Comparing the efficacy and safety of biosimilar BAT2506 with reference golimumab in patients with active psoriatic arthritis: 24-week results of a phase 3, multicenter, double-blind, randomized, parallel-group study

Comparing tocilizumab biosimilar BAT1806/BIIB800 with reference tocilizumab in patients with moderate-to-severe rheumatoid arthritis with an inadequate response to methotrexate: a phase 3, randomised, multicentre, double-blind, active-controlled clinical trial

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. A previous result in healthy Chinese male subjects demonstrated the pharmacokinetic (PK) similarity of LY05008 and the licensed product dulaglutide, with comparable safety and immunogenicity profiles. A well-controlled phase 3 study with an adequate sample size was subsequently conducted for safety and efficacy evaluation. In a multicenter, randomized, open-label, active comparator phase 3 study, Chinese adults diagnosed with type 2 diabetes mellitus (T2DM) were randomly assigned 1:1 to receive a subcutaneous injection of 1.5 mg LY05008 or dulaglutide once weekly for 24 weeks. The primary endpoint was the mean change in HbA1c from baseline to Week 24. The secondary endpoints included the mean change in HbA1c from baseline to Week 12; the proportion of patients who had achieved HbA1c ≤ 6.5% at Weeks 12 and 24; and the mean change in body weight, fasting plasma glucose (FPG) level, and 2-h postprandial plasma glucose (PPG) level from baseline to Weeks 12 and 24. Safety, PK, and immunogenicity profiles were also included for data analysis. A total of 440 patients were randomized to receive LY05008 (n = 222) or dulaglutide (n = 218). The mean changes in HbA1c from baseline to Week 24 in the LY05008 group and dulaglutide group were -1.44% and -1.41%, respectively, with a least square mean difference (LSMD) and 95% confidence interval (CI) of 0.06% (-0.08, 0.19) (p > 0.05). Efficacy equivalence could be demonstrated since the 95% CI between the reference drug and a biosimilar fell entirely within the range of (-0.4%, 0.4%). The mean changes in HbA1c from baseline to Week 12 in the LY05008 group and dulaglutide group were -1.47% and -1.39% (p > 0.05), respectively. At Week 12, 40.1% of patients who received LY05008 and 42.2% of those who received dulaglutide had a decrease in the HbA1c level to 6.5% or less, and 60.4% and 60.6% of patients in the LY05008 group and the dulaglutide group had a decrease in the HbA1C level < 7%, respectively. At Week 24, 41.0% and 43.6% of patients achieved an HbA1c ≤ 6.5%. 55.9% and 66.5% of patients in the LY05008 group and the dulaglutide group achieved the HbA1c goal of < 7%, respectively. The mean changes in body weight from baseline to Weeks 12 and 24 in the LY05008 group and dulaglutide group were -2.01 and -1.71 kg (p > 0.05) and -2.68 and -2.42 kg (p > 0.05), respectively. The mean changes in FPG level from baseline to Weeks 12 and 24 in the LY05008 group and dulaglutide group were -2.578 and -2.681 mmol/L (p > 0.05) and -2.222 and -2.690 mmol/L, respectively. In the LY05008 group and the dulaglutide group, the mean changes in 2-h PPG levels from baseline to Weeks 12 and 24 were -4.364 and -4.800 mmol/L(p > 0.05) and-3.502 and -4.217 mmol/L (p > 0.05), respectively. The common treatment emergent adverse events (TEAEs) in the LY05008 and dulaglutide groups were decreased appetite, diarrhea, upper respiratory tract infection, hyperuricemia, nausea, urinary tract infection, and vomiting. Most TEAEs were mild to moderate in severity. No significant differences were observed between the groups in terms of TEAEs. Hypoglycemic events were noted in 0.9% of patients who had received LY05008 and in 3.7% of those who had received dulaglutide. Serious adverse events were reported in 4.1% of patients in the LY05008 group and in 3.7% of patients in the dulaglutide group. The PK parameter Ctrough and immunogenicity profiles were similar across the two treatment groups. The primary endpoint was met in this study through the demonstration of equivalent efficacy in HbA1c reduction in Chinese adults with T2DM between LY05008 and dulaglutide. Overall, the biosimilar product LY05008 showed comparable safety, PK, and immunogenicity profiles against the reference drug dulaglutide. ClinicalTrials.gov identifier: CTR20221721.

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).

