Abstracts

Rationale: SPN-817, a synthetic, extended-release formulation of huperzine A, is under investigation for drug-resistant seizures, including focal onset seizures. A potent, reversible acetylcholinesterase inhibitor with potential procognitive effects, huperzine A has shown antiseizure effects in a broad array of preclinical seizure models, including the Genetic Absence Epilepsy Rat from Strasbourg model.

Methods: This is an ongoing, phase 2, multicenter, open‑label study (NCT 05518578) coordinated with the Australian Epilepsy Clinical Trials Network. Adults with treatment‑resistant epilepsy (adjudicated by Epilepsy Study Consortium, Inc.) underwent an 8-week screening period (including 6-week baseline seizure diary). Participants then initiated SPN-817 at 0.25 mg twice daily, with subsequent titration to optimal efficacy and tolerability (not exceeding 4 mg twice daily) planned over a ≤ 8-week titration period, followed by a 12-week maintenance period and a 4‑week taper or, if benefiting from treatment, participants could then enter an additional 52-week extension period. Safety and tolerability were primary outcomes. Efficacy measures were secondary outcomes, along with quality of life, and pharmacokinetics. We present results of an interim (May 1, 2024) data-cut.

Results: Of 41 treated participants (mean age: 39.5 years; 56.1 % female; 46.3% using ≥ 4 antiseizure medications; 92.7% with focal seizures) at the time of data-cut, 12 (29.3%) were ongoing in titration or maintenance, 15 (36.6%) had discontinued, and 14 (34.1%) had completed maintenance and enrolled in the extension period. Most participants required > 8 weeks for titration (median 11.4) and 95.1% during the titration period and 45.8% during the maintenance period experienced treatment-related adverse events (AEs), most commonly (titration, maintenance): nausea (48.8%, 12.5%), diarrhea (24.4%, 12.5%), and headache (22.0%, 4.2%). Only 7 of 23 subjects who experienced nausea or vomiting used an antiemetic. AEs during titration and maintenance led to discontinuation for 11/41 (26.8%) and 2/24 (8.3%) participants, respectively. All AEs were mild or moderate. One individual experienced serious AEs considered treatment‑related (dizziness and nausea). Median 28‑day seizure frequency was 11.3 at Baseline [n=36 full analysis set]. For subjects in the maintenance period, median 28-day seizure frequency was reduced by 54.5% (n=19), with 81.3%, 62.5% and 18.8% experiencing seizure reductions of ≥ 30%, ≥ 50%, and ≥ 75%, respectively; similar or larger reductions were observed in individuals with focal seizures (57.95% median reduction, n=16).

Conclusions: Adverse events were common during SPN-817 titration and largely cholinergic in nature. The potential benefit of a peripherally-acting antiemetic on medication tolerability should be evaluated. Individuals with treatment‑resistant epilepsy, including focal seizures, who underwent maintenance treatment with huperzine A showed meaningful seizure reductions, with over half experiencing ≥ 50% reduction in seizure frequency.

Funding: Supernus Pharmaceuticals, Inc.