A pharmacokinetics study of proposed bevacizumab biosimilar MYL-1402O vs EU-bevacizumab and US-bevacizumab

Matthew Hummel, Tjerk Bosje, Andrew Shaw, Mark Shiyao Liu, Abhijit Barve, Mudgal Kothekar, Mark A Socinski, Cornelius F Waller, Matthew Hummel, Tjerk Bosje, Andrew Shaw, Mark Shiyao Liu, Abhijit Barve, Mudgal Kothekar, Mark A Socinski, Cornelius F Waller

Abstract

Purpose: Bevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor-specific angiogenesis in some cancers. MYL-1402O is a proposed bevacizumab biosimilar.

Methods: The primary objective of this single-center, randomized, double-blind, three-arm, parallel-group, phase 1 study in healthy male volunteers was to evaluate bioequivalence of MYL-1402O to EU and US-reference bevacizumab, and EU-reference bevacizumab to US-reference bevacizumab. The primary pharmacokinetic parameter was area under the serum concentration-time curve from 0 extrapolated to infinity (AUC0-∞). Pharmacokinetic parameters were analyzed using general linear models of analysis of variance. Secondary endpoints included safety and tolerability.

Results: Of 111 enrolled subjects, 110 were included in the pharmacokinetic analysis (MYL-1402O, n = 37; EU-reference bevacizumab, n = 36; US-reference bevacizumab, n = 37). Bioequivalence was demonstrated between MYL-1402O and EU-reference bevacizumab, MYL-1402O and US-reference bevacizumab, and between EU- and US-reference bevacizumab where least squares mean ratios of AUC0-∞ were close to 1, and 90% CIs were within the equivalence range (0.80-1.25). Secondary pharmacokinetic parameters (AUC from 0 to time of last quantifiable concentration [AUC0-t], peak serum concentration [Cmax], time to Cmax, elimination rate constant, and elimination half-life) were also comparable, with 90% CIs for ratios of AUC0-t and Cmax within 80-125%. Treatment-emergent adverse events were similar across all three treatment groups and were consistent with clinical data for bevacizumab.

Conclusion: MYL-1402O was well tolerated and demonstrated pharmacokinetic and safety profiles similar to EU-reference bevacizumab and US-reference bevacizumab in healthy male volunteers. No new significant safety issues emerged (ClinicalTrials.gov, NCT02469987; ClinicalTrialsRegister.eu EudraCT, 2014-005621-12; June 12, 2015).

Keywords: Bioequivalence; Cancer; Monoclonal antibody; Pharmacokinetics; Phase 1.

Conflict of interest statement

M Hummel, A Shaw, MS Liu, and A Barve are employees of Viatris Inc and may hold stock with the company. T Bosje was an employee of PRA Health Sciences during the study and has since retired, and has nothing to disclose. M Kothekar was an employee of Biocon Research Ltd at the time of the study and may hold stock with the company. M Socinski has nothing to disclose. CF Waller is a consultant/advisory board member for Viatris Inc.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design: bioequivalence of MYL-1402O to EU and US-reference bevacizumab. IV, intravenous; R, randomization
Fig. 2
Fig. 2
a Mean serum bevacizumab concentration vs time (linear scale). b Mean serum bevacizumab concentration vs time (semi-log scale). All treatments were a single intravenous dose of 1 mg kg−1 in 25 mL over 90 min

