Key Points

Question  Does proposed biosimilar natalizumab (biosim-NTZ) PB006 match reference natalizumab (ref-NTZ) in terms of efficacy, safety, and immunogenicity in patients with relapsing-remitting multiple sclerosis (RRMS)?

Findings  In this randomized, double-blind phase 3 clinical trial, 264 adult patients with RRMS received treatment with either biosim-NTZ or ref-NTZ. At week 24, the model-based mean difference in the cumulative number of new active lesions was similar between treatment groups.

Meaning  The study demonstrated that biosim-NTZ matches the efficacy, safety, and immunogenicity of ref-NTZ in patients with RRMS.

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

Introduction

Disease-modifying therapies (DMTs), particularly targeted biologic medicines, have revolutionized health care in the treatment of chronic conditions such as multiple sclerosis (MS).1,2 However, DMTs are the primary drivers of health care costs after MS diagnosis,3-7 particularly in relapsing-remitting MS (RRMS), which accounts for 85% of initial diagnoses and is associated with the highest treatment costs of all MS subtypes.5,8,9

Due to continuously increasing health care costs, uniform access to DMTs remains difficult.10-12 In other therapy areas, such as rheumatology and oncology, the introduction of biosimilars, defined as medicines highly similar and with no clinically meaningful differences to an already marketed reference biologic medicine, demonstrated significant cost savings and improved treatment access.13-15 Biosimilar medicines may thus open the door for not only effective and safe, but also affordable biologic treatments for MS.

The humanized monoclonal antibody natalizumab was the first targeted biologic therapy to be approved for RRMS.16-18 Natalizumab binds to the α4 subunit of α4β1 and α4β7 integrins, inhibiting leukocyte adhesion to vascular adhesion molecules and disrupting leukocyte transmigration across the blood–brain barrier.16,17 In Europe and the US, natalizumab is indicated as monotherapy in patients with RRMS with high disease activity despite previous DMT or in rapidly evolving severe RRMS.18,19 In the US, it is also approved for use in adults with active moderate to severe Crohn disease who have had an inadequate response to, or are unable to tolerate, other therapy lines.18

PB006 is a biosimilar natalizumab (biosim-NTZ) and was developed by Polpharma Biologics SA as a proposed biosimilar to the reference natalizumab (ref-NTZ) in accordance with US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines, which require biosimilars to match the reference medicine in analytical comparability, bioequivalence, safety, efficacy, and immunogenicity, confirming no clinically relevant differences in performance across approved indications.15,20,21

Previous pharmacokinetic/pharmacodynamic and safety studies in healthy participants provided evidence to support PB006 phase 3 studies involving patients with RRMS.22,23 The primary objective of the Antelope study was to confirm equivalent efficacy between biosim-NTZ and ref-NTZ in patients with RRMS by assessing magnetic resonance imaging (MRI)–based end points supported by clinical, safety, and immunogenicity secondary end point analyses. The potential impact of switching from ref-NTZ to biosim-NTZ on efficacy outcomes and immunogenicity was also assessed in a subpopulation analysis.

Methods

Study Design

Antelope was a phase 3, multicenter, double-blind, active-controlled, randomized, parallel-group trial conducted at 48 centers across Belarus, Croatia, Georgia, Moldova, Poland, Serbia, and Ukraine. A statistical equivalence design was chosen to assess similarity between biosim-NTZ and ref-NTZ in efficacy, safety, and immunogenicity. The study was conducted in accordance with International Council for Harmonisation Good Clinical Practice, the Declaration of Helsinki,24 and relevant ethics committee or regulatory agency procedures. Independent ethics committees and health authorities approved the study before initiation, and patients or their legally authorized representatives signed statements of informed consent before enrollment and reconsent during the trial.

The trial initiated in October 2019 and completed in March 2021, with the last patient follow-up visit (24 weeks after last dosing) on August 23, 2021. A sensitivity analysis on a pre–COVID-19 per-protocol population was planned to account for any major deviations related to COVID-19. However, this analysis is not reported as there were no missing data to impute. The full trial protocol is available in Supplement 1. The study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.