Memorandum

FDA approves Novo Nordisk’s oral semaglutide under brand name Rybelsus – September 20, 2019

Executive Highlights

  • Novo Nordisk just announced FDA approval of oral GLP-1 agonist Rybelsus (once-daily oral semaglutide, 7 mg and 14 mg) for type 2 diabetes. Rybelsus will be available in the US beginning in 4Q19, according to Novo Nordisk’s announcement. See FDA’s accompanying statement here.

  • No firm information on pricing was provided, as coverage and access discussions with payers are still ongoing. However, Novo Nordisk did divulge in its statement that a savings card program will be available at launch for eligible commercially-insured patients to “keep out of pocket costs down to as little as $10/month.”

  • See below for a research summary on oral semaglutide and the PIONEER program as well as more information on class and commercial implications, pricing, upcoming studies for CV and renal indications, results from the phase 3 PIONEER program, our past coverage of oral semaglutide, dQ&A market research on oral vs. injectable medications, what to expect with future oral GLP-1s, and our biggest questions moving forward.

  • We look forward to hearing details on patient experience: how tolerability is perceived, who will be eligible for the savings card program, (government rules typically exclude patients on Medicaid or Medicare from any such programs), and what proportion of patients in need will be able to get the innovative new medicine virtually free, as the savings card will do, etc. Of course, which patients have PCPs who recognize this approval as important and understand the value of early and aggressive therapy is also key.

    • Patient experience will be even better for those who have HCPs who can guide them properly and make sure they have proper nutrition to go alongside therapy. We’re very glad to see Novo Nordisk spotlight this information in the company’s investor press release, as it’s clear that patient access through better pricing and reimbursement is a major lever to improving patient outcomes. We look to patient experiences in taking Rybelsus as equally important – perceptions and experiences on tolerability, particularly in the eyes of the PCP, will be important to uptake and performance.

  • Novo Nordisk expects to hear from FDA regarding a CV risk reduction indication for Rybelsus in 1Q20. The company submitted two NDAs for oral semaglutide on March 20, 2019 with a priority voucher, requesting FDA 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 (see below for more on Rybelsus’ potential CV and renal indications).

  • Rybelsus will first be manufactured in Denmark, with future supplies generated from manufacturing facilities in North Carolina. Last month, Novo Nordisk acquired another North Carolina factory for oral semaglutide tableting and packaging – we assume that this is still in the process of ramping up. As a reminder, Novo Nordisk announced oral sema would go into phase 3 back in 2015, along with a substantial investment in its $1.8 billion manufacturing facility in Clayton, NC. The 833,000 square foot facility will produce active pharmaceutical ingredients (API) for GLP-1 and insulin products and will soon be fully operational.

  • In the EU, Novo Nordisk submitted oral semaglutide in April 2019, with an EMA decision expected in early 2Q20. We would expect EMA to reach a similar decision to FDA, granting approval to oral semaglutide.

  • Want to learn more about the science behind delivering a peptide drug to the gut and ensuring proper absorption? See this valuable review in Science. This is definitely no small feat, and we heartily thank all of the researchers and scientists who worked on this complex scientific and technical challenge and all the patients and families of patients who were involved in the clinical trials.

In long-anticipated and major news for the type 2 diabetes community, Novo Nordisk just announced that FDA has approved its once-daily oral GLP-1 agonist under brand name Rybelsus for the treatment of type 2 diabetes. See below for information on class and commercial implications, pricing, upcoming studies for CV and renal indications, results from the phase 3 PIONEER program, our past coverage of oral semaglutide, dQ&A market research on oral vs. injectable medications, what to expect with future oral GLP-1s, and our biggest questions moving forward.

