Switching Between Adalimumab Reference Product and BI 695501 in Patients with Chronic Plaque Psoriasis (VOLTAIRE-X): A Randomized Controlled Trial

Abstract

Background: BI 695501 is an FDA-approved biosimilar to adalimumab reference product (RP). VOLTAIRE-X was a randomized clinical trial to assess outcomes with a biosimilar monoclonal antibody in line with the FDA requirements for designation as an 'interchangeable' biosimilar.

Objective: The aim of this study was to assess whether multiple switches between adalimumab RP and BI 695501 lead to equivalent pharmacokinetics and a similar safety and immunogenicity profile compared with continuous adalimumab RP.

Methods: We conducted a phase III, double-blind, randomized controlled trial between July 19, 2017, and April 16, 2019. There were 49 investigational sites across Europe and North America. Of 323 screened patients with moderate-to-severe chronic plaque psoriasis, 259 were treated with adalimumab RP during the run-in period. Of these, 118 and 120 were randomized to the continuous or switching arms, respectively. Interventions consisted of a run-in period with adalimumab RP 80 mg subcutaneously (SC) on Day 1, then 40 mg SC every other week (EOW) Weeks 2-12. Patients were then randomized to receive adalimumab RP 40 mg EOW Weeks 14-48 (continuous arm) or BI 695501 40 mg Weeks 14 and 16, adalimumab RP 40 mg Weeks 18 and 20, and BI 695501 40 mg EOW Weeks 22 to 48 (switching arm); all interventions were given SC. Primary endpoints were pharmacokinetics parameters, area under the plasma concentration-time curve (AUCτ,30-32) and maximum observed drug plasma concentration (Cmax,30-32), measured after the third switch during the Week 30-32 dosing interval.

Results: 238 patients (mean [standard deviation] age 44.9 [13.8]; 66.0% male) were treated in the switching (n = 118) or continuous arms (n = 120). Adjusted mean Cmax,30-32 was 7.08 and 7.00 μg/mL in the switching and continuous treatment arms, respectively; adjusted mean AUCτ,30-32 was 2025.8 and 1925.9 μg h/mL. Point estimate for mean ratio for AUCτ,30-32 was 105.2% (90.2% confidence interval [CI] 96.6-114.6), and 101.1% (90.2% CI 93.3-109.7) for Cmax,30-32. Both CIs were within a predefined bioequivalence range of 80.0-125.0%. Treatment-emergent adverse events led to discontinuation in 0.8% and 1.7% of patients in the switching and continuous treatment arms, and Psoriasis Area and Severity Index (PASI) scores were highly similar in the two arms across the entire trial period.

Conclusions: Pharmacokinetic equivalence was demonstrated, with highly similar efficacy and immunogenicity, and comparable safety observed in patients with chronic plaque psoriasis who received either adalimumab RP continuously or who switched between adalimumab RP and BI 695501.

Trial registration: ClinicalTrials.gov: NCT03210259 (registered July 2017); Eudract.ema.europa.eu: 2016-002254-20.

