AAN 2026: Long Half-Life and Long-Acting Injectable, What Pharmacists Should Know About RAP-219's Dosing Advantages for Focal Epilepsy

In an interview with Pharmacy Times at the 2026 American Academy of Neurology (AAN) Annual Meeting, William Motley, MD, program lead at Rapport Therapeutics, presented phase 2 data for RAP-219 in patients with drug-resistant focal epilepsy who also received responsive neurostimulation (RNS) device implantation—a study design that allowed objective electrographic seizure data to complement clinical outcomes. Twenty-four percent of patients achieved complete seizure freedom over the full 8-week treatment period despite a median baseline of 10 clinical seizures per month.

Pharmacy Times: Can you introduce yourself and explain your current role?

William Motley, MD: Hi. My name is William Motley. I’m the program lead at Rapport Therapeutics, a company based in Boston developing a drug for epilepsy.

Pharmacy Times: Can you give us a brief overview of the RAP-219 phase 2 trial—what you were studying and who the patients were?

Motley: Our phase 2 data, which we are presenting again tomorrow at AAN, represent a study of RAP-219 in patients with drug-resistant focal epilepsy. For the study, we selected patients who have responsive neurostimulation (RNS) devices. The RNS System is a therapeutic device, but for the purposes of this study, we were particularly interested in testing RAP-219 in these patients because the device also provides biomarker outputs that serve as an objective measure of how patients are doing. By studying RAP-219 in patients with the RNS System, we were able to obtain objective electrographic seizure data reflecting the drug’s effect.

Pharmacy Times: The trial showed that 24% of patients achieved complete seizure freedom over 8 weeks. How significant is that number in the context of focal-onset seizures?

Motley: That’s a great question. We have heard consistently from key opinion leaders in epilepsy that seizure freedom is a critical measure of how patients are doing—and a particularly important metric for gauging the degree to which a new drug can improve a patient’s quality of life. With that in mind, we were especially interested in tracking the proportion of patients who achieved seizure freedom. We assessed seizure freedom across the entire study period, from day 1 through day 56, and found that 24% of patients were completely seizure free for that entire duration. We were really pleased with that result, particularly given the baseline characteristics of the patients who entered the study—they had a median of 10 clinical seizures per month. That makes the result a meaningful and clinically significant change.

Pharmacy Times: Seizure reductions actually improved during the follow-up period after patients stopped treatment. What does that tell you about RAP-219’s mechanism of action?

Motley: RAP-219 is a negative allosteric modulator of AMPA receptors that are bound to an accessory protein called TARP gamma-8. TARP gamma-8 is expressed selectively in the forebrain, and by targeting AMPA receptors in this way, we believe we can broaden the therapeutic index and eliminate some of the dose-limiting tolerability effects associated with broader, less selective AMPA receptor inhibition.

Pharmacy Times: Can you tell us a bit more about the follow-up period data based on the mechanism of action?

Motley: The follow-up period data, which we are showcasing here at AAN, gave us an interesting opportunity to observe how patients did after stopping treatment. RAP-219 is a very potent and selective molecule with a very long half-life. After treatment ended, we followed blood levels of RAP-219 in patients and also monitored both biomarker outcomes and clinical seizure outcomes during the follow-up period. What we saw—and were genuinely pleased by—was that in the first 4 weeks after stopping treatment, both long-episode frequency reductions (the key biomarker output of the study) and clinical seizure outcomes actually improved compared to the treatment period itself. This follows a general trend observed across epilepsy studies, in which patients tend to do better the longer they are on antiseizure medications. In our case, we believe this is consistent with the pharmacokinetic data showing that RAP-219 was still present in patients’ systems during that follow-up window.

Pharmacy Times: For pharmacists managing patients with epilepsy, what are the practical implications of a drug whose therapeutic effects persist for weeks after the last dose?

Motley: We are very excited about advancing RAP-219 into phase 3 clinical trials, which will use a more traditional design evaluating clinical seizure outcomes over a 3-month period. Patients in those phase 3 studies will also have the opportunity to continue into an open-label extension and long-term safety study, which will give us the chance to appreciate the effects of RAP-219 across a broader population. In thinking about the specific implications of a long half-life medication, we see a great deal of opportunity for patient benefit. One of the things that patients with focal onset seizures fear most is missing doses, and we are hopeful that a long half-life could meaningfully reduce the consequences of an occasional missed dose. We are also very excited about a second development pathway for RAP-219: a long-acting injectable formulation. We believe this could be the first long-acting injectable medication developed for patients with focal onset seizures. That formulation is currently in IND-enabling studies, so it will be some time before it is available in clinical use, but we are optimistic about what it could offer patients.