Immunomodulation profile of the biosimilar trastuzumab MYL-1401O in a bioequivalence phase I study.

The initial Phase-I single centre, single dose, randomized, double-blind, cross-over study was planned to assess the pharmacokinetic and pharmacodynamic bioequivalence of the trastuzumab biosimilar (MYL-1401O) compared to the reference Herceptin®. Their respective immunomodulation profile presented in this paper involved healthy males receiving a single infusion of both monoclonals, separated by a washout period. Sixty parameters were assessed in total, including serum cytokines, peripheral mononuclear cell (PBMC) subsets, cell activation and response to recall antigens and mitogen, pre- and post- infusion, as well as a cytokine release assay (CRA) at baseline. Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6 h, and a modulation of mononuclear cell subset profile and activation level, notably CD16 + cells. Except for CD8 + T cells, there were no significant differences between Herceptin® and MYL-1401O. In CRA, PBMC stimulated with MYL-1401O or Herceptin® similarly secreted IL-6, TNF-α, IL-1ß, GM-CSF, IFN-γ, and IL-10, but no or low level of IL-2. Interestingly, some observed adverse events correlated with IL-2 and IFN-γ in CRA. MYL-1401O exhibited a very similar immunomodulation profile to Herceptin®, strongly supporting its bioequivalence. This approach may thus be included in a proof-of-concept study. CRA may be used as a predictive assay for the evaluation of clinical monoclonals.

A pharmacokinetic study comparing the biosimilar HEC14028 and Dulaglutide (Trulicity®) in healthy Chinese subjects.

This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar HEC14028 compared to reference Trulicity® (dulaglutide) in healthy male Chinese subjects. This study was a single-center, randomized, open, single-dose, parallel-controlled comparative Phase I clinical trial, including a screening period of up to 14 days, a 17-day observation period after administration, and a 7-day safety follow-up period. A total of 68 healthy male subjects were randomly assigned (1:1) to the test group (HEC14028) and the reference group (dulaglutide) (single 0.75 mg abdominal subcutaneous dose). The primary objective was to evaluate the pharmacokinetic characteristics of HEC14028 and compare the pharmacokinetic similarities between HEC14028 and dulaglutide. The primary PK endpoints were maximum plasma concentration (Cmax) and area under the blood concentration-time curve from zero time to the estimated infinite time (AUC0-∞). The study results showed that HEC14028 and dulaglutide were pharmacokinetically equivalent: 90% confidence interval (CI) of Cmax and AUC0-∞ geometric mean ratios were 102.9%-122.0% and 97.1%-116.9%, respectively, which were both within the range of 80.00%-125.00%. No grade 3 or above treatment emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to withdrawal from the trial, or TEAEs leading to death were reported in this study. Both HEC14028 and dulaglutide showed good and similar safety profiles, and no incremental immunogenicity was observed in subjects receiving HEC14028 and dulaglutide.

PB006: A Natalizumab Biosimilar.

PB006 (Tyruko®) is the first biosimilar of the reference monoclonal anti-α4-integrin antibody natalizumab. It is approved for use in the same indications for which reference natalizumab is approved, as a single disease-modifying therapy in adults with highly active relapsing-remitting multiple sclerosis (RRMS). PB006 has similar physicochemical and pharmacodynamic properties to those of reference natalizumab, and the pharmacokinetic similarity of the agents has been demonstrated in a study in healthy subjects. PB006 demonstrated clinical efficacy similar to that of reference natalizumab in patients with RRMS, and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of PB006 were similar to those of reference natalizumab, and switching from reference natalizumab to PB006 appeared to have no impact on tolerability or immunogenicity. The role of reference natalizumab in the management of RRMS is well established and PB006 provides an effective biosimilar alternative for patients requiring natalizumab therapy.

Survey of Data Package and Sample Size of Comparative Clinical Studies for Biosimilar Developments from PMDA Assessments.

