Eli Lilly and Company (LLY) Management to Discuss EASD Presentations Conference Call (Transcript)

About: Eli Lilly and Company (LLY)
by: SA Transcripts

Eli Lilly and Company (NYSE:LLY) EASD Presentations Conference Call October 4, 2018 1:00 PM ET


Kristina Wright - Investor Relations

Enrique Conterno - President of Lilly Diabetes and Lilly USA

Dan Skovronsky - President of Lilly Research Laboratories

Jeff Emmick - Vice President, Diabetes and Product Development

Ruth Gimeno - Vice President, Diabetes and Metabolic Research

Brad Woodward - Incretins Platform Team Leader


Louise Chen - Cantor Fitzgerald

Vamil Divan - Credit Suisse

Tim Anderson - Wolfe Research

Jami Rubin - Goldman Sachs

Chris Scott - JP Morgan

Andrew Baum - Citi

Jason Gerberry - Bank of America

Umer Raffat - Evercore

Steve Scala - Cowen and Company

Alex Arfaei - BMO Capital Markets


Ladies and gentlemen, thank you for standing by. Welcome to the EASD Investor Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. Instructions will be given at that time [Operator Instructions]. And as a reminder, this conference is being recorded.

I would now like to turn the conference over to our host, Kristina Wright. Please go ahead.

Kristina Wright

Good evening. And thank you to everyone for joining us on our diabetes update call. I'm Kristina Wright of the Investor Relations team. Joining me on tonight’s call are Enrique Conterno, President of Lilly Diabetes and Lilly USA; Dan Skovronsky, President of Lilly Research Laboratories; Jeff Emmick, Vice President, Diabetes and Product Development; Ruth Gimeno, Vice President, Diabetes and Metabolic Research; and Brad Woodward, Incretins Platform Team Leader.

During this call, we anticipate making projections and forward-looking statements based on our current expectations. Our actual results could differ materially due to a number of factors, including those listed on Slide 3 and those outlined in our latest Forms 10-K and 10-Q filed with the Securities and Exchange Commission. The information we provide about our products and pipeline is for the benefit of the investment community. It is not intended to be promotional and is not sufficient for prescribing decisions.

Now, I'll turn the call over to Enrique.

Enrique Conterno

Thanks, Kristina. And thank you to everyone who has joined us for this discussion about our dual GIP, GLP-1 receptor agonist. Today has been an exciting day for our diabetes business, capping off a big week with several important announcements about our pipeline and our current range of therapies, including the announcement of positive Phase 3 data for our Ultra Rapid Lispro insulin type 1 and type 2 diabetes; and along with Boehringer Ingelheim, presentations at the EASD Conference in Berlin for the CARMELINA trial, which study the impact of Trajenta on cardiovascular and kidney safety in adults with type 2 diabetes; as well the EASE program studied Jardiance as an adjunct to insulin in adults with type 1 diabetes.

Over the next hour, we will focus specifically on the Phase 2 dual GIP, GLP-1 receptor agonist data that were presented today. Ruth and Brad will walk you through the molecule and the data in just a moment. First, I'd like to start by offering some context and perspective. The graph on the left of Slide 4 shows that the U.S. GLP-1 market has grown considerably over the last four years. When Trulicity first launched in the U.S. in November of 2014, the GLP-1 class growth was in the mid teens. The entry of Trulicity acted as a catalyst to significantly accelerate the growth of the class. And now in 2018 with the launch of Ozempic along with the continued success of Trulicity, U.S. prescription growth for the class is in the high 20s.

Currently, only three out of every 10 type 2 diabetes patients who are receiving an injectable for the first time are getting a GLP-1 while the others are receiving basal insulin. With further innovation, including the potential entry of our dual GIP, GLP-1 receptor agonist, we believe that the number of people receiving an injectable incretin therapy could have a dramatic expansion. The chart on the right of Slide 4 underscores that continued strong performance of once weekly with Trulicity. Earlier this year, Trulicity became the U.S. market leader in new therapy starts on overall prescription within GLP-1 class, a testament to its powerful efficacy and unmatched patient experience.

Trulicity is not only leading the market in the U.S. but also it has become a leading treatment option for type 2 diabetes around the world. Trulicity is an important part of our growing diabetics business and it also has provided a window into the data that were presented today. We’re excited about the Phase 3 results with a weekly dual GIP and GLP-1receptor agonist integrating the action of both incretin into a single novel molecule, aiming to build for the clinical benefit seen with our selected GLP-1 receptor agonist. As I’ve previously said, we set a high bar for this molecule and our Phase 2 results did not disappoint.