Background Bevacizumab, an inhibitor of angiogenesis, has been approved in several anti-cancer therapies. This study compared the pharmacokinetic (PK) profiles, safety, and immunogenicity of a bevacizumab biosimilar, LY01008, with those of European Union – approved bevacizumab (Avastin®) in healthy Chinese males. Research Design and Methods In this double-blind, open-label, parallel-group study, healthy Chinese male subjects were randomized 1:1 to receive either LY01008 or Avastin® 3 mg/kg intravenously. 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 last quantifiable concentration (AUC0–t), and maximum serum concentration (Cmax). Secondary study endpoints included safety, tolerability, and immunogenicity. Results One hundred and twelve subjects were randomized to receive LY01008 (n = 56) or Avastin® (n = 56). The 90% CIs of the GMRs of AUC0–t, AUC0–∞, and Cmax of LY01008 to Avastin® were all within the bioequivalence margin. Other PK parameters, safety, and immunogenicity profiles were comparable across the two treatment groups. Conclusions This study demonstrated equivalent PK, comparable safety, and similar immunogenicity of LY01008 to Avastin® in healthy subjects, thus paving the way for further clinical evaluation. Trial Registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05110118).

A randomized trial comparing LY01011, biosimilar candidate, with the reference product denosumab (Xgeva®) in healthy Chinese subjects

SummaryBiosimilar teriparatide (INTG-8) was tested in a healthy population of males and postmenopausal females to assess pharmacokinetic bioequivalence to originator teriparatide comparator products. Primary pharmacokinetic comparison confirmed bioequivalence. Pharmacodynamics, safety, and tolerability were comparable to the originator products. INTG-8 was therefore confirmed to be biosimilar to originator products.IntroductionThe purpose of this present study was to demonstrate pharmacokinetic (PK) equivalence of a biosimilar teriparatide (INTG8) to EU- and US-approved teriparatide reference products in healthy men and postmenopausal women. Secondary objectives included comparison of the pharmacodynamics (PD), safety, and tolerability.MethodsOne hundred and five subjects randomly (1:1:1) received single subcutaneous 20 μg injection of teriparatide biosimilar, EU- and US-teriparatide on 3 consecutive days in this assessor-blind, three-period, single-dose, crossover study. Maximum serum concentration (Cmax), area under the curve (AUC) from time zero to t (AUC0-t), and AUC from time zero extrapolated to infinity (AUC0-∞) were primary PK parameters, analyzed by non-compartmental methods. The secondary PD endpoints were maximum observed effect (Emax), area under the effect curve (AUE) from time zero to the last measurable concentration (AUE0–t), and time to maximum observed effect (Tmax) for total serum calcium levels. Safety, tolerability, and immunogenicity were also evaluated. This study was registered with ctri.nic.in/ (CTRI/2020/10/028627) on 26 October 2020.ResultsBaseline demographics were similar across the three-treatment sequence groups. The 90% confidence intervals (CI) for the geometric mean ratios (test:reference) of Cmax, AUC0-t, and AUC0-∞ were within the predefined bioequivalence criterion of 80.00% to 125.00%, which demonstrated PK equivalence of teriparatide biosimilar to EU- and US-teriparatide for all primary endpoints. The PD comparability was demonstrated by similar serum calcium levels. Study treatments were generally well tolerated and showed no meaningful differences in safety or immunogenicity profiles. There were no deaths, or serious AEs were reported during this study.ConclusionThe study demonstrated PK bioequivalence of teriparatide biosimilar to the EU- and US-teriparatide reference products with comparable PD, safety, and immunogenicity profiles.

Dr Reddy's Laboratories Trastuzumab (DRL_TZ) is a biosimilar to Herceptin under development. The present study was conducted to evaluate efficacy, safety, pharmacokinetics (PKs), and immunogenicity of DRL_TZ in comparison with the reference medicinal product (RMP) along with concomitant weekly paclitaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This was a randomized, double-blind study in female patients with HER2-positive MBC, randomly assigned in a 1:1 ratio to receive either DRL_TZ or the RMP, that is, an innovator product sourced from the European region, along with additional chemotherapy, as first-line treatment for up to 24 weeks. The primary end point was the best overall response rate (ORR) as per RECIST 1.1 criteria. Progression-free survival rate at 6 months (PFS6), safety, immunogenicity, and PK parameters were assessed as secondary end points. A total of 164 patients were randomly assigned to receive either DRL_TZ or the RMP. Best ORR in the per-protocol population was comparable, 91.9% (93.3% CI, 83.2 to 96.3) versus 82.1% (93.3% CI, 72.0 to 89.1) in DRL_TZ and RMP arms, respectively; the difference between the arms was 9.8% with a 93.3% CI of -1.3 to 20.8. The PFS6 rate, safety, PK profile, and antidrug antibody incidence were comparable. An additional 44 patients were recruited in the postrandomization phase, in an open-label manner, and started on DRL_TZ to generate more data on efficacy, safety, and immunogenicity. The additional data with DRL_TZ, when pooled, were similar to the RMP data. DRL_TZ was found to have similar efficacy and comparable safety, PK, and immunogenicity profiles as the RMP.

