RAP-219 / Rapport Therap - LARVOL DELTA

Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Bipolar I Disorder (clinicaltrials.gov) - P2 | N=253 | Active, not recruiting | Sponsor: Rapport Therapeutics Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Bipolar Disorder • CNS Disorders • Psychiatry

Progress report on new epilepsy treatments: A summary of the Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII). II. Treatments in more advanced clinical development. (PubMed, Epilepsia) - "The treatments reviewed include bexicaserin, a selective 5-hydroxytryptamine (5-HT, serotonin) type 2C (5-HT2C) receptor superagonist investigated as a treatment for developmental and epileptic encephalopathies (DEEs); BMB-101, a selective 5-HT2C receptor agonist investigated for the treatment of absence seizures and DEEs; elsunersen, an antisense oligonucleotide designed for the treatment of early-onset SCN2A-DEE; EPX-100 (clemizole hydrochloride), an antihistamine endowed with agonist activity at 5-HT2A and 5-HT2B receptors, repurposed as a treatment for DEEs; ES-481, an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors containing the transmembrane AMPA receptor regulatory protein γ8 (TARP-γ8), under investigation for the treatment of drug-resistant epilepsy; ETX-101, a gene therapy in development for the treatment of SCN1A-positive Dravet syndrome; PrevEp-006 (intranasal seletracetam), a synaptic vesicle glycoprotein 2A..."

Journal • Absence Seizure Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Psychiatry • GRIN2B • NAV1 • SCN8A

FOCUS 2: Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures (clinicaltrials.gov) - P3 | N=312 | Recruiting | Sponsor: Rapport Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Epilepsy

FOCUS 2: Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures (clinicaltrials.gov) - P3 | N=312 | Not yet recruiting | Sponsor: Rapport Therapeutics Inc.

New P3 trial • CNS Disorders • Epilepsy

FOCUS 1: Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures FOCUS-1 (clinicaltrials.gov) - P3 | N=333 | Recruiting | Sponsor: Rapport Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Epilepsy

FOCUS 1: Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures FOCUS-1 (clinicaltrials.gov) - P3 | N=333 | Not yet recruiting | Sponsor: Rapport Therapeutics Inc.

New P3 trial • CNS Disorders • Epilepsy

Efficacy and Tolerability of RAP-219, a Potential First-in-class Negative Allosteric Modulator of γ8 Transmembrane AMPA Receptor Regulatory Protein: Impact on RNS Long Episodes and Clinical Seizures (AAN 2026) - "Conclusions In this proof-of-concept open-label study of RAP-219 using a novel objective biomarker, patients achieved statistically and clinically meaningful reductions in both LEs and CSs. RAP-219 was generally well tolerated."

Clinical • CNS Disorders • Epilepsy

Study Evaluating the Safety and Efficacy of RAP-219 in Adult Participants With Refractory Focal Epilepsy (clinicaltrials.gov) - P2 | N=30 | Completed | Sponsor: Rapport Therapeutics Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Epilepsy

A Long-term Study of the Safety and Effectiveness of RAP-219 in Adults With Focal Onset Seizures (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Rapport Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Epilepsy

Efficacy and Tolerability of RAP-219, a Potential First-in-Class Negative Allosteric Modulator of γ8 Transmembrane AMPA Receptor Associated Protein: Impact on RNS Long Episodes and Focal Seizures (AES 2025) - "Use of perampanel was exclusionary...The most common ASMs were lamotrigine, cenobamate, levetiracetam, zonisamide, and clobazam... The baseline characteristics of the patients enrolled in this innovative POC study testing the electrographic and clinical effect of RAP-219 in RNS patients with FOS are similar to those reported in contemporary Phase 2 and 3 studies. Efficacy, safety, and tolerability of RAP-219 (to be reported) as evaluated during the 8-week, open-label treatment trial are expected to be highly relevant to patients with drug-resistant FOS."

