Rapport Therapeutics said on October 20, 2026, that its experimental drug RAP-219 met the primary endpoint of a phase 2 trial in adults hospitalized with acute bipolar mania, with a modest but statistically significant advantage over placebo and no serious adverse events during three weeks of treatment. The results were disclosed in a company press release and have not been peer reviewed.
RAP-219 is described by the company as a potentially first-in-class negative allosteric modulator of AMPA receptors containing the TARPγ8 subunit, a mechanism intended to act on specific brain circuits. The U.S. trial randomized 253 adults with bipolar I disorder in an acute manic episode, defined as a score of at least 25 on the Young Mania Rating Scale (YMRS), to 0.75 mg of RAP-219 once daily after a two- or four-day titration, or to placebo, for three weeks as inpatients. All bipolar, anxiolytic and hypnotic medications were stopped during screening; lorazepam was allowed as a rescue medication at protocol-defined doses. Baseline YMRS scores averaged 36.9 in the drug group and 35.8 on placebo.
At week 3, YMRS total scores fell by 15.4 points on RAP-219 and 12.3 points on placebo, a placebo-adjusted least-squares mean improvement of 3.1 points (p=0.045). The separation grew over time, from 0.9 points at week 1 to 2.2 at week 2. On the prespecified secondary endpoint, the Clinical Global Impression–Bipolar mania severity score, the drug beat placebo by 0.4 points (p=0.024). All 11 YMRS items improved numerically versus placebo, with irritability, thought content, disruptive-aggressive behavior and sexual interest reaching nominal significance.
Treatment-emergent adverse events occurred in 51.6% of patients on RAP-219 and 52.8% on placebo, all mild or moderate, with no serious adverse events reported. Discontinuations due to adverse events were higher on the drug, 3.2% versus 0.8%. Agitation was the most common event on RAP-219 (16.7% versus 9.4%), typically in the first week with a median duration of two days; investigators judged it unrelated to treatment in more than 80% of cases in both groups. Nausea was reported in 5.6% versus 1.6%. Somnolence was rare (0.8% versus 3.1%), and orthostatic hypotension, akathisia and extrapyramidal symptoms were not reported. The safety figures come from an interim database lock on September 16, 2026; data from the eight-week post-treatment period will be presented later.
Why it matters
“Side effects drive discontinuation, and discontinuation drives relapse,” Abraham N. Ceesay, Rapport’s chief executive, said in the release. Jeffrey Sevigny, MD, the company’s chief medical officer, told Psychiatric Times, “This is important because tolerability issues lead many patients to discontinue their therapies.” 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, was quoted in the company release saying, “There hasn’t been a new mechanism to treat bipolar mania in decades,” and that “RAP-219 has the potential to become a mainstay of treatment for acute mania.”
The size of the benefit is the open question. A 3.1-point YMRS advantage at a p-value just under 0.05, in a trial of 253 patients, is an early signal rather than proof of clinical usefulness. The company says the tolerability profile, with no sedation signal and no reported movement side effects, is the differentiating feature, but those claims rest on three weeks of inpatient data. RAP-219 is also in phase 3 trials for drug-resistant focal epilepsy, known as FOCUS 1 and FOCUS 2, which are currently enrolling.
What to watch
Rapport plans an end-of-phase 2 meeting with the FDA in the first quarter of 2027 to discuss the data and the design of registrational trials, and expects to start two phase 3 trials in acute bipolar mania in the second half of 2027. Additional phase 2 data, including post-treatment safety, are to be presented at a future medical meeting. The company reported $436.1 million in cash and investments as of June 30, 2026, which it says funds operations into the second half of 2029.
The caveats
These are topline results announced by the sponsor, not a peer-reviewed publication, and full data have not been released. The trial covered only three weeks of inpatient treatment, with no information yet on what happens after discharge or on longer-term safety. The release does not disclose whether Sachs has a financial relationship with the company. Larger trials will be needed to establish whether the modest effect seen here translates into a meaningful benefit for patients.
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