Septerna Abandons Lead Asset SEP-786 Due to Unexpected Side Effects

Septerna, a biotech company focused on G protein-coupled receptors (GPCRs), has announced the discontinuation of its lead asset SEP-786 following unexpected adverse events in a phase 1 clinical trial. The decision comes just four months after the company's initial public offering (IPO) and has led to a significant drop in its stock price.

Clinical Trial Results and Safety Concerns

Septerna was conducting a phase 1 trial of SEP-786, an oral small molecule agonist of the parathyroid hormone 1 receptor (PTH1R), in healthy volunteers. The study revealed two unanticipated grade 3 events of elevated unconjugated bilirubin in the multiple ascending dose portion of the trial. While these events were not associated with increased levels of liver enzymes ALT, AST, and GGT, the company decided to discontinue dosing for the affected participants.

Jeffrey Finer, M.D., Ph.D., CEO of Septerna, stated, "We observed early signals of on-target pharmacological activity with SEP-786, with increases in serum calcium and corresponding decreases in endogenous PTH, reinforcing our commitment to developing an oral small molecule PTH1R agonist for hypoparathyroidism."

Company Response and Future Plans

Despite the setback, Septerna remains committed to its GPCR-focused approach. The company plans to:

1. Conduct non-clinical studies to identify the underlying mechanism for the adverse events.
2. Accelerate the development of next-generation PTH1R agonists from its portfolio of follow-on compounds.
3. Advance SEP-631, an MRGPRX2 negative allosteric modulator for mast cell diseases, into clinical trials later this year.

Jae Kim, M.D., Chief Medical Officer at Septerna, emphasized that the company's extensive preclinical research, including 28-day toxicology studies, had not predicted the risk of elevated bilirubin. He added, "We will expeditiously progress our PTH1R program with a next-generation candidate."

Financial Impact and Outlook

The news of SEP-786's discontinuation had an immediate impact on Septerna's stock price, which dropped 65% from $12.96 to $4.48 when markets opened on Tuesday. This decline represents a significant setback for the company, which had launched its IPO at $18 per share in October and maintained a strong stock performance throughout 2024.

Despite this setback, Septerna reports a strong financial position. The company raised $302.6 million in its IPO and had $137.5 million in cash and equivalents as of September. With these resources, Septerna expects its cash to last into at least the second half of 2027, providing ample runway for its revised development plans.