KOL Commentary

  • "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. Daniel Einhorn
  • "This is great news for providers and for patients, that an oral formulation of a GLP1RA will soon be available. The data to date for oral semaglutide are really impressive with regard to glucose metrics and also weight effects, looking overall a bit better than liraglutide and not quite as good as injectable semaglutide. So despite all of the challenges of having to take on an empty stomach and wait at least 30 minutes to eat, along with the very low oral bioavailibility of the tablet, this seems all to have been overcome with the present strategy/formulation yielding expected glycometabolic and weight effects.
    This clinical availability will address a lot of provider and patient hesitation to go to an injectable in order to get a GLP1RA on board, though quite frankly, the delivery systems of these medications have made the "injection" virtually painless and simply not a big deal at all for patients....yet it remains an emotional barrier for all parties involved. From a trialist perspective, this opens the door to possibly doing pragmatic trials of tablet vs. tablet (vs. combination of tablets) that makes operationalizing trials much easier if we do not have to include injectables and their placebos (e.g. a trial of oral sema vs. SGLT2i vs. the combination now becomes much more practicable.)" -- Dr. Darren McGuire (disclosure from Dr. McGuire: “I am a consultant for NN for the diabetes pipeline and am trial co-chair of SOUL evaluating CV outcomes with oral semaglutide, among myriad broader conflicts in this space).
  • "My hope is that this lowers the barrier for use of GLP-1RA’s in primary care.  An oral medication is perceived as easier to initiate.  The guidelines shouldn’t change per se because of this, but the ease of following the guidelines might have just become easier!" -- Dr. Anne Peters 
  • "I do think this is a great day for people with diabetes. I do hope that primary care providers whose practice and staffing have difficulty supporting injected therapies will avail themselves of this opportunity. That is the real opportunity afforded by Rybelsus." -- Dr. John Buse 
  • "I'm very happy to see this approval - my hope is access won't be the major challenge as it has been in the past with new GLP-1RAs due to cost. As a rule, we have under-utilized this class due to cost, side effects, and both patients and their providers not wanting injections-even weekly. At least one of these three challenges is not an issue with this new drug." -- Dr. Irl Hirsch 
  • "The development of an oral semaglutide formulation is a substantial scientific achievement that may catalyze renewed interest in development of innovative oral formulations of traditionally injected therapeutic peptides. Assuming a reasonable and competitive price in an already crowded pharmaceutical market for type 2 diabetes, oral semaglutide should become an important additional option for people with diabetes who may benefit from the attributes of the GLP-1 class, yet who may be reluctant to initiate injectable therapies." -- Dr. Dan Drucker
  • “Semaglutide already has proven itself to be a highly efficacious GLP-1 receptor agonist. The availability of an oral formulation had the potential to expand opportunities for even more patients to derive benefit from this molecule.” -- Dr. Alan Moses
  • “Simply put, I think primary care doctors will start using this more if they don’t die of sticker shock.” -- Dr. George Bakris

  • “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 DM. 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 DM. This is a true breakthrough that changes the face of oral therapy in diabetes.” -- Dr. James Gavin

  • “While weekly subcutaneous injections of semaglutide are seemingly best in class, and easy for people with type 2 diabetes to start, some health professionals still have problems in advising of and helping  with this, while some individuals will still find an extra daily tablet more acceptable.  Accordingly, the approval of an oral formulation of semaglutide is very welcome, even if the advised doses suggest that bioavailability from the gut is sometimes 100 times lower, thus with 99% of the drug going to waste. Cost and access may then also be an issue. Full data on the cardiovascular efficacy/safety of the oral formulation is not yet available (PIONEER 6 not being powered for this), but this study performed for licensing purposes is consistent if not confirmatory of the cardiovascular protection given by this class of medications to those already with extant cardiovascular disease.” -- Professor Philip Home

  • “In terms of glycemic control, oral semaglutide has the strongest potency among oral agents. So, if cost was not an issue (but it is), it would qualify as the first-line therapy to improve glycemic control. There is nothing major in the adverse event profile of oral semaglutide that would make it a second choice after DPP4i.  However, at this time, for CV risk reduction it cannot compete with oral SGLT-2 inhibitors that have a proven CV benefit and approved CV indication (empagliflozin and canagliflozin). The sponsor has asked the regulators for a CV indication based on the CVOT data with both subcutaneous and oral preparation. It remains to be seen if the regulators would be favorably inclined to grant such a request. I, however, remain skeptical given the overall quality and quantity of evidence. Collectively, the 2 trials have 391 MACE events (254 in SUSTAIN-6 and 137 in PIONEER-6) and the follow-up is 2.1 years and 1.3 years, both less than what is required for CV safety indication based on the 2008 FDA guidance. I would hope that a CV efficacy indication would require a higher quantum of evidence! With the exception of stroke findings, there are inconsistencies among the 2 trials with regards to impact on CV death and all-cause mortality (favorable impact in PIONEER-6), nonfatal MI (favorable impact in SUSTAIN-6) and hospitalization for heart failure (favorable impact in PIONEER-6). Regardless, if the FDA grants a CV indication, it would be a precedent-setting decision. We will soon learn about this, perhaps in the next six months.” -- Dr. Sanjay Kaul