BACKGROUND: The Japanese biosimilar guideline requires that the sponsors conduct clinical studies such as comparative pharmacokinetic (PK), pharmacodynamic (PD), or efficacy studies. In each biosimilar development, the sponsors consider the clinical data package, and thus clinical data packages vary among biosimilar developments. OBJECTIVES: The aim of this study was to elucidate the clinical data packages for the biosimilars approved in Japan. The details of clinical data packages and sample size for the regulatory approvals of biosimilars in Japan was reported. METHODS: We surveyed the clinical data packages and sample size based on the Pharmaceuticals and Medical Devices Agency (PMDA) website review reports between 2009 and 2023. RESULTS: Twenty-four biosimilars have been approved based on the comparative PK and efficacy studies, 10 biosimilars have been approved based on the comparative PK/PD study, and one biosimilar has been approved based on the comparative efficacy study. Regarding the sample size, comparative PK studies were conducted in healthy volunteers or patients for up to 300 cases, although the majority enrolled only 1-100 cases (68.1%, 32/47). Comparative PD studies enrolling 1-30, 31-60, and 61-90 cases totaled 4, 7, and 4 cases, respectively. Finally, comparative efficacy studies enrolling 1-300, 301-600, and 601-900 totaled 6, 10, and 11 cases, respectively. In particular, the oncology and rheumatology areas were the first and second disease areas recruiting 601-900 patients. CONCLUSION: Large numbers of patients were enrolled to conduct a comparative efficacy study. Efficient biosimilar development should be considered on the basis of the accumulation of scientific understanding of comparable features of biosimilars and their development.

Filgrastim biosimilar (EP2006): A review of 15 years' post-approval evidence.

Filgrastim is approved for several indications, including reduction of the incidence and duration of chemotherapy-induced neutropenia and for stem cell mobilization. The filgrastim biosimilar, EP2006, has been available in Europe since 2009, and in the United States since 2015. In this time, preclinical and clinical data used to support the approval of EP2006 have been published. These data established the biosimilarity of EP2006 to reference filgrastim in terms of structure, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity. Additional real-world evidence studies have also demonstrated equivalent efficacy and safety of EP2006 compared with reference filgrastim, both in the reduction of neutropenia and in stem cell mobilization in clinical practice. This review summarizes these preclinical, clinical, and real-world data, as well as the available cost-effectiveness data, for EP2006 since its approval 15 years ago.

Population Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim Biosimilar GP40141 and Reference Product in Healthy Volunteers to Evaluate Biosimilarity.

GP40141 is a romiplostim biosimilar. A Phase 1 clinical trial was previously conducted in healthy volunteers to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of GP40141 compared to the reference romiplostim (NCT05652595). Using noncompartmental analysis, the biosimilarity of PD end points was determined according to the classical criterion (0.8-1.25). PK end points were also in good agreement between GP40141 and the reference romiplostim; however, the confidence interval for the area under concentration-time curve from time 0 to the time of last measurement was slightly out of the bioequivalence range (0.91-1.29). Population PK/PD was used in the present study to characterize the individual PK and PD data of 56 healthy subjects in 2 cross-over periods of the Phase 1 clinical trial. Body weight and neutralizing antibodies to romiplostim were found to be important predictors of apparent volume of distribution and linear elimination constant, respectively. Within the framework of the conducted modeling, population estimates of PK/PD parameters were obtained, which were in agreement with literature data for the reference romiplostim. Additionally, values of intersubject variability, previously unreported for romiplostim in a healthy subject population, were derived. Covariate analysis, conducted during model development, as well as visual diagnostics and model-based simulations, demonstrated the absence of significant differences in PK and PD between GP40141 and romiplostim-ref.

Comparison of SB17 and reference ustekinumab in healthy adults: A randomized, double-blind, single-dose, phase I study.

