GTC Bio hosted its annual Diabetes Summit from April 9-11, 2018, in Boston, MA. This intimate gathering offered learning-filled discussion and insight on early- and late-stage candidates in diabetes, including Intarcia’s ITCA 650 (implantable exenatide mini pump), Beta Bionics’ bihormonal artificial pancreas, and FOXO1 inhibitors as a potential new class of insulin sensitizers, which took the spotlight in the first two days. The third day was packed with informative talks featuring updates from Novo Nordisk and Lilly, alongside a number of engaging panels. Read on in the full report below!
- Executive Highlights
- Detailed Discussion and Commentary
- Focus Group Discussions
- Historical Perspective and State of the Science & Industry
- Devices and Digital Aids in Diabetes Management
- Funding, Partnership, and Commercialization of Diabetes Technologies
- The Symbiotic Relationship between Industry, CROs and Academia
- Partnering with Novo Nordisk
- Panel: Industry Partnering with Academia & CROs to Advance Diabetes Research
- Funding & Commercialization of Diabetes Technologies
- Keynote Panel Discussion
Detailed Discussion and Commentary
Focus Group Discussions
Assessing Role of HbA1c in Diabetes Drug Development
Jane Chiang, MD (Diasome Pharmaceuticals, Cleveland, OH)
A Monday evening focus group discussed the need for outcomes beyond A1c in diabetes drug development. This was an interactive and participatory session among GTC Bio delegates, and we were very happy to see this all-important topic addressed early on in the conference agenda. Several participants referenced The diaTribe Foundation’s consensus conference on glycemic outcomes beyond A1c, acknowledging recent successes for the #beyondA1c movement – a diversity of stakeholders coming together behind this issue, agreed-upon definitions of hypoglycemia, and EMA encouraging CGM in clinical trials. At the same time, the conclusion from this conversation was that much more progress is needed; the movement is gaining momentum, but still has a long way to go. Of course, we agree with this! The recent label update for Novo Nordisk’s Tresiba (insulin degludec), which we characterized as a “partial victory,” serves as a good example at this intersection of progress and stalemate. By adding DEVOTE data to product information, FDA granted the first-ever comparative claim and implicitly recognized that severe hypoglycemia is a key outcome in diabetes care (in DEVOTE, Tresiba showed a 40% risk reduction for severe hypo vs. standard of care Lantus and a 53% risk reduction for severe hypo overnight, both p<0.001 for superiority). Equally important to note is what FDA left out of the US Tresiba label, and that is data from SWITCH 1 and SWITCH 2. These smaller studies also highlighted degludec’s hypoglycemia benefit over glargine, but they used a primary endpoint of “severe or blood glucose-confirmed symptomatic hypoglycemia” where DEVOTE defined severe hypo as requiring external assistance – this is more easily adjudicated and leaves no ambiguity about clinical significance. We’d argue that there may well be clinical significance in less severe forms of low blood sugar as well, but as GTC Bio delegates noted, there’s uncertainty around what FDA expects on this front and what “is” is different from what has been beyond a doubt proven. One researcher pointed out that hypoglycemia is widely regarded as a “safety” endpoint when it should be categorized under “efficacy.” Others spoke to the limited dataset we have correlating time-in-range and glycemic variability with hard outcomes. We see this data slowly but surely accumulating, and two post-hoc analyses of DEVOTE found a significant association between glycemic variability/all-cause mortality and between severe hypoglycemia/CV death. That said, this evidence needs to be replicated, and we certainly need a lot more of it to strengthen the argument for outcomes beyond A1c. There was clear consensus within this focus group about the limitations of A1c, which more often than not is meaningless to patients, and isn’t sufficiently informative for providers about any given individual’s mean glucose either. Delegates referenced this Clinical Diabetes paper which found that time-in-range matters to patients and that current therapies are falling short – the group called for FDA to take action toward addressing this patient need, and we’re optimistic that #beyondA1c can build on its momentum in 2018 and beyond.
Manufacturing & Regulatory Landscape for Cell Therapy in Diabetes
Felicia Pagliuca, PhD (Semma Therapeutics, Cambridge, MA)
Dr. Felicia Pagliuca, VP at Semma Therapeutics, chaired a focus group on the manufacturing, logistical, and financial hurdles to successfully developing a beta cell replacement therapy. While there are a fair number of preclinical candidates in the beta cell replacement competitive landscape, this has been a fairly slow-moving field due to significant challenges in creating and pushing forward these therapies. Dr. Pagliuca organized manufacturing challenges into three buckets: (i) complexity and novelty of raw materials; (ii) execution and a relative lack of experienced contract manufacturing organization (CMO) infrastructure; and (iii) complexity of analytics and product characterization in cell therapy. It’s no secret that creating a fully-functional beta cell – one that secretes insulin in response to glucose and eliminates the need for insulin in people with type 1 diabetes – is a complicated therapeutic prospect. But this focus group dove into the nuance of these obstacles, and Dr. Pagliuca was certainly well-suited to lead this discussion. Semma is a company born out of Dr. Doug Melton’s Harvard lab working to generate replacement islets from pluripotent stem cells (read some of our recent coverage on Semma here).
On raw materials: GTC Bio delegates discussed risk tolerance and liability in sourcing complex and expensive technology from other early-stage companies. According to Dr. Pagliuca, Semma uses a hands-on approach in working with vendors. That said, it’s hard to eliminate all risk, and this imposes an extra burden on early-stage companies (like Semma) that have very limited resources as is.
