The SOLO 1 and SOLO 2 phase 3 trials of the human monoclonal anti-body dupilumab for the treatment of eczema/atopic dermatitis (AD) have shown a high degree of efficacy and safety.
Those outcomes, according to one investigator, represent the first evidence for a treatment that can reliably improve out comes in patients with AD who require a systemic therapy to control their disease.
“The truth is that patients with atopic dermatitis are highly impacted. Dermatitis and itching is constantly on their minds,”said Dr. Kim Papp, dermatologist and president of the clinical research company Probity Medical Research Inc. in Waterloo, Ont. Dr. Papp, a trial investigator, said that other therapies for atopic dermatitis, including phototherapy and methotrexate, have limited efficacy in patients with extensive AD. Cyclosporine, while quite effective, cannot be used long-term because of its toxicity, he said.
In the trials, published in The New England Journal of Medicine (Dec. 15, 2016; 375(24):2335-2348), patients with moderate-to-severe AD with disease inadequately controlled by topical treatment were enrolled and randomly assigned in a 1:1:1 ratio to three treatment groups. Participants received 300 mg of subcutaneous dupilumab or a placebo weekly, or the same dose of dupilumab every other week, alternating with a placebo, for 16 weeks. Dupilumab is an antibody against interleukin (IL)-4 receptor alpha, which inhibits the signaling of the cytokines IL-4 and IL-13.
The primary outcomes for the trial were achievement of an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear), and a reduction of two or more points in IGA from baseline to week 16.
More than 1/3 clear or almost clear
Of the 671 patients in SOLO 1, 85 (38%) of the patients who received dupilumab every other week and 83 (37%) of those who received it weekly achieved the primary outcomes. In comparison, in the placebo group only 23 (10%) achieved primary outcomes (p<0.001) for both comparisons to placebo. The SOLO 2 trial had similar findings—84 (36%) of the every-other-week group, 87 (36%) of the weekly treatment group, and 20 (8%) of the placebo group reached the primary endpoints (p<0.001 for both).
Significantly more patients on active therapy in both trials achieved a 75% or better improvement in Eczema Area and Severity Index (EASI) scores than patients in the placebo group did over the 16 weeks of the study, as well (p<0.001 for all comparisons).
Most patients see improved QoL
However, these numbers do not adequately describe the improvement in patients’ disease and quality of life, said Dr. Papp, noting that because of the way the IGA score is evaluated a patient could improve from 90% skin coverage to a small patch of involved skin two cm square, and not be considered to have achieved the primary outcome.
“When you see a patient day zero, and they have 75 per cent or 80 per cent of their body covered with dermatitis, and their skin is lichenified and excoriated and they have areas with oozing and weeping on the skin because they have been scratching so vigorously, then a few weeks later their skin is normal, that is dramatic, ” Dr. Papp said in an interview with THE CHRONICLE OF SKIN & ALLERGY.
He noted most of the patients in the trial had significant improvement in their AD symptoms, and “in a good fraction of patients you get this dramatic improvement—normalization. The disease is basically gone.”
The dupilumab groups also saw improvements in other clinical end points, including pruritus, anxiety and depression symptoms, and quality of life.
No unusual safety signals
Safety-wise, there were more frequent injection-site reactions and conjunctivitis in the dupilumab groups than in the placebo groups, but nothing that stands out as exceptional, said Dr. Papp.
Interestingly, there was a lower rate of bacterial infections in the dupilumab groups compared to the placebo group.
“That reflects, I believe, the fact that we see skin infections more commonly in patients with atopic dermatitis than in patients who have normal skin. And certainly more frequently than in patients with psoriasis,” said Dr. Papp.
“That gets back to the normalization of barrier function. We would hope to see fewer of that sort of [infection] in effectively treated atopic dermatitis patients.”
IL-4 beta pathway key to AD
Another important implication of the strong results is that they suggest that IL-4 alpha pathway is the key to the pathway of AD disease progression, said Dr. Papp.
He said that much attention has historically been given to find ways to correct the barrier function in AD, yet the IL-4 pathway is not involved in barrier function maintenance. “Yet we see this amazing response, we control not only the dermatitis but we are normalizing the barrier,” he said.
This drives home the idea that AD is immunologicaly driven through the IL-4 pathway, said Dr. Papp.
Already, multiple products are being investigated for AD that target this pathway, Dr. Papp said. “Just as we have seen a burgeoning of effective therapies for psoriasis, we are going to see a burgeoning of effective therapies for atopic dermatitis. Dupilumab will be the first one out. Dupilumab has given us great insight, and it will give us the first opportunity to treat these patients who have for decades, for centuries, been in need of effective therapy.”
As this issue went to press, dupilumab was approved by the U.S. FDA for use in patients with moderate to severe eczema/atopic dermatitis.
The trade name of the product in the U.S. is Dupixent.
This article originally appeared in print in the March 2017 issue of The Chronicle of Skin & Allergy