OBJECTIVE: This study compared the pharmacokinetic (PK) characteristics of SB17 (Samsung Bioepis, Incheon, Republic of Korea), a proposed biosimilar of ustekinumab (UST) against reference UST (Stelara, Janssen Biotech, Horsham, PA, USA). MATERIALS AND METHODS: This double-blind, three-arm, parallel-group, single-dose study randomized 201 healthy adult subjects 1 : 1 : 1 to receive 45 mg of SB17, European Union-sourced UST (EU-UST) or United States of America-sourced UST (US-UST) via subcutaneous (SC) injection. Primary endpoints were area under the concentration-time curve from time zero to infinity (AUCinf) and maximum serum concentration (Cmax). Safety, tolerability, and immunogenicity were investigated. RESULTS: All 90% confidence intervals (CIs) for the ratios of AUCinf and Cmax between groups were within the predefined bioequivalence margin of 0.8 - 1.25. The geometric LSMeans ratios of AUCinf and Cmax were 0.99 and 0.90 for SB17/EU-UST, 1.01 and 0.94 for SB17/US-UST, and 1.02 and 1.05 for EU-UST/US-UST, respectively. The proportion of subjects with treatment-emergent adverse events (TEAEs) was comparable between SB17, EU-UST, and US-UST (68.7, 58.2, and 65.7%). No deaths, serious adverse events (SAEs), or severe TEAEs were reported. The incidence of subjects testing positive for post-dose anti-drug antibodies (ADAs) was 26.9%, 34.3%, and 34.3% in the SB17, EU-UST, and US-UST groups, respectively. Among the subjects with a positive ADA result at day 99/end of study, 53.8% (SB17 n = 5, EU-UST n = 12, and US-UST n = 11) were positive for neutralizing antibodies (NAbs). CONCLUSION: This study demonstrated bioequivalence of SB17, EU-UST, and US-UST in terms of PK. Safety, tolerability, and immunogenicity were also comparable between all groups.

Pharmacokinetics and pharmacodynamics of the proposed biosimilar denosumab GP2411 and reference denosumab in healthy males.

BACKGROUND: This Phase I study compared the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of GP2411 proposed denosumab biosimilar to reference denosumab (a monoclonal antibody for specific pro-resorptive conditions). RESEARCH DESIGN AND METHODS: Healthy males (28-65 years, 50-90 kg) were randomized to a single sub-therapeutic subcutaneous injection of 35 mg GP2411, EU-Xgeva® or US-Xgeva®, and followed for 39 weeks. The primary endpoints were AUCinf, AUClast, and Cmax. RESULTS: Four hundred ninety-two participants completed treatment. The 90% confidence intervals (CIs) (AUCinf, AUClast, and Cmax) and 95% CI of the geometric mean ratios of AUEC of % change from baseline in serum CTX were fully contained within the prespecified equivalence margins (0.80, 1.25), demonstrating similarity. The occurrence of treatment-emergent adverse events (TEAEs) with GP2411, EU-Xgeva® and US-Xgeva® was similar (72.9%, 76.0%, and 71.0% of participants, respectively). Most were Grade 1 or 2, <30% were treatment-related, and there was only one TEAE-related study discontinuation. Rates of positive anti-drug antibodies (ADAs) were similar (57.8%, 64.9%, and 69.1% of participants respectively), but immunogenicity was only borderline detectable and of very low magnitude. Ninety-nine percent of positive ADAs were transient. CONCLUSION: GP2411 demonstrated similarity with EU-Xgeva® and US-Xgeva® in PK, PD, safety, and immunogenicity in this population. CLINICAL TRIAL REGISTRATION: EudraCT 2019-001651-39.

Denosumab is a biological treatment that inhibits bone degradation. It is very effective in conditions characterized by elevated bone degradation, such as osteoporosis in women who have gone through the menopause, and in the treatment of specific bone cancers. However, the cost of the original patented denosumab ('reference denosumab') treatment may result in fewer eligible patients receiving denosumab treatment. A biosimilar is highly similar to the original treatment but at a lower price, enabling more patients to benefit.GP2411 is being developed as a proposed biosimilar to denosumab. This Phase I clinical trial was the first clinical trial to compare GP2411 to the EU and US versions of the reference denosumab (EU-Xgeva® and US-Xgeva®). All three products were given at a dose of 35 mg to 502 healthy males. The dose was lower than the dose that would be used in clinical practice to provide a more sensitive evaluation of similarity. Healthy males were chosen because they have fewer hormonal fluctuations than females, and are considered the most appropriate population for detecting differences in pharmacological effects of denosumab.The results demonstrate that GP2411 proposed denosumab biosimilar is highly similar to the reference products in absorption, distribution, and elimination, and other outcomes, including bone turnover. The incidence of adverse events was also comparable, most adverse events were very mild, and GP2411 was not associated with a higher rate of immune reactions.These results support its continued development and GP2411 may, in future, enable more patients to benefit from denosumab treatment.