On manufacturing: As the focus group continued, it was clear that issues related to raw materials feed directly into challenges surrounding execution and working with CMOs. In academia, people often use whatever combination of reagents is needed to make something work, but transitioning that to a manufacturing-ready process for clinical trials and into a commercial product may be challenging. This raises the question: When should researchers start to invest time, effort, and money into process development, internally or at a CMO? The consensus among delegates was “the earlier, the better.” A good CMO takes the system apart, restructures it with new equipment and reagents, and makes it more efficient. Rushing to get a product into clinical trials may be counterproductive if the product cannot be commercialized; a CMO can help make sure it can, in fact, be manufactured reproducibly and eventually commercialized. Process and product development should ideally occur simultaneously, though some delegates did point out that this can increase costs and demand continually re-proving the product. As one example, Dr. Zan Fleming explained that cell therapies make more difficult the bridging studies you can do with small molecules when the process changes. Dr. Pagliuca aptly pointed out that it’s unrealistic, with such a complex product, to think that things won’t change once it’s in the clinic, and researchers have to have realistic expectations on how to get from phase 1 to a commercial product, pouring in significant investment over years. Encouragingly, everyone in the room seemed optimistic about how FDA and the Center for Biologics Evaluation and Research (CBER) is approaching the uncharted territory of cell therapy (e.g. CAR-T therapy) with an open mind and flexibility on continual improvements.
On analytics and product characterization: In discussing this third and final hurdle, delegates referred to challenges on endpoints and outcomes. Dr. Pagliuca implied that in some ways, diabetes is a great target within the realm of cell therapy, because the pathophysiology is well understood, good animal models are available, and C-peptide is a high-quality biomarker. She also underscored that process is incredibly important for cell therapy because product consistency is key: Patient variability in immunology and physiological response affects endpoints, more so than with a small molecule, so product consistency becomes ever more important as you scale up to thousands and even millions of patients.
Ultimately, most of the hurdles mentioned during this focus group came down to the fact that this is a new and rapidly changing scientific frontier. One attendee compared beta cell replacement therapy to the state of antibody manufacturing 20 years ago, when cost and complexity was still very high for production. Two decades seems like a long time to wait, but might easily prove to be an ambitious timeline for widely-available beta cell replacement therapy. We’re glad to have so many smart people working to accelerate this timeline in diabetes and elsewhere, but also to have others working on life-changing technologies like closed loop systems at the same time.
Historical Perspective and State of the Science & Industry
The Emergence and Ascent of Regulatory Peptides in the Treatment of Metabolic Diseases: A Personal Perspective
Andrew Young, MD, PhD (Intarcia Therapeutics, Boston, MA)
Intarcia CSO Dr. Andrew Young positioned ITCA 650 as a solution to the modern-day adherence issue in diabetes care, and he characterized the implantable GLP-1 (exenatide) mini pump as the future of peptide therapy. To establish low adherence as a pervasive challenge in the real world, Dr. Young highlighted that only 15%-20% of medications (diabetes and otherwise) are refilled as prescribed in the US. He described the “efficacy gap” wherein a therapy doesn’t seem to perform as well in the real world as it does in RCTs, and he attributed 75% of this difference in outcomes to adherence. We’ve heard an uptick of commentary on the “efficacy gap” at recent diabetes conferences (see talks by Drs. Steven Edelman and William Polonsky from ADA Postgrad 2018), and thought leaders are certainly paying more attention to adherence as a factor in translating clinical trial results for real-world patients. As one example, AZ’s EXSCEL CVOT for Bydureon (exenatide once-weekly) was specifically designed without a run-in period, which is typically used to exclude participants with low adherence; the study protocol thus more closely resembled real-world treatment settings. In the end, the CVOT was neutral rather than positive, and many in the field have attributed these findings to elements of pragmatic study design, which likely led to lower adherence rates in EXSCEL vs. LEADER or SUSTAIN 6. Dr. Young also shared slides to show a steep drop off in persistence, with fewer than half of all patients who start on AZ’s Byetta (exenatide twice-daily) or Novo Nordisk’s Victoza (liraglutide once-daily) remaining on the medication after one year. Interestingly, persistence is no better for oral diabetes drugs, but Dr. Young did point out an inverse relationship between injection burden and adherence – that is, lower injection burden typically means higher adherence rate. Another one of his slides displayed a stepwise improvement in average adherence with reductions in injection frequency; from twice-daily GLP-1 agonists (like Byetta), to once-daily (e.g. Victoza), to once-weekly (e.g. Lilly’s Trulicity, AZ’s Bydureon, Novo Nordisk’s newly-launched Ozempic). We don’t yet know what will happen to adherence with even less frequent GLP-1 doses, but Intarcia hopes to find out with ITCA 650, which provides continuous subcutaneous release of exenatide for three-six months (initiation phase and maintenance phase, respectively). Dr. Young reviewed the company’s Medici platform technology. He explained the choice of exenatide over other GLP-1 molecules: For one, it has a relatively low therapeutic dose, which allows for a sufficient amount of active agent to be stored in the mini pump for several months without re-implantation. Moreover, he discussed how exenatide has impressive in vivo potency since it’s almost entirely immune to cleavage by normal peptidases. Ultimately, Dr. Young returned to his focus on adherence, suggesting that ITCA 650 may have a much smaller “efficacy gap” compared to existing GLP-1 agonists. This isn’t the first time we’ve heard an adherence emphasis from Intarcia management, and indeed, CEO Mr. Kurt Graves underscored this potential when the company first filed an NDA back in November 2016. We certainly see the value in this innovation. If the goal of diabetes care is not only to lower injection burden, but to reduce the daily burden of chronic disease management in general, then ITCA 650 is a homerun. Here’s a product that wouldn’t require daily or even weekly attention from the individual with diabetes (in most cases), and it would offer the robust glucose-lowering and weight loss associated with GLP-1s. As an added bonus, ITCA 650 could be priced very favorably once it’s launched, because we’ve heard that the company won’t have to work with PBMs – a potential very meaningful advantage.
