Memorandum

Amylin/Lilly/Alkermes announce extremely positive DURATION-3 superiority data; potential for major paradigm shift lies ahead – July 20, 2009

On July 20, 2009, Amylin/Eli Lilly/Alkermes announced very encouraging data from a 26-week open- label, head-to-head study (n = 467) comparing exenatide once weekly (EQW) to Lantus (Sanofi’s insulin glargine) in patients with type 2 diabetes. Patients randomized to EQW experienced an A1c reduction of-1.5% compared to -1.3% observed in the Lantus arm, with a baseline A1c of 8.3% for both arms. Patients in the EQW arm also experienced a statistically significant difference in weight change compared to Lantus (-5.8 lbs weight loss for EQW versus +3.1 lbs gain for Lantus respectively) and significantly fewer episodes of confirmed hypoglycemia (4% in the EQW group versus 19% in the Lantus group for patients on a metformin background and 20% versus 44% for patients on a metformin + sulfonylurea background, respectively). The most frequently reported adverse events were upper respiratory infections occurring in both treatment arms, and gastrointestinal events occurring in the EQW arm. From our view, the most important data from this trial was the nausea rate, which as we understand it was approximately 13%, significantly lower than nausea rates associated with Byetta. Nausea data for Lantus were not reported but we assume were low. The EQW nausea rate is comparable to the 14% nausea rate seen with liraglutide in LEAD-5. We are very excited about these data, as this is the first study to use one of the most aggressive insulin titrating regimens in comparing a GLP-1 to Lantus. We look forward to seeing the published data, which will be presented at a major upcoming medical meeting – we assume the company would submit this to ADA for 2010, which would be exciting to announce around the time of launch, potentially with a publication. We had originally become most excited about EQW when we heard the plans for the DURATION studies last year; we assumed that if the company was willing to go head-to-head versus the most commercially and clinically successful therapies, especially Lantus, they must have extreme confidence in the compound – having now seen multiple DURATION studies, we understand why.

  • Amylin announced encouraging data from a head-to-head study comparing exenatide once weekly to Lantus in patients with type 2 diabetes. Eligible subjects had previously failed to achieve adequate glucose control using metformin alone or in combination with a sulfonylurea. Patients were randomized to either weekly doses of 2 mg EQW or daily injections of Lantus at doses dependent on blood glucose levels. The study’s primary endpoint was A1c reduction with secondary endpoints including body weight reduction, cardiovascular health, hypoglycemia, and adverse events.
  • Notably, this study used an aggressive insulin titrating regimens in comparing EQW to Lantus. The DURATION-3 study used an insulin titration regimen with a target fasting plasma glucose (FPG) of 72-100 mg/dl. This aggressive titration regimen was the same used in the Lantus clinical trial INITIATE, which resulted in the greatest A1c reduction seen with Lantus. Previous head-to-head trials involving Lantus an a GLP-1 have used a less aggressive target FPG of <100 mg/dl. This fact makes the statistically fewer episodes of hypoglycemia and the A1c reduction of EQW even more impressive.
  • We are very excited with these data, as this is the only study since LEAD-5 to compare GLP-1 efficacy with insulin analogs. The current ADA treatment algorithm for type 2 diabetes favors insulin administration over GLP-1 use in patients who have failed previous treatments. However, these data illustrate that long-acting GLP-1s provide superior weight reduction and reduced incidence of hypoglycemia compared to Lantus. We believe that such data may increase the popularity of prescribing long-acting GLP-1s over insulin analogs in insulin- independent patients with type 2 diabetes, in addition to the convenience of a once weekly injection compared to daily injections of insulin.
  • We believe FDA would find these data useful. Given what a major problem obesity is in the US, we must believe FDA would find the combination of A1c reduction, weight loss, and convenience powerful. With nine million people with type 2 diabetes in the US alone failing their glycemic targets, and with the new Obama administration speaking frequently about the importance of prevention (including we assume, prevention of costly diabetes complications), we would assume the advisory committee would term this therapy transformative and that that characterization would aid the compound when discussions of approval arise.
  • The only piece of data left from a clinical perspective is how patients respond to the needle (23 gauge) and pen; the 90% study completion rate was a very good sign on that front. From a commercial perspective, the major questions in our view relate to regulatory pathway and physician acceptance. On the regulatory side, at the most recent FDA advisory committee meeting, we saw in spades that the committee seems to care about transformative compounds; on that note, EQW’s time may well have come. From a physician perspective, this seems much easier than Byetta and to have a much more attractive side effect profile, which should make a major difference. We’re staying very tuned.

-- by Mark Sorrentino, Sanjay Trehan, and Kelly Close