Rapport’s RAP-219 Delivers Significant YMRS Improvement in Phase 2

Rapport Therapeutics reported positive topline results on October 20, 2026, from a Phase 2 trial (NCT07046494) evaluating RAP-219 in adults with acute mania associated with bipolar I disorder. The randomized, double-blind, placebo-controlled study met its primary endpoint, demonstrating a statistically significant improvement in the Young Mania Rating Scale (YMRS) total score at Week 3.

Participants receiving RAP-219 experienced a mean 15.4-point reduction from baseline, compared with 12.3 points with placebo, producing a 3.1-point placebo-adjusted difference (p=0.045). The prespecified secondary endpoint, the Clinical Global Impression–Bipolar Version (CGI-BP) Severity of Mania score, also favored RAP-219, with a 0.4-point placebo-adjusted improvement (p=0.024).

The placebo-adjusted YMRS difference increased from 0.9 points at Week 1 to 2.2 at Week 2 and 3.1 at Week 3. All 11 YMRS items improved numerically relative to placebo, while irritability, thought content, disruptive-aggressive behavior and sexual interest reached nominal statistical significance.

Although both endpoints were met, the between-group YMRS difference remained modest relative to the improvement observed in each group. The results support an early efficacy signal, but do not establish the magnitude or durability of benefit beyond the three-week treatment period.

Trial Design and Patient Population

The US trial enrolled 253 adults with bipolar I disorder experiencing an acute manic episode, defined by a YMRS score of at least 25. Participants were randomized in a 1:1:2 ratio to RAP-219 following a two- or four-day titration, or placebo. The maintenance dose was 0.75 mg once daily, and treatment continued for three weeks in an inpatient setting.

During screening, medications indicated for bipolar disorder, as well as anxiolytics and hypnotics, were discontinued. Lorazepam was permitted as rescue medication at protocol-defined doses.

These conditions matter when interpreting the results. Medication withdrawal, inpatient monitoring and access to rescue treatment may differ from routine clinical practice. The trial therefore provides evidence of short-term activity under controlled conditions, rather than demonstrating effectiveness in broader real-world settings.

Short-Term Safety and Tolerability

Treatment-emergent adverse events (TEAEs) occurred in 51.6% of RAP-219 recipients and 52.8% of placebo recipients. Psychiatric TEAEs were reported in 34.9% and 33.1%, respectively. All reported TEAEs during treatment were mild or moderate, with no serious adverse events or severe TEAEs observed.

Agitation was the most common TEAE with RAP-219, occurring in 16.7% of participants versus 9.4% with placebo. Insomnia occurred in 14.3% versus 15.0%, while restlessness was reported in 8.7% versus 7.9%. Discontinuation due to a TEAE occurred in 3.2% of RAP-219 recipients compared with 0.8% receiving placebo. Somnolence was reported in 0.8% versus 3.1%, respectively.

Orthostatic hypotension, akathisia and extrapyramidal symptoms were not reported during the treatment period. However, the absence of these events over three weeks does not establish that RAP-219 has a superior safety profile to existing treatments. The study was not a head-to-head comparison, and longer-term safety data remain pending. The reported safety analysis was based on an interim database lock dated September 16, 2026.

Mechanism and Development Plans

RAP-219 is an investigational negative allosteric modulator of AMPA receptors that selectively targets transmembrane AMPA receptor regulatory protein gamma-8 (TARPγ8). This protein is expressed in discrete brain regions, including the hippocampus and neocortex. The approach is intended to modulate AMPA receptor activity with greater neuroanatomical selectivity than less targeted approaches.

The clinical findings do not yet establish that this selectivity translates into a meaningful advantage over available therapies.

Rapport plans to discuss the Phase 2 findings and registrational trial design with the US Food and Drug Administration (FDA) in the first quarter of 2027. Two Phase 3 trials in acute bipolar mania are expected to begin in the second half of 2027, subject to regulatory discussions. RAP-219 is also being evaluated in epilepsy, with the FOCUS 1 and FOCUS 2 Phase 3 trials enrolling patients with focal onset seizures.

As of June 30, 2026, Rapport reported $436.1 million in cash, cash equivalents and short-term investments, excluding restricted cash, which the company expects to fund operations into the second half of 2029.

Clinical Interpretation

RAP-219’s Phase 2 results demonstrate statistically significant improvements over placebo on clinician-rated measures of acute mania, alongside similar overall TEAE rates during three weeks of treatment. The increasing YMRS difference across the treatment period supports further evaluation, but the 3.1-point placebo-adjusted benefit and substantial placebo response leave the clinical magnitude of the effect to be clarified.

The inpatient setting, medication withdrawal, higher rate of adverse-event discontinuation with RAP-219 and pending post-treatment safety data also limit conclusions about routine use and longer-term tolerability. Phase 3 trials will need to confirm efficacy, characterize safety over a longer period and determine whether TARPγ8-selective modulation offers a clinically meaningful benefit over existing treatments. RAP-219 remains investigational, and its planned development timeline depends on regulatory discussions and future trial outcomes.

Reference

Rapport Therapeutics. Rapport Therapeutics Announces Positive Topline Results from its Phase 2 Trial of RAP-219 for the Treatment of Bipolar Mania. October 20, 2026

Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Bipolar I Disorder, ClinicalTrials.gov ID NCT07046494