In disappointing news, Intarcia received a Complete Response Letter (CRL) from FDA in 3Q17, but noted at the time that no new pivotal trials would be required prior to resubmission. Management seems entirely committed to this resubmission, and we hope it comes sooner rather than later, though no updates on timing have been publically disclosed. In additional, very little information has been shared regarding the reasons underlying the CRL, so we can only guess how long it may take for Intarcia to address FDA’s concerns and prepare for re-filing, but we remain optimistic that ITCA 650 will eventually reach the market and will help many people with type 2 diabetes. We also understand that the company is limited in what can be discussed – presumably, conversations are ongoing with FDA.
Dr. Young presented a pro/con list for developing a peptide-based therapy. On the pro side, he showed that peptides have ~half the attrition rate of small molecules: Peptide-based drug candidates have a mean 25% chance of making it through all stages of clinical development vs. 13% for small molecule candidates (and 32% for biologics). Dr. Young explained that peptide-based treatments have a higher chance of efficacy and a lower chance of toxicity because they’re already part of background physiology, which isn’t always the case for small molecule agents. There are 66 peptide therapies currently on the market, according to Dr. Young, and GLP-1 agonists represent a “good chunk” (seven, by our count – Victoza, Ozempic, Adlyxin, Bydureon, Byetta, Trulicity, and Tanzeum). On the con side, Dr. Young mentioned stringent cold chain requirements for transporting a peptide, shorter half-life, and greater manufacturing expense. He once again highlighted injectable administration as a deterrent for patient uptake, and also pointed out that developing a delivery system (e.g. pen, autoinjector, mini pump) adds to manufacturing expense and regulatory complexity. Indeed, the NDA for ITCA 650 was a whopping 1.3 million pages long, covering all aspects of this novel drug/device combo product.
New Treatments and New Targets for Diabetes
Domenico Accili, MD (Columbia University, New York, NY)
In spite of recent advancements in type 2 diabetes drugs (namely, positive CVOTs for GLP-1s and SGLT-2s), Columbia University’s Dr. Domenico Accili highlighted unmet need for a better insulin sensitizer. To be sure, reducing the frequency of CV events is an important priority in diabetes care. Dr. Accili positioned CV disease – the leading cause of death (40%) in the diabetes patient population – as an unmet medical need in and of itself. That said, he noted that even with cardioprotective diabetes drugs, a patient’s CV risk will still be significantly elevated vs. the background population. Adherence to SGLT-2s and GLP-1s remains a problem (Intarcia’s Dr. Andrew Young also touched on the adherence challenge in his keynote remarks – see above). Dr. Accili also implied that CV efficacy may be attenuated over time. In his view, an effective insulin sensitizer would revolutionize type 2 diabetes management by putting the disease into reverse and enhancing patient motivation (in which case, adherence and attenuation of efficacy become non-issues). In line with this ambition, Dr. Accili has been researching Foxo1 gene knockouts. He’s been working to optimize a mechanism that inhibits this gene and reduces hepatic glucose production without simultaneously raising liver fat or adding stress on the bones – both unintended consequences of some insulin sensitizing therapies. Dr. Accili described his goal as “selective modulation of glucose production vs. lipolysis, a way to induce all the beneficial effects of Foxo1 inhibition without getting the detrimental effects.” Six years ago, at the 2012 Keystone Symposia, Dr. Accili introduced us to the Foxo1 gene and the role it might play in insulin resistance and type 2 diabetes development. He has since turned this gene into a therapeutic target, and today at GTC, he shared evidence of early success in type 2 diabetes, concluding “we think we’re on the brink of a new generation of insulin sensitizers, albeit, in embryonic form.” We certainly see this as very exciting, albeit early-stage research, and we think the Foxo1 inhibitor class will be one to watch as it (hopefully) advances in the pipeline. Other diabetes thought leaders have echoed this opinion that insulin sensitizers should play a leading role in type 2 treatment. Dr. Ralph DeFronzo is perhaps one of the most vocal advocates of TZDs, particularly pioglitazone, for its insulin sensitizing nature, cardioprotection as seen in IRIS, and potential to preserve beta cell function.
