Efficacy and Safety of Proposed Biosimilar Natalizumab (PB006) in Patients With Relapsing-Remitting Multiple Sclerosis: The Antelope Phase 3 Randomized Clinical Trial

Abstract

Importance: Proposed biosimilar natalizumab (biosim-NTZ) PB006 is the first biosimilar monoclonal antibody therapy developed for multiple sclerosis (MS) treatment.

Objective: To evaluate matching efficacy, safety, and immunogenicity between biosim-NTZ and reference natalizumab (ref-NTZ) in patients with relapsing-remitting MS (RRMS).

Design, setting, and participants: The Antelope trial was a phase 3, parallel-group, randomized, active-controlled study, conducted between October 2019 and March 2021, with last patient follow-up visit on August 23, 2021. The study took place in 48 centers in 7 countries. Of 531 patients with RRMS aged 18 to 60 years screened, 266 were excluded before randomization in line with study criteria. Eligible participants had 1 or more documented relapse within the previous year and either 1 or more gadolinium-enhancing T1-weighted or 9 or more T2-weighted brain lesions, Kurtzke Expanded Disability Status Scale score of 0 to 5.0 (inclusive), and John Cunningham virus index of 1.5 or less at screening. One patient withdrew consent before dosing.

Interventions: Intravenous infusions every 4 weeks of biosim-NTZ, 300 mg, or ref-NTZ, 300 mg (1:1 randomization), from week 0 to week 44 (end-of-study visit: week 48). At week 24, the ref-NTZ group was rerandomized and 30 patients were switched to biosim-NTZ for the remainder of the study.

Main outcomes and measures: The primary end point was the cumulative number of new active lesions on magnetic resonance imaging (new gadolinium-enhancing T1-weighted lesions and new/enlarging T2-weighted lesions without double counting) over 24 weeks. Additional end points included further magnetic resonance imaging parameters, annualized relapse rate, and Kurtzke Expanded Disability Status Scale score. Safety, tolerability, and immunogenicity assessments included adverse events, laboratory evaluations, and positivity for anti-John Cunningham virus antibodies and antinatalizumab antibodies.

Results: A total of 264 participants (mean [SD] age, 36.7 [9.38] years; 162 [61.4%] female) received treatment with biosim-NTZ (n = 131) or ref-NTZ (n = 133). At week 24, the model-based mean difference in cumulative number of new active lesions between biosim-NTZ and ref-NTZ treatment groups was 0.17 (least square means [SE]: biosim-NTZ, 0.34 [0.34]; ref-NTZ, 0.45 [0.28]; 95% CI, -0.61 to 0.94 within the prespecified margins of ±2.1). No significant differences between treatment groups were observed across secondary efficacy end points, safety, tolerability, or immunogenicity assessments.

Conclusions and relevance: Biosim-NTZ matched ref-NTZ in efficacy, safety, and immunogenicity for patients with RRMS in the tested setting. This phase 3 trial supports proposed biosim-NTZ as a biosimilar alternative to ref-NTZ for treating RRMS.

Trial registration: ClinicalTrials.gov Identifier: NCT04115488.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Hemmer reported personal fees from Polpharma and Sandoz during the conduct of the study; personal fees from Novartis, Biocom, and TG Therapeutics outside the submitted work; a patent for genetic determinants of antibodies against interferon-beta issued and a patent for KIR4.1 antibodies in multiple sclerosis issued; served on scientific advisory boards for Novartis; served as data monitoring and safety committee member for AllergyCare, Polpharma Biologics SA, Sandoz, and TG therapeutics; speaker honoraria from Desitin paid to himself and his institution; grants from Regeneron for multiple sclerosis research paid to his institution; funding from the Multiple MS EU consortium, the Clinspect-M consortium funded by the Bundesministerium für Bildung und Forschung, and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy; ID 390857198). Dr Wiendl reported honoraria for serving on scientific advisory boards, speaker honoraria, and travel support from AbbVie, Actelion, Alexion, Amicus Therapeutics Inc, Argenx, Biogen, BMS/Celgene, Bristows, CSL Behring, Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft eV, EMD Serono, F. Hoffmann-La Roche Ltd, Fondazione Cariplo, Genzyme, German Ministry for Education and Research (BMBF), Gossamer Bio, Idorsia, IGES, Immunic, Immunovant, Janssen, Johnson & Johnson, Lundbeck, Merck, Neurodiem, NexGen, Novartis, PSI CRO, Sanofi, Swiss Multiple Sclerosis Society, Teva Pharmaceuticals, UCB Biopharma, WebMD Global, and Worldwide Clinical Trials and research support from Biogen, Merck, Novartis, Hoffmann LaRoche, Deutsche Forschungsgemeinschaft, and the Federal Government of Germany paid to their institution. Dr Selmaj reported personal fees from Polpharma Biologics SA during the conduct of the study; personal fees from Roche, Biogen, Novartis, BMS, TG Therapeutics, Sanofi, Celgene, and Merck outside the submitted work; in addition, Dr Selmaj had a patent for myelin patches issued. No other disclosures were reported.

Figures

Figure 1.. Overall Study Design

EOS indicates end of study; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy. aAssessed by the central reading center.

Figure 2.. CONSORT Diagram of Enrollment and Follow-up of Study Patients

MS indicates multiple sclerosis. aThe full analysis set included patients who were randomized and received ≥1 (complete or partial) infusion of the study drug. Patients were to be analyzed according to the treatment group to which they were randomized. bThe safety population included patients who received ≥1 (complete or partial) infusion of the study drug. Patients in this group were to be analyzed as treated. cThe per-protocol population included only patients who completed the 24-week treatment period without major protocol deviation that may have influenced the analysis of the primary end point and for whom sufficient postbaseline magnetic resonance imaging data were available. dThe per-protocol population comprised 229 patients who completed the 24-week treatment period without major protocol deviations and for whom sufficient postbaseline magnetic resonance imaging data were available (biosimilar natalizumab: n = 111; reference natalizumab: n = 118). eThe safety-switch population included patients in the safety population who received ≥1 infusion of the study drug after the rerandomization time point, independent of switching status. Patients in this group were to be analyzed as treated after rerandomization, also considering treatment before rerandomization.

Figure 3.. Primary Study End Point and Secondary Efficacy End Point

A, Exponentiated difference in cumulative number of new active lesions at week 24 between the biosimilar natalizumab and reference natalizumab groups (per-protocol population). B, Cumulative number of new active lesions over 48 weeks in the biosimilar natalizumab and reference natalizumab groups by primary randomization (full analysis set population).