Memorandum

Lilly’s Eight-study phase 3 SURPASS program for GLP-1/GIP dual agonist “tirzepatide” to begin by early 2019, potentially enabling 2022 submission – October 9, 2018

Executive Highlights
  • In a recent investor call (listen; slides), Lilly management discussed phase 2b results for GLP-1/GIP dual-agonist LY3298176 (now known by the scientific name tirzepatide), just presented at EASD 2018. The phase 3 SURPASS program for tirzepatide will contain eight studies, with the first (SURPASS 4; tirzepatide vs. insulin glargine in established CVD) set to begin in late 2018/early 2019. SURPASS also includes a superiority-powered CVOT and a head-to-head trial vs. semaglutide, and additional phase 3b/4 studies will investigate mechanism and clinical profile. Notably, Lilly hopes to use the same Trulicity autoinjector for these studies. Management slated regulatory submission for 2022. We’d love to see Lilly speak to FDA about CVOT standardization if it hasn’t already so that certain elements could be closer to standardization.

  • During Q&A, Lilly’s Senior Medical Director Dr. Brad Woodward who is also a global brand development leader there revealed that the 5, 10, and 15 mg doses of tirzepatide will all be continued into phase 3, and titration of these doses will be informed by a smaller 12-week dosing study. That study (n=111) evaluated a slower, step-wise titration that apparently decreased discontinuation rates to <5%, including for the 15 mg dose. To be sure, 15 mg tirzepatide was highly efficacious in phase 2b, conferring a 2.4% drop in A1c and ~25 pounds of weight loss at 26 weeks; however, one in four discontinued treatment due to adverse events (34% overall discontinuation rate), which Lilly attributed to more aggressive titration. A scheme that meaningfully attenuates side effects at this highly-efficacious dose would certainly be a big win.

Related to a presentation of very impressive phase 2b results at EASD 2018, Lilly simultaneously held an investor call dedicated to its once-weekly GLP-1/GIP dual agonist LY3298176 (now named tirzepatide), reflecting on the new data and providing a timeline for the phase 3, eight-study SURPASS program. Listen to the conference call here and check out the slides here. Also be sure to check out our coverage of the data presentation from EASD here; below, we’ve highlighted new info from the conference call, plus Q&A.

As released at EASD, the highest, 15 mg dose of tirzepatide conferred a rather unprecedented 2.4% drop in A1c (baseline 8.1%) and ~25 pounds of weight loss at 26 weeks, though one in four participants in this group discontinued treatment due to adverse events, and 34% discontinued overall. Fortunately, at the next lowest dose (10 mg), the side effects were attenuated somewhat with a level comparable with Trulicity 1.5 mg and with a 2.0% A1c drop, which is, in our opinion, a more acceptable trade-off in A1c and weight benefit (see summary figure below) though even at that level, the side effects are high.

SURPASS: Phase 3 Program

  • Dr. Brad Woodward (Senior Medical Director and Incretins Platform Team Leader), provided granularity on the phase 3 SURPASS program for tirzepatide. Eight individual studies will comprise SURPASS (see below), and the first to begin (SURPASS 4) will investigate tirzepatide vs. insulin glargine in people with established CV disease, set to begin in late 2018/early 2019. Of note, Lilly intends to use the Trulicity autoinjector to dose tirzepatide in SURPASS, which may help to maximize adherence. Management predicts that registration for the entire SURPASS program will be complete in 2021, and the program will allow for regulatory submission by 2022. While SURPASS includes all of the studies necessary to support registration and submission of tirzepatide (including in Japan), Lilly is also planning phase 3b and 4 studies (not pictured) to better understand the clinical profile and mechanism-of-action for the dual agonist. At EASD, we got the strong sense that no one in the field truly understands why this molecule or the combination of GIP with GLP-1 agonism seems so efficacious (some expressed downright confusion, arguing that GIP is traditionally the “bad guy”); we also note that tirzepatide favors GIP agonism over GLP-1 agonism, making this all the more important. We think any work Lilly can do to help HCPs understand how this molecule works will be very valuable down the line. To our understanding, none of these trials are yet posted on ClinicalTrials.gov.