“Insulin has been around for nearly 100 years, and it’s time to put it out of business.” Dr. Accili’s ambitions for Foxo1 knockouts extend to type 1 diabetes as well. He envisions a future where gut-targeted Foxo1 inhibitors cure type 1, thereby eliminating the need for insulin. He reviewed small studies conducted in animal models of type 1 diabetes and in humans. In mice, inactivating the Foxo1 endocrine progenitor cell was enough to reprogram it into an insulin-producing cell; when these cells were subsequently treated with sulfonylureas, Dr. Accili reported that they released insulin in a dose-dependent fashion, which suggests that they mimicked key functions of a beta cell. The human gut responded similarly when Foxo1 was inhibited: insulin-producing cells appeared and secreted the hormone in a dose-dependent manner. False hope for a cure has been a recurring issue for the type 1 diabetes community, and we’d hardly posit that Foxo1 inhibitors could have any chance of putting insulin out of business in the near or medium-term future, though we applaud Dr. Accili’s ambition. This pioneering work holds major implications for both type 1 and type 2 diabetes care.
Devices and Digital Aids in Diabetes Management
Update on Automated Glucose Control with the Bionic Pancreas
Steven Russell, MD, PhD (Harvard Medical School, Boston, MA)
In discussing the three primary challenges facing Beta Bionics’ bihormonal bionic pancreas – stable glucagon, accurate CGM, and insulin speed – MGH’s Dr. Steven Russell suggested that Novo Nordisk’s Fiasp (faster-acting insulin aspart) may offer a solution to the speed issue. Fiasp is the first FDA-approved product in a category of “ultra-rapid-acting” insulins, with a time to peak ~26 minutes faster than NovoLog (insulin aspart). Dr. Russell acknowledged that this may not seem like a meaningful difference – and indeed, thought leaders (most recently, Dr. Irl Hirsch at Endo Fellows) have been fairly critical about the magnitude of benefit that Fiasp offers over its predecessor – but then he framed ~26 minutes as two-fold greater insulin action in the first 30 minutes post-dose, which sounds quite significant in the closed loop setting. “One of our biggest hurdles is waiting for blood glucose to rise before giving insulin, so anything more rapid is great,” he explained. “We’re very excited about testing Fiasp in the Bionic Pancreas, and we think it might be the best way to reap the value of these ultra-rapid-acting insulins.” We could imagine Fiasp making a big difference in closed loop systems that administer automatic correction boluses (Novo Nordisk’s Onset 5 trial showed a postprandial benefit for Fiasp over NovoLog in pumps), but the advantage in onset speed may not have a large impact in the context of basal rate modulation; in Adam’s first 18 days using it in his DIY Loop rig, he saw no major difference in time-in-range, average glucose, or standard deviation vs. the previous 18 days using Humalog. That said, Adam spent a high portion of time in range at baseline (not huge room for improvement), and the plan is for Beta Bionics’ bihormonal system to deliver automatic corrections. We’re certainly intrigued by the role that faster-acting aspart could play in closed loop, especially if real-world outcomes for patients on MDI don’t differ all that dramatically with Fiasp vs. NovoLog. (That said, we note that not enough real-world data has been collected yet to determine whether this new drug offers a marginal or disruptive benefit; Fiasp only became available in the US in February. The small but statistically significant difference in postprandial glucose seen in phase 3 Onset trials could translate into tremendous quality of life improvements in the real world, as patients face less uncertainty around meals and might experience less fear of hypoglycemia, ultimately leading to better overall glucose control.) Dr. Russell also mentioned ultra-rapid-acting insulins in the pipeline that could help circumvent the speed obstacle for the bihormonal bionic pancreas down the line, including a phase 3 candidate from Lilly and Adocia’s phase 3-ready BioChaperone Lispro. In fact, Adocia management has already expressed interest in evaluating BC lispro in closed loop, and the company recently reported topline data from a phase 2 head-to-head trial in which the BioChaperone candidate demonstrated significantly faster offset vs. Fiasp. Faster offset in closed loop – including insulin-only – could prove extremely valuable in preventing hypoglycemia in instances such as exercise, where blood glucose decreases rapidly.
Dr. Russell confirmed that a phase 2b study evaluating Zealand’s liquid-stable dasiglucagon in the Beta Bionics bihormonal bionic pancreas is slated to start in “just a couple months” (July 2018), followed by a pivotal in June 2019. He alluded to recent topline data from Zealand’s immunogenicity trial, which found no anti-drug antibodies in response to dasiglucagon in 112 type 1s over 15 weeks. A pivotal trial with dasiglucagon is still on track to begin in June 2019, according to Dr. Russell, though timing for regulatory submission is hard to nail down since it will require approval of a new drug as well as a new device. Our AID competitive landscape also reflects this latest timing on the Beta Bionics dual hormone system.
Select Questions and Answers
Q: What’s one thing that keeps you up at night about this?
A: Having enough money to get to the point of launch. Dr. Ed Damiano has chosen to do this as a benefit corporation, taking in no venture money. Novo Nordisk and Lilly have both invested and both have seats on the board, which is unusual for these two companies. But Ed’s feeling is that he doesn’t want to take money from anyone who’s looking for an exit. The primary, overriding goal is non-profit, it’s to get access to as many patients as possible, so that definitely deters some investors. For now, my biggest worry is whether they’ll be able to raise enough money to get us to the completion of our pivotal trial. I don’t have any technical or efficacy or safety concerns.