Clinical • Late-breaking abstract • CNS Disorders • Epilepsy

RAP-219: A Differentiated ASM Targeting Restricted Brain Expression of Transmembrane AMPA Receptor Protein γ8 (AES 2025) - "This phase 1 PET study confirms the neuroanatomical specificity of TARPγ8 expression in healthy subjects. Target RO (50-70%) associated with maximal efficacy in preclinical models was achieved at RAP-219 plasma concentrations between 2.0 and 3.7 ng/mL in human subjects. The results allow selection of a dose range for phase 3 studies in focal epilepsy patients."

Back Pain • CNS Disorders • Epilepsy • Musculoskeletal Pain

A Long-term Study of the Safety and Effectiveness of RAP-219 in Adults With Focal Onset Seizures (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Rapport Therapeutics Inc.

New P2 trial • CNS Disorders • Epilepsy

Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Bipolar I Disorder (clinicaltrials.gov) - P2 | N=224 | Recruiting | Sponsor: Rapport Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Bipolar Disorder • CNS Disorders • Psychiatry

Study Evaluating the Safety and Efficacy of RAP-219 in Adult Participants With Refractory Focal Epilepsy (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Rapport Therapeutics Inc. | N=20 ➔ 30

Enrollment change • CNS Disorders • Epilepsy

Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Bipolar I Disorder (clinicaltrials.gov) - P2 | N=224 | Not yet recruiting | Sponsor: Rapport Therapeutics Inc.

New P2 trial • Bipolar Disorder • CNS Disorders • Psychiatry

Study Evaluating the Safety and Efficacy of RAP-219 in Adult Participants With Refractory Focal Epilepsy (clinicaltrials.gov) - P2 | N=20 | Active, not recruiting | Sponsor: Rapport Therapeutics Inc. | Trial completion date: Jun 2025 ➔ Sep 2025 | Trial primary completion date: Mar 2025 ➔ Jul 2025 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

Optimal Cut Point for Reduction in Long Episode Frequency to Predict Meaningful Change in Clinical Seizure Frequency (GlobeNewswire) - "Using a receiver operator characteristic (ROC) analysis, the data confirmed that a 30% reduction in LE frequency was the optimal cut point associated with a clinically meaningful (≥50%) reduction in clinical seizures, regardless of the antiseizure medication initiated, revealing a linear relationship between long episode and clinical seizure frequencies."

Clinical • Epilepsy

Antiseizure Effects with Selective TARPγ8 Negative Allosteric Modulators in Preclinical Seizure Models (GlobeNewswire) - "RAP-219 provided potent, dose-dependent antiseizure effects in pentylenetretrazol (PTZ) and corneal kindling preclinical seizure models, with maximal protection observed with 70% receptor occupancy and RAP-219 mean plasma concentration of 7 ng/mL."

Preclinical • Epilepsy

Rapport Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Update (GlobeNewswire) - "Continued momentum in the Phase 2a trial of RAP-219 in patients with refractory focal epilepsy, with topline results expected in the third quarter of 2025; Expect to initiate a Phase 2a trial in patients with bipolar mania in the third quarter of 2025, with topline results expected in the first half of 2027 ; Finalizing Plans to Conduct Phase 2a Trial in Diabetic Peripheral Neuropathic Pain (DPNP)."

New P2a trial • P2a data • Bipolar Disorder • Epilepsy • Peripheral Neuropathic Pain

Antiseizure Effects with Selective TARPγ8 Negative Allosteric Modulators in Preclinical Seizure Models (AAN 2025) - "TARPγ8 NAMs provided potent, dose-dependent antiseizure effects maintained after 7d in preclinical focal and generalized seizure models without impairing motor function, yielding a high therapeutic index. TARPγ8 NAMs may provide a new precision medicine option with improved tolerability for patients with epilepsy."

