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IMPORTANCE Neovascular age-related macular degeneration is the leading cause of blindness in individuals 50 years or older. The availability of a ranibizumab biosimilar product (SB11) may facilitate access to an effective alternative to this treatment. OBJECTIVE To demonstrate equivalence of efficacy, similar safety, and similar immunogenicity of SB11 compared with the reference ranibizumab. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-masked, parallel-group phase 3 equivalence study was conducted in 75 centers in 9 countries from March 14, 2018, to December 9, 2019, among 705 participants 50 years or older with neovascular age-related macular degeneration with active subfoveal choroidal neovascularization lesions. Analysis was performed on an intent-to-treat basis. INTERVENTIONS Intravitreous injection of SB11 or ranibizumab, 0.5 mg, every 4 weeks through week 48. MAIN OUTCOMES AND MEASURES Preplanned interim analysis after all participants completed the week 24 assessment of primary efficacy end points at week 8 for change from baseline in best-corrected visual acuity (BCVA) and week 4 for central subfield thickness (CST), with predefined equivalence margins for adjusted treatment differences of −3 letters to 3 letters for BCVA and −36 μm to 36 μm for CST. RESULTS Baseline and disease characteristics among 705 randomized participants (403 women [57.2%]; mean [SD] age, 74.1 [8.5] years) were comparable between treatment groups (SB11, 351; ranibizumab, 354). Least-squares mean (SE) changes in BCVA from baseline at week 8 were 6.2 (0.5) letters in the SB11 group vs 7.0 (0.5) letters in the ranibizumab group, with an adjusted treatment difference of −0.8 letter (90% CI, −1.8 to 0.2 letters). Least-squares mean (SE) changes in CST from baseline at week 4 were −108 (5) μm in the SB11 group vs −100 (5) μm in the ranibizumab group, with an adjusted treatment difference of −8 μm (95% CI, −19 to 3 μm). Incidences of treatment-emergent adverse events (231 of 350 [66.0%] vs 237 of 354 [66.9%]), including serious treatment-emergent adverse events (44 of 350 [12.6%] vs 44 of 354 [12.4%]) and treatment-emergent adverse events leading to study drug discontinuation (8 of 350 [2.3%] vs 5 of 354 [1.4%]), were similar in the SB11 and ranibizumab groups. Immunogenicity was low, with a cumulative incidence of antidrug antibodies up to week 24 of 3.0% (10 of 330) in the SB11 group and 3.1% (10 of 327) in the ranibizumab group. CONCLUSIONS AND RELEVANCE These findings of equivalent efficacy and similar safety and immunogenicity profiles compared with ranibizumab support the use of SB11 for patients with neovascular age-related macular degeneration.

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The apparent clearance of topiramate increased with co-medication of PHT, CBZ, OXC, and PB. This population PK model can be applied for optimizing topiramate dosage regimens in actual clinical practice.

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Objectives: Efficacy, safety, pharmacokinetics (PK), and immunogenicity of the biosimilar candidate SB8 was compared to its reference product bevacizumab (BEV) in patients with metastatic or recurrent nonsquamous non-small cell lung cancer. Methods: Patients were randomized (1:1) in a phase III, double-blind study to receive intravenous SB8 or BEV 15 mg/kg with paclitaxel/carboplatin every 3 weeks for 24 weeks, followed by SB8 or BEV maintenance monotherapy. The primary endpoint was best overall response rate (ORR) by 24 weeks. Secondary endpoints included survival outcomes, safety, PK, and immunogenicity. Results: 763 patients (SB8, n = 379; BEV, n = 384) were randomized; baseline characteristics were well balanced. Best ORR in the FAS was 47.6% and 42.8%, and best ORR in the PPS was 50.1% and 44.8% for SB8 and BEV, respectively. The risk ratio of best ORR was 1.11 (90% CI, 0.975−1.269), and the risk difference in best ORR was 5.3% (95% CI, −2.2%-12.9%). Median survival outcomes were comparable between SB8 and BEV: progression-free survival was 8.50 vs 7.90 months, respectively (HR [95% CI], 0.99 [0.83-1.18]; p = 0.9338); overall survival was 14.90 vs 15.80 months, respectively (HR [95% CI], 1.03 [0.83-1.28]; p = 0.7713); and duration of response was 7.70 vs 7.00 months, respectively (HR [95% CI], 1.05 [0.81-1.37]; p = 0.6928). Severity and incidence of treatment-emergent adverse events, PK, and immunogenicity were comparable between SB8 and BEV. Conclusion: This study demonstrated equivalence between SB8 and BEV in terms of best ORR risk ratio, with comparable safety, PK, and immunogenicity.

For unit root tests, we propose a new mean adjustment scheme, called recursive mean adjustment. For adjusting the mean of an observation at a time t, instead of the global sample mean, we use the recursive sample mean which is the sample mean of the observations up to the time t. The approach is simple and can be applied to a wide class of unit root tests. The recursive mean adjustment gives us tests with substantially higher powers compared with the tests based on the ordinary mean adjustment.

SummaryWhat is known and objective: SB5 is a biosimilar to the reference adalimumab (ADL) currently in development. The primary study objective was to demonstrate pharmacokinetic (PK) equivalence of SB5 to European Union-sourced adalimumab (EU-ADL), and United States-sourced adalimumab (US-ADL) in healthy subjects. Safety, tolerability and immunogenicity were also assessed as secondary objectives. Methods:In this phase I, single-blind trial, 189 healthy volunteers were randomized to a single 40 mg dose of SB5, EU-ADL or US-ADL and PK was evaluated for 71 days afterwards. Serum adalimumab concentrations were measured using an enzymelinked immunosorbent assay (ELISA) test. PK parameters were calculated based on actual sampling times relative to dosing and non-compartmental analysis methods, and equivalence was determined using predefined margins of 0.8-1.25.Results and discussion: Baseline characteristics and demographics were comparable between the three groups. Mean values of area under the concentration-time curve from time zero to infinity (AUC inf ), maximum serum concentration (C max ) and AUC from time zero to the last quantifiable concentration (AUC last ) were similar between groups, and 90% confidence interval for these parameters were within the predefined equivalence margins for all pairwise comparisons. No discontinuations due to treatment-emergent adverse events (TEAEs) or deaths were reported.Number and kind of TEAEs were comparable between the three groups and considered mild to moderate. The incidence of subjects with antidrug antibodies (ADA) and the overall incidence of neutralizing antibody (NAb) were comparable across the three groups.What is new and conclusion: The PK of SB5 was equivalent to that of EU-ADL and US-ADL. SB5 was well tolerated with similar safety and immunogenicity profile to EU-ADL and US-ADL. K E Y W O R D S bioequivalence, biosimilar, clinical pharmacokineticsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.