Epilepsy Agent RAP-219 Shows Promising Safety, Target Occupancy Across Phase 1 Studies

Steve Paul, MD

New data from the phase 1 PET and MAD-2 trials of RAP-219, a therapeutic in development for focal epilepsy, showed that treatment with the agent was generally well tolerated, with target exposures and receptor occupancy (RO) achieved within 5 days of dosing. These data, along with other phase 1 studies conducted to date, further support the therapy’s development in an ongoing phase 2a study that’s expected to have topline results released midway through this year.¹

The PET trial (RAP-219-103) and MAD-2 trial (RAP-219-104) were complementary studies in healthy volunteers investigating RAP-219. The PET trial, an open-label study, confirmed neuroanatomical expression of TARPγ8 and explored the relationship between pharmacokinetics (PK) and brain target RO. It included three dosing cohorts, with one mirroring the ongoing Phase 2a epilepsy trial (0.75 mg daily for 5 days, then 1.25 mg daily for 9 days) and others using lower doses to characterize the PK-RO relationship.

The MAD-2 trial, a double-blind, placebo-controlled study, assessed safety, tolerability, and dose escalation to achieve therapeutic levels more quickly. Its three cohorts featured escalating doses, with schedules ranging from shorter escalation periods to extended dosing (e.g., 1.75 mg for up to 24 days).

In the PET trial, treatment with the agent at the dosing regimen to be used in the phase 2a trial exceeded the target RO range associated with maximal efficacy in prior preclinical models (50-70%) within 5 days of dosing, while maintaining a differentiated tolerability profile generally consistent with prior phase 1 trial findings. In addition, the trial confirmed that TARPy8-containing AMPA receptors are primarily in the hippocampus and cortex, with minimal cerebellum and brainstem expression.

"These Phase 1 results reinforce our belief in RAP-219’s distinct profile and potential to deliver transformative outcomes for patients," Steve Paul, MD, cofounder and chair of the board of directors at Rapport, said in a statement.¹ "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."

RAP-219 aims to selectively target TARPγ8, a receptor-associated protein which is associated with the neuronal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, which is known as a clinically confirmed target for epilepsy. In the MAD-2 trial, the therapy was well tolerated, as all treatment-emergent adverse events were Grade 1 or 2 and generally consistent with its previously observed profile. Notably, there were no sedation or motoric impairments observed in treated patients, contrasting effects typically seen in many antiseizure medications.

Abe Ceesay

"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," Abe Ceesay, chief executive officer at Rapport, said in a statement.¹ "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."

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The ongoing phase 2a proof-of-concept study is rather unique in that it enrolls adult patients with drug-resistant epilepsy who have an implanted responsive neurostimulation (RNS) device, which continually captures intracranial electroencephalography data and records the frequency of long episodes (LE). Approximately 20 patients, aged 18-65 years old undergo an 8-week, open-label treatment period where they receive 0.75 mg/d RAP-219 for 5 days followed by 1.25 mg/d for the remainder of the treatment period. The follow-up period includes RNS System data collection, monthly pharmacokinetic insights, and clinical seizure diary collection.²

Investigators will use change in 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 as a key end point. Other major end points include LE frequency responder analysis, change in estimated electrographic seizures (EES), clinical seizure frequency, and additional iEEG biomarkers per 28 days.

Over the 4 phase 1 trials testing RAP-219 in healthy volunteers (n = 100), results have shown that the agent is generally well tolerated over up to 28 days, with no serious adverse events, no TEAEs above Grade 2, and no significant lab or ECG abnormalities. While three participants (3%) discontinued due to TEAEs, the trials demonstrated favorable tolerability across dosing regimens, supporting RAP-219's potential to selectively target TARPγ8-associated AMPA receptors and improve the therapeutic index of AMPA receptor modulation.¹

Recently, Martha Morrell, MD, a clinical professor of neurology at Stanford University School of Medicine, and chief medical officer at NeuroPace, sat down in an interview with NeurologyLive® to discuss how NeuroPace's RNS System will leverage big data to personalize epilepsy treatments like RAP-219, and the insights that have emerged from the accumulated data. In the clip below, she talked about the role that artificial intelligence plays in the collaboration between NeuroPace and Rapport, and how it contributes to the advancement of therapies for focal epilepsy.

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REFERENCES
1. CORRECTION -- Rapport Therapeutics Announces New Phase 1 Data, Further Supporting RAP-219's Transformative Potential for CNS Disorders. News release. January 9, 2025. Accessed January 9, 2025. https://www.globenewswire.com/news-release/2025/01/09/3007108/0/en/CORRECTION-Rapport-Therapeutics-Announces-New-Phase-1-Data-Further-Supporting-RAP-219-s-Transformative-Potential-for-CNS-Disorders.html
2. Motley WW, Friedman D, Davis KA, et al. Novel design of a focal epilepsy proof-of-concept study of RAP-219, a negative allosteric modulator of the y8 transmembrane AMPA receptor-associated regulatory protein (TARPy8). Presented at: 2024 American Epilepsy Society (AES) Annual Meeting; December 6-10; Los Angeles, CA.