  • “Ozempic is a fantastic treatment for T2DM and it should be used as first line therapy ahead of metformin. Now, patients have a choice between an oral versus an injectable preparation.” --Dr. Ralph DeFronzo 

  • “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.” --Dr. Timothy Bailey 

  • "Now that oral semaglutide has been approved, my question is why wouldn't most HCPs prescribe it over an injectable GLP-1 receptor agonist? Even though injecting is not as difficult as it used to be with modern devices, it is always going to be much easier for HCPs to just write a Rx for the tablet. I would expect oral semaglutide to do very well and provide much needed convenience for the GLP-1 RA class." --Dr. Charles Alexander 

  • "The recent approval of oral semaglutide is historic. This innovative tour-de-force drug development program provides a wealth of evidence for the use of oral semaglutide in patients with type 2 diabetes. Remarkably, the glycemic efficacy, weight loss and cardiovascular benefits of oral semaglutide were similar to that of subcutaneously administered GLP-1 receptor agonists. The availability of oral semaglutide should allow initiation of GLP-1 receptor agonist therapy earlier in the treatment paradigm and use in a much broader population of patients with diabetes." --Dr. Richard Pratley   

  • "I think that the availability of this first oral GLP-1 RA expands the possibilities to treat type 2 diabetic individuals with incretin-mimetic compounds. There is an unmet need to further establish the usefulness of GLP-1RA in the real world of the therapy of type 2 diabetes, given the beneficial metabolic, cardiovascular and renal effects of the class. Expending the therapeutic options, with an oral formulation that may  potentially better address meet the patient’s compliance and tolerability when compared with the injectable ones, will help move forward into this direction." --Dr. Francesco Giorgino 

  • "I believe that this is an exciting development. First, from the clinical science standpoint, to witness a successful formulation of a peptide into an orally administered compound, that is now approved for clinical use in the United States is a triumph in drug development, with implications potentially far beyond just GLP-1 RA class, or even diabetes as a therapeutic area. Second, we know that GLP-1 RA is a class that provides clinically meaningful benefits to patients with type 2 diabetes which, importantly, includes lower risk of major adverse cardiovascular events. However, with all of these compounds (until now) being injectables, this did pose a barrier to some clinicians and patients. Having this available in the oral formulation should remove this barrier, and hopefully help with implementation when it comes to the use of cardioprotective anti-diabetic agents." --Dr. Mikhail Kosiborod

Oral Semaglutide: Class and Commercial Implications

Many anticipate oral semaglutide will compete with other oral agents more so than injectable GLP-1 agonists. We anticipate that the oral administration will likely swing some individuals hesitant to use an injectable therapy toward the GLP-1 class – especially those interested in the compound’s potent weight loss and cardioprotective benefits. We’ve heard that cardiologists also shy away from injectable diabetes medications (they’re unfamiliar and seemingly more complicated to prescribe), which is one reason why SGLT-2s have thus far been more popular within that community of HCPs. With oral semaglutide on the market, cardiologists will hopefully begin considering GLP-1s for their patients with atherosclerotic CV disease as well. We remain enthusiastic about the potential for this therapy to bring more patients to the GLP-1 class who may otherwise be tentative about using an injectable therapy. We are also interested to better understand the degree to which more or fewer PCPs prescribe this medicine; given that a majority of type 2 diabetes is treated in primary care and not by a specialist, PCP uptake will be an essential factor in how patients experience this new drug. We also believe the therapy approval will bring more attention to the company’s once-weekly semaglutide offering, Ozempic.

  • Back at the company’s 2017 Capital Markets Day, management emphasized that oral semaglutide would primarily compete with DPP-4 and SGLT-2 inhibitors for its own share of second-line prescriptions – citing that these comprise 17% of US total prescriptions vs. 6% for GLP-1s, at that time. Head-to-head data vs. both Merck’s Januvia and Lilly/BI’s Jardiance work in its favor as far as clinical positioning goes, and it makes sense that Novo Nordisk would want to avoid cannibalizing its injectable GLP-1 business from Ozempic and Victoza as much as possible. That said, competitors with an SGLT-2 inhibitor in their pipeline (namely, Lilly) have argued that it will be hard for an oral GLP-1 to compete with existing orals on price (due to suboptimal bioavailability of oral semaglutide at present). On the pricing question, we’ll have to wait and see.

