Safety and Efficacy of Natalizumab as Adjunctive Therapy for People With Drug-Resistant Epilepsy: A Phase 2 Study

Abstract

Background and objectives: To explore efficacy/safety of natalizumab, a humanized monoclonal anti-α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy.

Methods: 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.

Results: 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%; p = 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; p = 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo.

Discussion: 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.

Trial registration information: The ClinicalTrials.gov registration number is NCT03283371.

Classification of evidence: 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.

Figure 1. Patient Disposition

^aThe intent-to-treat (ITT) population was defined as all participants who were randomized and received ≥1 dose of double-blind treatment. ^bThe safety population was defined as all participants who were randomized and received any dose of study treatment.

Figure 2. Change From Baseline Over Time in Log-Transformed Seizure Frequency

The overall relative percent change (95% confidence interval) over placebo from weeks 8–24 was −14.38 (−46.13, 36.09). LS = least squares.

Figure 3. Serum Concentration of Natalizumab, Saturation of α4-Integrin, and Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) Concentration

(A) Serum concentration of natalizumab 300 mg. (B) Saturation of α4-integrin. (C) sVCAM-1 concentration. GSD = geometric SD.