of obesity was highest in non-Hispanic blacks (39.1%), followed by Hispanics (33.3%), and non-Hispanic whites (29.3%). By education, adults without a high school diploma had a 42% higher obesity prevalence relative to college graduates (24.7% vs. 35.0%). These statistics are consistent with rates seen in the past, reflecting persisting structural inequalities that negatively impact minority and less-educated populations. The 42% (!) relative increase in obesity prevalence in those without high school diplomas compared to college graduates is incredibly striking. We would be interested to see a more granular, intersectional breakdown of obesity prevalence, to better understand any interaction effects between education and race/ethnicity.

  • Furthermore, The Robert Wood Johnson Foundation revised its State of Obesity Report to The State of Childhood Obesity, placing greater emphasis on obesity in youth and early intervention. Nationwide data showed that (i) 4.8 million children age 10-17 had obesity in 2017-18, (ii) 18.5% of children age 2-19 had obesity in 2015-16, and (iii) childhood obesity costs $14 billion annually in direct costs to the US healthcare system. Though the national obesity rate has stabilized over the past few years, childhood obesity remains high and health inequity persists. In the report, RWJF recommends addressing disparities in childhood obesity by promoting health equity via (i) applying a multisector, systems approach and (ii) focusing on communities with the highest rates of obesity first, particularly those with low historic investment and structural inequities related to poverty, racism, and other social and economic factors. This can be done by expanding SNAP, WIC, and education programs, as well as mobilizing local and federal governments to improve school meals and reinforce scientifically up-to-date nutrition standards. We are excited to see this rebrand to emphasize the importance of early intervention though we hope it does not take attention away from adult obesity. Childhood obesity puts individuals at greater risk for type 2 diabetes, high blood pressure, heart disease, and asthma. Given that 75-80% of adolescents with obesity will become adults with obesity, there is tremendous need for upstream action before children reach their teens. Given the ever-climbing obesity prevalence both in the US and internationally, it’s clear that we need far bigger investment and collaboration across public and private sectors to tackle the obesogenic environment that drives this epidemic. Most recently on this front, Novo Nordisk and UNICEF partnered on a three-year initiative to prevent global childhood overweight and obesity with on-the-ground interventions in Latin America and the Caribbean.

3. Approved Obesity Pharmacotherapies Continue to Underwhelm

Despite the plethora of new developments in obesity, the more veteran players in the field have strugglied to find a stable customer base and we find it unlikely that most will survive. Indeed, Pernix Therapeutics, holder of Nalpropion Pharmaceuticals and obesity therapy Contrave (naltrexone/bupropion), filed for bankruptcy in March 2019. Last year, Pernix led the formation of Nalpropion Pharmaceuticals with two other funds for the purpose of acquiring Contrave from bankrupt Orexigen for $74 million in 3Q18. At the time of bankruptcy, and concurrent sale of all Pernix assets to Highbridge capital for $76 million, all Pernix medications would continue to be made available, however, the long-term fate of Contrave is unknown. Sales of Vivus’s obesity therapy Qsymia (phentermine/topiramate) came in at $9.6 million in 3Q19 (-1% YOY, -4% sequentially), and Arena/Eisai’s Belviq (lorcaserin) pulled in $12.9 million (27% YOY, -23% sequentially) in 3Q19. Novo Nordisk’s Saxenda (liraglutide 3.0 mg) is certainly the front runner in obesity medications, jumping +46% YOY to $213 million in 3Q19 sales, and we’re reassured to see at least one compound doing fairly well commercially given the difficulty the field has had overall.    

  • To be sure, obesity pharmacotherapies continue to face enormous headwinds that have stalled their penetration into a broad patient pool. Obesity pharmacotherapies have historically struggled with a number of unyielding challenges – including poor reimbursement, treatment and disease stigmatization, under-diagnosis of obesity, and under-appreciation of obesity as a treatable medical disease – and in 2019, faced another challenge in light of the US Preventive Services Task Force (USPSTF) excluding pharmacotherapy from their recommendations for obesity management and treatment. In response to this exclusion, noted obesity KOLs – Drs. Adam Tsai, Caroline Apovian, and Lee Kaplan – penned a letter to the editor in JAMA criticizing the decision and defending the use of pharmacotherapies. They stressed that “obesity is not a lifestyle choice but rather a chronic metabolic disease” and that long-term use of pharmacotherapy is necessary to meaningfully address the disease, just as it is used in other chronic diseases such as hypertension and type 2 diabetes. It’s clear that further consistent messaging such as this will be necessary to shift the discussion around obesity medications and further boost the potential these treatments can have in curbing the enormous costs and effects of the obesity epidemic.

Top Five Most Highly Read Closer Look Reports in Obesity

Most Unexpected News/Things We Got Wrong

  • A number of noted obesity KOLs penned a letter to the editor in JAMA criticizing the US Preventive Services Task Force (USPSTF) for excluding pharmacotherapy from their recommendations for obesity management and treatment.  