  • Recently, the European Society of Cardiology released new guidelines on diabetes, prediabetes, and CVD, recommending both GLP-1s and SGLT-2 inhibitors as first-line treatment options in patients with high risk or established ASCVD. This represents the first time a major guideline has recommend first line usage of a non-metformin therapy in type 2 diabetes — a huge paradigm shift in the field. As both classes of drugs are pushed earlier in treatment (and possibly to prevention), we are curious to see (i) which patient populations each therapy will be targeted to; and (ii) how HCPs will choose one over the other. In our view, oral semaglutide is perfectly positioned to benefit from these new guidelines.

  • More broadly, we expect oral semaglutide to further accelerate growth for the highly innovative GLP-1 class by bringing more patients to the class. As a whole, the GLP-1 class continues to display exceptional growth from a large base, totaling $2.4 billion in 2Q19 (up 24% YOY from  2Q18 and 12% sequentially from 1Q19). Expectations are sky high for this first-ever oral GLP-1, with some analysts projecting that once established on the market, it could achieve $5 billion (!) in annual revenue. For context, current market leader Trulicity is roughly on pace for ~$4 billion in 2019 revenue.

Both Images Below from Novo Nordisk’s 2017 Capital Markets Day Presentation:

 

Pricing

It remains unclear where Rybelsus will be priced and what access will look like on various formularies, given ongoing discussions with payers. We’re glad to see that there will be an affordable savings card program simultaneously available with Rybelsus’ launch, though this has become more or less the expectation for diabetes manufacturers launching a new pharmaceutical product. List price will be key in regard to oral semaglutide’s broader reach (that said – some patients do pay list price for insulin because they will die without it – we see very few people doing that with oral semaglutide in the US,  just as that is virtually never seen with Ozempic). Ultimately, will Rybelsus be priced more as an oral therapy akin to DPP-4s and SGLT-2s, or closer to higher-priced injectable GLP-1s such as Ozempic and Trulicity? In order for Rybelsus to truly compete with existing oral therapies, we suspect price will have to be on the lower end of this spectrum, but oral semaglutide’s limited bioavailability as well as the costs of various ingredients (one in particular) may lead Novo Nordisk to set a higher-than-expected list price. To be sure, discussions around pricing for the therapy have been robust over the past few years, and this will remain one of the key points as Rybelsus’ launch later this year comes closer. One bright spot is that major US payers have thus far not created exclusive formularies for GLP-1 therapies, meaning several products within the class are covered for beneficiaries and manufacturers aren’t forced to pay rebates as large as those paid for insulin, as we understand it.

  • In its 1Q18 update, Novo Nordisk outlined three factors that would influence pricing for oral semaglutide:

    • the innovation required to develop the first oral peptide therapy for diabetes;  

    • the drug’s efficacy profile; and

    • manufacturing cost for the product – the latter will be affected by volume and how many are hearing about it and taking it

As far as success for Novo Nordisk is concerned, a critical area of work was optimizing cost of goods sold, as pricing oral semaglutide on par with injectable GLP-1 agonists will make it hard for oral semaglutide to compete with the value proposition of oral SGLT-2 inhibitors. We look back to AADE and one of the speakers there who implored diabetes specialists to “get GLP-1 to everyone who needs it!” – hopefully oral GLP-1 will be seen as an opportunity for those millions who have not yet taken it.

  • ICER released its draft evidence report for the effectiveness and value of oral semaglutide earlier this month, concluding that the therapy will produce “incremental benefit” vs. Jardiance (empagliflozin), Victoza (liraglutide), and Januvia (sitagliptin) in terms of MACE outcomes and other surrogate outcomes. In terms of QALYs gained, oral semaglutide (1.95) placed ahead of Victoza (1.81) and Januvia (1.76) and while behind Jardiance (1.99), the two were virtually the same score. In terms of cost-effectiveness, the report suggests (with broad uncertainty that even ICER admitted) that if oral semaglutide is priced the same as Ozempic (injectable semaglutide), then the therapy will not be as cost-effective as these comparators. However, the report ultimately concludes that “based on the current clinical evidence, with limited follow-up, and without knowing the eventual price for oral semaglutide, we are unable to draw conclusions on its cost effectiveness with any certainty. The ultimate value of oral semaglutide will be determined by the price that is set by the manufacturer and its long-term effectiveness.” 