    • We’re glad but not surprised to see a superiority-powered CVOT included here. While FDA did recently announce a two-day Ad Comm to discuss its 2008 CVOT mandate – leading to speculation that the agency is considering repealing or revising the requirement – the guidance still stands strong, for now. Moreover, the CVOT mandate has revolutionized the landscape of diabetes therapies: As cardioprotection comes more and more to be seen as a class effect of both GLP-1 agonists and SGLT-2 inhibitors, it grows ever-more-important that new diabetes therapies can also offer benefits on cardio-renal outcomes. We would tentatively think tirzepatide is in a strong position to do so, given (i) inherent GLP-1 agonism, and (ii) impressive effects on weight, a key CV risk factor, but we’re looking forward to collecting more insight on this front.

    • We’re also not surprised to see Lilly putting tirzepatide up against Novo Nordisk’s Ozempic (semaglutide). The launch of Ozempic in the US and EU earlier this year brought a new level of efficacy into the GLP-1 agonist class. For example, Ozempic has demonstrated superiority on both A1c lowering and weight loss vs. Lilly’s Trulicity (SUSTAIN 7); by all accounts, Ozempic is a monumental step forward in GLP-1 agonists. The semaglutide molecule is also in phase 3 for obesity (the STEP program) at a higher 2.4 mg dose (Ozempic doses are 0.5 and 1.0 mg); all four component studies are expected to complete in 2020. We’ll be very curious to see how STEP weight loss results stack up against the phase 2b data for tirzepatide, and we note that STEP 2 is enrolling only people with diabetes. While drawing comparisons across trials is inherently problematic, we can’t help but wonder how a high dose of semaglutide would stack up against tirzepatide.

  • A smaller 12-week dosing study of tirzepatide (n=111) evaluated a slower step-wise titration scheme and apparently decreased discontinuation rates to <5% in every study arm, including 15 mg. We do note that discontinuation rates due to adverse events was quite low in the larger phase 2b trial for lower dose arms, at 6% for 10 mg, 9% for 5 mg, and 4% for 1 m (vs. 4% for placebo and 11% for Trulicity). Thus, the 15 mg dose was the real sticking point; it would be a huge win for patients if Lilly can truly reduce side effects and discontinuations to a comparable level through smarter titration. We do remain curious why Lilly chose such an aggressive titration scheme for the larger phase 2b study, as the fact that this smaller study was conducted would seem to indicate that there was already substantial concern over side effects; it’s possible the company wanted to maximize efficacy at 26 weeks by getting participants on the max dose faster.

    • During Q&A, Dr. Woodward revealed that the 5, 10, and 15 mg doses of tirzepatide will all be investigated in phase 3. Titration of these doses will be informed by the 12-week dosing study mentioned above. Candidly, we’re very wary from a patient perspective (and also HCP since they do not have time to deal with lots of complaints) of the 15 mg dose. Given the high discontinuation rate (25% due to treatment, 34% overall) seen in this arm in phase 2b, we imagine most patients will have meaningful difficulty adhering to 15 mg in the real world, without the intensive support of clinical trial enrollment. That said, we will be curious to see if a slower titration (phase 2b escalated to 15 mg in only six weeks) will ameliorate the side effect profile; we fully expect Lilly to titrate more gently in phase 3.

Competitive Landscape

  • Mr. Enrique Conterno (President, Lilly USA and Lilly Diabetes – he’s a very big deal) briefly commented on the commercial implications of tirzepatide within the GLP-1 class, highlighting room for growth and expansion of injectable incretins. According to Mr. Conterno, only three out of every ten patients with type 2 diabetes receiving an injectable therapy are prescribed a GLP-1 agonist over basal insulin. That said, prescriptions for GLP-1 agonists continue to growth in the US, at a current YOY growth rate in the high 20s. He postulated that the addition of tirzepatide would only bolster class growth, once it reaches market (tentatively in ~2023); as evident below, the market entry of both Trulicity and Ozempic had a similar effect in spurring market growth. Moreover, we suspect that the new ADA/EASD consensus statement on managing hyperglycemia will also boost the GLP-1 class, as GLP-1s are now explicitly recommended as the first injectable therapy, before basal insulin; moreover, GLP-1s and SGLT-2 inhibitors are recommended for anyone with established cardiovascular disease (preferably an agent that has proven CV benefit). For our part, we think tirzepatide could offer a new level of efficacy in diabetes therapy, both in A1c-lowering and weight loss, but we’ll be keeping a close eye on tolerability data in phase 3. We would also love to see Lilly and others invest more in expanding access to GLP-1s already on the market. There’s no doubt that better therapies are a welcome addition to the diabetes treatment arsenal, but a dismal 7% of second-line prescriptions go to GLP-1s – a small fraction of those who could benefit from them.

