Septerna, Inc. (Nasdaq: SEPN) announced today the discontinuation of its Phase 1 clinical trial evaluating SEP-786, an oral small molecule agonist targeting the parathyroid hormone 1 receptor (PTH1R) for hypoparathyroidism treatment. The decision follows the occurrence of unexpected safety signals in the multiple-ascending dose (MAD) portion of the study.
Two participants in the MAD cohort experienced severe (Grade 3) elevations in unconjugated bilirubin levels, though notably without corresponding increases in liver enzymes ALT, AST, and GGT. While the elevated bilirubin levels proved reversible upon discontinuation of treatment, and no serious adverse events were reported, the company opted to terminate the trial to prioritize patient safety.
Dr. Jeffrey Finer, CEO and co-founder of Septerna, noted that despite the setback, the trial demonstrated promising pharmacological activity. "We observed early signals of on-target pharmacological activity with SEP-786, with increases in serum calcium and corresponding decreases in endogenous PTH," he stated, emphasizing the company's continued commitment to developing oral PTH1R agonists.
Unexpected Safety Signal Emerges
The safety concerns came as a surprise, as Dr. Jae B. Kim, Chief Medical Officer of Septerna, explained: "Our extensive preclinical research and toxicology studies did not predict the risk of this off-target effect of SEP-786." The company has initiated non-clinical studies to investigate the mechanism behind the observed bilirubin elevations.
The 28-day preclinical toxicology studies had shown SEP-786 to be generally well-tolerated, with no predicted risk of bilirubin elevation, highlighting the challenges in translating preclinical safety data to human trials.
Strategic Path Forward
Septerna maintains a robust pipeline of alternative PTH1R agonist candidates with distinct chemical structures from SEP-786. The company plans to accelerate the development of a next-generation candidate later this year, leveraging its Native Complex Platform™ technology.
Additionally, Septerna continues to advance its broader pipeline, including SEP-631, a selective oral small molecule MRGPRX2 negative allosteric modulator being developed for mast cell diseases, with clinical trials planned to begin later this year.
Financial Position Remains Strong
Following its successful IPO in October 2024, which raised $302.6 million in net proceeds, combined with existing resources of $137.5 million as of September 30, 2024, Septerna maintains a strong financial position. The company projects its current cash reserves will support planned operations into at least the second half of 2027, providing ample runway for advancing its pipeline programs.
