Dataset Information

Development of the Drug Product Formulation of the Bevacizumab Biosimilar PF-06439535 (Bevacizumab-bvzr).

ABSTRACT:

Background

PF-06439535 (bevacizumab-bvzr; Zirabev^®) is a biosimilar of bevacizumab reference product (RP; Avastin^®). This study describes the formulation development for PF-06439535.

Methods

PF-06439535 was formulated in several buffers and stored for 12 weeks at 40 °C to determine the optimal buffer and pH under stressed conditions. Subsequently, PF-06439535 at 100 and 25 mg/mL was formulated in a succinate buffer with sucrose, edetate disodium dihydrate (EDTA), and polysorbate 80, and in the RP formulation. Samples were stored at - 40 °C to 40 °C for ≤ 22 weeks. The physicochemical and biological properties relevant to the safety, efficacy, quality, or manufacturability were investigated.

Results

When stored at 40 °C for 13 days, PF-06439535 demonstrated optimal stability in histidine or succinate buffers and was more stable in the succinate formulation than the RP formulation, under both real-time and accelerated stability conditions. There were no significant changes in the quality attributes of 100 mg/mL PF-06439535 after storage at - 20 °C and - 40 °C for 22 weeks, and there were no changes in the quality attributes of 25 mg/mL PF-06439535 after storage at 5 °C (recommended storage temperature). Changes were observed at 25 °C for 22 weeks or at 40 °C for 8 weeks as expected. No new degraded species were observed in the biosimilar succinate formulation compared with the RP formulation.

Conclusions

Results demonstrated that 20 mM succinate buffer (pH 5.5) is the PF-06439535 preferred formulation, and that sucrose is an effective cryoprotectant for processing and frozen storage, and an effective stabilizing excipient for 5 °C liquid storage of PF-06439535.

SUBMITTER: Ingram RL

PROVIDER: S-EPMC9985529 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Development of the Drug Product Formulation of the Bevacizumab Biosimilar PF-06439535 (Bevacizumab-bvzr).

Ingram Rebecca L RL Weiser Sarah E SE

Drugs in R&D 20230222 1

<h4>Background</h4>PF-06439535 (bevacizumab-bvzr; Zirabev<sup>®</sup>) is a biosimilar of bevacizumab reference product (RP; Avastin<sup>®</sup>). This study describes the formulation development for PF-06439535.<h4>Methods</h4>PF-06439535 was formulated in several buffers and stored for 12 weeks at 40 °C to determine the optimal buffer and pH under stressed conditions. Subsequently, PF-06439535 at 100 and 25 mg/mL was formulated in a succinate buffer with sucrose, edetate disodium dihydrate (ED ...[more]

PMID: 36811761

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Project description:IntroductionPF-06439535 (bevacizumab-bvzr; Zirabev®) is a bevacizumab biosimilar. The stability profile and functional activity of PF-06439535 after dilution for intravenous infusion was evaluated following extended storage conditions.MethodsPF-06439535 drug product was diluted in 0.9% sodium chloride to produce final concentrations of 1.4 and 16.5 mg/mL of PF-06439535, representing clinically relevant low and high doses for intravenous infusion. Three drug product lots and three infusion bag types (polyolefin, ethylene vinyl acetate, and polyvinyl chloride) were tested. To simulate the potential preparation and administration conditions encountered in a clinical setting, prepared drug solutions were initially stored at 25 ± 5°C for 24 ± 2 h, and then at 5 ± 3°C for up to 6 weeks. Extended storage was followed by storage at 25 ± 5°C for 24 ± 2 h before testing. Physicochemical and biological stability were evaluated according to visual characteristics and pH, protein concentration, particulate content, the proportions of molecular weight variants and charge variants, and relative potency. A wide range of analytical techniques optimized for PF-06439535 assessment were employed, such as size-exclusion chromatography, non-reducing sodium dodecyl sulfate capillary electrophoresis, cation-exchange chromatography, far-UV circular dichroism spectroscopy, differential scanning calorimetry, and an in vitro cell-based bioassay.ResultsFor all concentrations, drug product lots, infusion bag types, and time points tested, there were no significant changes in protein concentration and no notable differences in visual characteristics (color, clarity, and visible particulates). The abundance of molecular weight variants and charge variants remained stable over the 6-week study period. There were no stability concerns with regard to sub-visible particles. There were no significant changes in primary, secondary, or tertiary structure. Finally, the in vitro relative potency of PF-06439535 was maintained throughout the study period.ConclusionsThe stability and biological activity of PF-06439535 was maintained after dilution and storage for up to 6 weeks at 2-8°C, demonstrating the integrity of diluted PF-06439535 under extended in-use conditions.