Funding, Partnership, and Commercialization of Diabetes Technologies
The Symbiotic Relationship between Industry, CROs and Academia
Alan Cherrington, PhD (Vanderbilt University, Nashville, TN)
Dr. Alan Cherrington offered wisdom from his personal experience working with private industry while employed by an academic institution (Vanderbilt). He implored academia to work with biopharma, and vice versa. He described this partnership model as a win-win setup that accelerates product development for the company and provides academics with access to high-quality compounds and resources. Dr. Cherrington argued that this symbiosis between industry, CROs, and academia is becoming more critical as funding from NIH and other sources becomes more elusive, even for researchers as established as himself. He shared his own story as an academic focused on liver glucose metabolism: Dr. Cherrington developed the use of catheterization, flow probes, and other instruments in a dog model to study physiology, originally looking at export and import of glucose from the liver. With these broadly applicable methods, he began receiving cold calls from biopharma companies two decades ago. Companies wanted more reassurance on their investment in candidates than mouse models could offer, and it was much easier for them to utilize the expertise and infrastructure Dr. Cherrington had developed than to go at it themselves. Dr. Cherrington convinced Vanderbilt to supply $200,000 for space, equipment, and staff, forming Metaclamp. The company’s primary work is on internal contracts, solving specific problems and answering very specific questions for biopharma – for clients including Merck, Novo Nordisk, Lilly, BI, Sanofi, GSK, BMS, Pfizer, Gilead, Abbott, and many others. Dr. Cherrington emphasized that this sort of work at an academic institution requires a special kind of doggedness, and that communication is key surrounding constraints, expectations, and goals with the university’s legal team and clients. Things like intellectual property and timeline on publishing findings (or whether they can be published at all) are very important to agree upon. We’re intrigued by this “best of both worlds” type of thinking, with strongly evokes the venture capital work that the Bill & Melinda Gates Foundation does as an investor in private industry, aimed at driving groundbreaking technology toward global health utilization. We see both models as innovative, barrier-breaking practices maximizing the impact of scientific advancement. Pharma offers speed, scale, compounds, technology, and clinical focus that are hard to find in academia, but pharma also struggles to rival the depth and breadth of experience, knowledge, and even creativity found in academic institutions. Leveraging this synergy demands a willingness to chip away at logistical and legal barriers, but Dr. Cherrington has shown that the payoff on both sides can be huge.
Partnering with Novo Nordisk
Mr. Aaron Schwartz (Novo Nordisk, Boston, MA)
Mr. Aaron Schwartz, Novo Nordisk’s Director of R&D Innovation Sourcing, discussed two key elements to the company’s new R&D strategy – (i) expanding into diabetes-adjacent indications and (ii) adopting a higher innovation threshold. Management mentioned both these prongs when announcing the revamped R&D approach on Novo Nordisk’s 3Q16 earnings call. Mr. Schwartz explained that Novo Nordisk has grouped CV disease, NASH, and CKD into a category of “serious chronic diseases”; in addition, the company remains deeply committed to the flagship diabetes program, to accelerating innovation in obesity, and to hemophilia and growth disorders. He described how a focus on “serious chronic diseases” is a natural follow-up to the success of Novo Nordisk’s GLP-1 business, which includes obesity drug Saxenda (liraglutide 3.0 mg) and GLP-1 agonist Victoza (liraglutide 1.2 mg or 1.8 mg). Even at a lower dose, liraglutide confers significant weight loss, and Victoza recently received a CV indication based on LEADER data (the first positive GLP-1 CVOT), hence a smooth expansion into treating CV disease. We’d add that liraglutide also demonstrated renal protection in LEADER (26% relative risk reduction for composite renal endpoint, p=0.004 vs. placebo), so we note the possibilities here for CKD therapy. Mr. Schwartz emphasized that Novo Nordisk is widely regarded as a leader in GLP-1 – Saxenda leads the obesity market (73% of pooled sales in 4Q17), Victoza currently leads the type 2 GLP-1 market (54% of pooled sales in 4Q17), and next-gen Ozempic (semaglutide) was just launched in the US. According to Mr. Schwartz, the expansion into adjacent disease areas has created new opportunities for partnerships with academia, contract research organizations (CROs), biotechs, startups, and KOLs. To this end, he detailed that the company is currently seeking innovation in diabetes, obesity, serious chronic diseases, protein technologies, and hemophilia. In diabetes, Novo Nordisk seeks novel peptides and peptide mimetics, insulins, GLP-1 agonists, and other glucose-controlling agents. Any proteins or peptides that address obesity or its comorbidities are also of interest, including those that impact appetite and/or energy expenditure. Novo Nordisk is broadly interested in candidates for NASH, CV disease (atherosclerotic or heart failure), and CKD, and is also looking for attenuative and curative therapies for type 1 diabetes. One phase 2 disease modification trial is ongoing right now, investigating the effect of liraglutide on preservation of beta cell function in type 1. We’ll be very curious to see what new partnerships emerge from this extensive wish list.
Mr. Schwartz addressed the second component of Novo Nordisk’s R&D strategy during Q&A, commenting that the bar for differentiation is rising, especially in diabetes. “In general in the pharma space, I don’t think incremental improvements will really fly anymore,” he said, adding that the hypoglycemia endpoints in studies of basal insulin Tresiba were used to demonstrate such differentiation. On the other hand, thought leaders have been more critical about Novo Nordisk’s next-gen mealtime insulin Fiasp, suggesting that this offers only marginal benefit over NovoLog rather than truly disruptive improvement. We definitely don’t agree with this; traditional “rapid-acting insulin” is simply not good enough, and we view any increase in speed as important and highly favorable. Still, this speaks to Mr. Schwartz’s point about needing to show dramatic difference from what’s already available. It follows that the bar for Novo Nordisk’s partnerships is quite high. Sometimes incremental first is needed to get to transformational and from many patients’ perspectives, they’ll take incremental any day over nothing. When a partnership is formed, Mr. Schwartz emphasized that Novo Nordisk takes a strong focus on building trusting, collaborative, sustainable relationships with a long-term goal of creating value for the partner and for patients. He noted that the company favors flexible agreements and an early start to conversations – even before in vivo mouse data is obtained. Formal partnering discussions can open with the first in vivo data for biologics and closer to IND filing for small molecules, nucleic acids, and gene therapy.