Pharmacokinetic similarity of switching SAR341402 insulin aspart biosimilar and NovoLog insulin aspart versus continuous use of NovoLog in adults with type 1 diabetes: The GEMELLI X trial.

AIM: To assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR-Asp) and the insulin aspart reference product (NovoLog; NN-Asp) leads to equivalent pharmacokinetic (PK) exposure compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: This multicentre, open-label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once-daily insulin glargine U100 as basal insulin to four 4-week periods of alternating multiple daily injections of SAR-Asp and NN-Asp (NN-Asp for the first 4 weeks, SAR-Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN-Asp (non-switching group). At week 16, a single dose (0.15 U/kg) of SAR-Asp in the switching group (n = 95) or NN-Asp in the non-switching group (n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax ) of SAR-Asp versus NN-Asp after the single dose at week 16. RESULTS: The extent of PK exposure was similar between the two treatments (SAR-Asp in the switching group and NN-Asp in the non-switching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8-1.25. For Cmax in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8-1.25. CONCLUSIONS: PK exposure of SAR-Asp (switching group) and reference NN-Asp (non-switching group) were similar, supporting interchangeability between these two insulin aspart products.

Pharmacokinetic and pharmacodynamic similarity of biosimilar natalizumab (PB006) to its reference medicine: a randomized controlled trial.

BACKGROUND: PB006 (Polpharma Biologics S.A; marketed as Tyruko®, Sandoz) is an approved biosimilar to natalizumab (Tysabri®; Biogen [ref-NTZ]). This multicenter, double-blind, randomized, single-dose study was conducted to demonstrate pharmacokinetic/pharmacodynamic (PK/PD) similarity between PB006 and ref-NTZ. RESEARCH DESIGN AND METHODS: Healthy participants (N = 453) were randomized to receive 3 mg/kg infusion of PB006, US-licensed, or EU-approved ref-NTZ before an 85-day follow-up. Primary PK endpoint was total natalizumab serum concentration over time; secondary PK endpoints explored concentration changes. Primary PD endpoints compared CD19+ cell counts and percentage α4-integrin receptor saturation, per natalizumab's mechanism of action. Secondary PD endpoints explored serum changes in sVCAM-1 and sMAdCAM-1, CD34+, and CD19+ cells. Safety, tolerability, and immunogenicity were assessed. RESULTS: The primary PK endpoint was met, with 90% confidence intervals (CIs) of the geometric mean for serum test/reference ratios contained within a prespecified margin (0.8-1.25). All primary PD endpoints were met, with 90% and 95% CIs within this similarity margin for baseline-adjusted CD19+ cell counts and percentage α4-integrin receptor saturation. All secondary endpoints were similarly contained, except sVCAM. No notable differences in safety, tolerability, or immunogenicity were observed. CONCLUSION: Similarity was confirmed, with PB006 demonstrating PK/PD behavior consistent with that of ref-NTZ. CLINICAL TRIAL REGISTRATION: EudraCT number 2019-003874-15.

PB006 (developed by Polpharma Biologics S.A; and marketed as Tyruko® by Sandoz) is an approved biosimilar to the reference medicine, natalizumab (Tysabri®, Biogen [ref-NTZ]) used to treat relapsing forms of multiple sclerosis. Approved biosimilar medicines have been shown to be as safe and effective as their reference medicines via different types of comparisons to the reference medicine, confirming that physicians and patients can expect the same clinical outcome.This study was conducted to confirm that PB006 acts the same way in the body as ref-NTZ. Healthy participants received one dose of either PB006, ref-NTZ from the US or ref-NTZ from Europe. During the study, blood samples were tested to confirm how much of each medicine was present in participants' blood, as well as to assess changes in immune cells or proteins related to how natalizumab works. The study also measured whether any treatment caused unwanted side effects or caused any changes in the immune system that may stop the medicine working.The results showed that PB006 behaved in the same way as ref-NTZ in the blood. All reported side effects were similar between groups and were as expected for this medicine, and neither PB006 nor ref-NTZ caused any important or unexpected changes to the immune system. This study showed that biosimilar natalizumab, PB006, behaves in the same way as ref-NTZ, and the same treatment outcomes can be expected.

