Safety, Tolerability, and Pharmacokinetics of RAP-219 in Healthy Volunteers
Abstract number :
2.372
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
1224
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Swamy Yeleswaram, PhD – Rapport Therapeutics, Inc.
Bradley Galer, MD – Rapport Therapeutics, Inc.
William Motley, MD – Rapport Therapeutics, Inc.
Stephen Greene, PharmD – Rapport Therapeutics, Inc.
Rationale: TARPγ8, a transmembrane AMPA receptor regulatory protein (TARP), is enriched in hippocampus, cortex, and amygdala and absent in hindbrain. Compounds targeting only AMPA receptors in complex with TARPγ8 provide a novel precision approach for seizure control. RAP-219, a TARPγ8 negative allosteric modulator, has been efficacious in preclinical seizure models without impairment on rotarod, demonstrating a wide therapeutic window. Safety, tolerability, and pharmacokinetics (PK) of RAP-219 in healthy, adult subjects were evaluated using single and multiple ascending dose (SAD and MAD) trials.
Methods: Healthy subjects aged 18-55y were recruited to the randomized, double-blinded, placebo-controlled trials. SAD: subjects were given a single oral dose of RAP-219 (0.25, 0.5, 1, 2, or 3 mg) or placebo. MAD: subjects were given a daily oral dose of RAP-219 (target doses: 0.25, 0.5, 0.75, or 1.25 mg/d) or placebo for 14 or 28 days (5 cohorts; Table 1).
Adverse events (AEs; treatment-emergent [TEAEs] and serious [SAEs]) were evaluated using the NCI-CTCAE v5.0 (Grade 1 to 5, mild to AE-related death). Dose-limiting toxicities and PK were also evaluated.
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.
MAD: Subjects (n=40) were randomized to an active dose regimen of RAP-219 or placebo (3:1 ratio; RAP-219, n=6/dose; pooled placebo, n=10). RAP-219 exhibited an approximately dose-proportional increase in Cmax and AUCtau with a median tmax of approximately 4h on Days 1, 14, and 28 across all cohorts. There were no Grade 2 or worse TEAEs and no SAEs in any cohort. The most common TEAEs (any RAP-219 dose) were sinus tachycardia, headache, insomnia, and medical device site reaction (n=3-4, 10%-13%). Cohorts 4 and 5 achieved or exceeded the target of 70% projected receptor occupancy (RO) throughout the dosing interval on Day 28 (Fig 1) and reported no treatment-related TEAEs. Dose dependency of the AEs was not observed.
Conclusions: Multi-day oral dosing of RAP-219 (0.75 mg/d, 5d; 1.25 mg/d, 23d) exceeded the target exposure (projected 70% RO) by Day 14 and achieved projected 80% RO by Day 28 with no related TEAEs. The mean Cmax on Day 28 following 1.25 mg/d of RAP-219 greatly exceeded the Cmax value following a single 3 mg dose of RAP-219, yet CNS TEAEs observed at the highest doses in the SAD trials were not observed in the MAD trial, confirming that the rapid rate of increase in exposures, rather than absolute exposures, is likely responsible. Thus, TEAEs may attenuate with a treatment regimen consisting of a lower initial dose titrated to reach the target dose with repeated administration and accumulation of RAP-219 over time, aided by the compound’s long terminal elimination half-life.
Funding: Funded by Rapport
Anti-seizure Medications