Positive Topline Results From Phase 2 Trial of RAP-219 for the Treatment of Bipolar Mania

Rapport Therapeutics has announced positive topline results from its phase 2 trial of RAP-219 for the treatment of adults with acute bipolar mania.¹ RAP-219 is an investigational and potential first-in-class, clinical-stage TARPγ8-specific AMPA receptor (AMPAR) negative allosteric modulator (NAM).

RAP-219 demonstrated statistically significant improvement in manic symptoms: The trial met its primary endpoint, with RAP-219 achieving a 3.1-point placebo-adjusted improvement in the Young Mania Rating Scale (YMRS) total score at week 3 (mean reduction from baseline of 15.4 points with RAP-219 vs 12.3 points with placebo (P=0.045). These results establish clinical proof-of-concept for RAP-219 and its novel TARPγ8-selective mechanism in bipolar mania.

“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,” said Abraham N. Ceesay, the chief executive officer of Rapport. “[Adverse] 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 our positive phase 2 focal epilepsy data, these results strengthen RAP-219’s profile across each indication we are pursuing and show it delivering on its potential as a pipeline-in-a-product with 2 indications that both represent multibillion dollar market opportunities. We look forward to engaging with the FDA on phase 3 in bipolar mania, alongside our ongoing phase 3 epilepsy programs.”

About the Study

The US-based, randomized, double-blind, placebo-controlled phase 2 trial enrolled 253 adult participants with bipolar I disorder (BD) experiencing an acute manic episode (YMRS≥25 at baseline). During the screening period, all treatments indicated for BD and all 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 participants received 0.75 mg of RAP-219 once daily (following a 2- or 4- day titration) or placebo for 3 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. Topline efficacy and safety data reported are from the 3-week treatment period. Safety data from the 8-week posttreatment period will be presented at a future medical conference.

Study Results

The trial met its primary endpoint, with RAP-219 achieving a statistically significant 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 YMRS items improved on RAP-219 compared with placebo at week 3, with improvements in irritability, thought content, disruptive-aggressive behavior, and sexual interest reaching nominal significance (P<0.05). RAP-219 also 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).

Notably, RAP-219 also demonstrated a statistically significant improvement in mania severity score vs 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).

“There hasn’t been a new mechanism to treat bipolar mania in decades. In this study, RAP-219 achieved statistically significant improvement in manic symptoms with an encouraging tolerability profile, underscoring the promise of this novel mechanism,” said Gary Sachs, MD, founding director of the Bipolar Clinic and Research Program at Massachusetts General Hospital and associate clinical professor of psychiatry at Harvard Medical School. “Importantly, clinical benefit was seen consistently across all measures, with the greatest improvements in symptoms that tend to drive hospitalization for acute mania patients. What is encouraging about the tolerability profile is what was not seen on RAP-219—the somnolence, akathisia, and extrapyramidal symptoms that often cause patients to discontinue treatment. Based on these results, RAP-219 has the potential to become a mainstay of treatment for acute mania.”

Safety and Tolerability

During the 3-week treatment period, based on safety and tolerability data, 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 noted TEAEs were mild or moderate in severity, and there were no serious adverse events (SAEs). Approximately 3.2% of patients on RAP-219 discontinued due to a TEAE, as compared with 0.8% placebo.

TEAEs occurring in ≥5% of participants in either group (RAP-219 vs placebo) were:

• Agitation (16.7% vs 9.4%)
• Insomnia (14.3% vs 15.0%)
• Restlessness (8.7% vs 7.9%)
• Anxiety (7.1% vs 5.5%)
• Headache (5.6% vs 10.2%)
• Nausea (5.6% vs 1.6%)

Those considered treatment related by the investigators were:

• Agitation (3.2% vs 1.6%)
• Insomnia (3.2% vs 0.8%)
• Restlessness (1.6% vs 0%)
• Anxiety (0.8% vs 0.8%)
• Headache (0.8% vs 4.7%)
• Nausea (3.2% vs 0.8%)

The most common TEAE on RAP-219 was agitation, generally occurring in the first week and lasting a median duration of 2 days in both the RAP-219 and placebo groups. In both groups, this was considered unrelated in >80% of patients. Adverse effects commonly associated with current bipolar mania medications, including orthostatic hypotension, akathisia, and extrapyramidal symptoms were not reported. Somnolence was reported less often with RAP-219 (0.8%) than placebo (3.1%).

“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, the chief medical officer of Rapport. “This is important because tolerability issues lead many patients to discontinue their therapies. These results continue to build our confidence in the safety profile of RAP-219, and the insights learned from this study will guide us in optimizing the phase 3 design in bipolar mania. Finally, we are deeply grateful to everyone who made this study possible, including participating patients and their families, the investigators and site staff, and our dedicated employees.”

Next Steps

These results support progression to phase 3 trials, which are expected to begin in the second half of 2027.

RAP-219 is also notably being evaluated for drug-resistant focal epilepsy.^2,3

References

1. Rapport Therapeutics announces positive topline results from its phase 2 trial of RAP-219 for the treatment of bipolar mania. News release. October 20, 2026. Accessed October 20, 2026. https://investors.rapportrx.com/news-releases/news-release-details/rapport-therapeutics-announces-positive-topline-results-its

2. Study evaluating the efficacy and safety of RAP-219 in adult participants with focal seizures FOCUS-1 (FOCUS 1). Clinicaltrials.gov. Accessed October 20, 2026. https://clinicaltrials.gov/study/NCT07563881?intr=RAP-219%20&viewType=Card&rank=2

3. Study evaluating the efficacy and safety of RAP-219 in adult participants with focal seizures (FOCUS 2). Clinicaltrials.gov. Accessed October 20, 2026. https://clinicaltrials.gov/study/NCT07594119?intr=RAP-219%20&viewType=Card&rank=1