Rapport Therapeutics’ Phase II bipolar mania study has met its primary endpoint, as it hopes to compete on the market with the drug’s original owner, Johnson & Johnson (J&J).
In the study (NCT07046494), acute bipolar mania patients treated with RAP-219 achieved a 3.1-point placebo-adjusted improvement in the Young Mania Rating Scale (YMRS) total score after three weeks of treatment. This was based on a mean reduction from baseline of 15.4 points with RAP-219 versus 12.3 points with placebo.
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All 11 YMRS items improved on RAP-219 compared to placebo, including improvements in irritability, thought content, disruptive-aggressive behaviour, and sexual interest reaching nominal significance.
RAP-219 also demonstrated a statistically significant improvement in mania severity score as measured by the Clinical Global Impression—Bipolar Version (CGI-BP) mania severity scale, meeting the pre-specified secondary endpoint.
The oral selective negative allosteric modulator (NAM), which targets transmembrane AMPA receptor regulatory protein γ8 (TARPγ8)-containing AMPA receptors, was also well-tolerated, with no severe treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) observed over the treatment period. The most common TEAE on RAP-219 was agitation, generally occurring in the first week and lasting a median duration of two days.
Rapport said the data establish clinical proof-of-concept for RAP-219 in bipolar and support progression to Phase III trials, which are expected to begin in the second half of 2027 following consultation with the US Food and Drug Administration (FDA).
Dr Gary Sachs, founding director of the Bipolar Clinic and Research Program at Massachusetts General Hospital and associate clinical professor of psychiatry at Harvard Medical School, said: “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. Importantly, clinical benefit was seen consistently across all measures, with the greatest improvements in symptoms that tend to drive hospitalisation 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.”
The biotech added RAP-219 to its pipeline through a 2023 licensing deal with J&J. The drug is also in studies for epilepsy and focal onset seizures.
J&J is still seeking a slice of its own on the bipolar market; its 2025 $14.6bn acquisition of Intra-Cellular was centred around the company’s psychiatric drug Caplyta (lumateperone). The deal was the largest M&A pharma transaction for that year. In September 2026, the drug showed benefit in a Phase III trial in bipolar disorder, with a 4.8-point greater reduction in YMRS total score versus placebo at three weeks, with twice as many patients treated with Caplyta achieving clinical response, defined as a ≥50% reduction in YMRS total score.
The drug was first approved by the FDA in December 2019 for treating schizophrenia in adults, with the label expanded since to include bipolar depression, major depressive disorder (MDD) and schizophrenia relapse prevention.
Bipolar disorder is a complex, lifelong condition which affects an estimated 37 million patients worldwide. Manic episodes, a defining feature of bipolar I disorder, can escalate quickly and often require hospitalisation, with treatment options remaining limited.
In March 2025, Biohaven announced that its pipeline candidate did not show benefit in a Phase II/III bipolar disorder trial. The Nasdaq-listed company’s stock fell by 13.77% on the news.
According to GlobalData, the bipolar disorder market across the seven major markets (7MM: the US, France, Germany, Italy, Spain, the UK, and Japan) is projected to grow from $5.6bn in 2024 to $9.4bn by 2034.
GlobalData is the parent company of Clinical Trials Arena.
