The FDA has placed a clinical hold on Rapport Therapeutics' investigational new drug (IND) application for RAP-219, a therapy being developed for diabetic peripheral neuropathic pain (DPNP). The agency is requesting additional information and amendments related to the trial's protocol design.
Rapport Therapeutics believes it can address the FDA's requests and will provide an update on the expected timing of the Phase 2a trial initiation once available. According to Rapport, the clinical hold is specific to the DPNP indication and does not impact other studies of RAP-219, including the ongoing Phase 2a trial for focal epilepsy and a planned proof-of-concept trial for bipolar disorder.
"We are pleased with the progress we’re making with RAP-219, particularly as we continue the execution of our phase 2a proof-of-concept trial in focal epilepsy," said Abraham N. Ceesay, chief executive officer of Rapport, in a statement. "The continued learnings from our ongoing clinical activities, including the MAD-2 and PET trials as well as our pharmaceutical development efforts, have only strengthened our confidence in the pipeline-in-a-product potential of RAP-219 as a potentially transformational treatment for focal epilepsy, peripheral neuropathic pain, and bipolar disorder."
Ongoing and Upcoming Trials
Rapport is currently conducting a second multiple ascending dose trial (MAD-2) of RAP-219, expected to be completed in the fourth quarter of 2024. This trial will explore additional dosing regimens to inform dosing for the Phase 2a trial targeting bipolar acute mania. Initial MAD trials showed RAP-219 was generally well-tolerated at target therapeutic exposures, with no serious adverse effects or drug-related treatment-emergent adverse events above Grade 1.
The company's Phase 1 human positron emission tomography (PET) trial in healthy adult volunteers is also underway. This trial utilizes a companion PET radiotracer to validate brain target receptor occupancy and brain region specificity across a range of RAP-219 doses and exposure levels. Topline results from the MAD-2 and PET trials are expected in the first quarter of 2025.
RAP-219 Mechanism of Action
RAP-219 is designed to selectively target TARPγ8, a receptor-associated protein linked to the neuronal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor), a clinically validated target for epilepsy. Rapport is also developing a long-acting injectable formulation of RAP-219 as a potential depot antiseizure medication, aiming to improve ease of use and patient adherence.
The Phase 2a proof-of-concept trial of RAP-219 in focal epilepsy is actively recruiting and screening patients. The trial is on track, with topline results expected in mid-2025. This trial enrolls adult patients with drug-resistant focal epilepsy who have an implanted responsive neurostimulation (RNS) device, which continuously captures intracranial electroencephalography data and records the frequency of long episodes. The patient population is demographically similar to those expected in future registrational trials.
Rapport Therapeutics presented on the mechanism of action for RAP-219 and the design of the Phase 2a trial for focal epilepsy at the International League Against Epilepsy 15th Annual European Epilepsy Congress and the 2024 Epilepsy Foundation Pipeline Conference in September 2024. The company will also present four poster presentations at the 2024 Annual Epilepsy Society meeting in December, focusing on preclinical data, SAD/MAD trial results, food effect data, and new analyses on the correlation between RNS-measured long episode and clinical seizure frequency in patients with refractory focal epilepsy.
