Dupilumab Promising for Atopic Dermatitis in Phase 3 Studies

Damian McNamara

October 01, 2016

VIENNA — The monoclonal antibody dupilumab, a new biologic that dually targets interleukin (IL)-4 and IL-13, significantly improved atopic dermatitis severity compared with placebo in two phase 3 trials.

"This is a much-needed therapy for patients who have few options," Eric L Simpson, MD, of the Oregon Health & Science University in Portland, told Medscape Medical News.

"Not only are there significant effects on itch and other skin symptoms, but the patients' overall quality of life is restored. Even symptoms of anxiety and depression improved in a relatively short amount of time," he said.

The findings from the SOLO 1 and SOLO 2 trials were presented during a late-breaking session here at the 25th European Academy of Dermatology and Venereology Congress. Results were simultaneously published online October 1, 2016 in the New England Journal of Medicine.

Dr Simpson and colleagues assessed 671 adults with atopic dermatitis in SOLO 1, and another 708 in SOLO 2, for whom topical medications were contraindicated or did not provide adequate control. The trials were identical, multinational, and double-blind. Participants were randomly assigned to receive subcutaneous placebo injections once a week or dupilumab 300 mg every week or every 2 weeks. No other medications were allowed.

Patients presented with moderate-to-severe disease, with a median 50% Body Surface Area (BSA) affected by atopic dermatitis and median duration of 25 years. At baseline, they had an Investigator Global Assessment (IGA) score of 3 or greater and an Eczema Area and Severity Index (EASI) score of 16 or higher. The primary endpoint was an IGA of 0 or 1 indicating "clear skin" (no or minimal atopic dermatitis) and an improvement of 2 or more IGA points at week 16.

"Clear or pretty clear skin is a pretty high bar for patients with 50% or more BSA, so we also looked at EASI 75 scores," said Dr Simpson.

Table 1. Improvements in Atopic Dermatitis at 16 Weeks

  Placebo Dupilumab every 2 weeks Dupilumab once weekly P value vs placebo
IGA (SOLO 1) 10% 38% 37% < .0001
IGA (SOLO 2) 9% 36% 36% < .0001
EASI-75 (SOLO 1) 15% 51% 53% < .0001
EASI-75 (SOLO 2) 12% 44% 48% < .0001

Change in pruritus was among the secondary outcomes. "Itch is the most important symptom for patients," Dr Simpson said.

"There was a significant reduction as early as week 2 in both dupilumab groups versus placebo, which continued to week 16," he reported. Compared with a 10% to 12% reduction on the Pruritus Numerical Rating Score in the placebo group, dupilumab was associated with reductions from 36% to 41%.

Treated patients also reported greater improvements in health-related quality of life versus placebo patients on both the Dermatology Life Quality Index (DLQI) and Patient-Oriented Eczema Measure (POEM).

"This disease has a very large impact on quality of life," said Dr Simpson. "We know there is a high comorbid prevalence of depression and anxiety in our patients with atopic dermatitis."

Participants completed the Hospital Anxiety and Depression Scale (HADS) at baseline and 16 weeks. On the HADS total, placebo patients improved 3.0 points compared with 5.2 points for both dupilumab groups in SOLO 1 (P = .0006 twice weekly dupilumab, P = .0003 weekly dupilumab). In SOLO 2, placebo patients improved 0.8 points compared with 5.1 and 5.8 points in the dupilumab twice weekly and weekly groups, respectively (both P < .0001).

"With HADS [anxiety and depression subscales], a much higher proportion achieved a clinically relevant reduction in their scores with dupilumab. It was highly significant and consistent in both studies," said Dr Simpson.

Adverse Events

Conjunctivitis, allergic conjunctivitis, and injection site reactions were the most common adverse events that occurred in at least 5% of patients. Rates were higher in the dupilumab groups versus the placebo group and all were considered mild to moderate, Dr Simpson said.

Atopic dermatitis exacerbations, injection site reactions, and nasopharyngitis were the most common treatment-emergent adverse events. The rates were similar across all three groups in both trials (SOLO 1: placebo, 65%; twice weekly dupilumab, 73%; and weekly dupilumab, 69%. SOLO 2: placebo, 72%; twice weekly dupilumab, 65%; and weekly dupilumab, 66%).

The key takeaway is all adverse events and serious adverse events were balanced across all groups. Dr Eric L Simpson

The mechanism behind the development of conjunctivitis remains unknown, Dr Simpson said in reply to a question from a member of the audience. He described all cases as mild to moderate.

"I have about 30 patients in this trial, and most of the patients who developed conjunctivitis responded to topical steroids or topical cyclosporine," he reported. "The key takeaway is all adverse events and serious adverse events were balanced across all groups."

Two patients died during the study. Both deaths occurred in patients randomized to dupilumab; however, Dr Simpson did not believe they were study-related. One was a suicide in a highly depressed patient, he said, and the other was associated with a severe asthma attack 8 weeks after the patient's last dupilumab dose.

Another meeting attendee asked Dr Simpson if he was surprised that the study did not reveal notable differences between dupilumab administered twice a week versus once a week. "Great question. We haven't looked at that yet," he responded.

Clearly dupilumab doesn't work for every patient, so it's not the solution for all atopic dermatitis patients — not yet. Dr Giovanna Zambruno

Session co-chair Giovanna Zambruno, MD, of the Istituto Di Ricovero e Cura a Carattere Scientifico in Rome, Italy, asked by Medscape Medical News to comment on the study, said, "It's interesting and promising. Dupilumab clearly can be useful considering what a chronic, disabling disease atopic dermatitis is, and that we have only a limited number of clinical tools compared to other conditions like psoriasis."

"Clearly dupilumab doesn't work for every patient, so it's not the solution for all atopic dermatitis patients — not yet," Dr Zambruno said.

Findings of extension studies beyond 16 weeks for the SOLO 1 and SOLO 2 trials will be presented at a future date.

Dr Simpson is a consultant and investigator for Regeneron/Sanofi, the sponsor of the studies. Dr Zambruno had no relevant financial relationships.

25th European Academy of Dermatology and Venereology (EADV) Congress: Abstract D3T01.1C. Presented October 1, 2016.


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