Small Molecule · RAP-219

RAP-219

Phase 3Rapport Therapeutics, Inc. (RAPP)

Investigational, potential first-in-class oral small molecule from Rapport Therapeutics: a negative allosteric modulator (NAM) of the AMPA receptor that is selective for AMPA receptors associated with the receptor-associated protein TARPγ8. Per the company, TARPγ8 is expressed in discrete forebrain regions including the hippocampus and neocortex, where focal seizures often originate, with minimal hindbrain expression, the rationale for a better-tolerated profile than broad AMPA antagonism. In Phase 3 for focal onset seizures (FOCUS-1/FOCUS-2) and with positive Phase 2 topline results in acute bipolar mania (2026-10-20); a Phase 3 in primary generalized tonic-clonic seizures and a long-acting injectable formulation are planned. Estimated half-life about 22 days.

Also known as: RAP-219, RAP 219, RAP219

Data current as of

Key facts

Modality
Small molecule
Mechanism
TARPγ8 NAM
Highest phase
Phase 3
Lead indication
Epilepsy
Developer
Rapport Therapeutics, Inc. (RAPP)
Trials
5 tracked · 3 recruiting · 46 sites
Next catalyst
Q4 2026 — Interim analysis (Epilepsy)

Mechanism of action#

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—ⓘ

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

Development timeline#

20252026202720282029TodayPhase 220 Oct 2026 — readout (met) — 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.5 Aug 2026 — phase change — Primary completion reached (registry actual date, 253 enrolled); the trial is Active, not recruiting during post-treatment follow-up. Positive topline announced 2026-10-20.5 Aug 2026 — Trial (portion) completed — Phase 2 RAP-219 bipolar mania trial reaches primary completion1 Apr 2026 — Conference presentation — Phase 2a follow-up data for RAP-219 in focal onset seizures presented at AAN 202610 Mar 2026 — Licensing deal — Rapport licenses Greater China rights to RAP-219 to Tenacia Biotechnology26 Sept 2025 — phase change — Phase 2a FOS-201 reached primary completion (registry actual date) after positive topline results for the 8-week treatment period were announced on 2025-09-08.8 Sept 2025 — readout (met) — Positive Phase 2a topline in drug-resistant focal onset seizures: 85.2% achieved ≥30% long-episode reduction (p<0.0001); median clinical seizure reduction 77.8% (p=0.01); 24% seizure-free over 8 weeks.25 Jul 2025 — phase change — Phase 2 trial RAP-219-BPM-201 (NCT07046494) in bipolar I disorder with acute mania started (registry actual start date).25 Jul 2025 — Trial started — Phase 2 trial of RAP-219 in bipolar mania starts10 Oct 2024 — phase change — Open-label Phase 2a proof-of-concept trial RAP-219-FOS-201 (NCT06377930) started in adults with drug-resistant focal onset seizures with an implanted RNS System (30 enrolled).Phase 331 Jul 2029 — upcoming — ClinicalTrials.gov estimated primary completion of Phase 3 FOCUS-1 (RAP-219 in focal seizures): July 2029.31 Dec 2026 — upcoming — Initial data from the open-label long-term safety trial of RAP-219 in focal onset seizures expected in Q4 2026.5 Aug 2026 — IND/CTA clearance — China NMPA approves IND for RAP-219 Phase 3 trials in focal onset seizures5 Jun 2026 — phase change — Pivotal Phase 3 FOCUS-1 (NCT07563881) started (registry actual start date). Rapport reported on 2026-08-05 that the Phase 3 program began in Q2 2026 with FOCUS-1 and FOCUS-2 both enrolling.5 Jun 2026 — Trial started — Phase 3 FOCUS-1 of RAP-219 in focal onset seizures starts
Phase change Readout Event UpcomingHover a marker for details.
Phase 3Jun 2026 – Jul 2029
  1. UpcomingClinicalTrials.gov estimated primary completion of Phase 3 FOCUS-1 (RAP-219 in focal seizures): July 2029.Epilepsy
  2. UpcomingInitial data from the open-label long-term safety trial of RAP-219 in focal onset seizures expected in Q4 2026.Epilepsy↗
  3. IND/CTA clearanceChina NMPA approves IND for RAP-219 Phase 3 trials in focal onset seizuresEpilepsy↗
  4. Pivotal Phase 3 FOCUS-1 (NCT07563881) started (registry actual start date). Rapport reported on 2026-08-05 that the Phase 3 program began in Q2 2026 with FOCUS-1 and FOCUS-2 both enrolling.Epilepsy
  5. Trial startedPhase 3 FOCUS-1 of RAP-219 in focal onset seizures startsEpilepsy
Phase 2Oct 2024 – 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.Bipolar disorder↗
  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.Bipolar disorder
  3. Trial (portion) completedPhase 2 RAP-219 bipolar mania trial reaches primary completionBipolar disorder
  4. Conference presentationPhase 2a follow-up data for RAP-219 in focal onset seizures presented at AAN 2026Epilepsy↗
  5. Licensing dealRapport licenses Greater China rights to RAP-219 to Tenacia Biotechnology↗
  6. Phase 2a FOS-201 reached primary completion (registry actual date) after positive topline results for the 8-week treatment period were announced on 2025-09-08.Epilepsy
  7. metPositive Phase 2a topline in drug-resistant focal onset seizures: 85.2% achieved ≥30% long-episode reduction (p<0.0001); median clinical seizure reduction 77.8% (p=0.01); 24% seizure-free over 8 weeks.Epilepsy↗
  8. Phase 2 trial RAP-219-BPM-201 (NCT07046494) in bipolar I disorder with acute mania started (registry actual start date).Bipolar disorder
  9. Trial startedPhase 2 trial of RAP-219 in bipolar mania startsBipolar disorder
  10. Open-label Phase 2a proof-of-concept trial RAP-219-FOS-201 (NCT06377930) started in adults with drug-resistant focal onset seizures with an implanted RNS System (30 enrolled).Epilepsy