Upcoming Studies: Potential Cardiovascular and Renal Indications

Even with approval, oral semaglutide’s clinical story has just begun, in terms of all the patients and broader ecosystem players it could help. Novo Nordisk is currently investigating oral semaglutide (or injectable semaglutide) in several trials that might impact oral semaglutide’s future label. A decision on a potential CV indication (for reducing risk of three-point MACE in people with type 2 diabetes and established CVD) for Rybelsus is expected in January 2020, based off of pooled data from SUSTAIN 6 and PIONEER 6. As a reminder, SUSTAIN 6 for Ozempic enrolled 83% with existing CVD and the 26% risk reduction on MACE was driven by stroke and MI; PIONEER 6 for oral semaglutide enrolled 85% with existing CVD and the 21% MACE benefit was driven by CV death and stroke. In terms of upcoming trials:

  • The SOUL CVOT of oral semaglutide was initiated in June 2019. The superiority-powered trial (n=9,642) enrolling people with type 2 and either CHD, CKD, PAD, or cerebrovascular disease is set to complete in July 2024, and if positive will likely support CV indications for both Ozempic and oral semaglutide (assuming that FDA does not grant CV indications for both of these therapies based on the current sNDA submission using data from SUSTAIN 6 and PIONEER 6 – we expect to hear on this in January 2020, when FDA will give its decision). Dr. Thomsen has also explained in the past that SOUL (originally the post-market CVOT for Ozempic, now for oral semaglutide) has been scaled to approximately the size of LEADER (~9,300 participants). However, the trial design will include an interim analysis that will enable early cessation if the primary endpoint is met sooner, given anticipated greater efficacy with semaglutide compared to liraglutide.

  • The FLOW renal outcomes trial also started in June 2019. First announced on Novo Nordisk’s 4Q18 call, the study will enroll 3,160 patients with type 2 diabetes and CKD (eGFR 25-75 ml/min/1.73 m2) for up to five years. Expected completion is August 2024, and the primary endpoint is a composite of persistent eGFR decline of ≥50%, reaching ESRD, and CV or renal death. Traditional MACE endpoints will also be measured. This is a highly-notable, first-ever renal outcomes trial among GLP-1s, and we’re thrilled by Novo Nordisk’s investment in renal disease. While the GLP-1 agonist class receives generally less attention than SGLT-2 inhibitors for potential impact on kidney disease, the data for GLP-1s is certainly promising (although less impressive so far than the SGLT-2 inhibitor class, which was further emphasized with REWIND results presented at ADA 2019 and subsequent thought leader reactions). Our current understanding is that positive results from FLOW will help to support renal indications for both Ozempic and oral semaglutide.

Phase 3 PIONEER Program

The ten-study phase 3 PIONEER program (n=9,543) started reading out in February 2018 and completed with PIONEER 6 in November 2018. See a full table of these studies and their results below. By and large, PIONEER has supported efficacy and tolerability of oral semaglutide; the combination of glucose-lowering and weight loss efficacy with a remarkable safety profile (especially on hypoglycemia) is unparalleled among oral agents, and even offers improvements over some existing injectable GLP-1 agonists. Excitement in the field for the first-ever oral GLP-1 agonist is undeniably high, and opportunities for earlier treatment intensification with GLP-1 agonist through oral dosing are tremendously important.

Trial

Enrollment

Comparator/Design

Timeline

PIONEER 1

704

Placebo

Completed December 2017; Topline results announced February 2018; Full results at ADA 2018

PIONEER 2

816

Lilly/BI’s Jardiance (empagliflozin)

Completed March 2018; Topline results announced May 2018; Full results at ADA 2019

PIONEER 3

1,864

Merck’s Januvia (sitagliptin)

Completed March 2018, Topline results announced June 2018; Full results at ENDO 2019

PIONEER 4

711

Novo Nordisk’s Victoza (liraglutide)

Completed March 2018; Topline results announced June 2018; Full results at ADA 2019

PIONEER 5

324

Moderate renal impairment

Completed May 2018; Topline results announced August 2018; Full results at ADA 2019

PIONEER 6

3,183

CVOT

Completed September 2018; Topline results announced November 2018; Full results at ADA 2019

PIONEER 7

504

Flexible dose escalation

Completed March 2019; Topline results announced June 2018

PIONEER 8

731

Insulin add-on

Completed August 2018; Topline results announced October 2018

PIONEER 9

230

Placebo and liraglutide in Japan

Completed August 2018; Topline results announced November 2018

PIONEER 10

336

Lilly’s Trulicity (dulaglutide) as an add-on to oral agents in Japan

Completed July 2018; Topline results announced September 2018

  • Looking for phase 2 data on oral semaglutide? See our coverage and the full publication in JAMA of phase 2 dose-ranging trial results of oral semaglutide. 

