Authors :
Presenting Author: Stephen Greene, PharmD – Rapport Therapeutics, Inc.
Marie Cohilis, n/a – Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, University of Leuven
Michel Koole, PhD – Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, University of Leuven
Kim Serdons, n/a – Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, University of Leuven
Marissa Herbots, n/a – Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven
Kathleen Sierens, n/a – Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven
Jan de Hoon, FBPhS – Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven
Koen Van Laere, MD, PhD, DrSc – Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, University of Leuven
Swamy Yeleswaram, PhD – Rapport Therapeutics, Inc.
Rationale:
Transmembrane AMPA receptor regulatory proteins (TARPs) are anatomically restricted accessory proteins. In preclinical PET studies, TARPγ8 was highly expressed in the cortex, hippocampus, and amygdala. RAP-219, a TARPγ8 negative allosteric modulator, offers a precision approach for the treatment of focal epilepsy. This phase 1 PET study aimed to confirm the neuroanatomic expression of TARPγ8 in humans and to establish the receptor occupancy (RO), safety, tolerability, and pharmacokinetics (PK) of RAP-219.Methods: Healthy adults (18-55 y) were enrolled in three cohorts: Cohort 1, 0.75 mg once daily (QD) D2-D6, followed by 1.25 mg QD until D15; Cohort 2, 0.25 mg QD for 15 days; Cohort 3, 0.25 mg QD D2-8, followed by 0.5 mg QD until D15.
D1 pre-dose baseline PET scans were obtained using an intravenous injection of a TARPγ8-specific tracer, [18F]JNJ-64511070 (185 MBq [5mCi] ±10), and arterial blood sampling. An oral dose of RAP-219 was administered on D2-D15. Serial blood samples were collected on D2 and D15. Post-dose PET scans were obtained on D15, 3-4 h after RAP-219 administration.
TARPγ8 RO was estimated using baseline and post-dose distribution volume and Lassen plots, assuming constant non-displaceable distribution volume between baseline and post-dose periods. Distribution volumes were determined by a two-tissue compartment model. Correlation between RAP-219 plasma concentrations (D15, 4 h post-dose) and estimated RO was determined using a sigmoid Emax model.
PK and adverse events (AEs) using NCI-CTCAE v5.0 grading (Grades 1 [mild] to 5 [AE-related death]) were summarized overall and by dose level.
Results: Sixteen subjects (mean age, 39 y; 94% male) were sequentially enrolled into Cohort 1 (n=6), Cohort 2 (n=6), and Cohort 3 (n=4).
Brain regions with the greatest mean distribution volume of TARPγ8 at baseline were the neocortex and mesial temporal lobe, including the hippocampus and amygdala. Target RO (50-70%) was achieved with RAP-219 plasma concentrations of 2.0-3.7 ng/mL.
The PK profile observed was mainly consistent with previous multiple-dose studies.
The most common TEAEs (≥3 subjects) included headache (n=7, 43.8%), fatigue (n=5, 31.3%), catheter site hematoma, abnormal dreams, disturbance in attention, and back pain (n=3, 18.8% each). No SAEs were observed in any cohort. Two subjects from Cohort 1 discontinued from the study. One subject discontinued due to a treatment-related TEAE (obsessive rumination, Grade 2) and the other due to other reasons.
Conclusions:
This phase 1 PET study confirms the neuroanatomical specificity of TARPγ8 expression in healthy subjects. Target RO (50-70%) associated with maximal efficacy in preclinical models was achieved at RAP-219 plasma concentrations between 2.0 and 3.7 ng/mL in human subjects. The results allow selection of a dose range for phase 3 studies in focal epilepsy patients. The RAP-219 PK, safety, and tolerability profiles observed in this study were consistent with those reported in previous phase 1 studies.
Funding: Rapport