Rapport Therapeutics – RAP-219 Phase 2 Clinical Trial
- rspace2
- Aug 27
- 6 min read
Executive Summary
Rapport has a phase 2 (P2) readout upcoming for RAP-219, a TARPy8 AMPA receptor modulator. The preclinical results are promising, but there is no significant data on the use of Long Episode (LE) reduction as an endpoint. Additionally, the sample size of the study is only 14, and the patients have severe focal epilepsy to be implanted with the RNS device. There are also concerns about neuropsychiatric side effects. Ultimately, I do believe this trial has a decent shot at succeeding, but there are too many risks in the trial and drug design for me to be comfortable with going long. I am staying on the sidelines with this one.
The catalyst is due in Q3 2025.
Background Information
Focal Onset Seizures/Focal Epilepsy
Focal epilepsy is a chronic neurological condition characterized by recurrent focal-onset seizures — seizures that begin in one area or network of cells on one side of the brain. It can occur at any age and may be caused by structural, genetic, infectious, metabolic, immune, or unknown factors. There are two types of focal-onset seizures that are based on awareness:
1. Focal aware seizure (simple partial)
a. Consciousness is preserved
b. Symptoms depend on the involved brain areas.
2. Focal impaired awareness seizure (complex partial)
a. Consciousness impaired or altered
b. May include automatisms (lip smacking, picking at clothes)
Motor-onset seizures involve kinetic movements, whereas non-motor-onset seizures primarily involve sensory symptoms, emotional changes, autonomic signs, and cognitive symptoms.
Diagnosis is typically made through an EEG. Structural causes can be detected with a brain MRI.
Approximately 3.3 million people in the US (~1%) live with epilepsy. Focal epilepsy comprises about 60% of all epilepsy cases.
Treatment includes anti-seizure medications (ASMs). First-line choices include lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, and lacosamide. Surgery, neuromodulation, and a ketogenic diet are considered if epilepsy is refractory to ASMs.
60-70% achieve reasonable seizure control with medication. However, the remaining patients develop drug-resistant focal epilepsy, the focus of this clinical trial.
Development History
There are five broad categories of ASMs.
1. Fast Na+ channel modulators
a. Work by preventing certain nerve cells from firing by stopping or reducing sodium influx into the cell through voltage-gated sodium channels.
b. Examples include carbamazepine, oxcarbazepine, lamotrigine, etc
2. SV2A Ligands
a. Bind to the synaptic vesicle protein 2A in the brain, which modulates neurotransmitter release.
b. Examples include levetiracetam and brivaracetam.
3. AMPA antagonists
a. Blocks the action of AMPA receptors, blocking the binding of glutamate, the main excitatory neurotransmitter.
b. The primary example is perampanel, which is a noncompetitive antagonist. It binds to a different receptor site than glutamate and prevents glutamate from binding.
4. CA2+ α2δ channel ligands
a. Interacts with the α2δ subunit of voltage-gated calcium channels. They modulate neurotransmission.
b. Examples include gabapentin and pregabalin.
5. Multi-target
a. Primarily modulate the GABA system, the primary inhibitory neurotransmitter.
b. Examples include valproate and topiramate.
RAP-219 is a TARPy8 AMPA receptor modulator. It targets the TARPy8 receptor, which has selectively high concentrations in the mesial temporal lobe and cerebral cortex, the primary origination points for focal seizures. Both RAP-219 and perampanel target the AMPA receptor. The higher selectivity of the TARPy8 receptor is designed to minimize adverse effects as compared to perampanel.
Perampanel
Perampanel has well-demonstrated clinical efficacy in focal onset seizures. Roughly 33% of drug-resistant focal-onset epilepsy patients showed a greater than 50% reduction in seizures when treated with perampanel in a phase 3 study. However, dizziness (30%), somnolence (18%), and ataxia (10%) are common adverse events. Additionally, the drug carries a psychiatric black box warning. Irritability, anger, aggression, and even homicidal ideation occurred at much higher rates (8%) in the treatment group compared to the placebo group (2%).
One aspect that is notably absent from the perampanel data is its effect on long episode reduction, the primary endpoint of the study in question.
ES-418
ES-418 is a TARP inhibitor that targets hippocampal excitatory glutamate transmission by disrupting protein-protein interactions between the AMPA receptor and the y-8 TARP. The trials on this drug have been small, but there does appear to be anti-seizure activity. It is unclear whether the molecule will be pursued in future stages of development. It is difficult to read into the results of this drug much.