    • In a plug for Lilly’s GLP-1 business, Mr. Conterno pointed out that, as of early 2018, Trulicity is the US market leader in new therapy starts for the GLP-1 agonist class as well as for overall prescriptions within the GLP-1 class (below right). However, this is more of an effect of other market dynamics than Trulicity gaining share on its own. The new prescriptions garnered by recent market additions (AZ’s Bydureon BCise, Novo Nordisk’s Ozempic) have only stolen market share from Novo Nordisk’s Victoza, while Trulicity has maintained stability. We’ll be particularly interested to see how REWIND (Lilly’s CVOT for Trulicity) will play into market dynamics after it reads out at ADA 2019 (topline release expected in 2018).

  • Management also briefly mentioned that positive phase 3 results for Ultra Rapid Lispro Insulin (URLi) were announced last week. According to Lilly, URLi demonstrated non-inferior A1c reduction vs. Humalog (insulin lispro) and significantly improved post-meal glucose control (1- and 2-hour PPG) in people with both type 1 and type 2 diabetes. These results were somewhat overshadowed by readouts for tirzepatide, the CARMELINA CVOT for DPP-4 inhibitor Tradjenta, and the EASE program for Jardiance in type 1 – all in the same day at EASD. Moreover, we’re not sure what to think about URLi until Lilly announces whether superiority on A1c lowering vs. Humalog was achieved, which will be critical to demonstrating meaningful benefit over existing mealtime insulin options. We’re not sure why Lilly wouldn’t have released this data with the topline results; we can imagine equally-likely scenarios in which Lilly wants to either (i) hype up a very positive result or (ii) explore the data more to lessen the impact of not meeting superiority on A1c – we’ll have to wait and see.

Questions and Answers

On Efficacy

Q: How far do you think the weight loss could have gone if patients were continued on drug longer, given that it had not plateaued at 26 weeks?

Dr. Woodward: The duration of the phase 2b trial was 26 weeks. Within our phase 3 program, we have longer duration studies planned that will give us a much better understanding of the potential for additional weight loss. So, we do note the same as you that these weight decreases have not plateaued at 26 weeks. The eventual endpoint of that will be seen in phase 3 studies.

On Safety and Tolerability

Q: How much, if any, of the weight loss was due to the GI upset versus the mechanism of the drug?

Dr. Woodward: The majority of GI side effects that we've seen are consistent with the GLP-1 receptor agonist class, and they were early during the titration period. The supplementary material in The Lancet publication shows the time course of those events, and we've actually seen relatively low prevalence of GI side effects throughout the course of longer treatment. As such, we would not expect the weight loss to be primarily driven by GI side effects. We have seen reported adverse events of decreased appetite, which you would expect. That's a known effect with GLP-1 receptor agonists, and that certainly could be contributing to some of the weight loss that we are seeing.

Q: What level of nausea, vomiting, and dizziness would be acceptable given the efficacy of the 15 mg dose? Was it any less easy to mitigate diarrhea with titration?

Dr. Woodward: What we've seen from a separate titration study that we've conducted to 12 weeks is that discontinuations were quite low, less than 5%. We have used that information to inform the titration steps for the phase 3 program, which gives us increased confidence that we'll see a better tolerability profile.

With respect to the prevalence of diarrhea, the supplemental figure in The Lancet publication continues to show that once patients get past the early titration period, the prevalence of these symptoms is relatively lower. As such, we don't think that that's going to be a long-term problem, although we do look forward to the phase 3 trials and understanding this in a larger cohort of patients over the long-term.

Q: After titration, were discontinuation and adverse events rates still higher in the 15 mg arm?

Dr. Woodward: I can confirm that the majority of discontinuations with 15 mg occurred during the early titration period. Once patients passed that period, the tolerability did improve and discontinuations decreased accordingly.