  • Want to learn more about the science behind delivering a peptide drug to the gut and ensuring proper absorption? See this great review in Science. This is definitely no small feat, and we heartily congratulate all of the researchers and scientists who worked on this complex scientific and technical challenge!

Notable Close Concerns Past Coverage of Oral Semaglutide

  • Novo Nordisk submits oral semaglutide to FDA, also requesting CV indications for Ozempic and oral semaglutide; Exclusive interview with NN's Chief Scientific Officer Mads Thomsen – March 20, 2019

    • “We want to position oral semaglutide as the world’s first biological treatment in a tablet for people with type 2 diabetes, and if accepted, people immediately after metformin have the ability to get the efficacy of a GLP-1 in a tablet. It also provides the opportunity to start and stay on a drug that is noninvasive. As seen in our PIONEER clinical trial programme, up to 80% of people taking oral semaglutide achieved well controlled blood sugar levels below the A1C target of <7%.” – CSO Dr. Mads Thomsen

    • In my view, there is no fight between GLP-1s and SGLT-2s. In PIONEER 2,  oral semaglutide demonstrated a statistically significant and superior improvement in A1c compared to empagliflozin. However, they have unique CV profiles – GLP-1s are recommended for atherosclerotic disease in people with type 2 diabetes and SGLT-2s are recommended for heart failure in people with type 2 diabetes.” – CSO Dr. Mads Thomsen

    • “In terms of treatment category for oral semaglutide, the target is any person with type 2 diabetes currently on metformin. From there, patients could intensify with basal insulin or high-dose Ozempic.” – CSO Dr. Mads Thomsen

  • ICER cost-effectiveness analysis indicates uncertain benefit for oral semaglutide if priced on par with Ozempic – September 13, 2019

  • Novo Nordisk Capital Markets Day 2017: Management shares ambition to have Ozempic and oral semaglutide be market leaders in their own right, with oral semaglutide competing with DPP-4s and SGLT-2s as second-line oral therapies – November 22, 2017

  • Novo Nordisk acquires North Carolina factory for oral semaglutide production – August 6, 2019

  • Novo Nordisk breaks ground on Clayton, NC manufacturing facility for GLP-1 agonist and insulin products – March 28, 2016

  • Novo Nordisk advances oral semaglutide into phase 3, announces $2 billion investment in new production facilities – August 26, 2015

Many in the larger diabetes community have been highly anticipating oral semaglutide’s approval for quite some time. A quick search of our Close Concerns Knowledgebase (or as we call it, “CCKB”) shows that “oral semaglutide” has been mentioned in nearly 200 separate articles over seven years! One of our first mentions of oral semaglutide comes from Novo Nordisk’s Capital Markets Day 2013, where CSO Dr. Mads Thomsen spoke highly of “OG217SC” and its impressive phase 1 results. For an even deeper historical dive, see Kelly’s interview in 2009 with CEO Lars Sørenson: “We think we can develop [an oral GLP-1]. That would be exciting for the early type 2 individuals where we are up against other oral medications. We are hopeful that there still may be potential for individuals with pre-diabetes and a high number of other risks (renal, CV) – we’ll be interested to see this what may happen on this front.

 