Pooled analysis of three pharmacokinetic studies comparing biosimilar MB02 and reference bevacizumab.

AIM: The aim of this study was to add robustness and provide further evidence on the bioequivalence, safety and immunogenicity between MB02 and reference bevacizumab. No similar study has been performed before with a biosimilar monoclonal antibody. METHODS: Population analysis by pooling data from three independent pharmacokinetic (PK) studies was performed. The studies had a single-dose, double-blind, three-arm, parallel-group design and two studies, MB02-A-02-17 and MB02-A-05-18, compared MB02 to EU- and US-bevacizumab in Caucasian subjects, while study MB02-A-04-18 compared MB02 and EU-bevacizumab in Japanese participants. Primary endpoints included maximum observed serum concentration (Cmax ), area under the serum concentration-time curve (AUC) from time zero and extrapolated to infinity (AUC0-∞ ) and AUC from time zero to the time of last quantifiable concentration (AUC0-t ). Secondary endpoints included other PK parameters, safety and immunogenicity. A sensitivity analysis using actual protein concentration as a correction factor was applied to primary PK parameters. RESULTS: Point estimates and 90% confidence intervals for the geometric mean ratios of primary PK parameters for MB02, EU- and US-bevacizumab were all contained within the predefined bioequivalence margins (80%-125%) for all pairwise comparisons. The same results for all pairwise comparisons were observed when protein-corrected primary PK parameters were analyzed. Safety and immunogenicity were similar between MB02 and the EU- and US-reference bevacizumab in healthy subjects. CONCLUSIONS: This pooled analysis of three comparable PK studies further supports the bioequivalence of biosimilar MB02 to EU- and US-reference bevacizumab. No clinically meaningful differences in safety or immunogenicity were observed.

Population Pharmacokinetics of MYL-1402O, a Proposed Biosimilar to Bevacizumab and Reference Product (Avastin®) in Patients with Non-squamous Non-small Cell Lung Cancer.

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.

Do the Outcomes of Clinical Efficacy Trials Matter in Regulatory Decision-Making for Biosimilars?

BACKGROUND: There is an increasing body of evidence supporting a more flexible approach in clinical data requirements for the approval of more complex biosimilar substances such as monoclonal antibodies (mAbs). OBJECTIVE: The aim of this paper is to further analyse the role of quality/chemistry, manufacturing and controls (CMC) and clinical data for the conclusion on biosimilarity and the decision on marketing authorisation (MA). METHODS: In the present study, we analysed the MA applications (MAAs) of all 33 mAbs and three fusion proteins evaluated by the European Medicines Agency (EMA) between July 2012 and November 2022 with special emphasis on all submitted rituximab (four products) and trastuzumab (seven products) biosimilar candidates, including withdrawn applications. For the two withdrawn applications, the comparative efficacy trials suggested biosimilarity, but the quality/CMC package was not accepted by EMA. We therefore investigated whether a negative MAA outcome could have been predicted based on the evidence generated in the quality/CMC packages, regardless of clinical trial data. For this purpose, we reviewed the respective European Public Assessment Reports (EPARs) or withdrawal assessment reports, and the first regulatory assessments for all these 36 MAAs (i.e. day 120 of the centralized procedure), which are not publicly available. During EMA review, where significant issues are identified which would preclude a marketing authorisation, these issues are raised as questions to the applicant and are classified as major objections (MO). RESULTS: In 67% of cases, the outcome of the quality and clinical assessment was the same, i.e. both the quality and clinical assessments either supported approval or did not support approval. In 11% of cases, MO were identified in the quality part of the submission but not in the clinical data. In 22% of cases, MO were raised on the clinical data package but not on the quality data. However, we found no instance where seemingly negative clinical data, including failed efficacy trials, led to a negative overall decision. In each instance, the failure to confirm similar clinical performance in all investigated aspects was eventually viewed as not being related to the biosimilar per se but as being due to imbalances in the trial arms, immaturity of secondary endpoint results, change in the reference product, or even chance findings. Furthermore, when performing an in-depth analysis of the quality and clinical packages of trastuzumab and rituximab biosimilars, we found that in no case were clinical trial data necessary to resolve residual uncertainties regarding the quality part. CONCLUSION: The results further support the argument that sufficient evidence for biosimilarity can be obtained from a combination of analytical and functional testing and pharmacokinetic studies which may also generate immunogenicity data. This calls into question the usefulness of comparative efficacy studies for the purposes of regulatory decision-making when approving biosimilar mAbs and fusion proteins.

