VOLTAIRE-X Findings in Patients With Chronic Plaque Psoriasis Supported Interchangeability

The VOLTAIRE-X randomized controlled trial determined the adalimumab biosimilar BI 695501 (adalimumab-adbm, Cyltezo; Boehringer Ingelheim) met the FDA’s criteria to be designated as interchangeable with the reference product (Humira).

Patients with moderate-to-severe plaque psoriasis received the reference product biweekly for 48 weeks or switched 3 times throughout the study between the reference product and biosimilar. The authors of the article describing the trial wrote that pharmacokinetic endpoints were equivalent and clinical outcomes were highly similar between groups.

Interchangeability

The investigators explained that the “interchangeable” designation is only used in the United States, and allows the interchangeable biosimilar to be substituted for its reference product by a pharmacist without prior approval of the prescriber, where allowed by state law.

The FDA’s criteria includes a demonstration of biosimilarity, the expectation that the biosimilar will produce the same clinical result as the originator in any given patient, and that the risk of switching between the biosimilar and reference product is not greater than the risk of using the reference product without switching. Cyltezo, based on the VOLTAIRE-X trial, is the first adalimumab biosimilar and the first monoclonal antibody to achieve interchangeable status.

VOLTAIRE-X was a phase 3 double-blind, randomized controlled trial conducted across 49 sites in Europe and North America, all of which used the US-licensed reference product. The trial aimed to assess whether multiple switches between the reference product and Cyltezo leads to equivalent pharmacokinetic parameters and a similar safety and immunogenicity profile compared to continuous treatment with the reference product.

After a run-in period of 14 weeks, patients were randomized to the continuous (n = 118 patients) and switching (n = 120 patients) arms and received adalimumab treatment every other week for a total of 48 weeks. The switching group switched between the reference product and biosimilar at weeks 14, 18, and 22. The authors described patient demographics and disease characteristics at baseline as “well balanced” between treatment arms.

Pharmacokinetic Endpoints Were Within Equivalence Margins

Primary pharmacokinetic endpoints were area under the plasma concentration-time curve (AUCτ,30-32) and maximum observed drug plasma concentration (Cmax,30-32) measured during weeks 30-32.

The authors reported that the primary pharmacokinetic endpoints fell within the bioequivalence range of 80-125%. The adjusted mean ratios of switching to continuous treatments for AUCτ,30-32 and Cmax,30-32 were 105% (90% CI, 97-115) and 101% (90% CI, 93%-110%).

Clinical Outcomes Were “Highly Similar” Between Groups

At week 32, 110 out of 118 (85%) and 94 out of 119 (79%) patients in the switching and continuous groups, respectively, had a 75% reduction in Psoriasis Area and Severity Index (PASI) scores. The authors commented, “PASI scores over time were highly similar in the two arms across the entire trial period.” Also at week 32, 83 of the112 (70%) and 77 of the 109 (65%) patients in the switching and continuous groups, respectively, had a static Physician’s Global Assessment (sPGA) response of 1 or lower (clear or almost clear).

Immunogenicity and Safety

Similar proportions of patients developed anti-drug antibodies, 101 out of 112 (90%) in the switching group and 104 out of 110 (95%) in the continuous group. Neutralizing antibodies were detected in 46 of 112 (41%) patients in the switching group and 46 of 110 (42%) in the continuous reference product group.

Treatment-emergent adverse events (TEAEs) considered related to study treatment were experienced by 14 (12%) and 22 (18%) of patients in the switching and continuous arms, respectively. The most common were injection-site erythema (n = 6) and arthralgia (n = 3). The investigators reported that fewer than 5% of patients experienced a severe TEAE, AE of special interest, or TEAE resulting in discontinuation of treatment, “with no notable difference between treatment groups.”

The authors concluded that switching 3 times between the adalimumab biosimilar BI 695501 and the reference product “resulted in pharmacokinetic equivalence, highly similar efficacy and immunogenicity outcomes, and comparable safety.” Based on this data, the biosimilar was approved by the FDA as interchangeable with the reference product. They added that despite speculation that multiple switches might increase immunogenicity, the results of VOLTAIRE-X found similar incidence of anti-drug antibodies in the continuous and switching groups.

Reference

Menter A, Cohen S, Kay J, et al. Switching between adalimumab reference product and BI 695501 in patients with chronic plaque psoriasis (VOLTAIRE-X): a randomized controlled trial. Am J Clin Dermatol. 2022;23(5):719-728. doi:10.1007/s40257-022-00708-w