References

    1. André T, Kotelevets L, Vaillant JC, Coudray AM, Weber L, Prévot S, Parc R, Gespach C, Chastre E. Vegf, Vegf-B, Vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa. Int J Cancer. 2000;86:174–181. doi: 10.1002/(sici)1097-0215(20000415)86:2<174::aid-ijc5>;2-e.
    1. Avastin [package insert] (2019) Genentech, Inc, South San Francisco
    1. Avastin [summary of product characteristics] (2020) Roche Pharma AG, Grenzach-Wyhlen
    1. Beniwal S, Kothekar M, Loganathan S, Vishweswaramurthy A, Marwah A, Pennella E, Sengupta N. Comparative pharmacokinetics of a proposed biosimilar bevacizumab Bmab-100 and reference product bevacizumab in a multicentre double blind randomized clinical trial in metastatic colorectal carcinoma (mCRC) patients. Ann Oncol. 2017 doi: 10.1093/annonc/mdx659.016.
    1. Blackstone EA, Joseph PF. The economics of biosimilars. Am Health Drug Benefits. 2013;6:469–478.
    1. Busse A, Lüftner D. What does the pipeline promise about upcoming biosimilar antibodies in oncology? Breast Care (Basel) 2019;14:10–16. doi: 10.1159/000496834.
    1. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2009;438:932–936. doi: 10.1038/nature04478.
    1. Casak SJ, Lemery SJ, Chung J, Fuchs C, Schrieber SJ, Chow ECY, Yuan W, Rodriguez L, Gwise T, Rowzee A, Lim S, Keegan P, McKee AE, Pazdur R. FDA's approval of the first biosimilar to bevacizumab. Clin Cancer Res. 2018;24:4365–4370. doi: 10.1158/1078-0432.CCR-18-0566.
    1. Chen Y-X, Yang Q, Kuang J-J, Chen S-Y, Wei Y, Jiang Z-M, Xie D-R. Efficacy of adding bevacizumab in the first-line chemotherapy of metastatic colorectal cancer: evidence from seven randomized clinical trials. Gastroenterol Res Pract. 2014;2014:594930. doi: 10.1155/2014/594930.
    1. Chopra R, Lopes G. Improving access to cancer treatments: the role of biosimilars. J Glob Oncol. 2017;3:596–610. doi: 10.1200/JGO.2016.008607.
    1. Drug and Device News New drug approvals. P T. 2019;44:446–459.
    1. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 suppl 16):15–18. doi: 10.1053/sonc.2002.37263.
    1. Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, Chinot OL. Bevacizumab (Avastin®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat Rev. 2020;86:102017. doi: 10.1016/j.ctrv.2020.102017.
    1. European Medicines Agency (2015) Guideline on similar biological medicinal products containing biotechnology-derived protein as active substance: non-clinical and clinical issues. European Medicines Agency. . Accessed 15 May 2020
    1. Han H, Silverman JF, Santucci TS, Macherey RS, d'Amato TA, Tung MY, Weyant RJ, Landreneau RJ. Vascular endothelial growth factor expression in stage I non-small cell lung cancer correlates with neoangiogenesis and a poor prognosis. Ann Surg Oncol. 2001;8:72–79. doi: 10.1007/s10434-001-0072-y.
    1. Hashimoto I, Kodama J, Seki N, Hongo A, Yoshinouchi M, Okuda H, Kudo T. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer. 2001;85:93–97. doi: 10.1054/bjoc.2001.1846.
    1. Hettema W, Wynne C, Lang B, Altendorfer M, Czeloth N, Lohmann R, Athalye S, Schliephake D. A randomized, single-blind, phase I trial (INVICTAN-1) assessing the bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects. Expert Opin Investig Drugs. 2017;26:889–896. doi: 10.1080/13543784.2017.1347635.
    1. Knight B, Rassam D, Liao S, Ewesuedo R. A phase I pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with bevacizumab in healthy male volunteers. Cancer Chemother Pharmacol. 2016;77:839–846. doi: 10.1007/s00280-016-3001-2.
    1. Kurebayashi J, Otsuki T, Kunisue H, Mikami Y, Tanaka K, Yamamoto S, Sonoo H. Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Jpn J Cancer Res. 1999;90:977–981. doi: 10.1111/j.1349-7006.1999.tb00844.x.
