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Rapport Therapeutics’ phase 2 bipolar mania study has hit its primary endpoint, furthering the biotech’s efforts to make RAP-219 a multi-indication blockbuster. However, the effect size fell short of the level targeted by Rapport and analysts ahead of the readout. RAP-219, a small molecule targeting TARPγ8, is in phase 3 development in patients with focal seizures. Last month, William Blair analysts named bipolar mania as a riskier indication and a major commercial opportunity. Based on this morning's phase 2 readout, Rapport plans to pursue the opportunity, with phase 3 trials slated to start next year, but the data leave room to question its likelihood of success. The phase 2 study linked RAP-219 to a 3.1-point placebo-adjusted improvement in the Young Mania Rating Scale (YMRS) total score at Week 3. The result was statistically significant, achieving the trial's primary endpoint. However, the results fell short of the 4-point placebo-adjusted improvement in YMRS that Rapport CEO Abe Ceesay called “the clinically meaningful threshold” at a TD Cowen event last month. Existing drugs have achieved 4- to 7-point placebo-adjusted improvements on YMRS, the CEO added. Despite that, Ceesay hailed the results as positive on a call with investors on Tuesday. “The data clearly meets a threshold of clinical meaningfulness,” Ceesay said. “Importantly, not only that placebo-adjusted difference hitting statistical significance, but that being corroborated by the secondary endpoint [achieving] statistical significance, as well as the individual measures in the YMRS.” William Blair analysts agreed with Ceesay. The analysts previously called a 4-point YMRS improvement the “minimal clinically important difference and bar for success.” But in a note to investors this morning, they referenced the initial 4-point target while making the case that the actual result represents a positive finding for Rapport. “There will be debate about the magnitude of efficacy ... but the actual move is still a 42% improvement over baseline in the treatment arm and within the range of approved therapies,” the analysts said. “Efficacy occurred across all 11 YMRS scale items, increasing in separation from Weeks one through three of treatment, and is supported by secondary endpoint efficacy.” The readout provides clinical proof of concept in an indication beyond epilepsy, building on RAP-219's multi-blockbuster potential heading into the pivotal program, the analysts said. The William Blair team compared RAP-219’s prospects to those of Vraylar, which they noted is on track for $4.3 billion in sales this year through AbbVie’s layering of indications. Vraylar is approved in four indications. Rapport’s ability to achieve a similarly broad label for RAP-219 depends in part on longer-term safety and tolerability data. The analysts are looking for signs the drug candidate can be used in the maintenance setting and to prevent symptom relapse. Rapport’s statement made no mention of suicidal ideation, an adverse event that affects Catalyst Pharmaceuticals’ rival seizure drug, Fycompa.