Panel: Industry Partnering with Academia & CROs to Advance Diabetes Research
Mr. Dennis Guberski (Biomere, Worcester, MA)
In a discussion on academia partnering with industry, panelists emphasized the importance of transparency, flexibility, and communication in both the partner relationship and candidate development. Biomere’s Mr. Dennis Guberski, who has spent 20 years running a preclinical contract research organization (CRO), but who also has experience working at NIDDK, explained the key differences between research and development. To secure clinical trial funding, you need to show that (i) you own the product, (ii) it works, and (iii) it’s safe, scalable, and needed. The first two are a matter of intellectual property and show that the candidate is predictable and works in humans, but Mr. Guberski suggested that the real key is scalability, a theme we’ve seen surface throughout this meeting. For example, in a lab, you may use a certain solvent to get something to work in animals, but FDA may not allow its use in humans. Typically, meeting these criteria is much easier when you involve a CRO as a partner, Mr. Guberski explained. He highlighted an inflection point where big pharma becomes interested in a given candidate, possibly after phase 1 or phase 2 trials. Unfortunately, he said FDA will often discount much of the work done outside of the pharmaceutical industry, where much of the clinical trial expertise tends to be found – making CROs that much more important. As one attendee noted, most investors don’t see academic institutions as truly independent sources of data, so CROs spend a lot of their time repeating work from institutions. Diasome’s Dr. Jane Chiang pushed the point of transparency during these stages: The pathway in partnerships is nowhere near standardized, and many don’t even know what it could look like when coming from academia. In her experience in biotech, people typically have a pathway in their head but don’t articulate it to their partner, at a time when they should be offering as many concrete details as possible. This leads to miscommunication and mismatched expectations, hindering progress. That said, she also shared experience in which individual paths suddenly diverged in a partnership, noting that sometimes the hardest part of a partnership is being able to say that it doesn’t work anymore. Novo Nordisk’s Mr. Aaron Schwartz furthered this point with a discussion on the importance of flexibility, calling transparency and trust paramount in scientific relationships. For example, he had a friend take a new technology out of a research institution in Boston and receive startup funding, but when he couldn’t get the tech to work, he promptly returned the money to investors.
Funding & Commercialization of Diabetes Technologies
Is it Time For a Patient Centered Approach to Treating Diabetes and Obesity
Joseph Cook (NuSirt Bio Pharma, Nashville, TN)
The highly respected Mr. Joseph Cook, President of NuSirt Biopharma, and renowned former CEO of Amylin, argued that patients must own their own healthcare. He used pharmaceutical TV ads to show that the diabetes/obesity field is lagging behind in cultivating patient engagement. First, Mr. Cook played a direct-to-consumer commercial for Novartis’ Cosentyx, a plaque psoriasis drug. The ad featured real patients, not actors, repeatedly using the “I” pronoun, taking ownership of their psoriasis care. Mr. Cook then played commercial clips for Orexigen’s obesity drug Contrave (naltrexone/bupropion extended-release), Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), and Lilly’s GLP-1 agonist Trulicity (dulaglutide) – only the last of these, in his opinion, meets an acceptable bar for patient engagement. A voice over in Orexigen’s ad spoke about people with obesity in the third-person. Actors represented different regions of the brain that typically interfere with weight loss (e.g. the hunger center, the craving center). This campaign was part of Orexigen’s anti-stigma strategy. When we first heard from the company about this plan, we did see potential to portray obesity as a serious medical disease by drawing attention to underlying neural mechanisms, thereby eliminating (or at least minimizing) patient blame. Perhaps these commercials did reduce stigma against obesity in the people who saw them, but they “missed the mark” according to Mr. Cook because they weren’t motivating for the person watching who had obesity him/herself. He asked, “when’s the last time you were motivated by a mechanism of action?” Contrave seemed to be having a strong year of sales in 2017, and management attributed revenue growth to Orexigen’s revamped marketing plan, but apparently the new commercial strategy wasn’t enough, because the company announced bankruptcy last month. It’s unclear what will happen to Contrave, but if the product does remain on the market in the hands of another company, we’d love to see promotional efforts that both combat stigma and foster patient engagement. In the Jardiance commercial, patients with type 2 diabetes were interviewed on the street about their treatment plan and their awareness of CV risk (this followed the SGLT-2’s new indication for the reduction of CV death). Mr. Cook positioned this ad as a step up from the Contrave commercial, but still emphasized room for improvement. He focused on one comment from a patient, who said “that’s the plan” instead of “that’s my plan.” Mr. Cook advocated that the entire diabetes community (sales reps, industry, HCPs, payers, etc.) adopt language that encourages patient ownership over health and healthcare. He saved the best for last, characterizing the Trulicity TV ad as a “true consumer engagement message.” In the commercial, real patients discuss their experience on the GLP-1 therapy, delivering powerful lines like “I can do more to lower my A1c” and “I take Trulicity once a week to activate my body to release insulin like it’s supposed to.” We agree that this last commercial felt the most empowering. Mr. Cook even suggested that this promotional approach has led to Lilly’s rising share of the GLP-1 agonist market (more so, he claimed, than the patient-friendly autoinjector): Indeed, Trulicity sales more than doubled YOY in 2017 to break $2 billion, and as of 4Q17, dulaglutide reflected 34% of pooled GLP-1 sales (up from only 25% in 4Q16).