I will now turn the call over to Ruth Gimeno to introduce our GIP, GLP-1 dual agonist.

Ruth Gimeno

Thank you, Enrique. Please turn to Slide 5. The molecule we are discussing today is our novel dual glucose-dependent insulinotropic polypeptide or GIP, and GLP-1 receptor agonist, LY3298176. This molecule is a 39 amino acid peptide that has been modified as lysine residue 20 with a 20 carbon fatty diacid. The peptide backbone is based on a native GIP sequence, but we introduced a number of amino acid changes that allow and to bind to and activate both the GIP and the GLP-1 receptor.

Based on in-vitro binding and signaling assay, our molecule has similar potency to native GIP peptide with respect to the GIP receptor, but is 5 to 10 fold less potent than native GLP-1 with respect to the GLP-1 receptor. The fatty acid modification results in a prolonged half life of approximately five days, supporting a once weekly dosing regimen. The molecule is administered by subcutaneous injections and the molecular weight is 4.8 kilodalton.

Slide 6 shows how our dual agonist activates both the GIP and GLP-1 receptor. This creates new pharmacology that reflects the combined action of GIP and GLP-1 on a number of different tissues and likely includes both direct and indirect effect. Let me take you through some key mechanisms. GLP-1 and GIP are both incretins that increase glucose-dependent insulin secretion by acting on pancreatic beta cells. Studies in preclinical models and in men have shown that the effects of GIP and GLP-1 on insulin secretion can be additive with both peptide contributing to glucose lowering. In addition to insulin secretion, GLP-1 and GIP also affects glucagon release with opposite effect in acute studies in-vivo and reflecting both direct and indirect mechanisms.

The weight loss effect of GLP-1 is due to inhibition of food intake in the brain. We know very little about the action of GIP on the brain, but we do know that GIP receptors are present is appetite, regulatory sensors. And it is possible that the GIP could interact with GLP-1 in the brain to potentiate its effect on both food intake and possibly modulate energy expenditures. However, this needs to be investigated further. Adipose tissue appears to be a specific target tissue for GIP since it expresses high levels of the GIP receptors. It has been clearly demonstrated that GIP can induce glucose uptake in adipose tissue, as well as it shows complex effects on lipid metabolism that depend on the metabolic stage of the individuals. The actions of GIP on adipose tissue require more study, but we believe that it could contribute to improvement in both glucose and lipid metabolism that we see with our dual agonists.

GLP-1, but not GIP, acts on the stomach to inhibit gastric emptying, which start to contribute to postprandial granular glucose control by GLP-1 but may also be linked to the gastrointestinal side effects of GLP-1. Recently, GLP-1 receptor agonist has been shown to provide cardiovascular and renal benefits and may also improve NASH. The mechanisms underline these benefits are not completely understood and at least some of them are likely indirect. We are encouraged by the significant weight loss, the strong triglyceride lowering effects and the improved insulin sensitivity we observed with our molecule, all of which are more pronounced than what we see with our GLP-1 receptor mono-agonist control. We anticipate that our dual GIP and GLP-1 receptor agonists will have beneficial effects on cardiovascular outcomes and other diabetic complications, but obviously this will need to be studied separately.

Overall, from what we know about GIP and GLP-1 pharmacology, we would expect the dual GIP and GLP-1 receptor agonists to have superior effects on glucose and body weight and this is why we tested this mechanism in clinical studies.

I will now pass the call over to Brad Woodward to walk you through the Phase 2 clinical trial data and our future plans.

Brad Woodward

Thank you, Ruth. And thank you for joining us for this investor webcast. I will briefly go through the Phase 2B design, evaluating our dual receptor agonists, the efficacy results, safety and our impressions. Then we will look forward to your questions later during the call. The full results of the Phase 2B study are in the The Lancet publication, which is available today. And further background information of the dual agonist from discovery to clinical proof-of-concept is now published in molecular metabolism. We are encouraged by these data and Lilly is committed to bringing forward innovation that is meaningful for patients living with diabetes.

