Comparative immunogenicity assessment of biosimilar natalizumab to its reference medicine: a matching immunogenicity profile

Abstract

Background: Biosimilar natalizumab (biosim-NTZ) is the first biosimilar monoclonal antibody of reference natalizumab (ref-NTZ) for treatment of relapsing forms of multiple sclerosis (MS). Within the totality of evidence for demonstration of biosimilarity, immunogenicity assessments were performed in healthy subjects and patients with relapsing-remitting MS (RRMS) to confirm a matching immunogenicity profile between biosim-NTZ and ref-NTZ.

Methods: Immunogenicity of biosim-NTZ versus ref-NTZ was evaluated in two pivotal clinical studies. In a comparative efficacy and safety study, patients with RRMS (n=264) received monthly infusions of biosim-NTZ/EU-ref-NTZ over 48 weeks. The primary endpoint period was Week 0 to Week 24. In a separate, comparative pharmacokinetic/pharmacodynamic (PK/PD) study, healthy subjects (n=450) received a single dose of biosim-NTZ, US-ref-NTZ or EU-ref-NTZ prior to an 85-day follow-up. In both studies, state-of-the-art, highly sensitive and drug tolerant bioanalytical assays were used to identify the proportion of participants with anti-drug antibodies (ADA) and neutralizing antibodies (NAb) against natalizumab over time.

Results: In the comparative efficacy and safety study, biosim-NTZ and EU-ref-NTZ demonstrated similar incidences of overall ADA (79.4% vs 73.7%, respectively) and NAb (68.7% vs 66.2%, respectively) at Week 24. ADA titers over time were also concordant throughout the study period. Switching treatment from EU-ref-NTZ to biosim-NTZ had no impact on treatment-related ADA/NAb or clinical responses. Likewise, the single-dose PK/PD study reported matching overall incidence of ADA between treatment groups and matching ADA titer profiles over time.

Conclusion: The immunogenicity profile of biosim-NTZ was confirmed to match that of ref-NTZ in healthy subjects and patients with RRMS by applying highly sensitive methods.

Keywords: anti-drug antibodies; biologic products; biosimilar; immunogenicity; immunology; multiple sclerosis; natalizumab; neutralizing antibodies.

Figure 1

Antelope study design and immunogenicity assessment schedule (Safety Set). Blue circles signify contact points for patients receiving biosim-NTZ. Orange circles signify contact points for patients receiving EU-ref-NTZ. Hemmer B, et al. (22). Reprinted by permission of JAMA Network. ADA, anti-drug antibody; biosim-NTZ, biosimilar natalizumab; EOS, end of study; NAb, neutralizing antibody; PML, progressive multifocal leukoencephalopathy; ref-NTZ, reference natalizumab.

Figure 2

PK/PD study design and immunogenicity assessment schedule (Safety set). Dark blue circles signify contact points for patients receiving biosim-NTZ. Brown and orange circles signify contact points for patients receiving US- and EU-ref-NTZ, respectively. *Subjects were admitted to the studio center on Day –1 and discharged on Day 3 with subsequent ambulatory visits from Day 5. ^†PK/PD sampling was performed via blood sampling, once pre-infusion and then at each ambulatory visit over 85 days post-infusion. Wessels H, et al. (23). Copyright © 2023 Polpharma Biologics S.A. reprinted by permission of Informa UK Limited, trading as Taylor & Francis Group https://www.tandfonline.com. ADA, anti-drug antibody; biosim-NTZ, biosimilar natalizumab; EOS, end of study; JCV, John Cunningham virus; NAb, neutralizing antibody; PD, pharmacodynamic; PK, pharmacokinetic; ref-NTZ, reference natalizumab.

Figure 3

Immunogenicity assay scheme applied for monitoring ADA/NAb immune response. Clinical samples were tested for immunogenicity using a tiered, one-assay strategy for the detection of ADA and NAb as recommended by health authorities to minimize a confounding influence of inter-assay variability. Samples sequentially passed through screening and confirmatory assays, followed by semi-quantitation and characterization of ADA and NAb in terms of titer assessment and evaluation of neutralizing capacity. ADA, anti-drug antibody; biosim-NTZ, biosimilar natalizumab; CCP, confirmatory cut point; NAb, neutralizing antibody; PSCP, plate-specific cut point.

Figure 4

Drug tolerance of validated ADA assay method: 100 ng/mL positive control. The screening cut-point was calculated by multiplying the mean negative control signal for the assay run by a normalization factor of 1.30 representing the 95^th percentile of the distribution of log-transformed signals for 50 individual samples of human serum. ADA, anti-drug antibody; biosim-NTZ, biosimilar natalizumab.

Figure 5

Box plot of ADA titers over time (Week 0–24) by treatment group (Antelope study). The ADA titer value represents the value of the highest dilution factor yielding a response greater than or equal to the cut point (threshold) multiplied by the MRD of 10; therefore, the minimum ADA titer value is 10. Descriptive statistics were used to analyze the data. Ninety-five percent confidence intervals of frequencies were calculated on the normal approximation. Boxes represent the Q1 (25^th percentile) to Q3 (75^th percentile) interquartile range, with the whiskers showing the minimum/maximum observations below/above the interquartile range; the horizontal line in each box represents the median value; the circles represent outlier values. ADA, anti-drug antibody; biosim-NTZ, biosimilar natalizumab; MRD, minimal required dilution; Q, quartile; ref-NTZ, reference natalizumab.

Figure 6

Serum natalizumab trough concentration over time (Week 8–24) by ADA category (Antelope study). (A) ADA-positive; (B) ADA-negative. Descriptive statistics were used to analyze the data. Ninety-five percent confidence intervals of frequencies were calculated on the normal approximation. Boxes represent the Q1 (25^th percentile) to Q3 (75^th percentile) interquartile range, with the whiskers showing the minimum/maximum observations below/above the interquartile range; the horizontal line in each box represents the median value; the circles represent outlier values. ADA, anti-drug antibody; biosim-NTZ, biosimilar natalizumab; ref-NTZ, reference natalizumab.

Figure 7

Box plot of serum drug concentration over time (Day 8–85) by ADA category (PK/PD study). (A) ADA-positive; (B) ADA-negative. Descriptive statistics were used to analyze the data. Ninety-five percent confidence intervals of frequencies were calculated on the normal approximation. n = number of subjects with data available. Boxes represent the Q1 (25^th percentile) to Q3 (75^th percentile) interquartile range, with the whiskers showing the minimum/maximum observations below/above the interquartile range; the horizontal line in each box represents the median value; the diamond symbol represents the mean value (geometric mean); the circles represent outlier values. ADA, anti-drug antibody; biosim-NTZ, biosimilar natalizumab; ref-NTZ, reference natalizumab.