AMSTERDAM – The novel biologic agent dupilumab showed strong dose-dependent efficacy in adults with moderate to severe atopic dermatitis not adequately controlled with topical medications in a 380-patient phase IIb dose-ranging study.
“Based on the results of this study, we’ll take the top two doses further to our phase III program. We’re also planning to conduct a maintenance study. At the end of 16 weeks of treatment, we’ll investigate lower-dose regimens that may be capable of maintaining clinical response,” Dr. Marius Ardeleanu said at the annual congress of the European Academy of Dermatology and Venereology.
Dr. Marius Ardeleanu
Dupilumab is an investigational fully human monoclonal antibody that addresses a novel target: It is directed against the interleukin-4 receptor alpha subunit (IL-4Ra). Through this effect it blocks IL-4 and IL-13, the drivers of the type 2 helper T-cell–mediated inflammation responsible for the hallmark symptoms of atopic dermatitis (AD), explained Dr. Ardeleanu of Regeneron Pharmaceuticals in Tarrytown, N.Y.
Participants in this 16-week, double-blind, international phase IIb study were randomized to placebo or one of five dupilumab dosing regimens ranging from a low of 100 mg given subcutaneously every 4 weeks to a maximum of 300 mg once weekly or every 2 weeks.
These patients had a significant disease burden. They were typically in their mid- to late 30s and had a 27-year disease history, a mean baseline SCORAD of 67 on a 0-100 scale, a baseline Eczema Area and Severity Index (EASI) score of 32, an Investigator’s Global Assessment of disease severity score of 3.5 on a 0-4 scale, and 50% body surface area involvement. Their mean average weekly self-rated itching score was 6.8 on a 0-10 scale.
The primary study endpoint was change in the EASI score from baseline to 16 weeks. The score dropped by 20% in placebo-treated controls and by significantly greater margins in all five dupilumab arms. The largest reduction in EASI score – nearly 80% – occurred in the group on 300 mg/wk, with the 300 mg every 2 weeks group showing about a 70% reduction.
Roughly 80% of patients on 300 mg/wk or every 2 weeks showed an EASI 50 response at week 16, meaning a 50% reduction from baseline in their score, which is considered clinically meaningful improvement. One-third of patients on either of these top two–performing regimens achieved an Investigator’s Global Assessment score of 0 or 1, which is virtual remission; none of the controls did. Overall weekly average pruritus scores dropped by more than 60% with weekly treatment at 300 mg and by slightly less with biweekly therapy at 300 mg.
Safety data were similar to those from a recently published earlier phase IIa study (N. Engl. J. Med. 2014; 371:130-9). There were no dose-limiting toxicities. Headache and injection site reactions were the only adverse events more common with dupilumab than with placebo in the phase IIb trial, with the incidence of injection site reactions showing a possible dose-response relationship.
In addition to the large phase III studies now being planned, which will also evaluate step-down maintenance therapy, another study has been scheduled to investigate the use of dupilumab in combination with topical corticosteroid therapy. The earlier phase IIa study provided evidence to suggest this combination has even greater efficacy than dupilumab alone, and with modest use of the topical agent, according to Dr. Ardeleanu.
Dupilumab is also being developed as a treatment for tough-to-control moderate to severe asthma. It showed positive results in a phase II study, with reduced asthma exacerbations and improved lung function, compared with placebo (N. Engl. J. Med. 2013; 368:2455-66).