On Slide 8, which shows the study design for the Phase 2B trial, the study enrolled 318 patients with type 2 diabetes and allowed a stable dose of metformin as background therapy. It was a six arm trial, including placebo, dulaglutide as an active comparator and four doses of dual agonist LY at 1, 5, 10 and 15 milligrams. The two higher doses of 10 and 15 milligrams were achieved by a rapid titration over two and six weeks respectively. The primary objective was changed from baseline and hemoglobin A1c at 26 weeks and secondary measures included body weight change, fasting glucose and preceptor goal, or categorical changes for hemoglobin A1c and weight.

On Slide 9 are the highlights of the efficacy finding. On the left panel, the dual GIP, GLP-1 receptor agonists represented in blue, was statistically significant in hemoglobin A1c changed from baseline across doses with 5, 10 and 15 milligrams, delivering at minus 1.6, minus 2.0 and 2.4 percentage point change, demonstrating a clear dose separation. Also, dulaglutide performed as expected with a reduction of 1.1% and placebo stayed relatively neutral during the course of the trial. Another way of looking at these data is the LS mean subtracted difference from dulaglutide in the dual agonist 15 milligram dose achieved an additional 1.3% A1c change from baseline, clearly achieving a high bar for efficacy.

On the right panel, weight loss has a solid dose response relationship. And from a baseline weight of 92 kilograms, the 5, 10 and 15 milligram doses achieved minus 4.8, minus 8.7 and minus 11.3 kilogram change from baseline to 26 weeks and notably have not yet plateaued. Dulaglutide performed as expected, delivering a minus 2.7 kilogram change. While the dual agonist 10 and 15 milligram doses were statistically significant with LS mean differences up to minus 8.6 kilograms comparing with 15 LY milligram dose to dulaglutide. We believe these results at A1c and weight reduction represent a significant advancement in incretin therapy with novel dual agonism of GIP and GLP-1.

Moving to Slide 10, the results just shared with you were in on treatment analysis and this current slide shows the Bayesian dose response model to primary analysis of the study. On the X-axis, the full study data are represented and are modeled with interpolated doses between the actual four doses given to patients at 1, 5, 10 and 15 milligrams. Lilly chose the dose response model quite simply to assist with identifying dose selection in Phase 3 and allowing probability assessments for internal company decision making. Again, a clear dose response relationship was seeing for hemoglobin A1c and weight. The analysis in grey is modified ITT without postrescue has a decrease of 1.9% A1c and approximately 9 kilogram with the dual agonist.

In red, which represents the modified ITT on treatment, the changes are greater not surprisingly and achieved a decrease of 2.3% A1c in a 10.4 kilogram weight reduction. To be clear, both the red and green lines represent the Bayesian dose response model of the dual agonists. Although, the data included defers with the grey being mITT without postrescue, which includes data after patients stop taking study drug. And the analysis in red is mITT while on treatment. The red on treatment analysis is what we believe represents the closest estimate of drug effect while patients are adherent to therapy. The message from this modeling is supportive of additional glycemic and weight efficacy with increasing doses.

Slide 11 depicts the A1c and weight loss results and preceptor goal. The A1c goal endpoints of less than 0.7% were less than or equal to 6.5% are commonly reported, and we also analyzed the proportion of patients that achieved normal glycemia for an A1c of less than 5.7% at week 26. The threshold for diagnosis of prediabetes is 5.7% and the threshold for diagnosis of diabetes is 6.5%, and we found these to be of interest when looking at the responses to therapy.

The dual agonism of GIP and GLP-1 was associated with up to 90% of patients achieving an A1c less than 7% at 26 weeks, and there were good responses also at the 5 and 15 milligram doses. Notably, almost one in three patients treated with the dual agonist 15 milligram dose achieved a normal A1c, a differentiated response from dulaglutide which achieved this in 2% of patients treated. We have not seen this type of response previously and are encouraged by the normalization of A1c, although, we look forward to seeing the response in our larger trial.

I'll mention this again with safety on the next slide but the incidents of hypoglycemia was relatively low even though the molecule achieved a high proportion of patients achieving glycemic control. We don't yet know the clinical implication of treating to less than 5.7 and the benefit of reaching this level, but we know it is important to have a low risk of hypoglycemia and thus far that is what we are seeing.

A potential question is the finding of a lower proportion of patients achieving targets that LY 15 milligrams than 10 milligrams, we believe this is a feature of the analysis using logistic regression in LOCF, or Last Observation Carried Forward analysis, as this carry forward data from patients missing values or prematurely discontinuing therapy for any reason. This may have a downward effect on both the A1c and weight target data as a potential explanation, we understand in future studies it'll be important to show benefit for these targets across doses.

