Boston, Massachusetts, and San Diego, California, USA, October 20, 2026
Rapport Therapeutics has announced positive topline results from its Phase 2 clinical trial evaluating RAP-219 in adults experiencing acute mania associated with bipolar I disorder. The investigational therapy met the study’s primary and secondary endpoints, demonstrating statistically significant improvements in manic symptoms compared with placebo after three weeks of treatment. The findings also showed an encouraging tolerability profile, with no severe treatment-emergent adverse events or serious adverse events reported during the treatment period. The results establish clinical proof of concept for RAP-219’s novel TARPγ8-selective mechanism of action in bipolar mania and support the company’s plans to advance the candidate into Phase 3 development. Rapport expects to discuss the Phase 2 findings and potential pivotal trial design with the U.S. Food and Drug Administration (FDA) in the first quarter of 2027.
RAP-219 Meets Primary and Secondary Phase 2 Endpoints
The randomized, double-blind, placebo-controlled Phase 2 trial enrolled 253 adults with bipolar I disorder experiencing an acute manic episode. Participants received RAP-219 at a dose of 0.75 mg once daily, following a two- or four-day titration period, or placebo for three weeks in an inpatient setting. The study’s primary endpoint measured changes in the Young Mania Rating Scale (YMRS), a clinician-administered assessment used to measure the severity of manic symptoms. At Week 3, RAP-219 achieved a statistically significant 3.1-point improvement over placebo in the YMRS total score, with a mean reduction from baseline of 15.4 points in the RAP-219 group compared with 12.3 points in the placebo group. The difference was statistically significant, with a reported p-value of 0.045. The trial also met its prespecified secondary endpoint, demonstrating a statistically significant improvement in mania severity on the Clinical Global Impression–Bipolar Version scale, with a placebo-adjusted difference of 0.4 points (p=0.024). These results indicate that RAP-219 improved measures of acute manic symptoms in the study population, although further clinical evaluation will be needed to confirm its efficacy and establish its overall benefit-risk profile.
Novel Mechanism and Encouraging Tolerability Profile
RAP-219 is an investigational small-molecule therapy developed to selectively target TARPγ8-associated AMPA receptors, which are involved in excitatory neurotransmission in the brain. Rapport is investigating this mechanism as a potential approach to treating neurological and psychiatric disorders. In the Phase 2 bipolar mania trial, all 11 items assessed by the YMRS improved numerically compared with placebo. Improvements in irritability, thought content, disruptive-aggressive behaviour and sexual interest reached nominal statistical significance. The company reported that RAP-219 was generally well tolerated during the three-week treatment period, with treatment-emergent adverse events classified as mild or moderate and no severe treatment-emergent adverse events or serious adverse events observed. These preliminary safety findings are encouraging, but longer-term safety data from the eight-week post-treatment period have not yet been reported. Additional follow-up and larger trials will be important to assess the durability of treatment effects, safety over time and the potential role of RAP-219 in clinical practice. The findings are particularly relevant because tolerability can influence treatment adherence among people living with bipolar disorder, where managing acute symptoms and preventing future episodes are important clinical goals.
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Rapport Plans Phase 3 Development for Bipolar Mania
Following the positive topline findings, Rapport plans to meet with the FDA in the first quarter of 2027 to discuss the Phase 2 results and the design of a registrational development programme. The company expects to initiate two Phase 3 trials evaluating RAP-219 for acute bipolar mania in the second half of 2027, subject to regulatory discussions and development progress. Rapport is also advancing RAP-219 in focal onset seizures, where its pivotal Phase 3 FOCUS 1 and FOCUS 2 studies are enrolling participants. The broader programme reflects the company’s strategy of evaluating its precision-medicine approach across multiple conditions affecting the central nervous system. However, RAP-219 remains investigational and is not approved for treating bipolar mania. Its potential clinical use will depend on the results of subsequent trials and applicable regulatory review. The Phase 2 findings represent an important milestone for Rapport Therapeutics as it advances a new investigational mechanism for acute bipolar mania. Further clinical evidence will be needed to determine whether RAP-219 can deliver meaningful and sustained benefits for patients.
Source: Rapport Therapeutics press release
