Authors: Joel S. Owen, Russell J. Rackley, Matthew A. Hummel, Stefan Roepcke, Hannah Huang, Mark Liu, Tazeen A. Idris, Sundara Moorthi Nainar Murugesan, Ashwani Marwah, Subramanian Loganathan, Gopinath Ranganna, Abhijit Barve, Cornelius F. Waller & Mark A. Socinski

Date: Oct 4th, 2023

Link: https://doi.org/10.1007/s13318-023-00855-3

Abstract –

Background and Objectives: MYL-1402O is a bevacizumab (Avastin®) biosimilar. Pharmacokinetic and safety similarity of MYL-1402O and reference Avastin® authorized in the European Union (EU-Avastin®) and the US (US-Avastin®) was demonstrated in healthy subjects (phase I, NCT02469987). The key objectives of this study were to establish a population pharmacokinetic (PopPK) model on pooled data from the phase I and phase III clinical studies to assess pharmacokinetic linearity of MYL-1402O and Avastin® across dose ranges, to assess the pharmacokinetic similarity of MYL-1402O and Avastin® in patients with non-squamous non-small cell lung cancer (nsNSCLC), and to explore potential covariates to account for systematic sources of variability in bevacizumab exposure.

Methods:Efficacy and safety of MYL-1402O compared with EU-Avastin® was investigated in a multicenter, double-blind, randomized, parallel-group study in patients with stage IV nsNSCLC (phase III, NCT04633564). PopPK models were developed using a nonlinear mixed effects approach (NONMEM® 7.3.0).

Results: The pharmacokinetics of Avastin® and MYL-1402O were adequately described with a two-compartment linear model. Fourteen covariates were found to be statistically significant predictors of bevacizumab pharmacokinectics. The impact of each covariate on area under the concentration-time curve, half-life, and maximum plasma concentration was modest, and ranges were similar between the treatment groups, MYL-1402O and EU-Avastin®, in patients with nsNSCLC. The pharmacokinectics of bevacizumab appeared to be linear.

Conclusions: PopPK analysis revealed no significant differences between pharmacokinetics of MYL-1402O and Avastin® in patients with nsNSCLC. The developed PopPK model was considered robust, as it adequately described bevacizumab pharmacokinetics in healthy participants and nsNSCLC patients.

Conflict of Interest Statement: JO, SR, HH are consultants from Simulation Plus Inc. for Viatris for Pharmacometric analyses. MS; Research/grant funding from Spectrum, Novartis, Lilly, Genentech, and AstraZeneca; speaker bureau for Genentech, AstraZeneca, Guardant, Bristol Myers Squibb, Novartis, and Bayer. CW: Member of advisory board of Viatris. RR, MH, ML, TI, GR, AB: Full time employees of Viatris and may hold stock of Viatris. AM, SL, SN: Full time employees of Biocon and may hold stock of Biocon

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

Date: Apr 17th, 2021

Link: https://link.springer.com/article/10.1007/s00432-021-03628-0

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.

Conclusions: 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).

Funding: Open Access funding enabled and organized by Projekt DEAL. This study was supported by Viatris Inc, Canonsburg, PA, and Biocon Ltd, Bangalore, India.

Authors: M.A. Socinski, C. Waller, T. Idris, I. Bondarenko, A. Luft, K. Beckmann, A. Vishweswaramurthy, S. Loganathan, G. Ranganna, A. Barve

Date: Sep 1st, 2020

Link: https://www.annalsofoncology.org/article/S0923-7534(20)41701-6/fulltext

Abstract –

Background: MYL-1402O (MYL, proposed biosimilar to Avastin), has been developed and extensively characterized using state-of-the-art physicochemical and functional tests.

Methods: This was a multicenter, randomized, double blind, equivalence study to evaluate comparative efficacy and safety of MYL with Avastin in patients with Stage IV metastatic nsNSCLC. Patients received combination therapy of study treatment with carboplatin-paclitaxel (CP) up to 18 weeks (6 cycles) followed by 24 weeks (8 cycles) of monotherapy. The primary endpoint was overall response rate (ORR) at 18 weeks, based on RECIST 1.1 assessed by an independent review (IR) at any time point during the first 18 weeks. The equivalence margin for ratio of ORR (90% confidence interval [CI]) was 0.73, 1.36; and for difference in ORR (95% CI) was ± 12.5%. Sample size of 670 was determined adequate to evaluate equivalence. Key secondary endpoints included assessment of progression free survival (PFS), overall survival (OS), safety and immunogenicity up to 42 weeks.

Results: 671 patients (MYL: 337, Avastin: 334) were randomized. The ratio of ORR (90% CI) was 0.96 (0.83, 1.12) and the difference in ORR (95% CI) was -1.6 (-9.0, 5.9) between treatment arms. The CIs were within the pre-defined equivalence margin for ratio and difference in ORR. At Week 42, the median PFS (95% CI) in months for IR was 7.6 (7.0, 9.5) in MYL arm and 9.0 (7.2, 9.7) in Avastin arm (p = 0.0906); PFS for investigator assessment was 7.8 (7.0, 9.5) in MYL arm and 7.3 (7.0, 8.9) in Avastin arm (p = 0.4748). Median OS was not reached at 42 weeks; OS rate was 70.0% and 75.4% for MYL and Avastin, respectively (p = 0.1185). Safety was comparable between MYL and Avastin; Serious adverse events occurred in 17.6% vs. 16.7% with treatment related adverse events leading to death in 2.4% vs. 1.5% patients. The incidence of treatment emergent anti-drug antibodies (6.5% vs. 4.8%) was comparable between MYL and Avastin.

