RAP-219 / Rapport Therap - LARVOL DELTA

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

Study Evaluating the Safety and Efficacy of RAP-219 in Adult Participants With Refractory Focal Epilepsy (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Rapport Therapeutics Inc. | Not yet recruiting ➔ Recruiting | Initiation date: Jun 2024 ➔ Sep 2024

Enrollment open • Trial initiation date • CNS Disorders • Epilepsy

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). I. Drugs in preclinical and early clinical development. (PubMed, Epilepsia) - "These include AMT-260, a gene therapy designed to downregulate the expression of Glu2K subunits of kainate receptors, in development for the treatment of drug-resistant seizures associated with mesial temporal sclerosis; BHV-7000, a selective activator of heteromeric Kv7.2/7.3 potassium channels, in development for the treatment of focal epilepsy; ETX101, a recombinant adeno-associated virus serotype 9 designed to increase NaV1.1 channel density in inhibitory γ-aminobutyric acidergic (GABAergic) neurons, in development for the treatment of SCN1A-positive Dravet syndrome; GAO-3-02, a compound structurally related to synaptamide, which exerts antiseizure activity at least in part through an action on cannabinoid type 2 receptors; LRP-661, a structural analogue of cannabidiol, in development for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex; OV329, a selective inactivator of GABA aminotransferase, in..."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Immunology • NAV1

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

New P2 trial • CNS Disorders • Epilepsy