Proposed Natalizumab Matches Reference Biosimilar in Phase 3 Data

Bernard Hemmer, MD

A phase 3 clinical trial comparing the effect of different biosimilars in patients with relapsing-remitting multiple sclerosis (RRMS) found that proposed biosimilar natalizumab (biosim-NTZ) PB006 matched the efficacy, safety, and immunogenicity of reference natalizumab (ref-NTZ).

The emergence of biosimilar medicines provides potential for affordable treatment of multiple sclerosis (MS) without reducing efficacy, according to the study article. The investigational natalizumab is the first biosimilar monoclonal antibody therapy to be developed for treating multiple sclerosis.

"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," investigators wrote.

Phase 3 Clinical Trial Interventions

Between October 2019-March 2021, Bernard Hemmer, MD, Department of Neurology, Technical University of Munich, Klinikum rechts der Isar, Munich & Munich Cluster for Systems Neurology (SyNergy), and investigators, conducted the phase 3, parallel-group, randomized, active-controlled Antelope clinical trial across 7 countries in 48 treatment centers. The final patient follow-up took place in August 2021.

After screening 531 patients with relapsing-remitting multiple sclerosis who were 18-60 years of age, investigators included 266 patient that met the study criteria, which consisted of: one or more documented relapse within the previous year; at least 1 gadolinium-enhancing T1-weighted or, 9 or more T2-weighted brain lesions; Kurtzke Expanded Disability Status Scale score of 0-5.0; John Cunningham virus index of 1.5 or less.

Participating patients were randomized 1:1 to receive intravenous infusions of either the proposed or reference natalizumab at 300 mg, every 4 weeks. At week 24, 30 of the patients in the reference group were rerandomized to the proposed group until the investigation completed at week 44.

Examining the Endpoints

The mean age of the 264 patients was 36.7 years, and 61.4% of the population was female. For the first portion of the study, the proposed biosim-NTZ group consisted of 131 patients, while the ref-NTZ group consisted of 133. The primary endpoint analysis showed the cumulative number of new active lesions between the 2 groups was within the prespecified margins.

Sensitivity analyses were employed to confirm these data in addition to corrected stratification factor analysis to examine the influence of erroneous stratification and analysis using multiple imputation.

After the rerandomization of those in the ref-NTZ group, investigators observed no significant differences between the 3 treatment groups when assessing secondary efficacy endpoints, safety, or tolerability. This included secondary magnetic resonance imaging (MRI) and clinical outcomes.

Investigators noted that when the primary endpoint was assessed at week 24, the annual relapse rate (ARR) of both groups were in line with the preceding AFFIRM phase 3 trial of natalizumab, which had similar population baseline charateristics.

"The proposed biosim-NTZ PB006 is the first biosimilar monoclonal antibody therapy to be developed for MS," they wrote. "The clinical efficacy, safety, and immunogenicity of the proposed biosimilar natalizumab matched the reference natalizumab in the tested setting, with no clinically relevant differences observed. The results from this phase 3 trial support biosimilarity of proposed biosimilar natalizumab PB006 to its reference medicine in RRMS."

The study, "Efficacy and Safety of Proposed Biosimilar Natalizumab (PB006) in Patients With Relapsing-Remitting Multiple Sclerosis: The Antelope Phase 3 Randomized Clinical Trial" was published in JAMA Neurology.