Categorical weight loss of 5%, 10% and 15% was also assessed. As expected with the mean weight change already reported, there were sizeable proportions of patients that achieved weight reductions of 10% or higher or 15% or higher. As an example, nearly one in four patients achieved 15% or greater weight loss with LY 15 milligram compared to 2% on dulaglutide.

As Ruth shared earlier, we are interested by the effects of the unimolecular GIP, GLP-1 is having on glucose, beta cell function, appetite suppression, adipocytes, lipids and other key indicators. Further work is needed and is planned, but the pharmacodynamic and clinical results seen in the Phase 2B trial are certainly encouraging for patients and the next wave of innovation in diabetes incretin research.

Advancing to Slide 12, we provide a high level summary of the safety and tolerability data from the trial, and a more complete assessment can be referenced in the The Lancet publication. The profile was similar to what we have seen with GLP-1 receptor agonist class with no new adverse events identified. The most common AEs were gastrointestinal with nausea, vomiting and diarrhea occurring mostly during the titration or early initiation phase of the trial and the events were generally mild to moderate in severity.

Nausea and vomiting with LY 5 and 10 milligrams were not dissimilar to dulaglutide; although, there were some numerical differences; although with LY 15 milligrams, there was increased reports and incidents of all three; nausea, vomiting and diarrhea. Discontinuation of study drug due to an adverse event occurred in 9%, 6% and 25% of people in the LY 5, 10 and 15 milligrams dose groups respectively compared to 11% in the dulaglutide group. The 10 milligram dose arm performed well from a tolerability perspective, and our goal is to improve the overall profile of titration, particularly at the 15 milligram dose.

Based on a separate titration study that has now completed, we evaluated a slow stepwise titration up to 15 milligrams and observed what we believe supports improved tolerability, evidenced by 5% or fewer of patients discontinuing therapy due to an adverse event when treated for 12 weeks. We have confidence that a slower stepwise titration in Phase 3 as a good probability of achieving a favorable profile.

Going back to the safety data shown here and measures of interest, hypoglycemia occurred at a low incidence with slight numerical differences. Importantly, there were no severe hypoglycemic events and the incidents of documented symptomatic hypoglycemia less than 70 milligrams per deciliter was 6% or less across all treatment arms including dulaglutide. Treatment emergent antidrug antibodies were observed at generally low titers and there was now pharmacokinetic or pharmacodynamic correlation nor any association with hypersensitivity events that was observed.

Also, regarding pancreatic safety, pancreatic enzymes are reported in the publication supplement and show a similar change from baseline of LY doses up to 15 milligrams to that observed with dulaglutide for lipase and amylase, and limited yet similar numbers of patients that had close baseline increases greater than 3 times the upper limited normal. Two events of pancreatitis were observed; one non-serious without radiographic evidence; and another after the patient had discontinued drug in the event associated with the gallstone. These events were consistent with what has been observed with the marketed GLP-1 receptor agonist class. All of these safety measures and other AEs of interest will be monitored in Phase 3 program which takes us to Slide 13.

Lilly has previously shared that we are taking this molecule forward into Phase 3 clinical study, and we have both completed and ongoing regulatory interactions to support global development. We are still finalizing the details of our Phase 3 program, but this is what we are currently planning. The SURPASS program for Lilly’s dual receptor agonist and type 2 diabetes will initiate yet this year, or very early in 2019, we expect the registration program to conclude in 2021 and pending data allow for global submissions in 2022.

The initial SURPASS studies are shown here and include comparative efficacy and safety to semaglutide, insulin degludec and glargine, as well as co-administration data with oral antiglycemic medicines, including SGLP-2 inhibitors, metformin and sulfonylurea. This is a complete program that support registration but we are also planning Phase 3B and 4 studies and sub-studies to understand the clinical profile of the molecule and the mechanism of actions.

The cardiovascular safety will be assessed with the program level meta-analysis of events, with SURPASS 4 enrolling patients with higher cardiovascular risk and established cardiovascular disease. Additionally, we will conduct the SURPASS CVOT, or cardiovascular outcome trial, powered for cardiovascular risk reduction and superiority. I’ll say that we are excited by these data and the potential benefit for patients. The SURPASS clinical program will provide us with a much better understanding of the clinical utility of dual agonism of GIP and GLP-1, and offer an important step forward in diabetes research.

I will now pass the call over to Enrique Conterno for summary comments before we begin the Q&A portion of the meeting. Enrique?

