Rapport Therapeutics Announces Positive Results for RAP-219 in Bipolar Mania Trial

Rapport Therapeutics, a clinical-stage biotechnology company based in Boston and San Diego, announced positive results from its Phase 2 trial of RAP-219 for the treatment of bipolar mania. The trial, conducted in the United States, involved 253 adults with bipolar I disorder experiencing an acute manic episode (YMRS≥25 at baseline). During the screening period, all treatments indicated for bipolar disorder and anxiolytics and hypnotics were discontinued. Lorazepam was allowed as a rescue medication at protocol-defined doses, and its use required an adverse event (AE) to be recorded, regardless of whether the symptom(s) were judged to be due to a pre-existing condition.

Eligible patients received 0.75 mg of RAP-219 once daily (following a two- or four-day titration) or placebo for three weeks in an inpatient setting. Mean baseline YMRS total score was 36.9 in the RAP-219 arm and 35.8 in the placebo arm. The trial met its primary endpoint, with RAP-219 achieving a 3.1-point least squares (LS) mean improvement over placebo in YMRS total score at Week 3 (p=0.045). RAP-219, treated patients had an LS mean decrease of 15.4 points in YMRS total score at Week 3 from a baseline of 36.9. All 11 items measured by the YMRS improved on RAP-219 compared to placebo at Week 3, with improvements in irritability, thought content, disruptive-aggressive behavior, and sexual interest reaching nominal significance (p<0.05).

The trial also demonstrated a statistically significant improvement in mania severity score versus placebo at Week 3 as measured by the Clinical Global Impression, Bipolar Version (CGI-BP) mania severity scale, the pre-specified secondary endpoint (0.4; p=0.024). RAP-219 showed progressive improvement in the placebo-adjusted YMRS scores over the 3-week treatment period (0.9 at Week 1, 2.2 at Week 2, and 3.1 at Week 3).

Rapport Therapeutics reported that RAP-219 was well-tolerated. During the three-week treatment period, the incidence of treatment-emergent adverse events (TEAEs) was similar between RAP-219 and placebo (51.6% vs 52.8%), as was the incidence of psychiatric TEAEs (34.9% vs 33.1%). All TEAEs were mild or moderate in severity, and there were no serious adverse events (SAEs); 3.2% of patients on RAP-219 discontinued due to a TEAE compared with 0.8% placebo. The most common TEAE on RAP-219 was agitation, generally occurring in the first week and lasting a median duration of two days in both the RAP-219 and placebo groups. In both groups, this was considered unrelated in >80% of patients.

Rapport Therapeutics plans to meet with the U.S. Food and Drug Administration (FDA) in the first quarter of 2027 to discuss the Phase 2 data and registrational trial design for RAP-219 in bipolar mania. Initiation of two Phase 3 trials of RAP-219 in acute bipolar mania is expected in the second half of 2027. Additional data from the Phase 2 trial will be presented at a future medical meeting.

For people with bipolar disorder, the challenge isn't just finding a treatment that's efficacious. It's finding one they can tolerate and stay on. Side effects drive discontinuation, and discontinuation drives relapse. RAP-219 has the potential to break that cycle with the first new mechanism of action for bipolar mania in decades. Together with its positive Phase 2 focal epilepsy data, these results strengthen RAP-219’s profile across each indication it is pursuing and show it delivering on its potential as a pipeline-in-a-product with two indications that both represent multibillion dollar market opportunities.