Rapport Therapeutics announced positive results from its Phase 1 positron emission tomography (PET) and multiple ascending dose (MAD-2) trials of RAP-219, a small molecule precision medicine being developed for central nervous system (CNS) disorders. The data indicate that RAP-219 achieved target receptor occupancy (RO) associated with maximal efficacy in preclinical models within five days of dosing, while also demonstrating a differentiated tolerability profile.
RAP-219's Target Engagement and Tolerability
The PET trial (RAP-219-103) was an open-label study in healthy volunteers designed to confirm neuroanatomical expression of TARPγ8 and establish the relationship between pharmacokinetics (PK) and brain target RO with RAP-219. The trial confirmed that the expression of TARPγ8-containing AMPA receptors is enriched in the hippocampus and cerebral cortex and is minimal in the cerebellum and brain stem.
The MAD-2 trial (RAP-219-104) was a double-blind, placebo-controlled trial in healthy volunteers designed to further evaluate safety and tolerability with continued dose escalation, as well as to shorten the time to reach predicted therapeutic levels of RAP-219. RAP-219 was generally well tolerated, with all treatment-emergent adverse events (TEAEs) being Grade 1 or 2 and consistent with tolerability observed in prior Phase 1 trials. Notably, no sedation or motoric impairments were observed.
Steve Paul, M.D., Rapport cofounder and chair of the board of directors, stated, "These Phase 1 results reinforce our belief in RAP-219’s distinct profile and potential to deliver transformative outcomes for patients. The data demonstrate that neuroanatomical specificity can be achieved through RAP-219’s selective targeting of a receptor-associated protein, and RAP-219 was able to quickly achieve target engagement and therapeutic exposures in the brain while maintaining a generally favorable tolerability profile. Additionally, the data provide further support for the dosing regimen selected for our ongoing Phase 2a trial in focal epilepsy."
Ongoing Phase 2a Trial in Focal Epilepsy
Rapport Therapeutics is currently conducting a Phase 2a proof-of-concept trial to evaluate RAP-219 in patients with refractory focal epilepsy. Topline results from this trial are expected in mid-2025. The trial design incorporates an 8-week, open-label treatment period where patients receive 0.75 mg/d RAP-219 for 5 days followed by 1.25 mg/d for the remainder of the treatment period.
The primary endpoint of the Phase 2a trial is the change in long episode (LE) frequency per 28 days during the second 4-week interval of the open-label treatment period compared with the frequency across retrospective and prospective baseline. Secondary endpoints include LE frequency responder analysis, change in estimated electrographic seizures (EES), clinical seizure frequency, and additional iEEG biomarkers per 28 days.
RAP-219: A Precision Medicine Approach
RAP-219 is a clinical-stage AMPA receptor negative allosteric modulator designed to achieve neuroanatomical specificity through its selective targeting of AMPA-associated protein, TARPγ8. The selective targeting of TARPγ8 may provide a differentiated approach to treating neurological disorders, potentially leading to improved activity, tolerability, and a higher therapeutic index compared to traditional neuroscience medications.
Abe Ceesay, chief executive officer of Rapport, commented, "Due to the non-specific nature of currently available and other investigational treatments, many patients continue to endure significant side effects, which limit therapeutic efficacy and diminish their quality of life. RAP-219 was designed to overcome such limitations, and we believe these compelling new data support our approach as we advance our Phase 2a trial in focal epilepsy, with topline results expected in mid-2025."