Q: Anti-drug antibodies range from 31%-49% across the groups. What is your confidence that the long-ish trials that you talked about won’t show an impact on efficacy?

Dr. Woodward: With respect to the anti-drug antibodies [ADAs], our perspective is that we will continue to evaluate this in phase 3, although we do have good information from the phase 2b program. We have not seen any impact on the pharmacokinetic profile – in other words, no reduction in drug levels with respect to the [ADAs]. These have been relatively low titers, generally, when they have been observed. We also have not seen any reduction in the pharmacodynamics, treatment response, or glycemic response with the presence of [ADAs] nor any association with hypersensitivity events. We look forward to further study in phase 3, but this is the information that we currently have that appears reassuring.

Q: How do the cases of acute pancreatitis compare to dulaglutide or other GLP-1 data from phase 2 trials?

A: The safety data that we've seen thus far is consistent with what we know about the GLP-1 receptor agonist class. There were two events of pancreatitis within this phase 2b trial. One event was early and was considered non-serious by the investigator. The patient had some abdominal discomfort, but went for a CT scan and radiographic imaging, and there was no confirmation of pancreatitis with the radiographic imaging. The second case was in a patient who had been off of study drug for almost a month and a half and developed cholecystitis and secondary acute pancreatitis. We've not seen any other indication that there is a risk with GIP, and the changes in amylase and lipase, which are a known response from GLP-1 therapy, seem consistent with what we've seen from dulaglutide with our dual agonist.

On Future Studies and Development

Q: Are you taking both the 10 and 15 mg doses into phase 3 development?

Dr. Woodward: Yes, the 10 mg and 15 mg doses, as well as the 5 mg dose, will be in phase 3.

Q: Is the SURPASS CVOT designed similarly to REWIND with a healthier patient population or more like Novo Nordisk’s studies with established CV disease?

Dr. Woodward: Most importantly, this CVOT is a superiority trial for MACE event reduction, but we have not finalized the design of this trial. We think it's important to have a representative population enrolled, but we have not narrowed down the population yet, whether it would be entirely secondary prevention or would include a balance of primary and secondary prevention.

Q: GIP has been described in the literature as far back as 20 years ago. Why hasn’t industry development been quicker?

Dr. Ruth Gimeno (VP, Diabetes Research and Clinical Investigation): I think sometimes we ignore some of these existing hormones. Certainly, there has been some literature describing GIP as an obesogenic hormone and reports of GIP resistance linked to hyperglycemia. We believe by having GLP-1 together with a GIP component, we can actually reverse that GIP resistance, and I think that was an important component of developing the dual agonist.

Q: Given that other GLP-1/GIP candidates (Merck and Roche) have been dropped in development, what is unique about yours?

Dr. Gimeno: Our molecule is the first molecule that is biased towards GIP activity – an important differentiator. We've purposefully designed this molecule to fully engage the GIP receptor before reaching the dose-limiting tolerability issues of the GLP-1 receptor. This is the most likely hypothesis for the difference between different molecules. In this space, every agonist can be slightly different. These molecules also have differences in terms of pharmacokinetics and biodistribution which could certainly contribute as well.

Q: What are your thoughts in terms of initiating a phase 3 obesity program?

Dr. Woodward: With respect to obesity, we're certainly encouraged by these data overall, and we're looking at what other ways that this could be developed. Our primary focus is looking at type 2 diabetes today, and we're pleased to announce the introduction of the SURPASS program. But we will continue to look at other opportunities more broadly.

Q: Might you look for an indication in NASH or renal function?

Dr. Daniel Skovronsky (CSO): Right now our focus is on the type 2 diabetes indication. We're really excited about the potential of the drug there. Of course, we're open to exploring other potential applications of this molecule, and the data suggests great potential in various paths. We'll continue to think about that into the future.

Q: Titration may temper side effects, but can you confirm it has no impact on either A1c reduction or weight loss?

Dr. Woodward: We would not expect the titration to have a negative impact on efficacy of the product.

Q: Could the Trulicity pen device be used for this drug?

Dr. Woodward: We are looking to begin the phase 3 trials with a single-use auto injector. We really want to replicate the Trulicity experience here and have a positive patient experience on the trials and commercially when this comes to market.

 

--by Peter Rentzepis, Ann Carracher, and Kelly Close