Enrique Conterno

Thank you, Brad. And before we go to the Q&A session, let me briefly sum up. We’re excited to advance our dual GIP, GLP-1 receptor agonist is the next phase study as a potential treatment for type 2 diabetes. This molecule is being developed to become a next generation once weekly incretin that could strength Lilly's position in the first injectable space and more broadly, fuel Lilly’s growth position as a diabetes leader.

In order to meet the increasingly high expectations of the market, we expect to launch first with a multiyear lead in a new class of GIP and GLP-1 receptor dual agonist, allowing us to provide a potential new option for the millions of people with type 2 diabetes. Our goal is to continue to exceed expectations for glycemic control and weight loss. The numbers we saw in the Phase 2 trial are encouraging, but we have more work ahead to understand the full safety and efficacy profile of this molecule.

We plan to replicate Trulicity's injection experience, the unmatched experience of people who use Trulicity, driven by its once weekly dosing ease of use and efficacy is a model that we transform. We aim to deliver a meaningful cardiovascular benefit. The industry knows that cardiovascular safety is stable space for diabetes medicine and cardiovascular medicine is the ultimate goal. And finally, we look forward to starting our Phase 3 trials, which will be in either late this year or early in 2019. This concludes our prepared remarks.

Now, I'll turn the call over to Kristina to moderate the Q&A session.

Kristina Wright

Thanks, Enrique. We'd like to take question from as many callers as possible. So we ask that you limit your questions to two or to a single question with two parts. Lisa, please provide the instructions for the Q&A session, and we’re ready for the first caller.

Question-and-Answer Session


Thank you [Operator Instructions]. Our first question will come from the line of Louise Chen with Cantor. Please go ahead.

Louise Chen

So my first question here is on the weight loss. You have noted that the weight loss had not plateaued yet. Where do you think the weight loss could go if patients were on the drug longer? And then second question I had was that how much, if any of the weight loss, was due to the GI offset versus the mechanism of the drug. Anything that you could help us there would be great, thanks.

Brad Woodward

Sure, I can take that question. So the duration of the study during the Phase 2B trial is 26 weeks. So within our Phase 3 program, we have longer duration studies planned that will give us 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 end point of that will be seen in Phase 3 studies.

Back to the potential relationship between the decrease in weight and the GI side effects, 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 and the 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. So 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 of GLP-1 receptor agonist, and that certainly could be contributing to some of the weight loss that we're seeing.


Next question comes from Vamil Divan with Credit Suisse. Please go ahead.

Vamil Divan

So two questions please, one, the antidrug antibodies, so the publication shows the range from 31% to 49% across the groups and you've mentioned the targets are quite low. Just given, if you can give perspective on what you -- just thoughts on that level of antibodies and your confidence that the longest trials you've talked about won't show an impact on the efficacy side? And then the second question, going back to the side effects and you mentioned the longer titration period for the 15 milligram dose. I'm just curious what level of nausea or vomiting do you think would be acceptable given the efficacy of a 15 milligram dose? And I guess we thought that maybe diarrhea maybe something that's less able to be mitigated by titration. Would you agree with that or not, or do you all three of those can be brought down with a slower titration period? Thanks.

Brad Woodward

Sure, I'll take the question about tolerability first. So, what we've seen from a separate titration study that we've conducted at 12 weeks, and that's the one that I referenced is that the discontinuations that we observed were actually quite low less than 5%. We have used that information to inform the titration steps for the Phase 3 program, so that gives us increase confidence that will see a better tolerability profile for that. With respect to the prevalence and diarrhea in particular back to the supplement figure and The Lancet's publication, continues to show that once patients get pass that early titration period and with improved titration, the prevalence of these symptoms is relatively lower. So 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 on a larger cohort of patients long-term.

With respect to the antidrug antibodies, our perspective on this is that we'll continue to evaluate this in Phase 3. Although, we do have good information from the Phase 2B programs, and we have not seen any impact on the pharmacokinetics profile, so no reduction of drug levels with respect to the antidrug antibodies. These have been relatively low titers generally when they have them observed. And we also have analyzed and have not seen any reduction in the pharmacodynamic or treatment response or glycemic response with the presence of ADAs nor any association with hypersensitivities. So, we look forward to further study in Phase 3 but this is the information that we currently have that appears reassuring.


Thank you. Next is Tim Anderson with Wolfe Research.