Conflict of interest statement

Alan Menter received grant support from AbbVie, Argenx, Novartis, Pfizer, Sun Pharma, and UCB; he reported consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Biocon, Janssen Biotech, LEO Pharma, Novartis, Sun Pharma, and UCB; honoraria for lectures/presentations/speaker bureaus from AbbVie, Amgen, Eli Lilly, Janssen, Sun Pharma, and UCB; travel support from Boehringer Ingelheim, Eli Lilly, and Sun Pharma; and participated in data safety monitoring/advisory boards for Amgen and Boehringer Ingelheim. Stanley Cohen received grant support from AbbVie, Amgen, BMS, Genentech, Lilly, Pfizer, and Roche; he reported consulting fees from AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Genentech, and Pfizer; honoraria from Novartis and Pfizer; and participated in a data safety monitoring board for Gilead Sciences. Jonathan Kay received grant support from Aker BioMarine, Alliance for Lupus Research, AMPEL BioSolutions, Gilead Sciences, Novartis, Pfizer, and UCB; he reported royalty fees from UpToDate; consulting fees from AbbVie, Alvotech, Boehringer Ingelheim, Celltrion Healthcare, Horizon Therapeutics, Jubilant Radiopharma, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Samsung Bioepis, Sandoz, Scipher Medicine, and UCB; and participated in data safety/advisory boards for Bristol Myers Squibb, Inmagene, and Kolon TissueGene. Vibeke Strand reported consulting fees from AbbVie, Amgen, Arena, Aria, AstraZeneca, Bayer, Bioventus, BMS, Boehringer Ingelheim, Celltrion, Chemocentryx, EMD Serono, Flexion, Galapagos, Genentech/Roche, Gilead, GSK, Horizon, Ichnos, Inmedix, Janssen, Kiniksa, Eli Lilly, Merck, MiMedx, Novartis, Pfizer, Regeneron, Rheos, R-Pharma, Samsung, Sandoz, Sanofi, Scipher, Servier, Setpoint, Sun Pharma, Tonix, and UCB. Alice Gottlieb received honoraria as an advisory board member and consultant for AnaptsysBio, Avotres Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb Co., GSK, Janssen, Eli Lilly, Leo, Novartis, Pfizer, Sun Pharmaceuticals, UCB, Dermavant, and Xbiotech; and received research/educational grants from Boehringer Ingelheim, Janssen, Novartis, UCB, and Sun Pharmaceutical Industries, Inc. Stephen Hanauer received grant support from AbbVie, Allergan, Amgen, Celgene, Genentech, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Pfizer, Prometheus, Receptos, Takeda, and UCB; he reported consultancy fees from AbbVie, Allergan, Amgen, Arena, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cosmos, Catalys Pacific, Covance, Genentech, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Progenity, Prometheus, Receptos, Salix, Samsung Bioepis, Seres Therapeutics, Sorriso, Takeda, TLL Pharma, UCB, and VHSquared; speaker fees from AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Takeda; and participated in data safety monitoring boards for Arena, Boehringer Ingelheim; Bristol Myers Squibb, Gossamer, Prometheus, and Protagonist. Susanne Buschke, Karl-Heinz Liesenfeld, Jennifer Schaible, Dorothy McCabe, and Benjamin Lang reported being employees of Boehringer Ingelheim. Sravan Kumar Eduru was previously employed by Boehringer Ingelheim.

© 2022. The Author(s).

Figures

Fig. 1

Study design. aAdalimumab RP 80 mg loading dose on Day 1 and then 40 mg/0.8 mL or 40 mg/0.4 mL EOW from Week 2 to Week 12. bFirst PK sampling interval (adalimumab RP only). cBI 695501 40 mg/0.8 mL at Week 14 and Week 16, adalimumab RP 40 mg/0.8 mL EOW at Week 18 and Week 20, and then BI 695501 40 mg/0.8 mL EOW from Week 22 to Week 48. dAdalimumab RP 40 mg/0.8 mL EOW from Week 14 to Week 48. ePrimary endpoints assessment period, and the second PK sampling interval (Week 30–32) in switching (BT) and continuous (BR) arms. BSA body surface area, EOW every other week, PASI psoriasis area and severity index, RP reference product, sPGA Static Physician’s Global Assessment

Fig. 2

CONSORT diagram of patient flow. AE adverse events, RP reference product

Fig. 3

Area under the drug plasma concentration–time curve and maximum observed drug plasma concentration during the dosing interval Week 30–32 (pharmacokinetic seta)b. aAll patients who received study treatment and for whom at least one primary pharmacokinetic parameter was available. bAnalyzed using an ANCOVA model, accounting for the impact of treatment (switching vs continuous arms), logarithm of PASI improvement (the ratio of PASI response at Week 14 and at Week 1), weight at Week 14, stage (prior to or after the blinded sample size reassessment), and AUCτ,12–14 or Cmax,12–14. AUC area under the concentration–time curve, CI confidence interval, Cmax maximum observed adalimumab plasma concentration, PASI Psoriasis Area and Severity Index