Project description:BackgroundPF-06439535 is a bevacizumab biosimilar. We aimed to compare the efficacy and safety of PF-06439535 with that of reference bevacizumab (Avastin®) sourced from the EU (bevacizumab-EU), each with paclitaxel and carboplatin, in the first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC).MethodsIn this double-blind, parallel-group study, we recruited patients from 159 centers in 27 countries. Participants were randomized 1:1 to receive PF-06439535 plus paclitaxel and carboplatin or bevacizumab-EU plus paclitaxel and carboplatin on day 1 of each 21-day cycle for 4-6 cycles, followed by blinded monotherapy with PF-06439535 or bevacizumab-EU until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study. Randomization was stratified by region, sex, and smoking history. The primary endpoint was objective response rate (ORR) in accordance with RECIST 1.1, based on responses achieved by week 19 and confirmed by week 25.ResultsBetween 21 May 2015 and 14 November 2016, 719 patients were randomized to the PF-06439535 group (n = 358) or the bevacizumab-EU group (n = 361). As of data cutoff for analysis of the primary endpoint (8 May 2017), 45.3% (95% confidence interval [CI] 40.01-50.57) of patients in the PF-06439535 group and 44.6% (95% CI 39.40-49.89) of patients in the bevacizumab-EU group achieved an objective response by week 19 that was confirmed by week 25. The unstratified ORR risk ratio was 1.015 (95% CI 0.863-1.193; 90% CI 0.886-1.163), and the unstratified ORR risk difference was 0.653% (95% CI - 6.608 to 7.908); all three CIs fell within pre-specified equivalence margins. Using final data after study completion (22 December 2017), no notable differences in progression-free survival or overall survival were observed between the groups. The most frequently reported grade 3 or higher treatment-emergent adverse events were hypertension, neutropenia, and anemia. There were no clinically meaningful differences in safety, pharmacokinetics, or immunogenicity across treatment groups.ConclusionAmong patients with advanced non-squamous NSCLC, PF-06439535 demonstrated similarity to bevacizumab-EU in terms of efficacy. Safety profiles for the two treatments were comparable.Trial registrationClinicalTrials.gov, NCT02364999.FundingPfizer.

Project description:PurposeBevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor-specific angiogenesis in some cancers. MYL-1402O is a proposed bevacizumab biosimilar.MethodsThe 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.ResultsOf 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.ConclusionMYL-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).

Project description:BACKGROUND:This double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira®) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10-25 mg/week). We report results for the first 26 weeks of treatment. METHODS:Patients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (-12%, 15%). Secondary efficacy endpoints to week 26 included ACR20/50/70, change from baseline Disease Activity Score based on high-sensitivity C-reactive protein [DAS28-4(CRP)], European League Against Rheumatism (EULAR) response, DAS28-4(CRP) of less than 2.6, and ACR/EULAR remission. QuantiFERON-TB testing was performed at screening and week 26. RESULTS:Patients (78.7% of whom were female and whose mean age was 52.5 years) had a mean baseline RA duration of 6.8 years. The mean baseline DAS28-4(CRP) values were 5.9 (PF-06410293) and 6.1 (adalimumab-EU). The observed week-12 ACR20 values were 68.7% (PF-06410293) and 72.7% (adalimumab-EU) in the intention-to-treat population. With non-responder imputation, the treatment difference in week-12 ACR20 was -2.98% and corresponding CIs-95% CI (-10.38%, 4.44%) and 90% CI (-9.25%, 3.28%)-were entirely contained within the equivalence margins (symmetric and asymmetric, respectively). The secondary efficacy endpoints were similar between arms. Over 26 weeks, injection-site reactions occurred in 1.7% versus 2.0%, hypersensitivity events in 4.4% versus 8.4%, pneumonia in 0.7% versus 2.0%, and opportunistic infections in 2.4% versus 1.7% in the PF-06410293 and adalimumab-EU arms, respectively. One death due to myocardial infarction occurred (adalimumab-EU arm). Rates of anti-drug antibody incidence were 44.4% (PF-06410293) and 50.5% (adalimumab-EU). CONCLUSIONS:The study results demonstrate that efficacy, safety, and immunogenicity of PF-06410293 and adalimumab-EU were similar during the first 26 weeks of treatment in patients with active RA on background MTX. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02480153 . First posted on June 24, 2015; EU Clinical Trials Register EudraCT number: 2014-000352-29 . Start date: October 27, 2014.

Dataset Information

Development of the Drug Product Formulation of the Bevacizumab Biosimilar PF-06439535 (Bevacizumab-bvzr).

Background

Methods

Results

Conclusions

Publications

Development of the Drug Product Formulation of the Bevacizumab Biosimilar PF-06439535 (Bevacizumab-bvzr).

Similar Datasets

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