Rapport and RAP-219
RAP-219 is being tested in an open-label phase 2 trial. The study design is well-summarized in the slide below, taken from the recent Rapport corporate presentation.
There are several important factors to note for the trial. First, the sample size of the trial is small; there are seven females and seven males enrolled. Second, the trial uses a reduction in long episodes as a primary endpoint. Long episodes are defined as “prolonged abnormal electrographic activity that does not return to baseline within 30-60 seconds.” Most LEs tend to be electrographic (sub-clinical) and detected directly at the epileptogenic cortex. The NeuroPace RNS System, an FDA-approved closed-loop neurostimulator for focal epilepsy, detects these. All 14 patients enrolled in the study have the device implanted. During LEs, the device will deliver a specific electrical pulse to the epileptogenic site to stop a clinical seizure. The device records all LEs.
Preclinical Results
The main reason to be optimistic about the readout of the drug is the preclinical results. Unlike many other disease models, preclinical mouse models tend to be highly predictive of efficacy in humans. In focal seizures, this model is the corneal mouse kindling test/model (CKT). Seizures in mice are produced by repeated, brief electrical stimulations delivered through the cornea. All drugs with proven efficacy in focal seizures performed well on the corneal mouse kindling model, with perampanel being one of the most potent performers. Compounds that have an ED50 <10mg/kg almost always emerge as clinically useful for focal seizures. The ED50 of RAP-219 is 0.02mg/kg.
I could not find any examples of compounds that performed poorly on the CKT and then were approved. Likewise, there are only a few examples of false positives. MK-801 and GYK1-52466 performed well on the CKT but were unusable clinically due to severe AEs.
I am less optimistic about the usefulness of the rotarod model in predicting AEs in humans, but the data from that test were excellent as well.
Phase 1 Results
The PK/PD profile looks excellent.
From the clinical PET scans, it appears the drug is reaching the target areas in the brain.
The main cause for concern here is the potential for neuropsychiatric side effects. From their single-ascending dose (SAD) study:
“Results: SAD: Subjects (n=41) were randomized to RAP-219 or placebo (3:1 ratio; RAP-219, n=6/dose; pooled placebo, n=11). RAP-219 exhibited slightly less than dose-proportional increases in Cmax and AUC0-144 values with a median tmax of 4h. Elimination was biphasic (mean t1/2, 278h). No Grade 3 or worse TEAEs were observed. The most common TEAEs (any RAP-219 dose) were sinus tachycardia, anxiety, and dizziness (n=4-5, 13.3%-16.7%), mostly in the 2 and 3 mg groups.”
Rapport claims the side effects are due to the quick titration schedule. However, I am skeptical of this claim, as typically, AEs are dose-dependent. The MAD study seemed to have fewer neuropsychiatric side effects, but there is cause for concern. Additionally, the dosages used for many patients in the MAD are lower than the dosages that will be used in phase 2.
Discussion
I would expect this drug to have very similar results to perampanel. The preclinical data are excellent and tend to be highly predictive of efficacy in focal seizures. The AE profile from the SAD phase 1 study raised some alarms around neuropsychiatric side effects.
Although perampanel showed efficacy in focal seizures in a drug-resistant population, about 33% achieved a 50% reduction compared to about 15% in the placebo group. This difference is not massive, given the N of that study was 321 compared to an N of 14 in the phase 2 study. This study would not be adequately powered to detect that difference. Rapport hopes to compensate for that using the LE endpoint.
There is no data on how perampanel affects LEs. From the papers on the correlation between LE and seizure reduction, it is almost a given that perampanel will reduce LEs, but the magnitude is uncertain. I have no idea if this study is adequately powered to detect the reduction.
This study relies on a third-party device to detect and record LEs. Rapport is trying to offset the costs of running a much larger trial by using a surrogate endpoint. It could work, but it is a large risk.
The patients in this study have severe drug-resistant focal epilepsy to qualify for the RNS implant.
The AE profile could be much worse in this study. The current generation of ASMs will always carry significant AEs, and it isn't easy to profile when they appear in studies. Given that this study is smaller than phase 1, I would not expect the AEs to kill the drug yet, but it is always a risk.
Conclusion
The data give reason for cautious optimism for the upcoming readout for RAP-219 in focal epilepsy. However, the setup is not ideal for the reasons highlighted above. Therefore, I am staying on the sidelines with this one. Other ASMs in the pipeline, such as $DRUG’s, are likely more derisked and have a higher probability of working.
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