Rapport Therapeutics (NASDAQ:RAPP) reported positive top-line results from a Phase II proof-of-concept trial of RAP-219 in adults with acute bipolar mania, meeting both its primary and secondary endpoints and supporting plans to advance the candidate into Phase III development.
The three-week, placebo-controlled monotherapy study enrolled 253 patients with DSM-5-defined bipolar mania and baseline Young Mania Rating Scale, or YMRS, scores of at least 25. Patients were randomized to receive placebo or RAP-219, following either a two- or four-day titration to a 0.75 mg dose. The treatment period was conducted in an inpatient setting, followed by an eight-week safety follow-up.
Primary and Secondary Endpoints Met
Chief Medical Officer Jeff Sevigny said RAP-219 produced a statistically significant placebo-adjusted improvement of 3.1 points on the YMRS at week three, the study’s primary endpoint. The treatment arm recorded an absolute reduction of 15.4 points on the scale.
The drug candidate also met its secondary endpoint, with a statistically significant 0.4-point placebo-adjusted improvement on the Clinical Global Impression Bipolar Severity Mania scale at week three. Sevigny said the treatment effect versus placebo widened during the three-week dosing period on both measures.
In a prespecified exploratory analysis, all 11 individual YMRS items numerically favored RAP-219 over placebo. Four items—irritability, thought content, disruptive and aggressive behavior, and sexual interest—reached nominal statistical significance at week three. Improvements in irritability and disruptive or aggressive behavior also achieved nominal significance at week two.
“The data clearly support us advancing to Phase III,” Chief Executive Officer Abe Ceesay said. He added that the company views the results, along with previously reported Phase II data in focal onset seizures, as supporting development of RAP-219 across neurology and psychiatry.
Safety Profile and Discontinuations
Rapport said RAP-219 was generally well tolerated. There were no severe or serious adverse events during the treatment period, and all treatment-emergent adverse events were mild or moderate. Discontinuations due to adverse events were 3.2% in the RAP-219 arm and 0.8% in the placebo arm.
The most frequently reported treatment-emergent adverse events occurring in at least 5% of patients were agitation, insomnia, restlessness, anxiety, headache and nausea. Nausea was the only event reported at least twice as often among RAP-219-treated patients as among placebo recipients, Sevigny said.
Agitation, the most common adverse event in the RAP-219 group, generally occurred in the first week, lasted a median of two days, and was considered unrelated to treatment by investigators in more than 80% of cases, according to the company.
Sevigny also said adverse events commonly associated with atypical antipsychotics—including somnolence, dizziness, akathisia and other extrapyramidal symptoms—were either not reported or occurred at low rates in the study. Rescue lorazepam use was permitted and occurred in slightly more than half of patients in both study arms.
Phase III Plans
Rapport expects to hold an end-of-Phase-II meeting with the Food and Drug Administration in the first quarter of 2027 and anticipates beginning its bipolar mania Phase III program in the second half of 2027.
The company said it is considering testing a higher 1.25 mg dose in Phase III. That dose has been evaluated in the company’s focal onset seizure program and is being studied in Phase III trials in that indication. Rapport believes higher exposure and receptor occupancy at 1.25 mg could potentially improve efficacy and produce earlier clinical effects.
Management is also considering enrolling patients in certain regions outside the U.S. for Phase III trials. Sevigny said the company believes such regions have historically generated stronger signals in bipolar mania studies, in part because patients are more commonly enrolled directly from inpatient settings.
Rapport plans to run two parallel Phase III studies following FDA discussions. The company also expects to include an open-label extension study to generate information on longer-term use of RAP-219.
Broader Pipeline Milestones
Chief Financial Officer Troy Ignelzi said Rapport expects to report initial long-term safety data for RAP-219 in focal onset seizures during the fourth quarter of 2026. In the first half of 2027, the company expects to initiate a trial in primary generalized tonic-clonic seizures. It also anticipates reporting Phase I pharmacokinetic data for a long-acting injectable formulation in the third quarter of 2027 and Phase I results for pipeline candidate RAP-641 in the second half of the year.
By the end of 2027, Rapport expects to have five Phase III trials underway: two in focal onset seizures, two in bipolar mania and one in primary generalized tonic-clonic seizures.
About Rapport Therapeutics (NASDAQ:RAPP)
Rapport Therapeutics, Inc is a clinical-stage biopharmaceutical company focused on developing precision medicines for central nervous system disorders. The company’s approach is designed to selectively target receptor-associated proteins that regulate synaptic receptors, with the goal of improving therapeutic selectivity and reducing the side effects associated with broader-acting neurological medicines.
Rapport’s lead product candidate, RAP-219, is an orally administered small molecule being developed for neurological conditions, including focal epilepsy.
