Pooled Analysis Supports Bioequivalence Between MB02 and Reference Bevacizumab

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A pooled analysis of 3 studies confirmed the bioequivalence, safety, and immunogenicity between MB02 and reference bevacizumab.¹

Invasive tumor growth requires angiogenesis, regulated by the vascular endothelial growth factor (VEGF). Bevacizumab, an immunoglobulin G1 monoclonal antibody, inhibits angiogenesis by binding to VEGF. The drug prevents cancerous, endothelial cells from interacting with VEGF receptors.

During 2020, bevacizumab treated breast (2.26 million cases), lung (2.21 million cases), and colon/rectum cancer (1.93 million cases) the most—but the high cost made the treatment option limited. Bevacizumab, or Avastin, is one of the most expensive drugs on the market. The New England Journal of Medicine reported bevacizumab extended life by 4.7 months at a cost of $42,800 – $55,000.²

For more people to afford treatment, researchers created MB02, a biosimilar to the reference product, bevacizumab. MB02 went into the market in 2021 for the European Union and in April 2022 for the United States.¹

The pooled analysis came from 3 independent pharmacokinetic studies, all single-dose, double-blind, three-arm, parallel-group design. Two of the studies—MB02-A-02-17 and MB02-A-05-18—compared the biosimilar MB02 to the European and United States versions of the reference product, bevacizumab, in Caucasian participants aged 18 – 55 years old. Meanwhile, the third study, MB02-A-04-18 compared MB02 and European bevacizumab in Japanese patients aged 20 – 55 years old. The pooled analysis included 276 male participants, with 35% on MB02 (n = 100), 25% on European-Union-bevacizumab (n = 100), and 28% on US-bevacizumab (n = 76). Body Mass Index (BMI) ranged from 18.60 – 29.80 kg/m2.

The study, led by B. Miguel-Lillo, of the Medical Department of mAbxience Research S.L. in Madrid, Spain, evaluated the primary endpoint of maximum observed serum concentration and area under the serum concentration time curve from time 0 to infinity. They also examined for secondary endpoints of pharmacokinetic parameters, safety, and immunogenicity. The 3 trials only included male participants, as females exposed to bevacizumab may suffer from long-lasting ovarian failure, lowered fertility and risk of bevacizumab exposure during pregnancy.

“Within biosimilars field, the [pharmacokinetic] similarity exercise is a critical part of the biosimilar development as differences in structure may impact [pharmacokinetic] parameters,” the investigators wrote. “Therefore, a clinical pharmacology study is the best tool to establish biosimilarity.”

MB02 was evaluated in both analytical and clinical comparability studies, examining the similarity of MB02 to bevacizumab in terms of physicochemical, structural, and functional characterization. Studies found similarity regarding structure, purity, stability, and biological functions.

In the first study—MB02-A-02-17—the investigators only observed pharmacokinetic similarity between MB02 and European Union-approved bevacizumab and similarity between both reference bevacizumab—but similarity was not found between MB02 and US approved bevacizumab until the post-hoc sensitivity analysis. The study also demonstrated a difference in protein concentration between MB02 and both US and European Union reference products.

In the second study—MB02-A-05-18—the team observed pharmacokinetic similarity and bioequivalence of MB02 to both European Union and US-approved bevacizumab. The study had tried to discard the impact of protein content.

The final study—MB02-A-04-18—demonstrated pharmacokinetic similarity of MB02 to reference European Union-approved bevacizumab (US-approved bevacizumab had not been studied in this trial). The study also found comparable safety and immunogenicity profiles between biosimilar and reference product.

In the 3 studies, participants received a 3 mg/kg single 90-minute intravenous (IV) dose of either bevacizumab or MB02. Participants completed specific examinations and assessments for 8 days. Afterward, they could go home, unless they experienced clinical abnormalities requiring hospitalizations. Then, participants returned to the trial site for the collection of pharmacokinetic and immunogenicity samples, as well as safety assessment.

MB02 was considered bioequivalent to bevacizumab since the 90% CIs for the geometric mean ratios was in the interval of 0.80 – 1.25. The investigators found maximum observed serum concentration and area under the serum concentration-time curve was slightly higher in the MB02 group than both bevacizumab group. Though, pharmacokinetic parameters were similar across MB02 and the two bevacizumab groups, such as the median time to serum bevacizumab peak concentration delaying and occurring at 4 hours after the IV infusion.

Adverse effects were reported 482 times in 67.4% participants (n = 186), which was higher in the both the European Union bevacizumab group (n = 166) and US bevacizumab group (n = 169) than MB02 (n = 148). Most adverse effects were mild in severity. The most frequently reported adverse events were headache, nausea, fatigue, epistaxis, diarrhea, with nasopharyngitis and headache being the most common.

“In terms of safety and immunogenicity, the dose was well tolerated, and no remarkable differences between MB02 and the reference bevacizumab, whether EU-approved or US-licensed, where observed,” the investigators wrote. “Frequency, severity and causality of recorded [treatment emergent adverse events] were comparable and similar in nature across all treatment groups.”

Ultimately, all 3 studies reflected the bioequivalence of MB02 to reference bevacizumab. Also, Miguel-Lillo and colleagues wrote how vital protein concentration may contribute to variation in the serum drug concentration.

“The lots of bevacizumab (MB02, [European Union]- and US-bevacizumab) used in this study showed a difference that resulted in the subjects treated with [European Union]- and US-bevacizumab receiving an approximately 12 – 14% lower bevacizumab dose than subjects in the MB02 group,” the investigators wrote. “This variability in protein concentration did not impact the study results and [pharmacokinetic] similarity was demonstrated between MB02 and both reference bevacizumab products.”

^References

1. ^{Miguel-Lillo B, Sánchez-Vidaurre S, Pérez Díaz L, Paravisini A. Pooled analysis of three pharmacokinetic studies comparing biosimilar MB02 and reference bevacizumab. Pharmacol Res Perspect. 2023;11(6):e01139. doi:10.1002/prp2.1139}
2. ^{Mandal, A. Avastin (Bevacizumab) Price. https://www.news-medical.net/health/Avastin-(Bevacizumab)-Price.aspx#:~:text=One%20study%20published%20in%20the,cost%20of%20%2442%2C800%20to%20%2455%2C000. Accessed December 5, 2023.}