Biosimilar Natalizumab-sztn Shows Comparable Efficacy and Safety to Tysabri in RRMS

Biosimilar natalizumab demonstrates comparable efficacy, safety, and immunogenicity to reference drug, Tysabri, in patients with relapsing-remitting multiple sclerosis (RRMS), supporting its potential as a cost-effective treatment option. | Image Credit: Vitalii Vodolazskyi - stock.adobe.com

Natalizumab-sztn (Tyruko; Sandoz) expressed efficacy and safety in patients with relapsing-remitting multiple sclerosis (RRMS) to confirm matching immunogenicity profiles between the biosimilar and reference natalizumab (Tysabri; Biogen), according to a study published in Frontiers in Immunology.^1,2

Multiple sclerosis (MS), a chronic inflammatory disease, is characterized by central nervous system lesions that can cause severe physical, cognitive, and other neurological defects.³ The approval of a biologic medicine in the 1990s changed MS treatment with disease-modifying therapies (DMTs). As reference biologic medications lost market exclusivity, biosimilars to branded reference biologics entered the market, potentially offering more cost-effective treatment options and expanding access to high-efficacy DMTs in MS.¹

Two randomized, comparative clinical trials compared natalizumab-sztn and reference natalizumab within the clinical development program of biosimilar natalizumab. The Antelope study (NCT04115488) enrolled patients with RRMS, and the second study measured pharmacokinetics (PK) and pharmacodynamics (PD) in healthy patients (EudraCT: 2019-003874-15).

Researchers conducted the Antelope study, a multicenter, double-blind, active-controlled, randomized, parallel-group trial, to assess the similarity in efficacy, safety, and immunogenicity of prolonged treatment with biosimilar natalizumab and the European (EU) approved reference natalizumab. Patients with RRMS were randomized to receive intravenous infusions of either 300 mg biosimilar or 300 mg of reference natalizumab every 4 weeks for 12 visits, totaling 12 infusions. Researchers rerandomized reference natalizumab at week 24 and switched 30 patients to continue treatment with the biosimilar for 24 weeks.

Researchers conducted a single-dose, randomized, double-blind, parallel-group PK/PD study in healthy patients (n = 453) to demonstrate similarity between natalizumab-sztn and US-licensed or EU-approved reference natalizumab. Patients were randomized based on their body weight to receive a 1 hour, 3 mg/kg infusion of biosimilar natalizumab, US reference product, or EU reference product.

The Antelope study enrolled 264 patients with RRMS, with 131 patients receiving biosimilar natalizumab and 133 patients receiving the EU reference product for over 48 weeks. The PK/PD comparative study enrolled 450 healthy participants—149 participants received biosimilar natalizumab, 150 received the US reference product, and 151 received the EU reference product.

Natalizumab-stzn and the EU reference product showed similar incidences of overall anti-drug antibody (ADA) (79.4% vs 73.7%, respectively) and neutralizing antibodies (NAb) (68.7% vs 66.2%, respectively) at week 24. The PK/PD comparative study found no detectable differences in ADA or NAb response dynamics between the biosimilar group and the US or EU reference natalizumab, supporting these findings. Natalizumab-sztn, US natalizumab, and EU natalizumab yielded similar overall incidences of treatment-emergent ADA (87.2%, 92%, and 86.8%, respectively).

Antelope showed that switching patients with RRMS from EU natalizumab to the biosimilar did not impact their treatment-related ADA/NAb immune or clinical responses. Before switching, 43.4% of patients in the switch arm (n = 30) tested ADA-positive, and 30% tested NAb-positive at week 24. Additionally, the PK/PD study demonstrated a matching overall incidence of ADA between treatment groups and matching ADA titer profiles over time.

The Antelope study reported few infusion-related reactions, with 10 occurring in the biosimilar group and 5 in the EU reference group. Patients switching from EU natalizumab to biosimilar natalizumab at week 24 experienced erythema and hypersensitivity reactions. The PK/PD study reported no hypersensitivity reactions.

The study highlights the absence of standardized methodology and reference materials for ADA testing, and the researchers cautioned to approach comparison of different assay outputs with caution. Post-authorization pharmacovigilance should monitor the ongoing evaluation of the incidence of progressive multifocal leukoencephalopathy (PML) for natalizumab-sztn so that the prescribing information for all natalizumab products advises close monitoring for symptoms of PML.

“We have demonstrated that the immunogenicity profiles of biosim-NTZ and ref-NTZ are indistinguishable in healthy subjects and patients with RRMS in the tested setting. These findings confirm the biosimilarity of biosim-NTZ and ref-NTZ with no safety or efficacy concerns identified to be associated with immunogenicity,” the study authors concluded.

References

1. Chamberlain P, Hemmer B, Höfler J, et al. Comparative immunogenicity assessment of biosimilar natalizumab to its reference medicine: a matching immunogenicity profile. Front Immunol. 2024;15:1414304. Published 2024 Dec 19. doi:10.3389/fimmu.2024.1414304

2. Biosimilar approvals. The Center for Biosimilars^®. January 7, 2025. Accessed March 24, 2025. https://www.centerforbiosimilars.com/biosimilar-approvals

3. Greenberg B, Giovannoni G. A place for biosimilars in the changing multiple sclerosis treatment landscape. Mult Scler Relat Disord. 2023;77:104841. doi:10.1016/j.msard.2023.104841