Abstracts

Rationale: Padsevonil (PSL; UCB0942) is an investigational drug for treatment of epilepsy. In vitro binding studies demonstrated high affinity of PSL to synaptic vesicle 2 (SV2) proteins and moderate affinity to the benzodiazepine site on GABAA receptors (Wood et al., AES 2017). Here we describe two Positron Emission Tomography (PET) studies that have been conducted to evaluate receptor occupancy (RO) at the two molecular targets for which PSL has affinity – SV2A and GABAA. Methods: Two PET studies were conducted in healthy volunteers; one using the SV2A tracer [11C]UCB-J (N=11) and the other using [11C]flumazenil (FMZ, N=7) – a validated PET probe for the GABAA receptor. PET scans were acquired in both studies at baseline and then at various intervals after a single dose (SD) of PSL (6.25mg up to 100mg) in the case of the UCB-J study, or at steady state (using either 200mg or 400mg bid for 4 days) in the FMZ study. Venous blood samples were collected for pharmacokinetic (PK) analysis of PSL and, in the case of UCB-J, arterial blood samples were also collected to support full kinetic modelling-based occupancy calculations. Derived SV2A occupancy data were then used in conjunction with a population-PK (pop-PK) model to allow simulations of receptor occupancy in various possible PSL dosing regimens to inform dose regimen choice for further clinical evaluation. Results: In the UCB-J study, a clear exposure (plasma PK) SV2A RO relationship was seen and at the highest dose (100mg SD), there was complete saturation of SV2A (>99%) around Tmax (2h post dose) with significant occupancy measured after 24h (>60%) when plasma levels were approaching limits of quantification. Using pop-PK modelling of the PK and SV2A RO data, simulations of bid dosing regimens projected receptor occupancy to be greater than 90% for SV2A over the entire dosing interval for 90% of a population treated with 400mg and 300mg bid and greater than 90% for 75% of a population at 100mg bid dosing.In the FMZ study, based on the mean of maximum GABAA RO values within an individual, 6 of the 7 volunteers had RO levels above the limit of sensitivity (≥5%). The detectable RO was transient and the mean was 6.4% for the PSL 200mg bid group and 13.4% for the 400mg bid group. No clear relationship between plasma PK-derived PSL exposure and GABAA RO was observed. Conclusions: These two PET studies have clearly demonstrated quantifiable coverage for both molecular targets (SV2A and GABAA) and indicate that the 400 mg bid dose selected for the proof of concept study achieves the desired target occupancy for SV2A and GABAA. For SV2A, there is sustained high level (>90%) RO at doses above 100mg bid and at GABAA there is transient but quantifiable occupancy at doses of 200mg bid or above. The GABAA occupancy at 200mg bid is approaching the lower limit of quantification. These studies will allow a quantitatively based dosing rationale for future clinical studies with PSL. Funding: UCB Pharma-sponsored.