RAP-219 for Epilepsy#

Phase 3RecruitingEpilepsy indication →

RAP-219, a TARPγ8-selective AMPA receptor negative allosteric modulator, for focal onset seizures (and, later, primary generalized tonic-clonic seizures). The open-label Phase 2a trial RAP-219-FOS-201 (NCT06377930) in 30 adults with drug-resistant focal onset seizures and an implanted RNS System met its primary endpoint on RNS-recorded long episodes: 85.2% of patients had a ≥30% reduction (p<0.0001) and median long-episode frequency fell 71.0%; median clinical seizure frequency fell 77.8% (p=0.01), 72.0% had a ≥50% reduction and 24% were seizure-free over the 8-week treatment period (topline 2025-09-08).

Readouts

  • July 2029AnticipatedRegistry resultsNCT07563881

    ClinicalTrials.gov estimated primary completion of Phase 3 FOCUS-1 (RAP-219 in focal seizures): July 2029.

  • Q4 2026AnticipatedInterim analysisNCT07219407

    Initial data from the open-label long-term safety trial of RAP-219 in focal onset seizures expected in Q4 2026. ↗

  • 2025-09-08ReportedTopline datametNCT06377930

    Positive Phase 2a topline in drug-resistant focal onset seizures: 85.2% achieved ≥30% long-episode reduction (p<0.0001); median clinical seizure reduction 77.8% (p=0.01); 24% seizure-free over 8 weeks. ↗

RAP-219 for Bipolar disorder#

Phase 2ActiveBipolar disorder indication →

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.

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#

NCT07594119RAP-219-FOS-302Phase 3Recruitingn=312

Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures

Started Sept 2026· Primary completion Jul 2029· 2 sites across 1 country

United States

NCT07563881RAP-219-FOS-301Phase 3Recruitingn=333

Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures FOCUS-1

Started Jun 2026· Primary completion Jul 2029· 3 sites across 1 country

United States

NCT07219407RAP-219-FOS-901Phase 2Recruitingn=30

A Long-term Study of the Safety and Effectiveness of RAP-219 in Adults With Focal Onset Seizures

Started Dec 2025· Primary completion Feb 2028· 7 sites across 1 country

United States

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.

NCT06377930RAP-219-FOS-201Phase 2Completedn=30

Study Evaluating the Safety and Efficacy of RAP-219 in Adult Participants With Refractory Focal Epilepsy

Started Oct 2024· Primary completion Sept 2025· 12 sites across 1 country

United States

metprimaryResponder proportion with ≥30% reduction in RNS-recorded long episodes (LEs) from baseline over the 8-week treatment period — 85.2% of patients (mITT N=27); median LE frequency reduction 71.0% (p=0.0001) (p<0.0001 (exact binomial vs 10% null))

Open-label, single-arm Phase 2a met its primary long-episode endpoints with high statistical significance; RAP-219 generally well tolerated.

metsecondaryClinical seizure frequency over the 8-week treatment period (median % change, ≥50% responders, seizure freedom) — Median clinical seizure reduction 77.8%; 72.0% with ≥50% reduction; 24.0% seizure-free (mITT-CS N=25) (77.8% median reduction p=0.01; responder and seizure-freedom p<0.0001)

Key secondary clinical seizure endpoints reached statistical significance versus prespecified null rates (no placebo arm).

Sources#

  1. Form 8-K Exhibit 99.1: Rapport Announces Positive Topline Results from Phase 2a Clinical Trial of RAP-219 in Patients with Focal Onset Seizures (2025-09-08) — Rapport Therapeutics, Inc. (SEC EDGAR)
  2. 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)
  3. RAP-219-BPM-201: Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Bipolar I Disorder — ClinicalTrials.gov
  4. RAP-219-FOS-201: Study Evaluating the Safety and Efficacy of RAP-219 in Adult Participants With Refractory Focal Epilepsy — ClinicalTrials.gov
  5. RAP-219-FOS-301 (FOCUS-1): Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures — ClinicalTrials.gov
  6. RAP-219-FOS-302: Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures — ClinicalTrials.gov
  7. RAP-219-FOS-901: A Long-term Study of the Safety and Effectiveness of RAP-219 in Adults With Focal Onset Seizures — ClinicalTrials.gov
  8. 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)
  9. Rapport Therapeutics Partners with Tenacia Biotechnology to Advance RAP-219 in Greater China (2026-03-10) — PharmaShots