We felt Mr. Cook’s message was an important one, and we appreciated the role he carved out for manufacturers to play in cultivating health citizenship (through marketing and commercialization activities). It’s no secret that adherence remains a challenge in real-world diabetes/obesity care; handing someone a GLP-1 agonist or an SGLT-2 inhibitor won’t lower A1c, won’t stimulate weight loss, and won’t prevent CV events if patients don’t take the medicine as prescribed, which is usually adjunct to lifestyle modification. Beyond DTC ads, we hope to see more pharmaceutical companies leveraging digital health platforms to support patients on their products. A good example in obesity is Novo Nordisk’s SaxendaCare program: High-dose liraglutide is an effective weight loss agent, but for maximum success on the drug, patients also need to engage in a diet/exercise regimen; for help accomplishing this, they can sign up for SaxendaCare to receive encouraging emails and calls from a coach. Support strategies like this could also address the “efficacy gap” that exists between RCTs and the real world, and digital health has exciting potential to mimic some of the frequency of contact and motivation that participants get when enrolled in a clinical trial. Mr. Cook urged companies to collect patient feedback earlier and more frequently in designing products, digital health supports, etc. We certainly see a key role for patients to play in drug/device development.
Select Questions and Answers
Comment: I think the word “compliance” is in the trenches. When we say “compliance,” it means “I’m the doctor, and here’s what I’m telling you to do.” We call it “adherence” now. That’s how we bring the patient to decide for himself what’s good for him.
A: I’m hopeful. In a clinical trial we ran recently, we set a threshold of 80% adherence for patients to stay enrolled. It took a considerable amount of effort to keep people at 80% – in a trial where they were being compensated, mind you. So, there’s a fundamental issue. Why aren’t all patients at 100% in a clinical trial? It’s not side-effects, so what is it? I’m delighted that you’re finding that the word “adherence” is stimulating positive change.
Q: You could say it’s really a matter of mindset and education, and education as early as possible. Should we start in school, before the onset of obesity?
A: I couldn’t agree more with you. I’ve been on a tear lately about how physical education has been eliminated from many US public schools. We’re also eliminating home ec, classes that teach basic values about how to live a healthier life. We’ve abandoned a lot of education about what it takes to live a responsible, healthy life.
Mr. Thomas Seoh (Kinexum, Washington, DC): At the Metabesity congress last Fall, Professor Philip Home gave a talk on this topic, suggesting that we have to intervene early, in schools, to prevent childhood obesity.
A: That was a more despondent view. I’m hopeful that we can change diabetes and obesity in adults!
Dr. Jane Chiang (Diasome, Cleveland, OH): When I was a medical student, I did a home visit for one of my patients who was pregnant. She was maybe 18 years-old, and I had been telling her to do A, B, and C. She wanted a healthy delivery; she came to all of her appointments. But then I saw her in her home life, and I saw that it was impossible for her to do any of the things I had asked. We look at healthcare from our eyes, but we really have to look at treatment from the patient perspective. It reminds me of love languages, and it’s really the same thing for the folks we’re trying to help. If we don’t speak to them in their language, change will never happen.
Comment: I’m an MIT student, and my thesis is on diabetes management. I’ve analyzed data from the Joslin Diabetes Center on the DO IT program. My analysis shows that people who participate during the later stages of their diabetes benefit a lot – their chance of hospitalization reduces tremendously. The problem is that insurance companies are not actually funding this program. So, many patients can’t afford it. We’re curating a model right now at MIT to show that you can save billions of dollars by investing in these programs, and you also improve the quality of life of patients.
A: I think the DCCT told us that we can make a real difference in quality of life, but cost was prohibitive, because of high frequency of touch. When I talk with insurance companies, they say they need a 2:1 payout within 12 months, because they don’t know if they’ll be covering that life 12 months from now. I’m not a big fan of a one payer system, and I don’t want to get political about it, but I think what we need to do is take the essense of what’s been proven at Joslin and a number of other places, and figure out how we can democratize that. Just having new tools or apps or technologies won’t be the solution. We have to repopulate our brain into thinking through the patient lens first. When I was at Amylin, every time we interviewed a patient, we heard more stories about things that mattered to them that were so different from what we were trying to do. I was amazed at how much knowledge patients had about themselves, and how little we had incorporated that into our thinking.
