Phase 3 Antelope Trial Highlights Similarities in Efficacy, Safety With Biosimilar Natalizumab

Article

The biosimilar form of natalizumab demonstrated similarities to the FDA-approved form in the primary efficacy end point of cumulative number of new active lesions over 24 weeks.

Bernhard Hemmer, MD, director of the department of neurology at the Technical University of Munich

Bernhard Hemmer, MD

In the recently published phase 3 Antelope trial (NCT04115488), biosimilar natalizumab (biosim-NTZ), or PB006, the first biosimilar monoclonal antibody developed for multiple sclerosis (MS), matched reference natalizumab (ref-NTZ; Tyasbri; Biogen) in efficacy, safety, and immunogenicity in treating patients with relapsing-remitting MS (RRMS).

After 24 weeks of treatment, the model-based mean difference in cumulative number of new active lesions between biosim-NTZ and ref-NTZ treatment groups was 0.17 (95% CI, –0.61 to 0.94). in the full analysis set population, annualized relapse rate (ARR) was similar at 24 weeks (biosim-NTZ, 0.21; ref-NTZ, 0.15) and 48 weeks (biosim-NTZ, 0.17; ref-NTZ, 0.13). All told, the findings supported biosim-NTZ as a biosimilar alternative to ref-NTZ for treating relapsing-remitting MS.

Lead investigator Bernhard Hemmer, MD, director of the department of neurology at the Technical University of Munich, and colleagues analyzed 264 patients with RRMS who had 1 or more documented relapse in the previous year and either 1 or more gadolinium-enhancing T1-weighted or 9 or more T2-weighted brain lesions. Patients were randomly assigned 1:1 to intravenous infusions every 4 weeks of 300 mg of biosim-NTZ or 300 mg of ref-NTZ, starting at visit 1 (week 0) through to visit 12 (week 44). At week 24, patients in the ref-NTZ group underwent rerandomization, whereby 30 patients switched for the remainder of the study.

Eligible participants were aged 18 to 60 years, had Kurtzke Expanded Disability Status Scale (EDSS) score of 0 to 5, and were not on a disease-modifying therapy. Overall, 239 patients (90.5%) completed the 48-week study. After database lock, it was determined that 1 or more of the 3 stratification factors (absence/presence of gadolinium-enhancing lesions, presence of T2 lesions, John Cunningham human polyomavirus [JCV]) were incorrectly recorded at randomization in 62 of the original 265 patients (23.4%).

Since the study was blinded and the randomization was performed according to the entered strata, the integrity of the data was not affected. A sensitivity analysis based on the corrected stratification factors confirmed the primary end point in the per-protocol population, showing a model-based mean difference of 0.06 (SE, 0.08) between ref-NTZ and biosim-NTZ. Between the 2 groups, the mean cumulative number of new active lesions was 1.5 (standard deviation [SD], 3.72) in the biosim-NTZ group vs 2.3 (SD, 5.68) in the ref-NTZ group.

All told, the change from baseline in EDSS score was minimal and similar between both treatment groups at 24 weeks and 48 weeks. For those who switched over at week 24, the change from that time point to week 48 was minimal and similar between all treatment groups (biosim-NTZ, –0.10 [SD, 0.50]; ref-NTZ, –0.02 [SD, 0.31]; ref-NTZ/biosim-NTZ switch, –0.03 [SD, 0.33]).

"Even though no biosimilar has been approved for treating MS, off-label rituximab and its biosimilars are extensively used," Hemmer et al wrote. "In Sweden, off-label prescriptions of rituximab and its biosimilars for MS treatment have been reported at more than 50% compared with initiations of other new DMTs, showing that biosimilars may provide an effective and affordable treatment option in MS."

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Between the different treatment groups, the rates of treatment-emergent adverse events (TEAEs) were similar, occurring in 64.9%, 68.9%, and 73.3% of patients on biosim-NTZ, ref-NTZ, and ref-NTZ/biosim-NTZ, respectively. Nervous system disorders, which ranged from 23.3% to 26.7% across groups, and infections and infestations, which ranged from 29.8% to 50.0% across groups, were the most reported TEAEs. Notably, there were no fatal or National Cancer Institute Common Terminology Criteria for Adverse Events grade 4 TEAEs reported.

In total 12 patients, 8 on biosim-NTZ and 4 on ref-NTZ, experienced TEAEs that led to study drug discontinuation. During the treatment period (48 weeks) or follow-up visit (24 weeks), there were no observed cases of progressive multifocal leukoencephalopathy in either group. Regarding immunogenicity, at week 24, 79.4% (n = 104) and 74.0% (n = 98) of those in the biosim-NTZ and ref-NTZ treatment groups respectively, were confirmed positive for treatment-emergent antidrug antibodies.

The study investigators wrote, "The consistently higher ADA-positive values reported across all treatment groups in the Antelope trial are considered to be due to the higher sensitivity of the assay used vs the reference clinical program, which applied an ADA assay known to have relatively low sensitivity due to drug interference. Similarly higher ADA-positive values have been reported in another study of ref-NTZ that detected higher ADA levels in patients receiving natalizumab when using a more sensitive radioimmunoassay assay."

REFERENCE
1. Hemmer B, Wiendl H, Roth K, et al. Efficacy and safety of proposed biosimilar natalizumab (PB006) in patients with relapsing-remitting multiple sclerosis: the Antelope phase 3 randomized clinical trial. JAMA Neurol. Published online January 23, 2023. doi:10.1001/jamaneurol.2022.5007
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