Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial

Abstract

This multinational, randomized, double-blind trial, (ClinicalTrials.gov identifier NCT02149121) was designed to demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA). Adults with active RA were treated with CT-P10, United States-sourced RTX (US-RTX; Rituxan®), or European Union-sourced RTX (EU-RTX; MabThera®) at weeks 0 and 2. The co-primary pharmacokinetic endpoints were area under the serum concentration–time curve (AUC) from time zero to last measurable concentration (AUC0–last), AUC from time zero to infinity (AUC0–∞), and maximum concentration (Cmax) after two infusions. The primary efficacy endpoint was change from baseline to week 24 in Disease Activity Score using 28 joints-C-reactive protein (DAS28-CRP). Pharmacodynamics, immunogenicity, and safety were also assessed. 372 patients were randomly assigned to CT-P10 (n = 161) or RTX (n = 211 [US-RTX, n = 151; EU-RTX, n = 60]). For the co-primary pharmacokinetic endpoints, 90% confidence intervals (CI) for ratios of geometric means (CT-P10/US-RTX, CT-P10/EU-RTX or EU-RTX/US-RTX) all fell within the equivalence margin of 80–125%. Adjusted least squares (LS) mean (standard error) change from baseline in DAS28-CRP at week 24 was −2.13 (0.175) for CT-P10 and −2.09 (0.176) for RTX. The 95% CI (−0.29, 0.21) of the estimated treatment difference between CT-P10 and RTX (−0.04) was entirely within the efficacy equivalence margin of ±0.5. Pharmacodynamics, immunogenicity, and safety profiles were similar for CT-P10 and RTX. The pharmacokinetics of CT-P10, US-RTX, and EU-RTX were equivalent. CT-P10 and RTX were also equivalent in terms of efficacy and displayed similar pharmacodynamic, immunogenicity, and safety profiles up to week 24.

Pharmacokinetic Similarity and Comparative Pharmacodynamics, Safety, Efficacy, and Immunogenicity of DRL_RI Versus Reference Rituximab in Biologics-Naïve Patients with Moderate-to-Severe Rheumatoid Arthritis: A Double-Blind, Randomized, Three-Arm Study

“…Additionally, all treatment groups showed B-cell depletion below 20% of LLN within 10 h after first infusion, with nearly complete depletion occurring within 48 h. B-cell suppression was sustained until week 24 and was comparable across the three treatment groups. B-cell depletion kinetics observed with DRL_RI and the reference products in this study were consistent with those published for rituximab in RA patients in the REFLEX and DANCER trials [22,23] and in candidate rituximab biosimilars studies [18][19][20].…”

“…The mean change in DAS28-CRP (−1.63) observed with DRL_ RI at week 24 was comparable to improvements reported in DAS28 from baseline to week 24 in the REFLEX (−1.90) and DANCER (−2.05) trials [22,23]. A comparable mean reduction (−2.13) in DAS28-CRP at week 24 from baseline was published for another potential biosimilar [18]. As mentioned earlier, given the different patient populations included in the various studies, these values cannot be directly compared across studies.…”

“…Geometric mean C max values were also comparable with published values. Geometric mean C max, first infusion and C max, second infusion values were 331-348 µg/mL and 402-421 µg/mL, respectively, in the different groups, and 320-362 µg/mL and 367-478 µg/mL, respectively, in several published PK similarity studies of proposed rituximab biosimilars in RA patients [18][19][20][21]. A comparable reduction was seen in DAS28-CRP from baseline to weeks 4, 8, 12, and 16 between DRL_RI and reference rituximab (RTX-US and RTX-EU).…”

Prospects for Anti-B-Cell Therapy in Immuno-Inflammatory Rheumatic Diseases

“…Снижение стоимости лечения дорогостоящими ГИБП и, как следствие, увеличение доступности инновационной терапии у пациентов, живущих в странах с ограниченными экономическими ресурсами, является при- оритетной задачей здравоохранения всех стран мира. Эта проблема частично решена благодаря разработке биоаналогов (biosimilars) ГИБП, широкое применение которых в клинической практике стало возможным благодаря окончанию срока действия патентов для многих оригинальных ГИБП [335][336][337][338][339], включая РТМ [340][341][342][343] В 2001 г. в России была основана биотехнологическая компания «БИОКАД», занимающаяся производством биоаналогов и оригинальных ГИБП. В настоящее время на разных стадиях разработки находятся ряд ГИБП, предназначенных для лечения аутоиммунных заболеваний, включая РТМ [344] Хотя бы одна НЛР / серьезная НЛР (СНЛР) была зарегистрирована у 48 (44,9%) пациентов в группе Ацеллбия ® + МТ и у 22 (43,1%) в группе ПЛ + МТ (р=0,974).…”

Changes of cytokine profile measures during the treatment of rheumatoid arthritis with rituximab biosimilar (Acellbia, BIOCAD) and the original drug (MabThera, F. Hoffmann-La Roche Ltd., Switzerland)

“…Одной из приоритетных задач современного здравоохранения всех стран мира является увеличение доступности инновационной терапии для пациентов, что было частично решено благодаря разработке биоаналогов (biosimilars) ГИБП, широкое применение которых в клинической практике стало возможным после окончания срока действия патентов для многих оригинальных ГИБП, включая РТМ [19,20]. В настоящее время завершаются клинические испытания ряда биоаналогов РТМ [21] -CP-P100 (Celltrion/Hospira) [22,23], PF-05280586 (Pfizer) [24] и др.…”