Terns Pharmaceuticals halts oral GLP-1 drug TERN-601 after mixed Phase 2 results

Terns Pharmaceuticals said on Oct. 21 that it will stop developing TERN-601, an experimental once-daily oral GLP-1 pill for obesity, after 12-week mid-stage trial data showed weight loss the company called too modest and safety concerns that included liver enzyme elevations ^[2]. The company's shares fell more than 16% in extended trading after the announcement ^[2].

Modest weight loss and a high dropout rate

In the Phase 2 trial, TERN-601 helped patients lose up to 4.6% more weight than those on placebo over 12 weeks, according to the company ^[2]. Terns said that was not enough to justify further investment ^[2].

"The threshold for a truly differentiated oral GLP-1RA therapy — one that delivers safety, tolerability and efficacy — is high," Chief Executive Officer Amy Burroughs said, adding that the data "did not meet this threshold and likely preclude further development" ^[2].

About 11.9% of the 134 people in the study stopped taking the drug because of side effects, mostly gastrointestinal problems such as nausea and vomiting ^[2]. The company said those side effects were generally mild or moderate ^[2].

A liver signal

Three patients had serious liver enzyme elevations after treatment ended ^[2]. Two of those cases were linked to the drug, including one confirmed by a liver biopsy ^[2]. Terns said the liver issues were unexpected, because earlier studies had not shown similar problems ^[2].

Andy Hsieh, an analyst at William Blair, said he was not surprised by the liver toxicity signal. He noted that TERN-601 shares a similar chemical structure, known as a pharmacophore, with Pfizer's danuglipron and lotiglipron, two obesity drugs Pfizer discontinued over liver safety concerns ^[2].

Terns also said it does not plan to invest further in metabolic disease ^[2]. It will focus instead on its lead cancer drug TERN-701, which targets chronic myeloid leukemia, a type of blood cancer ^[2].

Why it matters for patients

TERN-601 was an experimental drug in mid-stage testing, not an approved medicine, so this decision does not change the availability, labeling or tested safety record of GLP-1 drugs already on the US market, such as semaglutide (Ozempic, Wegovy, Rybelsus) and tirzepatide (Mounjaro, Zepbound). Those are different molecules and were not part of this trial ^[2].

For people who have been waiting to see whether an oral GLP-1 pill reaches the market, the news removes one candidate from the pipeline. The results also illustrate the three things companies and regulators weigh before an obesity drug advances: how much more weight people lose than those on placebo, how many stop treatment because of side effects, and whether lab tests turn up organ-related problems ^[2].

The timing of the liver cases is notable because the patients were monitored after the 12-week treatment period ended, not only while they were taking the drug ^[2]. It has not been reported whether those patients' liver enzymes returned to normal, whether they needed treatment, or which doses they received.

It also has not been reported whether these liver findings have any bearing on other experimental oral GLP-1 drugs in development.

What happens next

Terns said it will not invest further in metabolic disease and will concentrate on TERN-701 for chronic myeloid leukemia ^[2]. The company has not said when it will publish full trial results or whether it will seek a partner to continue work on TERN-601; those plans have not been disclosed ^[2].