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Natalizumab Demonstrates Some Impact on Drug-Resistant Epilepsy

SAP Partner | <b>NYU Langone Health</b>

Despite not achieving statistical significance, there was greater relative reduction in seizure frequency over placebo in those with a structural etiology for focal epilepsy than those without, laying the foundation for future research.

A recently conducted analysis of natalizumab (Tysabri; Biogen) use in patients with drug-resistant focal epilepsy revealed some relative change in seizure frequency with no unexpected safety findings. The threshold to demonstrate efficacy was not met; however, investigators noted that the results warranted possible exploration of anti-inflammatory therapies in this patient population.1

Lead author Jacqueline A. French, MD, director, Translational Research and Clinical Trials in Epilepsy, NYU Langone Grossman School of Medicine, and colleagues randomized 66 participants with at least 6 seizures during the 6-week baseline period 1:1 to either intravenous (IV) natalizumab 300 mg (n = 32) or placebo (n = 34) every 4 weeks for 24 weeks. They evaluated change from baseline in log-transformed seizure frequency from weeks 8 to 24 of the placebo-controlled period, with a predefined success threshold of 31% relative reduction.

At the conclusion of the study, investigators found least-squares (LS) mean change from baseline in log-transformed seizure frequency of –0.58 (standard error [SE], 0.165) for natalizumab 300 mg and –0.43 (SE, 0.162) for placebo, corresponding to a relative change over placebo of –14.4% (95% CI, –46.1% to 36.1%; P = 0.51).

"Despite not meeting the efficacy threshold, there were no unexpected safety findings, and pharmacodynamic evidence indicating a consistent mechanism of action suggests that there is good reason to continue exploring agents that target inflammatory processes specific to the [central nervous system] to manage drug-resistant epilepsy," the study authors wrote.

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During weeks 8-24, 31.3% (n = 10) of natalizumab-treated patients had at least 50% reduction in seizure frequency from baseline compared to 17.6% (n = 6) for placebo (OR, 2.09 [95% CI, 0.64-6.85]; P = 0.22). Additionally, the relative change over placebo during that time period for seizure-free days gained was 46.81% (95% CI, –9.39 to 137.85; P = 0.12). Patients treated with natalizumab also demonstrated a decrease of 21.34% (95% CI, –44.70 to 11.90; P = .18) over placebo in focal to bilateral tonic-clonic seizure frequency, whereas focal seizure frequency increased 6.61% (95% CI, –35.49 to 76.17; P = .80).

Adverse events (AEs) were reported in 75% (n = 24) and 65% (n = 22) of participants receiving natalizumab 300 mg vs placebo. Seizure, the only serious AE observed, occurred in 3% (n = 1) of participants in each treatment group. Urticaria in the natalizumab group (n = 1) and seizure in the placebo group (n = 1) were the 2 AEs that led to discontinuation. Notably, there were no clinically relevant changes in laboratory tests and no reported cases of progressive multifocal leukoencephalopathy.

The pattern towards a separation in effect between placebo and natalizumab started after the first 4 weeks of treatment, coinciding with when a4 integrin saturation plateaued. Natalizumab, a humanized monoclonal anti-a4-integrin antibody, had serum concentration peak at week 20, with a geometric mean of 27.69 μg/mL (SE, 1.842), and then stabilized at week 24.

A subgroup of 32 patients with an adjudicated presence of structural etiology for focal epilepsy at baseline was also evaluated. Despite not reaching statistical significance, investigators observed a greater reduction in seizure frequency in the natalizumab-treated group (n = 20) over placebo (–30.29 [95% CI, –64.84 to 38.21]; P = .29) compared with the subgroup of participants without structural etiology for focal epilepsy (–5.89% [95% CI, 56.32 to 102.73]; P = .87).

The study authors concluded that "future considerations include refining the population of interest to those patients with active neuroinflammation and [blood-brain barrier] damage using imaging-associated markers and increasing the number of trial participants.”

Biogen is currently attempting to gain FDA approval for a subcutaneous form of natalizumab. In April, the FDA sent a complete response letter (CRL) in regards to Biogen’s submission of a supplemental biologics license application for the novel subcutaneous administration of the therapy. The CRL, indicating that the agency cannot approve the filing as submitted, is currently being evaluated by Biogen as it determines the next steps.2

1. French JA, Cole AJ, Faught E, et al. Safety and efficacy of natalizumab as adjunctive therapy for people with drug-resistent epilepsy: a phase 2 study. Neurology. Pubslished online September 14, 2021. doi:10.1212/WNL.0000000000012766
2. Biogen Provides Regulatory Update on the Supplemental Biologic License Application (sBLA) for Subcutaneous Administration of TYSABRI® (natalizumab). News release. April 28, 2021. Accessed September 27, 2021. https://www.biospace.com/article/releases/biogen-provides-regulatory-update-on-the-supplemental-biologic-license-application-sbla-for-subcutaneous-administration-of-tysabri-natalizumab-/