  • NEJM study forecasted that the prevalence of obesity in the U.S. will spike to 49% by 2030, with no state at a prevalence less than 35% and prevalence surpassing 50% in 29 states. The worrisome projections, worse than we might have imagined, showed high predictive accuracy, and when compared to years with published results, were within 10% of the reported estimate 96% of the time.

Key Questions for 2020

  • What will happen with payer coverage and patient access with the best obesity therapies? What further outcomes improvements will be shown, particularly in terms of CVD and CKD?

  • Will more payers and employers continue to invest in coaching that has shown to work favorably, particularly within certain populations?  There will be much more to be included on these players in digital health in our technology reflections to follow!

  • How much movement can we expect on using the microbiome to target and develop obesity therapies? Will we see greater infrastructure or regulation around this type of therapeutic? The hype in microbiome research is greater than ever, but we’re waiting for more largescale applicability.

  • How will newly approved prescription obesity devices (namely BAROnova’s TransPyloric Shuttle and Gelesis’ Plenity) fare on the market following their approvals in 2019? What kind of uptake will we see, and how might health care providers best integrate these new tools into their prescribing practices?

  • Can branded obesity drugs outside Saxenda survive and will any be able to drive improvements in reimbursement and uptake? Can we expect significant gains before weight loss is tied to long-term outcomes (and will those studies be funded)? Do payers actually care about truly long-term results, given patient churn? Ostensibly they are all always taking on higher obesity cost.

What’s Coming in 2020?

The list below covers late-stage pipeline products with expected milestones in 2019 – notably, this list is far shorter than it has been in previous years, and perhaps this is unsurprising with Sanofi exiting diabetes and CVD and obesity R&D and with J&J and Merck effectively out of investment in both diabetes and obesity R&D investment as well. We acknowledge that this list may not be 100% complete, though we’ve tried to be as comprehensive as possible based on the most recent public updates. If you notice anything missing, please write us.

  • Novo Nordisk’s semaglutide: The first four phase 3a trials assessing semaglutide in obesity are expected to complete at varying dates in 2020. STEP 1 (n=1,950) will examine weight management, STEP 2 (n=1,200) weight management in type 2 diabetes, STEP 3 (n=600) maximizing weight loss, and STEP 4 maintaining weight loss (n=900). STEP 5 in sustained weight loss, and STEP 6 in East Asian populations are expected to complete in 2021. Of note, the SELECT CVOT for semaglutide in people with overweight and obesity has also been initiated, though the study is not expected to complete until September 2023.

  • Novo Nordisk’s human amylin analog: Phase 1 results for AM833 in obesity expected in 1H20. Novo Nordisk’s CSO Dr. Mads Thomsen previously outlined a likely combination of GLP-1 semaglutide with the once-weekly amylin analog in a December 2018 interview.

  • Rhythm’s setmelanotide: Rhythm on track to complete NDA submission for MC4R agonist setmelanotide in POMC and LEPR deficiency obesity to the FDA in 4Q19 or 1Q20. Full results from the phase 3 trials will also be published, though a date was not specified. 

  • BI and Zealand’s (GLP-1/glucagon dual agonist): As per Zealand’s 1Q19 update, the dual agonist is expected to enter phase 2 in 2020.
  • AZ’s MEDI0382 (GLP-1/glucagon dual agonist): Phase 2 trial in people with diabetes and overweight/obesity is expected to complete in March 2020
  • Gelesis’s Gelesis200 (hydrogel capsule): Clinical trial optimized for glycemic control and weight loss in people with type 2 diabetes is ongoing, with results expected in 2020

Top Obesity KOL Quotes of 2019

From "US Adult Obesity Prevalence Expected to Rise to 50% by 2030; Severe Obesity to Rise to 24%"

  • Dr. Alan Garber (Harvard Medical School): “Obesity seems to be one of the inevitable outcomes of our present social structure.”
  • Dr. Timothy Garvey (Nutrition Obesity Research Center, University of Alabama at Birmingham): These rising rates [of obesity] will exert an even greater impact on patient suffering and social costs driven in large part by the complications of obesity including type 2 diabetes, cardiovascular disease, sleep apnea, immobility/disability, and osteoarthritis, as well as psychological factors associated with the disease such as depression, stigmatization, and disordered eating […] Obesity has a large genetic component that interacts with environment to determine who will have the disease and its severity. We basically have the same obesity susceptibility genes that we have had for centuries. The rising rates of obesity are linked to the worsening obesogenic nature of our environment, for example, ready access to high portions of calorie dense foods and sedentary life patterns […] The report by Ward et al. is another warning flare – it’s time to get serious regarding our built environment, access to unprocessed foods, and public education.”
  • Dr. Samuel Klein (Washington University School of Medicine): “This study should serve as a wake-up call that obesity is a national health crisis that is not going away and will keep getting worse […] The environmental influence on body weight regulation suggests that solutions to the obesity epidemic must address the environment. Government-industry-school system-community-media partnerships are needed to support and promote healthy eating and physical activity behaviors.

 

--by Rhea Teng, Ursula Biba, Martin Kurian, Ani Gururaj, Albert Cai, and Kelly Close