RAP-219 Meets Key Endpoints in Acute Bipolar Mania Trial
Key Clinical Summary
- RAP-219 significantly improved manic symptoms compared with placebo after 3 weeks in a United States phase 2 trial enrolling 253 adults with bipolar I disorder.
- Treatment-emergent adverse events occurred in 51.6% of RAP-219 recipients and 52.8% of placebo recipients; all were mild or moderate in severity.
- Manufacturer Rapport Therapeutics plans to initiate two phase 3 trials in the second half of 2027.
Investigational RAP-219 met the primary and secondary endpoints in a randomized, double-blind, placebo-controlled trial of adults experiencing acute bipolar mania, manufacturer Rapport Therapeutics announced on October 20, 2026.
The company reported a 3.1-point least squares (LS) mean improvement over placebo on the Young Mania Rating Scale (YMRS) after 3 weeks, alongside comparable overall adverse event rates between treatment groups.
Study Findings
The inpatient trial enrolled adults with baseline YMRS scores of at least 25. Participants were randomized to RAP-219 at 0.75 milligrams once daily after titration or placebo for 3 weeks.
Treatments indicated for bipolar disorder, anxiolytics, and hypnotics were discontinued during screening. Lorazepam was permitted as rescue medication at protocol-defined doses.
At week 3, LS mean reductions in YMRS total scores (baseline = 36.9) were 15.4 points with RAP-219 and 12.3 points with placebo, a statistically significant difference (p = .045). Investigators saw improvement in all screener items, including improvements in irritability, thought content, disruptive-aggressive behavior, and sexual interest.
RAP-219 also demonstrated significantly significant improvement over placebo in mania severity score as measured by the Clinical Global Impression–Bipolar Version, meeting the trial’s secondary endpoint (0.4; p = 0.024).
No serious adverse events occurred during the trial. Mild and moderate treatment-emergent adverse effects were reported in both groups (RAP-219 = 51.6% vs placebo = 52.8%). Adverse events prompted discontinuation in 3.2% of RAP-219 recipients versus 0.8% of placebo recipients. The most common adverse event was agitation, which tended to happen during the first week of treatment and lasted approximately 2 days in both groups. However, the company reported that in 80% of affected patients, these adverse effects were considered unrelated to treatment.
Other common, treatment-related adverse events included insomnia, restlessness, anxiety, headache, and nausea.
Expert Commentary
“In this proof-of-concept study, RAP-219 demonstrated statistically significant improvement across measures of mania symptoms as well as a favorable tolerability profile,” said Jeffrey Sevigny, MD, chief medical officer, Rapport Therapeutics.
Sevigny said insights from the study would guide optimization of the phase 3 design and emphasized the role of tolerability in treatment continuation.
Rapport plans to meet with the US Food and Drug Administration in the first quarter of 2027 to discuss the findings and registrational trial design. Additional phase 2 results, including post-treatment safety data, will be presented at a future medical meeting.
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