A phase-I randomized euglycemic clamp study to demonstrate the pharmacokinetic and pharmacodynamic equivalence of an insulin degludec biosimilar (B01411) with the reference product in healthy Chinese volunteers.

BACKGROUND: B01411 is a biosimilar candidate manufactured by Jilin Huisheng Biopharmaceutical Co. Ltd for the reference insulin degludec (Tresiba) (IDeg). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of the two IDeg products and to assess the PK/PD similarity of B01411 compared with the reference IDeg product. RESEARCH DESIGN & METHODS: A single-center, single-dose, randomized, crossover, open-labeled, phase I, euglycemic clamp study in healthy Chinese subjects to examine the bioequivalence of B01411 (0.4 U/kg) compared with the reference IDeg product. Blood samples were collected at a predefined time for the analysis of blood glucose (BG), IDeg, and C-peptide concentrations. The glucose infusion rate (GIR) was adjusted to maintain the BG at approximately 0.28 mmol/L below baseline throughout the clamp. RESULTS: Thirty-two subjects (20 males and 12 females) were enrolled, 31 of whom received both treatments. The 90% confidence intervals for the ratio of the least-squares geometric means for AUCIDeg,0-24 h, AUCGIR,0-24 h, IDegmax, and GIRmax were all in the range of 0.80-1.25. Only one adverse event of puncture site bruising occurred once in a subject in the B01411 group. CONCLUSION: B01411 exhibited a pharmacokinetic and pharmacodynamic similarity to the reference product. Both IDeg products were well tolerated. CLINICAL TRIAL REGISTRATION: http://www.chinadrugtrials.org.cn/index.html#. Identifier is CTR20192122.

Evaluation of Truncated AUC as an Alternative Measure to Assess Pharmacokinetic Comparability in Bridging Biologic-Device Using Prefilled Syringes and Autoinjectors.

Pharmacokinetic (PK) comparisons between therapeutic biologics have largely been based on the total area under the concentration-time curve (AUC) and the maximum concentration (Cmax ). For biologics with a long half-life, a PK comparability study may be long in duration and costly to conduct. The goal of this study was to evaluate whether a truncated AUC (tAUC) can be used to assess PK comparability when bridging prefilled syringe (PFS) and autoinjector (AI) treatment options for biologics with a long half-life. Fifteen biologics license applications (BLAs) were included to determine the concordance and geometric percent coefficient of variation (%CV) between tAUCs evaluated on days 7, 14, 21, and 28 and AUC evaluated to infinity (AUC0-inf ). Concordance is established if the tAUCs are comparable with AUC0-inf . Trial simulation was performed to examine the effect of the absorption rate constant (ka ) and sample size on the concordance of tAUCs. The tAUCs evaluated on day 14, 21, and 28 had 100% concordance with AUC0-inf for all 15 BLAs. The concordance of tAUC evaluated at day 7 was 87.5%. Based on the trial simulation, tAUC evaluated to day 28 post-dose can achieve high concordance (≥85%) for biologics exhibiting linear or nonlinear elimination with a ka of ≥0.1/day and with a sample size of 70 subjects per arm. tAUC appears to be a promising alternative PK measure, relative to AUC0-inf , for PK comparability assessments.