Tim Anderson

You can find GIP described in the literature as far back as 20 years ago, yet it's only today that we have results from a Phase 2 trial. I'm wondering why development by industry hasn't gone faster, it would have been some of the development challenges? And then second question, GIP is a novel mechanism. Naturally, there is some unknown and risks there. When you think about the potential mechanism based or off target toxicities, what things are at the top of the list that could be either theoretical or from animal studies or human studies? Thank you.

Ruth Gimeno

Why has development not done fast as GIP, it is a good question. I think sometimes we ignore some of these existing hormones. Certainly, there has been some literature early on describing GIP as an obesogenic hormone. We believe this is clearly not the case. There has also been reports of GIP resistance and this has been clearly linked to hypoglycemia. So we believe by having GLP-1, together with the GIP component, we can actually reverse that GIP resistance. And I think that was an important component of being able to develop that dual agonist.

With respect to safety risks, we actually -- I can't think of a specific theoretic and safety risk with GIP. And everything we've seen from our adverse event profile is actually very consistent with the GLP-1 class. Obviously, I think these results will spur a lot of work in terms of GIP, mechanism of action biology. But at this point in time, we do not have any specific safety concerns that are related to GIP.


And next question comes from Jami Rubin with Goldman Sachs.

Jami Rubin

Just a couple, just first for clarification. You're giving us 12-week discontinuation rates but this is a 26-week efficacy study. Can you just reconcile those two? And then also just back to the 15 milligram dose, just curious your thoughts on that, because we did see the highest -- the greatest efficacy, the greatest weight loss, but also the highest GI side effects. Is this a workable dose? And if you could compare and contrast the dose titration differences between this study and your longer duration Phase 3 study, because presumably, we will get a better idea of the GI side effect profile through a different titration program. But I'm wondering if you could just talk about those differences? Thanks.

Brad Woodward

The discontinuations that we observed in the Phase 2B trial that we've shared here today, if it was due to an adverse event, it was more commonly during that early titration period, which was accelerated. So looking at 12-week data from the separate study that's registered on clinicaltrials.gov, we actually saw very low discontinuation during that titration period. So, we were able to get patients up to a 15 milligram dose inside of 12 weeks. So that level of information is reassuring. We have not yet posted the Phase 3 trials on clinicaltrials.gov or have we shared the exact titration plans for that. But we are encouraging and confident that with a slow stepwise titration that this could lead to a better tolerability profile overall.


And next from Chris Scott with JP Morgan.

Chris Scott

Just two here, maybe just sticking on the 15 milligram dose for a second since you do have that data in house. What are the levels of nausea and vomiting you're seeing with the titration? Can we think about those nausea rates kind of in line with some of the lower doses or Trulicity or are we still getting nausea and vomiting rates above those lower doses? My second question was on the CV outcome study. Should we think about design similar to REWIND with healthier patient population, or one that maybe looks more similar to some of the noble studies in more advanced patients? Thanks so much.

Brad Woodward

With the actual titration study that we've conducted, we're sharing the discontinuation rates today. We look forward to disclosing the full results of that trial in the near future at the beginning of next year. Regarding the cardiovascular outcome trial, I think what's important for the study is that it is a superiority trial. We're looking for major adverse cardiovascular event reduction. But within this study, I think 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’d be entirely secondary prevention or would include a balance of primary and secondary prevention.


And next question comes from Andrew Baum with Citi.

Andrew Citi

Given your comments over titration, should I see you taking both the 15 and the 10 milligram into Phase 3 development? And the second question and this really relates to your competition. You dropped your oxyntomodulin like agents due to underwhelming hyperglycemic effects, and there’s clearly a competitor out there that's pursuing that mechanism. Merck and Roche both have briskets, which have been dropped in development. So I guess the question is what is unique about yours which was problematic with the two other members of the class, which have already been dropped? Is it the levels of relative agonism, is it the binding epitope? Give us some idea of the unique characterization to help us understand the competitive risk that others seek to also replicate what you’ve achieved today?

Brad Woodward

To answer your first question around which doses we’re taking into Phase 3. Yes, I would confirm that the 10 milligram and 15 milligram, as well as the 5 milligram are going into Phase 3 for development. So that we have -- we do have confidence around the titration plans to achieve that level of dosing. And I’ll let Ruth to respond to the differentiation question.

