Senior Medical Director, Clinical Development Biogen
Rationale: There is an unmet need for therapies that improve seizure control in drug‑resistant epilepsy. Evidence suggests that inflammation may play a role in the pathogenesis of epilepsy (Fabene, Nat Med 2008;14:1377; van Vliet, Brain 2007;130:521; Sotgiu, BMC Neurol 2010;10:84; Ravizza, Neurobiol Dis 2008;29:142; Luo, J Mol Neurosci 2014;54:767). Leukocyte–endothelial interactions as a target for anti-epileptic drug development is underexplored. Blocking α4 integrins on leukocytes may improve seizure control by reducing leukocyte–vascular interactions and stabilizing blood–brain barrier function at the disease site (Fabene 2008). OPUS (ClinicalTrials.gov NCT03283371) is a multicenter, randomized, double-blind, placebo-controlled, Phase 2 study of natalizumab in drug-resistant focal epilepsy. Natalizumab is a humanized monoclonal anti-α4-integrin antibody that is marketed for the treatment of multiple sclerosis under the brand name Tysabri. Tysabri is also approved for the treatment of Crohn’s disease in the United States. Methods: Adults with drug-resistant focal epilepsy on a stable regimen of one to five antiepileptic drugs and ≥6 seizures during the six-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every four weeks for 24 weeks during the placebo-controlled period. Randomization was stratified by presence/absence of structural etiology for focal epilepsy and seizure frequency (≥24 vs. < 24 seizures) during the baseline period. The primary efficacy outcome was change from baseline in log-transformed seizure frequency (number of seizures per 28 days) during weeks 8–24 of treatment. Countable seizure types were focal aware with motor, focal with impaired awareness, and focal to bilateral tonic-clonic. Determination of sample size was based on the assumption of 31% relative reduction in seizure frequency in the treated group over placebo group. Results: Of 32 and 34 participants dosed in the natalizumab and placebo groups, 30 (94%) and 31 (91%) completed the placebo-controlled treatment period. The median percent change from baseline in seizure frequency during weeks 8–24 was -19.3% for natalizumab and -8.5% for placebo. The estimated relative change in seizure frequency of natalizumab versus placebo was -14.4% (95% CI: -46.1%, 36.1% p=0.51). The proportion of participants with ≥50% reduction from baseline in seizure frequency during weeks 8–24 was 31.3% for natalizumab and 17.6% for placebo (OR=2.09; 95% CI: 0.64, 6.85 p=0.22). Adverse events (AEs) were reported in 24 (75%) and 22 (65%) participants receiving natalizumab versus placebo. One (3%) participant in each treatment group had a serious AE of seizures that led to study withdrawal. Conclusions: While there was evidence of a treatment effect, the natalizumab-treated group of participants did not achieve a 31% relative reduction in seizure frequency over the placebo group, the study’s predefined threshold for therapeutic success. The safety profile was consistent with that of natalizumab in other indications. Funding: Please list any funding that was received in support of this abstract.: This study was supported by Biogen.