    1. Liu Y-N, Huang J, Guo C, Yang S, Ye L, Wu S-T, Zhang X-F, Yang X-Y, Han C-C, Pei Q, Huang L, He Q-N, Yang G-P. A randomized, double-blind, single-dose study to evaluate the biosimilarity of QL1101 with bevacizumab in healthy male subjects. Cancer Chemother Pharmacol. 2020;85:555–562. doi: 10.1007/s00280-019-04014-x.
    1. Markus R, Chow V, Pan Z, Hanes V. A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men. Cancer Chemother Pharmacol. 2017;80:755–763. doi: 10.1007/s00280-017-3416-4.
    1. Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:411–419. doi: 10.1093/annonc/mdm345.
    1. Nishida N, Yano H, Komai K, Nishida T, Kamura T, Kojiro M. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 2 are related closely to the prognosis of patients with ovarian carcinoma. Cancer. 2004;101:1364–1374. doi: 10.1002/cncr.20449.
    1. Rader RA. (Re)defining biopharmaceutical. Nat Biotechnol. 2008;26:743–751. doi: 10.1038/nbt0708-743.
    1. Roviello G, Bachelot T, Hudis CA, Curigliano G, Reynolds AR, Petrioli R, Generali D. The role of bevacizumab in solid tumours: a literature based meta-analysis of randomised trials. Eur J Cancer. 2017;75:245–258. doi: 10.1016/j.ejca.2017.01.026.
    1. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550. doi: 10.1056/NEJMoa061884.
    1. Tajima N, Martinez A, Kobayashi F, He L, Dewland P. A phase 1 study comparing the proposed biosimilar BS-503a with bevacizumab in healthy male volunteers. Pharmacol Res Perspect. 2017;5:e00286. doi: 10.1002/prp2.286.
    1. Thatcher N, Thomas M, Paz-Ares L, Ostoros G, Pan Z, Goldschmidt JH, Hanes V. Randomized, double-blind, phase 3 study evaluating efficacy and safety of ABP 215 compared with bevacizumab in patients with non-squamous NSCLC. J Clin Oncol. 2016;34(15 suppl):9095. doi: 10.1200/JCO.2016.34.15_suppl.9095.
    1. US Food and Drug Administration (2015) Scientific considerations in demonstrating biosimilarity to a reference product guidance for industry. US Food and Drug Administration. . Accessed 15 May 2020
    1. US Food and Drug Administration (2016) Clinical pharmacology data to support a demonstration of biosimilarity to a reference product guidance for industry. US Food and Drug Administration. . Accessed 15 May 2020
    1. US Food and Drug Administration (2019) Development of therapeutic protein biosimilars: comparative analytical assessment and other quality-related considerations guidance for industry. US Food and Drug Administration. . Accessed 15 May 2020
    1. Wang J, Qi L, Liu L, Wang Z, Chen G, Wang Y, Liu X, Liu Y, Liu H, Tong Y, Liu C, Lei C, Wang X. A phase I, randomized, single-dose study evaluating the biosimilarity of TAB008 to bevacizumab in healthy volunteers. Front Pharmacol. 2019;10:905. doi: 10.3389/fphar.2019.00905.
    1. Zhang H, Zhu X, Wei H, Li C, Chen H, Li X, Wu M, Liu J, Chen G, Zhou H, Zheng S, Ding Y. A phase I, randomized, double-blinded, single-dose study evaluating the pharmacokinetic equivalence of the biosimilar IBI305 and bevacizumab in healthy male subjects. Int J Clin Pharmacol Ther. 2019;57:167–174. doi: 10.5414/CP203349.
    1. Zhi J, Chen E, Major P, Burns I, Robinson B, McKendrick J, Rittweger K, Abt M, Goldstein D. A multicenter, randomized, open-label study to assess the steady-state pharmacokinetics of bevacizumab given with either XELOX or FOLFOX-4 in patients with metastatic colorectal cancer. Cancer Chemother Pharmacol. 2011;68:1199–1206. doi: 10.1007/s00280-011-1606-z.

Source: PubMed

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