Lilly and Novo Bet on Amylin Drugs to Extend Obesity Treatment Beyond GLP-1s

In a Phase 2 trial in patients with obesity and Type 2 diabetes, people receiving the highest-dose combination lost an average of 23.3% of their body weight at 48 weeks, compared with 14.8% for those taking only a high dose of tirzepatide. The figures came from an efficacy analysis that assumed patients remained on treatment. The trial was relatively small, and Lilly will need to confirm the results in Phase 3 trials that are set to begin later this year.

Benjamin Bikman, a professor at Brigham Young University and an expert on metabolic health and insulin resistance, called the results encouraging. He said adults with Type 2 diabetes typically lose less weight on these therapies than those without diabetes. Bikman also said the combination could help patients who started on tirzepatide alone but saw their weight loss plateau.

Lilly is developing eloralintide as both a standalone treatment and as part of the combination. Leerink Partners analyst David Risinger forecasts $23.2 billion in annual sales for Lilly's eloralintide products by the end of 2035. He expects the standalone drug to launch first in 2029, followed by the combination in 2030. Risinger told CNBC that millions of people, potentially more than 10 million, have tried GLP-1s and failed because of efficacy, tolerability, or genetic factors, and he sees the amylin analog as a major new alternative both as monotherapy and combination therapy. He sees greater potential for standalone eloralintide because of the large independent patient pool.

Lilly still sees an opportunity for pairing the medications. Ken Custer, president of Lilly Cardiometabolic Health, said in an interview that patients may not get what they need from a drug like tirzepatide or from eloralintide on its own. Tolerability remains a concern. In the trial, 10.8% to 27% of patients taking both drugs discontinued treatment due to side effects, depending on the dose, compared with 2.9% of those on tirzepatide alone. Dr. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women's Hospital, said 27% is not a good number. Bikman said tolerability in Phase 3 will be as important as efficacy because a therapy is only effective if patients can remain on it.

Novo has spent years pursuing a similar strategy. Its experimental amylin-based drug cagrilintide has shown meaningful weight loss as a standalone treatment in a late-stage trial. Combining it with semaglutide, together called CagriSema, has produced even greater weight loss in clinical studies. CagriSema is expected to launch early next year, followed by standalone cagrilintide and a higher-dose version of CagriSema in 2028. Novo is also developing amycretin, or zenagamtide, a single molecule targeting both GLP-1 and amylin for obesity and Type 2 diabetes. The Danish drugmaker is testing it as a once-weekly injection and a daily oral tablet, and the drug showed promising Phase 2 results earlier this year.

The first and so far only amylin therapy was approved in the U.S. more than two decades ago as an add-on mealtime injection for people with diabetes who use insulin. Its adoption was limited in part because it required multiple injections a day. New therapies are designed to target the amylin pathway in ways that may be easier to use and more effective.