A randomized, double-blind, 3-arm, parallel study assessing the pharmacokinetics, safety, tolerability and immunogenicity of AVT04, an ustekinumab candidate biosimilar, in healthy adults.

BACKGROUND: This study assessed pharmacokinetic (PK) similarity, safety, and immunogenicity of AVT04, a candidate biosimilar, compared with reference product (RP) ustekinumab (EU-approved and US-licensed Stelara®). METHODS: Healthy subjects (N = 298) were randomized 1:1:1 to receive one 45 mg dose of AVT04, EU-RP, or US-RP. The primary PK parameters were Cmax and AUC0-inf. PK similarity was demonstrated if the 90% confidence intervals (CI) for the ratio of geometric means were all contained within the prespecified margins of 80% and 125%. Additional PK parameters, including AUC0-t, were also assessed. Safety and immunogenicity were also assessed until Day 92. RESULTS: After pre-specified protein content normalization, the 90% CI for the ratio of geometric means for primary PK parameters were all contained within the pre-specified bioequivalence margins of 80% and 125%, supporting demonstration of PK similarity between AVT04 and both EU- and US-RP. Secondary PK parameters supported the analysis. Safety and immunogenicity profiles were comparable across all three treatment arms, although the study was not powered to detect small differences in these parameters. CONCLUSION: Results supported a demonstration of PK similarity between candidate biosimilar AVT04, US-RP and EU-RP. Similar safety and immunogenicity were also shown.Clinical trial registration: www.clinicaltrials.gov identifier is NCT04744363.

A phase I study comparing the biosimilarity of the pharmacokinetics and safety of recombinant humanized anti-vascular endothelial growth factor monoclonal antibody injection with Avastin® in healthy Chinese male subjects.

BACKGROUND: The biosimilar landscape for malignancies continues to grow, with several biosimilars for reference product bevacizumab currently available. Bevacizumab has been shown to be well tolerated; however, the safety of recombinant humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody injection remains unclear. This study aimed to compare the pharmacokinetics (PK), safety, and immunogenicity of recombinant humanized anti-VEGF monoclonal antibody injection to that of Avastin® in healthy Chinese male volunteers. METHODS: A randomized, double-blind, single-dose, and parallel-group study was performed on 88 healthy men who randomly (1:1) received either the test drug as an intravenous infusion of 3 mg/kg or Avastin®. The primary PK parameter was area under the serum concentration-time curve (AUC) from time zero to last quantifiable concentration (AUC0-t). Secondary endpoints included maximum observed serum concentration (Cmax), AUC from 0 extrapolated to infinity (AUCinf), safety, and immunogenicity. Serum bevacizumab concentrations were measured using a validated enzyme-linked immunosorbent assay (ELISA). RESULTS: The baseline characteristics were similar among the two groups. The 90% confidence interval (CI) for the geometric mean ratio of AUC0-t, Cmax and AUCinf between the test group and reference group were 91.71%-103.18%, 95.72%-107.49% and 91.03%-103.43%, respectively. These values were within the predefined bioequivalence margin of 80.00%-125.00%, demonstrating the biosimilarity of the test drug and Avastin®. Eighty-one treatment-emergent adverse events were reported, with a comparable incidence among the test group (90.91%) and the reference group (93.18%). No serious adverse events were reported. The incidence of ADA antibodies in the two groups was low and similar. CONCLUSION: In healthy Chinese men, PK similarity of recombinant humanized anti-VEGF monoclonal antibody injection to Avastin® was confirmed, with comparable safety and immunogenicity. Subsequent studies should investigate recombinant humanized anti-VEGF monoclonal antibody injection in patients setting. TRIAL REGISTRATION: Registered 08/10/2019, CTR20191923.

Trastuzumab Charge Variants: a Study on Physicochemical and Pharmacokinetic Properties.