Secukinumab biosimilar BAT2306 versus reference secukinumab in patients with moderate-to-severe plaque psoriasis: a multicentre, double-blind, randomised, active-controlled, phase 3 trial.

Dr. Reddy's Laboratories rituximab (DRL_RI; Dr. Reddy's Laboratories SA, Basel, Switzerland) is under development as a rituximab biosimilar. Study RI‐01‐002 (Clinical Trials Registry ‐ India/2012/11/003129), comparing DRL_RI to the reference medicinal product (RMP) MabThera® (Roche, Grenzach‐Wyhlen, Germany), demonstrated pharmacokinetic (PK) equivalence and showed comparable pharmacodynamic, efficacy, safety, and immunogenicity profiles. We used data from the same study to perform population PK and PK–pharmacodynamic analyses: first exploring possible factors influencing the PK similarity assessment between products and then performing simulations to investigate the impact of tumor size on rituximab PK. Nonlinear mixed‐effects models for PK, tumor size, tumor size–PK, and tumor response were developed independently. The final PK model included drug product as a dose‐scaling parameter and predicted a 6.75% higher dose reaching the system in RMP‐treated patients. However, when tumor size was included in the tumor size–PK model, the drug product effect was no longer observed. The model rather indicated that patients with larger tumor size have higher clearance. Further simulations confirmed that higher baseline tumor size is associated to slightly lower rituximab exposure. Tumor response, described by a continuous‐time Markov model, did not differ between drug products. Both had higher effects during the first 20 weeks of treatment. Also, the model described a subpopulation of nonresponders to treatment (42%) with faster transitions to a worse state. The different rituximab exposure initially detected between drug products (6.75%) was shown using PK/PK–pharmacodynamic analysis to be attributed to a tumor size imbalance between treatment groups. PK/PK–pharmacodynamic analyses may contribute to PK similarity assessments.

FRI0088 SAFETY, IMMUNOGENICITY AND EFFICACY OF THE PROPOSED BIOSIMILAR MSB11022 (MODIFIED FORMULATION) COMPARED WITH ADALIMUMAB REFERENCE PRODUCT IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS: AURIEL-RA, A RANDOMISED, DOUBLE-BLIND, PHASE III STUDY

TQB2440 compared with reference pertuzumab for HER2-positive, ER/PgR-negative, early or locally advanced breast cancer: a multicenter, randomized, double-blind, parallel-controlled, phase III equivalence trial

Background This study compared pharmacokinetic (PK) similarity, pharmacodynamic, safety, and immunogenicity of AVT03, a candidate biosimilar, with reference product (RP) denosumab (Prolia). Methods Healthy male participants (N = 209) were randomized 1:1 to receive one 60 mg dose of either AVT03 or RP. PK similarity was demonstrated if the 90% confidence intervals (CI) for the ratio of geometric means for the primary PK parameters (Cmax and AUC0-inf for EMA; Cmax and AUC0-t for FDA and PMDA) were within the prespecified margins of 80.00% and 125.00%. Secondary PK parameters assessed were AUC0–24, Tmax, Kel, t1/2, Vz/F, and CL/F. The serum biomarker of bone resorption, CTX-1 was evaluated to compare pharmacodynamic (PD) profiles. Safety and immunogenicity were also assessed. Results The 90% CI for the ratio of geometric means for primary PK parameters was contained between the pre-specified margins of 80.00% and 125.00% (Cmax [102.23, 113.64]; AUC0-inf [107.17, 118.87]; AUC0-t [107.72, 120.42]), supporting demonstration of PK similarity between AVT03 and RP. Secondary PK parameters supported the analysis. PD, safety and immunogenicity profiles were comparable between the two arms. Conclusion Results supported a demonstration of PK similarity between AVT03 and RP denosumab. Comparable PD, safety and immunogenicity profiles were also shown. Clinical trial registration The clinical trial is registered at https://www.clinicaltrials.gov under identifier NCT05126784.

