RAP-219 · program

RAP-219 for Bipolar disorder

Phase 2ActiveRapport Therapeutics, Inc. (RAPP)

Indications for RAP-219: Epilepsy · Phase 3 Bipolar disorder · Phase 2

RAP-219, a TARPγ8-selective AMPA receptor negative allosteric modulator, for acute mania in bipolar I disorder, which the company calls the first new mechanism for bipolar mania in decades. The randomized, double-blind, placebo-controlled US Phase 2 trial RAP-219-BPM-201 (NCT07046494) enrolled 253 inpatients with an acute manic episode (YMRS ≥25), who received RAP-219 0.75 mg once daily or placebo for three weeks. Topline results (2026-10-20): the primary endpoint was met, with a 3.1-point placebo-adjusted improvement in YMRS total score at Week 3 (LS mean reduction 15.4 vs 12.3; p=0.045) and a significant improvement in CGI-BP mania severity (0.4; p=0.024). TEAE rates were similar to placebo (51.6% vs 52.8%); all were mild or moderate, there were no serious adverse events, and no orthostatic hypotension, akathisia or extrapyramidal symptoms were reported. Discontinuation for adverse events was 3.2% vs 0.8%. Rapport plans an FDA meeting in Q1 2027 and the start of two Phase 3 trials in 2H 2027.

Data current as of

Development timeline

Phase 2Jul 2025 – Oct 2026
  1. metPositive Phase 2 topline for RAP-219 in acute bipolar mania: 3.1-point placebo-adjusted YMRS improvement at Week 3 (p=0.045); CGI-BP mania severity also significant (p=0.024); well tolerated.↗
  2. Primary completion reached (registry actual date, 253 enrolled); the trial is Active, not recruiting during post-treatment follow-up. Positive topline announced 2026-10-20.
  3. Trial (portion) completedPhase 2 RAP-219 bipolar mania trial reaches primary completion
  4. Licensing dealRapport licenses Greater China rights to RAP-219 to Tenacia Biotechnology↗
  5. Phase 2 trial RAP-219-BPM-201 (NCT07046494) in bipolar I disorder with acute mania started (registry actual start date).
  6. Trial startedPhase 2 trial of RAP-219 in bipolar mania starts

Readouts

  • 2026-10-20ReportedTopline datametNCT07046494

    Positive Phase 2 topline for RAP-219 in acute bipolar mania: 3.1-point placebo-adjusted YMRS improvement at Week 3 (p=0.045); CGI-BP mania severity also significant (p=0.024); well tolerated. ↗

Clinical trials in Bipolar disorder

NCT07046494RAP-219-BPM-201Phase 2Activen=253

Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Bipolar I Disorder

Started Jul 2025· Primary completion Aug 2026· 📍 22 sites across 1 country (United States)

metsafetySafety and tolerability over the 3-week treatment period — TEAEs 51.6% vs 52.8%; no SAEs; discontinuation due to TEAE 3.2% vs 0.8%; agitation 16.7% vs 9.4%; somnolence 0.8% vs 3.1%

Well tolerated; all TEAEs mild or moderate; no orthostatic hypotension, akathisia or extrapyramidal symptoms reported (interim database lock 2026-09-16).

metsecondaryCGI-BP mania severity at Week 3 — 0.4-point improvement vs placebo (p=0.024)

Prespecified secondary endpoint reached statistical significance.

metprimaryChange from baseline in Young Mania Rating Scale (YMRS) total score at Week 3 — LS mean difference vs placebo -3.1 points (RAP-219 -15.4 vs placebo -12.3; baseline 36.9 vs 35.8) (p=0.045)

Met the primary endpoint; all 11 YMRS items numerically favoured RAP-219, with irritability, thought content, disruptive-aggressive behaviour and sexual interest nominally significant.

Formulations

FormulationRouteRegimenPharmacokinetics
RAP-219 oral tablet (once daily)
Phase 2a focal onset seizures (RAP-219-FOS-201): 0.75 mg oral tablet daily for 5 days, then 1.25 mg daily for the rest of the 8-week treatment period. Phase 2 bipolar mania (RAP-219-BPM-201): 0.75 mg once daily after a 2- or 4-day titration, for 3 weeks inpatient. Phase 3 FOCUS-1/FOCUS-2: daily oral tablets at low/medium/high dose arms (dose levels not disclosed on the registry).
OralOnce dailyt½ 528 h

Mechanism of action (compound-wide)

Negative allosteric modulator of AMPA-type glutamate receptors that is selective for receptors complexed with the auxiliary subunit TARPγ8 (transmembrane AMPA receptor regulatory protein gamma-8, gene CACNG8). Because TARPγ8 is expressed mainly in forebrain regions such as hippocampus and neocortex and minimally in the hindbrain, the company's hypothesis is that region-selective dampening of AMPA signalling can suppress seizures (and mania) while avoiding the dose-limiting adverse effects of non-selective AMPA antagonists. A Phase 1 PET study with a companion radiotracer was run to confirm brain target occupancy and regional specificity.

TargetActionAffinity
TARPγ8primaryCACNG8NAM—ⓘ
AMPA receptorNAM—ⓘ

← Full RAP-219 compound page (identity, identifiers, all indications)

Sources

  1. Form 8-K Exhibit 99.1: Rapport Therapeutics Reports Second Quarter 2026 Financials and Provides Business Update (2026-08-05) — Rapport Therapeutics, Inc. (SEC EDGAR)
  2. RAP-219-BPM-201: Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Bipolar I Disorder — ClinicalTrials.gov
  3. Rapport Therapeutics Announces Positive Topline Results from its Phase 2 Trial of RAP-219 for the Treatment of Bipolar Mania (2026-10-20, wire copy) — Rapport Therapeutics, Inc. (via GlobeNewswire / BioSpace)
  4. Rapport Therapeutics Partners with Tenacia Biotechnology to Advance RAP-219 in Greater China (2026-03-10) — PharmaShots