Background: Post-translational modifications in bioprocessing and storage of recombinant mAbs are the main sources of charge variants. While the profile of these kinds of variants is considered an important attribute for the therapeutic mAbs, there is controversy about their direct role in safety and efficacy. In this study, the physicochemical and pharmacokinetic (PK) properties of the separated charge variants belonging to a trastuzumab potential biosimilar, were examined. Methods: The acidic peaks, basic peaks, and main variants of trastuzumab were separated and enriched by semi-preparative weak cation exchange. A panel of analytical techniques was utilized to characterize the physicochemical properties of these variants. The binding affinity to HER2 and FcγRs and the PK parameters were evaluated for each variant. Results: Based on the results, the charge variants of the proposed biosimilar had no significant influence on the examined efficacy and PK parameters. Conclusion: During the development and production of biosimilar monoclonal antibodies, evaluating the effect of their charge variants on efficacy and PK parameters is needed.

Pharmacokinetic similarity study comparing the biosimilar candidate, LY05008, with its reference product dulaglutide in healthy Chinese male subjects.

BACKGROUND: Dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been approved for improving glycemic control and reducing the risk of cardiovascular (CV) adverse events. This study compared the pharmacokinetic (PK) profiles, safety, and immunogenicity of LY05008, a biosimilar candidate, to a licensed product dulaglutide in healthy Chinese male subjects. RESEARCH DESIGN AND METHODS: In this double-blind, open-label, parallel-group study, healthy Chinese male subjects were randomized 1:1 to receive either LY05008 or dulaglutide subcutaneously. Primary study endpoints were PK parameters such as the area under the concentration-time curve (AUC) from time zero to infinity (AUC0 - ∞), AUC from time zero to the last quantifiable concentration (AUC0-t), and maximum serum concentration (Cmax). Safety and immunogenicity profiles were also included for data analysis. RESULTS: 82 subjects were randomized to receive LY05008 (n = 41) or dulaglutide (n = 41). The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of AUC0 - ∞, AUC0-t and Cmax of LY05008 to dulaglutide were all within the bioequivalence limits of 80%-125%. Other PK parameters, safety, and immunogenicity profiles were comparable across the two treatment groups. CONCLUSION: This study demonstrated PK similarity of LY05008, a dulaglutide biosimilar, to dulaglutide in healthy Chinese male subjects, with comparable safety and immunogenicity data. TRIAL REGISTRATION: The trial is registered at the Chinese Clinical Trial Registry (Identifier No. ChiCTR2200066519).

Pharmacokinetics, pharmacodynamics, safety and immunogenicity of recombinant, fully human anti-RANKL monoclonal antibody (MW031) versus denosumab in Chinese healthy subjects: a single-center, randomized, double-blind, single-dose, parallel-controlled trial.

BACKGROUND: MW031 is a biosimilar candidate of denosumab (Prolia®). This study aimed to compare the pharmacokinetics, pharmacodynamics, safety and immunogenicity of MW031 to denosumab in healthy Chinese participants. RESEARCH DESIGN AND METHODS: In this single-center, randomized, double-blind, parallel-controlled, single-dose trial, participants were given 60 mg MW031 (N = 58) or denosumab (N = 61) by subcutaneous injection and observed for 140 days. The primary endpoint was the bioequivalence of PK parameters (Cmax, AUC0-∞), and secondary endpoints including PD parameter, safety, and immunogenicity. RESULTS: A comparison of main PK parameters showed that the geometric mean ratios (GMR) (90% confidence intervals [CIs]) of AUC0-∞ and Cmax for MW031 over denosumab were 105.48% (98.96%, 112.43%) and 98.58% (92.78%, 104.75%), respectively. The inter-CV values of AUC0-∞ and Cmax for MW031 ranged from 19.9% to 23.1%. PD parameter (sCTX) in the MW031 and denosumab groups were similar, and the positivity rates of immunogenicity were 0% in both groups. This study also showed similar safety profiles in both groups, and there were no drug-related, high-incidence and previously unreported adverse reactions. CONCLUSION: This trial confirmed similar pharmacokinetic profiles of MW031 and denosumab in healthy male participants, and pharmacodynamic profile, immunogenicity and safety were comparable for both drugs. TRIAL REGISTRATION: NCT04798313; CTR20201149.