8-K: Septerna Halts Phase 1 Trial of SEP-786, Shifts Focus to Next-Generation PTH1R Agonist

Septerna discontinues its Phase 1 clinical trial of SEP-786 due to unexpected safety events and plans to advance a next-generation PTH1R agonist.

Summary

• Septerna, Inc. has decided to discontinue the Phase 1 clinical trial of SEP-786, an oral small molecule agonist of the parathyroid hormone 1 receptor (PTH1R) being developed for hypoparathyroidism.
• The decision was prompted by two severe (Grade 3) events of elevated unconjugated bilirubin in the multiple-ascending dose (MAD) portion of the trial.
• No liver injury, cholestasis, or hemolysis were observed, and there were no serious adverse events (SAEs) in the Phase 1 trial.
• Septerna plans to advance a next-generation PTH1R agonist towards the clinic later this year.
• The company had $137.5 million in cash, cash equivalents, and marketable securities as of September 30, 2024.
• Combined with $302.6 million in net proceeds from the IPO in October 2024, Septerna expects its cash position to support planned operations into at least the second half of 2027.
• Septerna is also preparing to initiate a clinical trial for SEP-631, a selective oral small molecule MRGPRX2 negative allosteric modulator for mast cell diseases, later this year.

Sentiment

Score: 5

Explanation: The news is mixed. The discontinuation of the trial is negative, but the company is well-funded and has other programs in development. The sentiment is neutral.

Positives

• Early signals of on-target pharmacological activity were observed with SEP-786.
• Septerna has multiple attractive PTH1R agonists in its pipeline.
• The company is well-funded, with cash runway into at least the second half of 2027.
• Septerna is on track to initiate a clinical trial for SEP-631 later this year.

Negatives

• The Phase 1 trial of SEP-786 was discontinued due to unexpected severe adverse events.
• Two participants experienced Grade 3 elevated unconjugated bilirubin levels.
• Preclinical toxicology studies did not predict the risk of bilirubin elevation.

Risks

• The discontinuation of the SEP-786 trial may delay the development of a treatment for hypoparathyroidism.
• Unexpected safety issues may arise with other product candidates.
• Clinical trials may not be successful.
• The company's cash runway is dependent on its ability to manage expenses and achieve milestones.

Future Outlook

Septerna plans to select a next-generation PTH1R product candidate to accelerate toward the clinic later this year and initiate a clinical trial for SEP-631 later this year. The company expects its current cash position to support its planned operations into at least the second half of 2027.

Management Comments

• 'We observed early signals of on-target pharmacological activity with SEP-786... reinforcing our commitment to developing an oral small molecule PTH1R agonist for hypoparathyroidism,' said Jeffrey Finer, M.D., Ph.D., chief executive officer and co-founder of Septerna.
• 'We plan to expeditiously progress our PTH1R program with a next-generation candidate,' said Jae B. Kim, M.D., Chief Medical Officer of Septerna.

Industry Context

The discontinuation of SEP-786 highlights the risks inherent in drug development, particularly in early-stage clinical trials. The company's pivot to next-generation compounds and focus on other programs demonstrates a strategy to mitigate risk and maintain momentum.

Comparison to Industry Standards

• Many biotechnology companies experience setbacks in clinical trials, and Septerna's response of shifting focus to other candidates is a common strategy.
• Companies like Amgen and Ascendis Pharma are also developing treatments for hypoparathyroidism, making it a competitive landscape.
• The cash runway of Septerna into the second half of 2027 is relatively strong compared to other clinical-stage biotech companies, providing financial flexibility.

Stakeholder Impact

• Shareholders may be concerned about the discontinuation of the SEP-786 trial.
• Patients with hypoparathyroidism may face a delay in the development of a new treatment option.
• Employees may experience uncertainty as the company shifts its focus.

Next Steps

• Septerna plans to select a next-generation PTH1R product candidate to accelerate toward the clinic later this year.
• Septerna plans to initiate a clinical trial for SEP-631 later this year.
• Septerna will conduct non-clinical studies to investigate the mechanism behind the observed bilirubin elevation.

Key Dates

Keywords

SEP-786, PTH1R agonist, hypoparathyroidism, clinical trial, bilirubin, Septerna, SEP-631, MRGPRX2, mast cell diseases, GPCR, biotechnology