SEP-786

Trial decision follows unanticipated events of elevated unconjugated bilirubin levels Company advancing multiple next-generation PTH1R agonists with distinct and unrelated chemical structures relative to SEP-786 Feb. 18, 2025 -- Septerna, Inc. (Nasdaq: SEPN), a clinical-stage biotechnology company pioneering a new era of GPCR drug discovery, today announced its decision to discontinue the Phase 1 single- and multiple-ascending dose (SAD/MAD) clinical trial of SEP-786 in healthy volunteers. SEP-786 is an oral small molecule agonist of the parathyroid hormone 1 receptor (PTH1R) being developed for the treatment of hypoparathyroidism. Septerna’s decision follows the observation of two unanticipated severe (Grade 3) events of elevated unconjugated bilirubin in the MAD portion of the Phase 1 trial, both of which were without elevations in ALT, AST, and GGT liver enzyme levels. Dosing was discontinued for both study participants, and the bilirubin elevations were reversible. Importantly, there were no events of liver injury, cholestasis, or hemolysis across all participants, and there were no serious adverse events (SAEs) in the Phase 1 trial. “After careful evaluation of SEP-786 and in the context of our robust PTH1R agonist program, we’ve made the decision to discontinue the SEP-786 Phase 1 trial. 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,” said Jeffrey Finer, M.D., Ph.D., CEO and co-founder of Septerna. “Strategically, for each of our programs, we identify a diverse portfolio of follow-on compounds that are chemically distinct. We have multiple attractive PTH1R agonists from which we plan to select a next-generation candidate to accelerate toward the clinic later this year to quickly regain momentum with our PTH1R program.” In completed 28-day preclinical toxicology studies, SEP-786 was generally well-tolerated, without predicted risk of bilirubin elevation. In response to these Phase 1 events, Septerna has initiated non-clinical studies to investigate the underlying mechanism behind the observed effect. “Our extensive preclinical research and toxicology studies did not predict the risk of this off-target effect of SEP-786,” said Jae B. Kim, M.D., Chief Medical Officer of Septerna. “We plan to expeditiously progress our PTH1R program with a next-generation candidate. In addition, we are on-track with SEP-631, our selective oral small molecule MRGPRX2 negative allosteric modulator for mast cell diseases, which we are preparing for clinical initiation later this year. We look forward to sharing more on our progress in the future.” The Company’s cash, cash equivalents, and marketable securities totaled $137.5 million as of September 30, 2024. Together with the $302.6 million in net proceeds from the company’s IPO completed in October 2024, Septerna expects its current cash position to support its planned operations into at least the second half of 2027. Septerna, Inc. is a clinical-stage biotechnology company pioneering a new era of GPCR drug discovery powered by its proprietary Native Complex Platform™. Its industrial-scale platform aims to unlock the full potential of GPCR therapies and has led to the discovery and development of its deep pipeline of oral small molecule product candidates focused initially on treating patients in three therapeutic areas: endocrinology, immunology and inflammation, and metabolic diseases. Septerna was launched by preeminent drug discovery company builders and scientific leaders in the biochemistry, structural biology, and pharmacology of GPCRs. For more information, please visit www.septerna.com. The content above comes from the network. if any infringement, please contact us to modify.