Phase 3 study findings support a proposed natalizumab biosimilar (PB006) as the first biosimilar alternative to reference natalizumab (Tysabri) for treatment of relapsing-remitting multiple sclerosis (MS).
Biosimilar natalizumab (biosim-NTZ) PB006 matched reference natalizumab (ref-NTZ, Tysabri) in efficacy, safety, and immunogenicity for patients with relapsing-remitting multiple sclerosis (RRMS), supporting proposed biosim-NTZ as a biosimilar alternative to ref-NTZ for treating RRMS.
This was the first phase 3 trial to compare biosim-NTZ to ref-NTZ. Currently, there are no natalizumab biosimilars approved in the United States or European Union.
The proposed biosim-NTZ PB006 is the first biosimilar monoclonal antibody developed for MS treatment, and no clinically relevant difference were found in this trial between the proposed biosimilar and the reference drug, according to the study published in JAMA Neurology.
The parallel-group, randomized, active-controlled Antelope trial took place between October 2019 and March 2021 in 48 centers across Belarus, Croatia, Georgia, Moldova, Poland, Serbia, and Ukraine. The last patient follow-up visit was on August 23, 2021.
Patients in these countries aged 18 to 60 years who had 1 or more documented relapses 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 (inclusive), and John Cunningham virus (JCV) index of 1.5 or less at screening were eligible. A total of 264 participants received treatment with biosim-NTZ (n = 131) or ref-NTZ (n = 133).
The primary end point was cumulative number of new, active lesions on MRI (new gadolinium-enhancing T1-weighted lesions and new/enlarging T2-weighted lesions without double counting) of the brain over 24 weeks. Other end points included further MRI parameters, annualized relapse rate, and Kurtzke Expanded Disability Status Scale score. The assessments for safety, tolerability, and immunogenicity included adverse events (AEs), laboratory evaluations, and testing positive for anti-JCV) antibodies and antinatalizumab antibodies.
Administration of the drugs for participants consisted of intravenous infusions every 4 weeks of 300-mg biosim-NTZ or 300-mg or ref-NTZ (1:1 randomization), from week 0 to week 44, with an end-of-study visit at week 48. The ref-NTZ group was rerandomized at week 24, and 30 patients were switched to biosim-NTZ for the rest of the study.
After the administration of either the biosimilar or its reference, the model-based mean difference in cumulative number of new active lesions between the biosim-NTZ and ref-NTZ treatment groups at week 24 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).
Additionally, no significant observed differences between treatment groups across the secondary efficacy end points, safety, tolerability, or immunogenicity assessments were found.
“Notably, the overall AE profile for patients who switched from ref-NTZ to biosim-NTZ was similar to patients continuing ref-NTZ treatment and did not indicate any new or increased risks associated with switching to biosim-NTZ.”
The most reported treatment-emergent adverse events among all treatment groups were nervous system disorders and infections and infestations. Importantly, the study investigators found that 1 or more of the 3 stratification factors (absence/presence of gadolinium-enhancing lesions, presence of T2 lesions, JCV status) were incorrectly recorded at randomization for 62 of 265 patients after database lock. The imbalanced strata risk was found to be low, and the integrity of the data was not affected.
An aspect of the study that might be considered a limitation is the small sample size in the ref-NTZ/biosim-NTZ switch subgroup.
The researchers concluded that, “The results from this phase 3 trial support biosimilarity of proposed biosimilar natalizumab PB006 to its reference medicine in RRMS.”
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