Ruth Gimeno

Yes, let me tell you about this GLP-1, GIP dual agonist first. Our molecule is the first molecule that is biased toward GIP activity. We think that that is an important differentiator. We purposefully designed this molecule so we could fully engage the GIP receptor before we reach the dose limiting tolerability issues with GLP-1 receptor. I would point to that as probably the most likely hypothesis for difference between different molecules. I do want to point out that in this space, every agonist can be slightly different. These molecules also have differences in terms of pharmacokinetics by distributions and these could certainly contribute as well.

With respect to oxyntomodulin, we do have an oxyntomodulin molecule in Phase 1 clinical development and we believe that this is a separate class. We need to evaluate what it looks like in terms of efficacy and safety independently of this molecule.


Next we have Jason Gerberry with Bank of America.

Jason Gerberry

Just wanted to follow up on Chris Schott’s question. So the titration study, you were able to use a slower stepwise titration and get AEs 5%? Or was that discontinuation down the 5%? And was that something that you saw with 15 milligram? And then my second question is what your thoughts are in terms of initiating a Phase 3 obesity program?

Brad Woodward

So 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’ll continue to look at other opportunities more broadly. With respect to the titration, the comparator data here is that 12 weeks compared to 26 and the number that is shown for the Phase 2B trial is a discontinuation rate of 25% due to an adverse event at that endpoint at the end of the trial. So what gives us more confidence is the 12-week study had a discontinuation rate due to an adverse event of 5% with more slower stepwise titration. So those are the comparative numbers.


Next we have Geoff Meacham with Barclays.

Unidentified Analyst

This is Jason on for Geoff. Thanks so much for taking question and congratulations on the data. I've quick question regarding the discontinuation -- sorry to push on this. But once you reach steady state, so after that initial titration phase. Were the discontinuation rates and rates of adverse events still higher in the higher doses between the 10 and 15 or were they comparable? And then you mentioned in your press release about looking at other indications. I appreciate its early days. But is there some thought that there could be an indication potentially in NASH or renal functions alluding to your proposed indirect effects on Slide 6?

Brad Woodward

I will answer the first question around the discontinuation and then we will look to Dan or Enrique to speak to the other part with other indications. The discontinuation is I think what we would highlight again is that the discontinuations at 5 and 10 milligrams with still the 10 milligrams delivering a fairly strong response in A1c in weight. Those discontinuations in AE rates were very similar to what we see with dulaglutide, which was the active comparator in the trial. The discontinuation rates at the 15 milligram dose, I can confirm that the majority of those did occur during the early titration period. So, once patients are passed that period, we see that the tolerability does improve and we would expect discontinuations to decrease accordingly.

Dan Skovronsky

I'll take the question on other indications. I'll let Brad answer -- this is Dan. Right now, our focus is on the type 2 diabetes indications, we're really excited about potential of the new drug there. But of course we’re open to forming other potential applications with this molecule and certainly the data suggests where it’s at. We'll continue to think about that in the future.


We have a question from Umer Raffat with Evercore.

Umer Raffat

I think your slides mentioned the two, but just want to get more granularity on this, so that Phase 2 trial about 100 patients which completed early this summer, not the one that was reported today. I think you investigated an alternate dose titration strategy. Maybe can you tell us a bit more about what exactly that strategy is, what you learned and what the continuation of GI rates were? And then secondly and I think this came up earlier in the call as well, the antidrug antibody rate. What’s the neutralizing antibody rate on that? Thank you.

Brad Woodward

With the titration, we look forward to sharing more information about the titration study at a later time, as well as confirming what we will be utilizing for the Phase 3 program. I can confirm again that we've looked at different starting doses. We've looked at different steps. And what we have learned from this is that a slow stepwise titration of getting patients to that 15 milligram doses would improve the tolerability. So I do appreciate the question but we look forward to disclosing that information at a later time.

With respect to the antidrug antibodies, the presence of the antibodies was of low titers as I've shared. And we’re still evaluating and do not have full data yet with respect to the neutralizing antibody. Although, I think the important thing to recognize here is that with the titers being low and they're being not getting any PK or PD effect the presence of neutralizing, I would only tell part of the story, it's the neutralizing effects and other effects. Now this is not unique to this molecule, we have seen other approved GLP-1 receptor agonists that have known antidrug antibodies associated with them. So we look forward to sharing the neutralizing data once that is available at later disclosure and once we have that information.


We have Steve Scala with Cowen.