Keynote Panel Discussion
Brian Bloomquist, PhD (Eli Lilly, Indianapolis, IN)
Lilly Senior Director Dr. Brian Bloomquist framed obesity care as a form of diabetes prevention, and he expressed enthusiasm that advanced obesity drugs will achieve weight loss on par with bariatric surgery. He pointed to Novo Nordisk’s next-gen GLP-1 agonist semaglutide (now branded as Ozempic for type 2 diabetes), which showed remarkable weight loss efficacy in phase 2 trials – 14% weight loss with the highest dose vs. 2% with placebo and only 8% with Saxenda. Novo Nordisk management anticipates superiority with semaglutide over Saxenda in phase 3 as well, which is slated to start later this year (the STEP pivotal program for semaglutide in obesity + the first-ever obesity CVOT, called SELECT). We’ll be looking for secondary endpoint data on diabetes prevention with semaglutide, similar to how Saxenda lowered risk for new-onset diabetes in the SCALE study. For Lilly’s part, Dr. Bloomquist shared a positive outlook on phase 2 DACRA-042 and phase 1 DACRA-089, two dual amylin calcitonin receptor agonists acquired through a partnership with KeyBioscience. To our knowledge, no study timing has been announced on either of these candidates, but Dr. Bloomquist implied that Lilly will be keenly interested in weight loss results once new trials are underway; management has also alluded to these body weight effects of DACRA on recent earnings calls. Down the line, Dr. Bloomquist forecast that a DACRA + a next-gen GLP-1 could provide best-in-class weight loss benefit, and in effect, might demonstrate profound efficacy in diabetes prevention. Most of this is still speculative, but our ears perked up (big time) at the possibility of Lilly conducting an obesity trial or (especially) a diabetes prevention one – Dr. Bloomquist acknowledged that the company has not historically focused on either disease, instead choosing to prioritize type 1 and type 2 diabetes. But he added, “we have an internal debate at Lilly constantly about this,” about whether or not it would make smart business sense to expand the diabetes portfolio into obesity and/or prediabetes. At this year’s Biotech Showcase (hosted concurrently with JPM in San Francisco), Dr. Bloomquist described Lilly’s approach to obesity as developing for diabetes first, getting a product approved and on the market, and later building on an obesity indication (or a NASH indication, for that matter). We’re excited by the prospect of Lilly investing more meaningfully in obesity care, because this experienced company could drive commercial success in a challenging market, although this could still be several years off. In the meantime, Novo Nordisk and Sanofi (with its GLP-1/glucagon dual agonist) are pushing forward with clinical trials in obesity.
Dr. Bloomquist also highlighted Lilly’s new collaboration with Sigilon to develop a beta cell encapsulation therapy for type 1 diabetes. “We’re really excited about this. There’s a long way to go, but it’s a unique tool to prevent a foreign body reaction which limits the effectiveness of existing therapeutic transplantation approaches to type 1 diabetes.” He characterized this as another example of Lilly’s broadening R&D scope; although it still falls within the realm of type 1 diabetes care, the goal to “cure” this disease by eliminating the need for daily insulin or chronic immunosuppression is brand new for Lilly.
Andrew Young, MD, PhD (Intarcia Therapeutics, Boston, MA)
During a panel discussion on diabetes prevention and what more industry can do, Intarcia CSO Dr. Andrew Young remarked “we’re already in the business of prevention.” He elaborated, “when we’re treating diabetes, we’re trying to avert a much more serious outcome down the road.” This explains the buzz surrounding positive diabetes CVOTs, which showed that glucose-lowering drugs (SGLT-2s, GLP-1s, and to a certain extent, TZD pioglitazone) can help prevent MACE events, heart failure, and CV death. Dr. Brian Bloomquist, Senior Director at Lilly, endorsed this view; he suggested that Lilly is already very involved in secondary prevention with SGLT-2 inhibitor Jardiance (indicated for the reduction of CV death). With these comments, Drs. Young and Bloomquist alluded to a major challenge in developing preventative therapies – FDA can’t and won’t approve a product for prediabetes until prediabetes is defined as a disease. At the same time, they revealed a possible solution – frame prediabetes as a condition that confers excess CV risk, that perpetuates morbidity and mortality. Several diabetes thought leaders have emphasized that prediabetes elevates an individual’s CV risk, even before A1c, fasting glucose, or post-meal glucose rise to threshold for a type 2 diagnosis (read insights from Dr. John Buse at Keystone 2017, or from Prof. Jaakko Tuomilehto at IDF 2017). Experts are now urging diabetes care providers to treat type 2 with CV risk reduction front of mind, and it follows that we should also be approaching prediabetes with CV risk mitigation strategies. JDRF’s Dr. Julia Greenstein offered the type 1 perspective, and she suggested that the field reframe “type 1 prevention” as “treating antibody positivity” instead. We thought this rebranding was supremely interesting, with important applications for type 1 and type 2 diabetes alike. We’ll be curious to see if language shifts in the coming months so that experts are talking about treating prediabetes because it’s a CV risk equivalent, and about treating antibody positivity. We suspect this could be compelling over time in getting preventative therapies through the regulatory process. We note that there have been some recent advances on this front. Panel moderator Dr. Zan Fleming pointed out that metformin is already approved for people with prediabetes in the UK. EMA guidance includes a section on prediabetes drug development, outlining that studies should enroll participants who did not respond to lifestyle intervention, should use a primary endpoint of cumulative diabetes incidence or time to diagnosis while also collecting data on CV risk factors, etc. That said, the field clearly has a long way to go, and with US prediabetes prevalence of 84.1 million (according to the latest CDC Diabetes Report Card), prevention is only becoming more urgent.
-- by Ann Carracher, Payal Marathe, and Kelly Close