Safety and Efficacy of Natalizumab as Adjunctive Therapy for People With Drug-Resistant Epilepsy
Jacqueline A. French, Andrew J. Cole, Edward Faught, William H. Theodore, Annamaria Vezzani, Kore Liow, Jonathan J. Halford, Robert Armstrong, Jerzy P. Szaflarski, Sarah Hubbard, Jagdish Patel, Kun Chen, Wei Feng, Marco Rizzo, Jacob Elkins, Gabrielle Knafler, Kimberly A. Parkerson, on behalf of the OPUS Study Group, Pavel Klein, Selim Benbadis, Evelyn Tecoma, Antoaneta Balabanov, David Vossler, Aatif Husain, Alex Boro, Joel Oster, Michael Gelfand, Mohamad Koubeissi, Joseph Sirven, Jay Harvey, Mounzer Kassab, Edward Hogan, Ki Hyeong Lee, Robert Beach, Hae Shin, Rani Sarkis, Stephen Flitman, William Honeycutt, Ricardo Ayala, Ramon Bautista, Michel Berg, Melissa Carran, David Kudrow, Tricia Ting, Jose Rafecas
Abstract
<h3>Background and Objectives</h3> To explore efficacy/safety of natalizumab, a humanized monoclonal anti–α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy. <h3>Methods</h3> Participants with ≥6 seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed. <h3>Results</h3> Of 32 and 34 participants dosed in the natalizumab 300 mg and placebo groups, 30 (94%) and 31 (91%) completed the placebo-controlled treatment period, respectively (one participant was randomized to receive natalizumab but not dosed due to IV complications). Estimated relative change in seizure frequency of natalizumab over placebo was −14.4% (95% confidence interval [CI] –46.1%–36.1%; <i>p</i> = 0.51). The proportion of participants with ≥50% reduction from baseline in seizure frequency was 31.3% for natalizumab and 17.6% for placebo (odds ratio 2.09, 95% CI 0.64–6.85; <i>p</i> = 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo. <h3>Discussion</h3> Although the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted. <h3>Trial Registration Information</h3> The ClinicalTrials.gov registration number is NCT03283371. <h3>Classification of Evidence</h3> This study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab.