Septerna, Inc. Reports Strong Phase 1 Results For Oral MRGPRX2 NAM SEP-631, Sets Plan For Phase 2 Trials In Chronic Spontaneous Urticaria

Septerna, Inc., a clinical-stage biotechnology company developing oral small-molecule medicines that target GPCR pathways, announced positive results from its Phase 1 clinical study of SEP-631. This investigational therapy is a selective oral negative allosteric modulator of the receptor MRGPRX2, which plays a key role in mast-cell-driven diseases. Based on these findings, the company plans to move SEP-631 into Phase 2 development for chronic spontaneous urticaria (CSU) and continue studying its potential in other related conditions.

Jae Kim, M.D., the Chief Medical Officer of Septerna, explained that the results are an important milestone not only for SEP-631 but also for the company’s Native Complex Platform, which helps recreate functional GPCR complexes outside of cells for more accurate drug discovery. He noted that the strong suppression of icatibant-induced skin wheals seen in the study is consistent with what the team observed in preclinical research. This provides clinical confirmation that SEP-631 effectively targets the MRGPRX2 pathway. He added that the consistency of the results suggests that SEP-631 could become a differentiated oral treatment option for patients with mast-cell-related diseases, and the company is now focused on advancing the program into Phase 2 to bring meaningful benefits to patients.

Phase 1 of the study included healthy volunteers and was designed as a randomized, double-blind, placebo-controlled trial. It involved single-ascending dose groups, multiple-ascending dose groups, and a food-effect assessment. Researchers evaluated safety, tolerability, pharmacokinetics, and pharmacodynamic activity.

Across all dose levels, SEP-631 was well-tolerated. The rate of side effects was similar to placebo, and there were no severe or serious adverse events. Lab results and ECG findings showed no clinically meaningful abnormalities. Pharmacokinetic data indicated that SEP-631 has a half-life of about 24 hours, supporting once-daily oral dosing. Food had no meaningful impact on drug exposure, which means patients would not require food-related dosing restrictions.

Pharmacodynamic activity was measured using an icatibant-induced skin wheal test, a commonly used approach for evaluating mast cell activation and drug target engagement. Advanced short-wave infrared imaging was used to capture accurate measurements. SEP-631 showed strong and consistent suppression of wheal formation at the evaluated doses. 

Complete inhibition was observed at doses as low as 10 mg once daily when tested with a 10 µg/mL icatibant challenge. With the higher 100 µg/mL challenge, the inhibition was dose-dependent, with near-complete suppression achieved at 90 mg and 200 mg doses. These results match the drug’s expected mechanism and show clear evidence of effective MRGPRX2 pathway blockade in humans.

Septerna plans to begin a Phase 2b trial for SEP-631 in chronic spontaneous urticaria in the second half of the year, following the completion of ongoing long-term toxicology studies. This planned study will be global, randomized, double-blind, and placebo-controlled. It will evaluate once-daily SEP-631 in adults with moderate to severe CSU who continue to have symptoms despite using second-generation antihistamines. 

After this study starts, the company also intends to initiate an open-label trial in chronic inducible urticaria, focusing specifically on symptomatic dermatographism. In addition to urticaria, Septerna is exploring the potential of SEP-631 in other mast-cell-driven diseases where MRGPRX2 is thought to play a role. The conditions being prioritized for further evaluation include atopic dermatitis, interstitial cystitis, migraine, and asthma.