Danuglipron

Terns Pharmaceuticals has shelved its investigational obesity pill after the drug was far less efficacious in a mid-stage trial than in earlier studies. The California biotech’s shares $TERN opened down about 11% on Wednesday morning, the day after the data were released . After three months of treatment, the GLP-1 agonist, codenamed TERN-601, cut the weight of patients with obesity by a statistically significant margin over placebo. But the magnitude of the weight loss was poor. The top dose — 750 mg once a day — produced a weight reduction of just 3.0 percentage points over placebo. A lower dose — 500 mg per day — was actually better than the high dose. Patients using a fast titration scheme to reach this dose saw their weight drop by 4.6 points over placebo, whereas those upping their dose to 500 mg more slowly had weight loss of 3.6 points more than placebo. These findings come as a shock after the pill’s highly promising showing in Phase 1 . Back in September 2024 , Terns said a 740 mg daily dose cut patients’ weight by 4.9 percentage points more than placebo after patients took the pill for just a month. In the mid-stage trial, safety was also less than ideal. Of the 134 participants treated with TERN-601, 11.9% quit treatment because of adverse events, and a further 8.2% had to have their dose modified. Most side effects were gastrointestinal. Three patients had grade 3 liver enzyme elevations during the post-treatment follow-up stage of the trial, and two of those patients, both of whom were in the 500 mg treatment arm, had profiles consistent with drug-induced liver injury. One had a liver biopsy, which supported the liver injury theory. The third patient with high liver enzymes had gallstones, so the investigator felt that the increase in liver enzymes was unlikely to be drug-related. However, drug-induced liver injury could not be definitively ruled out, according to Terns. Similar elevations were not reported in earlier trials, but analysts from Jefferies pointed out that TERN-601 has structural similarities to Pfizer’s GLP-1 pill danuglipron , which the drugmaker culled in April because of the risk of liver injury. Terns CEO Amy Burroughs said that the limp data “likely preclude further development,” given how high the threshold for a differentiated oral GLP-1 is. Terns will now back away entirely from the metabolic space. Its new lead candidate is a BCR-ABL inhibitor called TERN-701, which is in a Phase 1 trial in chronic myeloid leukemia. Terns believes it could be best-in-class, and said it expects to have data this quarter. TERN-601’s performance in Phase 2 points to the grave difficulty of developing a GLP-1-based pill. Eli Lilly’s orforglipron could soon be approved for obesity, but its Phase 3 data came in weaker than expected. And like Terns, Viking Therapeutics had a Phase 2 disappointment for its pill on both efficacy and safety, though the weight loss produced by its GLP-1/GIP agonist was higher than what Terns’ drug achieved. Then there’s Pfizer which, as well as discontinuing danuglipron, quietly dropped a Phase 1-stage GLP-1 pill codenamed PF-06954522 in August. It did pick up a new oral candidate via its purchase of Metsera last month, though that drug is not yet in the clinic. Regor Therapeutics has kept its obesity pill in development despite its efficacy in Phase 2 looking similar to TERN-601’s. (Regor’s drug had milder side effects, though.) And despite the challenges, major companies like Roche, AstraZeneca, Merck and Structure Therapeutics — to say nothing of obesity leaders Novo Nordisk and Eli Lilly — continue to work on weight loss pills.