Oral vs. Injectable Medication: Market Research

  • Oral GLP-1 has major potential to expand the highly efficacious class to more people. Doubtless, aversion to injectables has historically been a barrier to better glycemic control for some who could certainly benefit from GLP-1 or insulin therapy. Market research and patient insights firm dQ&A asked about preferred administration method of type 2 diabetes therapies (n=3,499) in 2Q16. Their findings are consistent with this conclusion.
    • dQ&A respondents who were taking only oral therapies strongly preferred to stay on orals. In the survey, preference for a daily oral medication (such as oral semaglutide) was highest among those taking only orals, relative to those on other therapies – 34% ranked it as their #1 choice of administration method. Preference for a weekly injection (such as Ozempic) was lowest in this group – only 2% ranked it as their #1 choice.
    • Those not taking any medications were similarly in favor of orals. Only 4% of this group ranked a weekly injection as their ideal administration method vs. 25% for a daily oral medication. 
    • Those taking an injectable (insulin, GLP-1 agonist, or both) also preferred orals over injectables, though there was less of a difference compared to the oral only and no medication groups. Among those taking insulin only, 17% ranked a daily oral medication as their #1 choice vs. 12% for a weekly injection. Among those taking GLP-1s only, 14% ranked daily orals as #1 vs. 12% for weekly injectables, and among those taking both insulin and a GLP-1, 15% ranked daily orals as #1 vs. 10% for weekly injections.
  • Of course, these results don’t take into account differences between oral vs. injectable therapies (e.g., atherosclerotic vs. heart failure/renal benefit). However, they do suggest the potential for higher interest in an oral GLP-1, particularly amongst those not already on an injectable. This research also corroborates Novo Nordisk’s long-term commercial strategy for its trio of GLP-1 agonists, with oral semaglutide competing with SGLT-2 and DPP-4 inhibitors for second-line prescriptions, and injectable GLP-1 initiated slightly later in disease development but still considered before insulin (slide 10). 
  • dQ&A’s survey compared implantable therapy, weekly oral medication, daily oral medication, weekly injection, and daily injection – write Richard Wood for more information on dQ&A and this dataset.

What’s Next in Oral GLP-1?

Broadly speaking, it appears that the next push in the oral GLP-1 field will be a shift to small molecule candidates (instead of larger peptide drugs), which might allow for cheaper manufacturing costs, better bioavailability, enhanced patient experience by eliminating fasting requirements, and ultimately lower costs for patients. We’re thrilled to see so much investment in this therapy class, which signifies both the high demand for what these therapies could offer for patients and the large potential ROI for sponsors that can successfully develop them. 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 are both well-positioned to investigate this, as they have a GLP-1 and SGLT-2 in their portfolio. Moreover, both companies have sponsored studies showing superior benefits with GLP-1 + SGLT-2 coadministration vs. either monotherapy alone (DURATION-8 and AWARD 10).

  • Novo Nordisk is developing another oral GLP-1 (“OG2023SC”) which is set to soon enter phase 2 following phase 1 completion in December 2018. This next-gen oral GLP-1 agonist comes from the same series of compounds that led to semaglutide and presents two exciting possibilities: It could either be dosed to give higher efficacy than oral semaglutide, or efficacy could match oral semaglutide but come at a lower price (i.e. lower COGS through greater bioavailability). Currently, Novo Nordisk is considering development of 2023 in type 2 diabetes, obesity, and NASH. If 2023 were developed to minimize COGS with a similar level of efficacy as oral semaglutide, it would be a huge win for patients and could even translate to more affordable generics far, far down line.

  • 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 candidate. The 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. 

EMA Submission and Decision

  • Novo Nordisk submitted oral semaglutide to EMA in April 2019, with a decision expected in early 2Q20. We would expect EMA to reach a similar decision to FDA, granting approval to oral semaglutide.

Close Concerns Questions

  • How will FDA decide on a potential CV indication for oral semaglutide based off of pooled data from SUSTAIN 6 and PIONEER 6? How will the agency consider the heterogeneity among components of the primary three-point MACE endpoint in both of these trials?

  • How will patients view the fasting requirement for oral semaglutide? How might this interact with other requirements for medicines they are already taking? Will this pose a barrier in the real world in terms of delivering efficacy?

  • How is tolerability different among Rybelsus and Ozempic and Victoza?

  • Presumably, FDA opted against an Advisory Committee to discuss oral semaglutide’s approval because the safety data was so robust. Were there other reasons?

  • Will we see even more investment in next-gen oral GLP-1s? How could a small molecule oral GLP-1 that is actually more expensive to manufacture (initially, due to lower bioavailability) help to drive down costs for the system (less time required by doctors to teach, easier to prescribe, patients may be more engaged and/or adherent)?

  • How will payers consider the first ever oral GLP-1, and how might this affect reimbursement and formulary positioning?

  • What commercial strategy is Novo Nordisk planning for Rybelsus’ launch? How is the company planning on reaching different physicians, and what do they hone in on as their primary messaging strategy? What will the primary means be to drive awareness and education?

  • How much movement will occur between patients switching from Victoza/Ozempic over to oral semaglutide? How many more patients will be introduced to the GLP-1 class rather than merely move to a lower-margin (initially) formulation?

 

--by Martin Kurian, Rhea Teng, Ursula Biba, Payal Marathe, and Kelly Close