PurposeMB02 is a biosimilar to bevacizumab that has demonstrated similar physicochemical and functional properties in in vitro studies to the reference bevacizumab (Avastin®). This study aims to assess the pharmacokinetic (PK) similarity of MB02 to the reference bevacizumab in Japanese population.MethodsThis double-blind, randomized, parallel-group, single-dose PK study, was performed in healthy Japanese male volunteers. Subjects were equally randomized (1:1) to receive a single (3 mg/kg) IV dose of MB02 or reference bevacizumab. PK assessments were done up to 70 days post-dose. Non-compartmental parameters were calculated. PK similarity was determined using predefined equivalence range (0.80–1.25) for the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC0–∞). Immunogenicity samples were taken pre-dose and up to day 70. Safety was assessed throughout the study.ResultsIn total, 48 subjects (24 in each treatment group) were dosed. Consequently to the observed similar PK profile, the 90% confidence interval for the geometric means ratio for the primary PK endpoint, AUC0–∞, was within the predefined equivalence range (0.981–1.11). Forty-seven treatment-emergent adverse events (TEAEs) were reported in 20 subjects (41.7%) with comparable incidence among MB02 and reference bevacizumab groups (22 and 25, respectively), none of them was severe or serious. Anti-drug antibodies incidence was low and similar between treatment groups.ConclusionsPharmacokinetic similarity of MB02 to reference bevacizumab was evidenced in Japanese healthy subjects, with comparable safety and immunogenicity profile between treatments. This study supports the biosimilarity of MB02 to reference bevacizumab in Japanese population. ClinicalTrials.gov identifier: NCT04238650.

Background This study compared efficacy, pharmacokinetics (PK), immunogenicity, and safety between AVT06, proposed biosimilar to reference product (RP) aflibercept (Eylea®), in participants with neovascular age-related macular degeneration (nAMD). Methods In this randomized, double-masked, multicenter, active-controlled trial, treatment naïve participants received intravitreal injections of AVT06 or RP (2 mg) over 48 weeks. The primary endpoint was the change from baseline to Week 8 in best-corrected visual acuity (BCVA). Secondary endpoints included BCVA improvements and changes in Central Subfield Thickness (CST). PK, immunogenicity, and safety were also assessed. Results The 90% and 95% confidence intervals (−0.60, 2.14 and −0.86, 2.40, respectively) in least squares mean difference in BCVA letter score from baseline to Week 8 were contained within the pre-specified equivalence margin of ETDRS BCVA letter score of [−3.5 to 3.5], supporting the demonstration of comparative efficacy. Secondary efficacy outcomes were also comparable. PK analyses supported systemic safety. There were no clinically meaningful differences in immunogenicity profiles. Safety profiles were similar; most treatment-emergent adverse events were mild and unrelated to the study drug. Conclusions Results supported a demonstration of comparable efficacy between AVT06 and RP aflibercept. Similar PK, immunogenicity, and safety profiles were also shown. Clinical trial registration ClinicalTrials.gov identifier is NCT05155293; ClinicalTrialsRegister.eu identifier is 2021‐003651‐42.

SummaryThis 78-week (18-month) study conducted in 479 postmenopausal women with osteoporosis evaluated the efficacy, pharmacodynamics, pharmacokinetics, safety, and immunogenicity of candidate biosimilar CT-P41 relative to US reference denosumab. CT-P41 had equivalent efficacy and pharmacodynamics to US-denosumab, with similar pharmacokinetics and comparable safety and immunogenicity profiles. PurposeTo demonstrate equivalence of candidate biosimilar CT-P41 and US reference denosumab (US-denosumab) in postmenopausal women with osteoporosis. MethodsThis 78-week (18-month), double-blind, randomized, active-controlled Phase 3 study (NCT04757376) comprised two treatment periods (TPs). In TPI, patients (N = 479) were randomized 1:1 to 60 mg subcutaneous CT-P41 or US-denosumab. At Week 52, those who had received CT-P41 in TPI continued to do so. Those who had received US-denosumab were randomized (1:1) to continue treatment or switch to CT-P41 in TPII. The primary efficacy endpoint was percent change from baseline in lumbar spine bone mineral density at Week 52. Efficacy equivalence was concluded if associated 95% confidence intervals (CI) for least squares (LS) mean group differences fell within ± 1.503%. The primary pharmacodynamic (PD) endpoint was area under the effect curve for serum carboxy-terminal cross-linking telopeptide of type I collagen through the first 26 weeks, with an equivalence margin of 80–125% (for 95% CIs associated with geometric LS mean ratios). ResultsEquivalence was demonstrated for CT-P41 and US-denosumab with respect to primary efficacy (LS mean difference [95% CI]: − 0.139 [− 0.826, 0.548] in the full analysis set and − 0.280 [− 0.973, 0.414] in the per-protocol set) and PD (geometric LS mean ratio [95% CI]: 94.94 [90.75, 99.32]) endpoints. Secondary efficacy, PD, pharmacokinetics, and safety results were comparable among all groups up to Week 78, including after transitioning to CT-P41 from US-denosumab. ConclusionsCT-P41 was equivalent to US-denosumab in women with postmenopausal osteoporosis, with respect to primary efficacy and PD endpoints.