Preclinical • CNS Disorders • Epilepsy

Rapport Therapeutics Announces New Phase 1 Data, Further Supporting RAP-219's Transformative Potential for CNS Disorders (GlobeNewswire) - P1 | N=NA | "MAD-2 trial results are summarized below: RAP-219 was generally well tolerated. All TEAEs were Grade 1 or 2 and generally consistent with tolerability observed in prior Phase 1 trials. Unlike with many anti-seizure medications, no sedation or motoric impairments were observed with RAP-219, consistent with target biology and preclinical observations. Target exposures and RO were achieved within 5 days of dosing across various dosing regimens. A Phase 2a proof-of-concept trial is currently underway to evaluate RAP-219 in patients with refractory focal epilepsy, with topline results expected in mid-2025."

P1 data • P2a data • CNS Disorders • Epilepsy

Rapport Therapeutics Announces New Phase 1 Data, Further Supporting RAP-219's Transformative Potential for CNS Disorders (GlobeNewswire) - P1 | N=NA | "The PET data demonstrated that Cohort 1 (the dosing regimen utilized in the ongoing Phase 2a trial in focal epilepsy) exceeded the target RO range associated with maximal efficacy in prior preclinical models (50%-70%) within five days of dosing, while maintaining a differentiated tolerability profile generally consistent with prior Phase 1 trial findings. The trial confirmed that the expression of TARP8-containing AMPA receptors is enriched in the hippocampus and cerebral cortex and is minimal in the cerebellum and brain stem. Collectively, data from the PET and MAD-2 trials demonstrated that plasma concentrations and associated target RO could be achieved within 5 days."

P1 data • CNS Disorders

Safety, Tolerability, and Pharmacokinetics of RAP-219 in Healthy Volunteers (AES 2024) - "Multi-day oral dosing of RAP-219 (0.75 mg/d, 5d; 1.25 mg/d, 23d) exceeded the target exposure (projected 70% RO) by Day 14 and achieved projected 80% RO by Day 28 with no related TEAEs. The mean Cmax on Day 28 following 1.25 mg/d of RAP-219 greatly exceeded the Cmax value following a single 3 mg dose of RAP-219, yet CNS TEAEs observed at the highest doses in the SAD trials were not observed in the MAD trial, confirming that the rapid rate of increase in exposures, rather than absolute exposures, is likely responsible. Thus, TEAEs may attenuate with a treatment regimen consisting of a lower initial dose titrated to reach the target dose with repeated administration and accumulation of RAP-219 over time, aided by the compound's long terminal elimination half-life."

Clinical • PK/PD data • Cardiovascular • CNS Disorders • Epilepsy • Insomnia • Mood Disorders • Pain • Psychiatry • Sleep Disorder

Impact of Food on the PK and Tolerability of RAP-219 in Healthy Volunteers (AES 2024) - "Results from this initial evaluation of the effect of high-fat, high-calorie meal on RAP-219 PK suggest that there was a slight increase in Cmax and AUC0-144 as well as a slight delay in RAP-219 absorption under fed conditions compared to fasted. This study informs and supports ongoing clinical development. More robust FE studies are planned to fully characterize the effect of food on RAP-219 PK."

Clinical • CNS Disorders • Epilepsy

Antiseizure Effects with Selective TARPγ8 Negative Allosteric Modulators in Preclinical Seizure Models (AES 2024) - "Here, two TARPγ8 negative allosteric modulators (NAMs), RAP-219 and RTX-1738, were assessed in preclinical seizure models. Subjects were adult male CF-1 mice (Charles River, Portage, MI).RAP-219 (single dose, po, vs vehicle): pentylenetetrazol (PTZ) and corneal kindling (CK) models... Selective inhibition of AMPA receptors containing TARPγ8 provided potent, dose-dependent antiseizure effects that were maintained after 7-day dosing period in preclinical models of focal and generalized seizures. Exposures that produced antiseizure effects did not impair motor function, yielding a high therapeutic index. TARPγ8 NAMs may provide a new precision medicine option for patients with epilepsy with improved tolerability."

Preclinical • CNS Disorders • Epilepsy