Steve Scala

Titration made temporary side effects, but can you confirm it has no impact on efficacy, either HbA1c reduction or weight loss, or is the efficacy diminished in some way? And then second question is I am surprised that in a diabetes update call, the REWIND trial hasn't been mentioned even if it confirm that the data is coming at the end of the year. The primary completion was in August and MACE is a pretty clear endpoint. I would imagine the data is within Lilly and being analyzed. So Enrique, are you as confident as ever that REWIND will be a successful trail? Thank you.

Ruth Gimeno

So, Brad, I guess will take first question and then we'll got Enrique respond to the REWIND question.

Brad Woodward

The titration algorithm being slow and stepwise, we think what's important in the Phase 3 design is that patients would be at a target dose for a required period of time to assess that A1c. But I think the regulators will expect that too, they were able to demonstrate differentiation of dose and improving benefit risk with higher doses. So that will be the expectation. So the answer is no. We would not expect the titration to have a negative impact on efficacy of the product.

Enrique Conterno

And on the REWIND, our perspective and views on REWIND have not changed from previous discussions. We of course are getting pretty close. And we expect that this quarter we will be basically disclosing top line results for that very important trial.


And we have Alex Arfaei with the BMO Capital Markets.

Alex Arfaei

If you look at the Novo Nordisk GIP, GLP-1 data, the A1c and weight loss benefits with that drug were primarily seen in patients with baseline A1c of less than 8.5%. Have you conducted any subgroup analysis to see if the benefits observed with your drug are consistent regardless of A1c? And following up on the obesity question, I am curious about that, because the weight loss looks like quite compelling given that if you have a profile that's at least similar to some glutide. I'm curious why not you're moving ahead with them more aggressively? And then finally, is there any reason that the Trulicity pen device cannot be used for this drug? Basically, is there any additional formulation work that still needs to be done? Thank you.

Ruth Gimeno

I'll take the Novo GIP, GLP molecule. We have not conducted a subgroup analysis to look for effects depending on baseline HbA1c. I would like to note that the baseline HbA1c was very typical to what we see in general Phase 2 diabetic studies. With respect to obesity, I'll let Brad comment. But I would like to point out, if you look at the molecular metabolism paper, we have MAT data in both obese and type 1 diabetic patients. And as you might expect, we do see even more weight loss in the obese population.

Brad Woodward

I'll answer the last question first and that's just to confirm that we are looking to begin the Phase 3 trials with an autoinjector, single use autoinjector. And we really want to replicate the Trulicity experience here and have a positive patient experience from the trials and eventually, commercially when this comes to market. With respect to the obesity question, I think we have addressed that and we're encouraged by the response that we're seeing in type 2 diabetes population and the degree of weight loss that we've seen with 12.7% on average at the highest dose. We look forward to being able to share more information around our plans for this molecule. And I'll let you know that we are evaluating other opportunities with this at the current time.


It's from [indiscernible] with Guggenheim Partners.

Unidentified Analyst

Filling in here for Seamus Fernandez, couple of quick ones from me, I guess the first one is. Are there any opportunities here to extend to every other week or even monthly dosing profile for the drug? And the second question, how do the cases of acute pancreatitis compared to dulaglutide or other GLP-1 data from other Phase 2? Thanks.

Brad Woodward

So, for the first question around different dosing schedules for this, we think that the molecule is really engineered and designed to have half life that would support once weekly dosing. So that's our intent to bring it forward into Phase 3 dosing, the half life is five days. And at this point, we don’t think that that would support every other week dosing. With respect to the events of pancreatitis, as I shared at the 50 days 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 CT scan and radiographic imaging, and there was no confirmation of pancreatitis with the radiographic imaging. The second case was in a patient that had been off of study drug for almost a month and a half, and developed cholecystitis and secondary acute pancreatitis. So that's what we know from this. 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 seemed consistent with what we've seen from dulaglutide with our dual agonist.


[Operator Instructions] We have no further questions at this time.

Kristina Wright

Okay, we have no more questions. Enrique, you will go ahead and wrap up.

Enrique Conterno

As I said in my opening remarks, we set a high bar for these trials and we've hit the mark. We look forward to keeping you updated on the developing for our dual GIP, GLP-1 receptor agonist, as well as the rest of our diabetes pipeline and portfolio. We appreciate your participation in today's call. We hope that this call was helpful in understanding the opportunity ahead for us for Lilly Diabetes for Lilly and the potential to bring the next generation diabetes treatment to patients.

Please follow-up with our Investor Relations team if you have questions we have not addressed on the call. Enjoy the rest of your day. Thank you.


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