Conclusions: MYL is equivalent to Avastin, given in combination with CP, as measured by ORR. Other efficacy endpoints, safety and immunogenicity were comparable.

Authors: Mark A. Socinski, Matthew Hummel, Tjerk Bosje, Andrew Shaw, Mark Shiyao Liu, Mark Baczkowski, Abhijit Barve, Mudgal Kothekar, Eduardo J. Pennella

Date: May 30th, 2017

Link: https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.e14034

Abstract –

Background: MYL-1402O is a proposed bevacizumab biosimilar. The similarity of MYL-1402O to Avastin has been demonstrated in physicochemical analyses, and nonclinical studies.

Methods: This single-center, randomized, double blind, three-arm, parallel-group, study was conducted in healthy adult male volunteers. The primary objective of this study was to establish PK similarity of A to B and C, and B to C. Subjects were randomized to receive either A, B or C 1 mg/kg over 90 minutes as an intravenous infusion. Dose was selected based on the lower dose in the linear range of PK and acceptable safety in healthy volunteers. Bioequivalence was to be concluded if the 90% CIs of the ratios (A/B, A/C and B/C) of LS means of the natural log transformed AUC0-inf were within 80% to 125%. AUC0-t, Cmax, tmax, kel and t½ were assessed as secondary PK parameters.

Results: A total of 111 subjects (37/treatment) were enrolled and 110 [37 (A), 36 (B), 37(C)] were included in the analysis. Bioequivalence was demonstrated between A and B, A and C and between B and C. LS mean ratios were close to 1, and 90% CIs were within 0.80 to 1.25 for all of the comparisons. The secondary PK parameters were also comparable with the 90% CIs for ratios of AUC0-t and Cmax within 80%-125%. A total of 313 TEAEs were reported, 116 by 33 (89%) subjects who received A, 99 by 29 (78%) subjects who received B and 98 by 28 (76%) subjects who received C. Most TEAEs were consistent with the clinical data of bevacizumab (Avastin). No serious or unexpected TEAEs were reported. TEAEs were grade 1 or grade 2 in severity. The anti-drug antibodies are being evaluated (pending results).

Conclusions: These results confirm bioequivalence of Myl-1402O vs. EU-Avastin and US-Avastin. All treatments were well tolerated and no significant safety issues emerged.

Authors: S. Beniwal, M. Kothekar, S. Loganathan, A. Vishweswaramurthy, A. Marwah, E. Pennella, N. Sengupta

Date: Nov 1st, 2017

Link: https://www.annalsofoncology.org/article/S0923-7534(19)56130-0/fulltext#relatedArticles

Abstract –

Background: The availability of biosimilars may provide more affordable treatment options for patients with cancer. Bmab-100 is a proposed bevacizumab biosimilar.

Methods: This multicentre double blind randomized active controlled parallel design study comparing Bmab-100 and Avastin®, was performed in 136 first line mCRC patients [129 in pharmacokinetic (PK) population]. The primary objective of the study was to demonstrate PK bioequivalence of Bmab-100 and Avastin following a single dose based on primary PK parameters: AUC0-t and Cmax, evaluated after dosing in Cycle 1. Patients were randomized to Bmab-100 or Avastin arm and received bevacizumab at 7.5 mg/kg along with XELOX (oxaliplatin and capecitabine) chemotherapy for up to 6 cycles. Each cycle consisted of a 21-day period. Twelve PK samples were collected during Cycle 1 for the assessment of primary PK parameters. A validated Enzyme Linked Immunosorbent Assay was used for the quantitation of Avastin and Bmab-100 in patient serum samples.

Results: The study included 84 male and 52 female patients of Asian origin and the demographic profile was similar in the Bmab-100 and Avastin arms with respect to age, height, weight, body surface area and survival expectancy. The primary PK parameters were similar for both the products; demonstrated by the point estimates of the ratio (%) of least square means of natural log-transformed Cmax and AUC0-t of Bmab-100 to reference product bevacizumab [Cmax: 92.91% and AUC0-t (AUC 0-504): 95.79%]. In addition, the 90% CIs were within the pre-defined bioequivalence range of 80% to 125% (Cmax: 85.86 and 100.54%; AUC0-504: 87.56% and 104.79%), confirming the single dose PK equivalence of Bmab-100 and Avastin. No suspected unexpected serious adverse reactions were observed during the study.

Conclusions: These results establish the single dose PK bioequivalence of Bmab-100 and Avastin and in addition to the comparable disease control rate, immunogenicity observed in the study, strongly support the prospective for Bmab-100 as an affordable biosimilar bevacizumab.

Funding: Biocon Research Limited (a subsidiary of Biocon Limited), India and Mylan GmbH, Switzerland