Abstracts

Rationale:
Padsevonil (PSL; UCB0942) is an antiepileptic drug (AED) candidate combining high affinity synaptic vesicle 2A,B,C binding with partial agonism at the benzodiazepine site of the GABAA receptor.
Method:
Phase 2, double-blind, randomized, placebo (PBO)-controlled dose-finding trial (EP0091; NCT03373383) in adults (≥18 years) with drug-resistant focal seizures (≥4 observable seizures/28 days), who had failed ≥4 AED regimens and were on a stable dose of 1–3 AEDs. Patients were randomized 1:1:1:1:1 to PSL 50/100/200/400mg twice daily (bid) or PBO. PSL was initiated at 50mg bid and up-titrated over 3 weeks followed by 1-week stabilization (during which a dose reduction [to 25/75/150/300mg bid] was allowed for tolerability reasons) and 12-week Maintenance. Primary efficacy outcomes were change in log-transformed observable focal seizure frequency and ≥75% responder rates (≥75% reduction in observable focal seizure frequency) from Baseline to Maintenance. Results410 patients started the trial and received ≥1 dose of PSL 50/100/200/400mg bid (n=81/83/82/81) or PBO (n=83). Patients represented a severely affected population with high seizure frequency and high number of lifetime AEDs (Table 1). 322 (78.5%) patients completed the trial; 88 (21.5%) discontinued, most commonly due to adverse events (14.6%). 405 patients had post-Baseline seizure frequency data and were included in efficacy analyses (PSL 50/100/200/400mg bid n=80/82/81/81; PBO n=81). Least square mean change in log-transformed observable focal seizure frequency was −0.46/−0.49/−0.49/−0.41 with PSL 50/100/200/400mg bid vs −0.28 with PBO (percent reduction over PBO: 17.2 [95% CI: −3.8, 33.9] / 19.1 [−1.2, 35.4]; p=0.128 / 19.2 [−1.2, 35.5]; p=0.128 / 12.4 [−9.7, 30.1]; p=0.248); 75% responder rates were 13.8%/12.2%/11.1%/16.0% vs 6.2% (odds ratios: 2.72 [95% CI: 0.88, 8.39] / 2.37 [0.76, 7.41]; p=0.192 / 2.16 [0.68, 6.89]; p=0.192 / 3.14 [1.05, 9.42]; p=0.124). Median percent reductions in observable focal seizure frequency/28 days were 28.8%/31.9%/36.6%/15.7% with PSL 50/100/200/400mg bid vs 20.6% with PBO (median differences vs PBO: 7.4/10.0/8.2/2.4); 50% responder rates were 33.8%/31.7%/25.9%/32.1% vs 21.0%. Among patients who completed Maintenance, 6.1%/1.5%/8.2%/6.9% (n=66/68/61/58) patients on PSL 50/100/200/400mg bid vs 0% (n=70) on PBO were free from all seizures. The most common treatment-emergent adverse events (TEAEs) with PSL (≥20% of patients) were somnolence, dizziness, and fatigue (Table 2). More patients on PSL than PBO discontinued due to TEAEs and a dose-dependent pattern was seen. No clinically relevant signals were observed for hematology, blood chemistry, urinary parameters, vital signs, ECGs, and echocardiograms.
Conclusion:
Both primary outcomes did not reach statistical significance in any dose group. Numerical improvements were observed for PSL dose groups vs PBO; however, these did not show a dose-dependent response. PSL was generally well tolerated and the safety profile was as expected based on its pharmacology and previous trials.
Funding:
:UCB Pharma-sponsored