Septerna Halts SEP-786 Trial, Focuses on Next-Gen Oral PTH1R Agonist

Septerna, Inc., a company at the forefront of GPCR drug discovery, has decided to halt its Phase 1 clinical trial of SEP-786, following unexpected findings of elevated unconjugated bilirubin levels in participants. SEP-786 is an oral medication targeting the parathyroid hormone 1 receptor (PTH1R), developed for treating hypoparathyroidism. The trial, which involved healthy volunteers, was discontinued after two serious but reversible Grade 3 bilirubin elevation events occurred. These incidents did not coincide with rises in liver enzymes such as ALT, AST, and GGT, and no liver injuries or other adverse health conditions were reported across all participants.

Dr. Jeffrey Finer, CEO and co-founder of Septerna, explained that despite early indications of the drug’s pharmacological activity, the decision to discontinue was made after thorough evaluation. The compound showed potential by increasing serum calcium and reducing endogenous PTH levels, but the unexpected bilirubin issues prompted caution. The company remains committed to its PTH1R agonist program, which includes developing a variety of chemically distinct compounds. Septerna aims to choose a next-generation candidate to push forward into the clinic later this year to sustain the momentum of this program.

Preclinical toxicology studies over 28 days had shown that SEP-786 was generally well-tolerated and did not predict the risk of bilirubin elevation. In light of the Phase 1 trial results, Septerna has commenced non-clinical studies to identify the cause of these unexpected effects. Dr. Jae B. Kim, Chief Medical Officer of Septerna, reinforced the company’s commitment to advancing their PTH1R program with new candidates. He also mentioned that preparations are underway for SEP-631, a selective oral molecule modulator for mast cell diseases, which is expected to begin clinical trials later this year.

As of September 30, 2024, Septerna reported having $137.5 million in cash, cash equivalents, and marketable securities. Following an IPO in October 2024 that raised $302.6 million, the company expects its financial resources to support operations until at least the second half of 2027.

Septerna, based in South San Francisco, is pioneering the development of GPCR therapies using its proprietary Native Complex Platform™. This platform is designed to unlock the potential of GPCR drug development, initially focusing on three therapeutic areas: endocrinology, immunology and inflammation, and metabolic diseases. The company's foundation is rooted in extensive expertise in biochemistry, structural biology, and pharmacology, aiming to transform treatment approaches through innovative drug discovery.