Next Stop FDA Approval? Dupilumab Improves Symptoms in Moderate-to-Severe AD

Friday, April 01, 2016 | Atopic Dermatitis , Regeneron , Sanofi

Dupilumab helps improve the signs and symptoms of moderate-to-severe atopic dermatitis (AD) in adults, according to two late stage clinical trials.

The U.S. Food and Drug Administration (FDA) granted dupilumab Breakthrough Therapy designation in AD in November 2014. U.S. regulatory submission for dupilumab is planned for Q3 2016.

Regeneron and Sanofi's dupilumab is an investigational fully human monoclonal antibody that blocks interleukin-4 receptor alpha subunit (IL-4Ra). Through this effect, it also blocks IL-4 and IL-17, which are known to drive the type 2 helper T-cell–mediated inflammation that is responsible for the hallmark symptoms of AD.

In the studies, known as LIBERTY AD SOLO 1 and SOLO 2, treatment with dupilumab monotherapy significantly improved measures of overall disease severity, skin clearing, itching, quality of life, and mental health.

"These are the first Phase 3 studies of a systemic therapy to demonstrate a significant improvement in moderate-to-severe atopic dermatitis, a chronic, debilitating inflammatory disease that impacts over one million Americans," says George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories in a news release. "These data provide strong evidence that the IL-4 and IL-13 signaling pathway is a fundamental driver of inflammation in atopic dermatitis."

A total of 1,379 adult patients with moderate-to-severe AD were enrolled in the identically-designed SOLO 1 and SOLO 2 trials. Patients were enrolled if they were not adequately controlled with topical medications, or if topical treatment was not medically advisable. All patients were assessed via the 5-point Investigator's Global Assessment (IGA) scale, ranging from 0 (clear) to 4 (severe); entry criteria required a baseline score of 3 or 4. Patients were also assessed using the Eczema Area and Severity Index (EASI) and other measures. Patients were randomized into one of three treatment groups: dupilumab 300 mg subcutaneously once per week, dupilumab 300 mg subcutaneously every two weeks, or placebo for 16 weeks following an initial dupilumab loading dose of 600 mg subcutaneously, or placebo. Results at 16 weeks included the following:

For SOLO 1 and SOLO 2, respectively, 37 and 36 percent of patients who received dupilumab 300 mg weekly, and 38 and 36 percent of patients who received dupilumab 300 mg every two weeks, achieved clearing or near-clearing of skin lesions (IGA 0 or 1), compared to 10 and 8.5 percent with placebo (p less than 0.0001). This was the primary endpoint of the study in the U.S.

For SOLO 1 and SOLO 2, respectively, the percent improvement in EASI from baseline was 72 and 69 percent in patients who received the 300 mg weekly dose, and 72 and 67 percent for patients who received dupilumab 300 mg every two weeks, compared to 38 and 31 percent for placebo (p less than 0.0001).

For SOLO 1 and SOLO 2, respectively, 52.5 and 48 percent of patients who received dupilumab 300 mg weekly, and 51 and 44 percent of patients who received dupilumab 300 mg every two weeks, achieved EASI-75 compared to 15 and 12 percent with placebo (p less than 0.0001). This was the key secondary endpoint in the US and one of the primary endpoints in the EU.

For the 16-week treatment period, the overall rate of adverse events (65-73 percent dupilumab and 65-72 percent placebo) was comparable between the dupilumab groups and the placebo groups. The proportion of patients who completed the treatment period was 88-94 percent for dupilumab and 80.5-82 percent for placebo. The rate of serious adverse events was 1-3 percent for dupilumab and 5-6 percent for placebo. Serious and severe infections were also numerically higher in the placebo groups in both studies (0.5-1 percent dupilumab and 2-3 percent placebo). Adverse events that were noted to have a higher rate with dupilumab treatment across both studies included injection site reactions (10-20 percent dupilumab; 7-8 percent placebo) and conjunctivitis (7-12 percent dupilumab; 2 percent placebo); approximately 26 percent of patients in both studies reported a history of allergic conjunctivitis at study entry. No patient discontinued therapy due to injection site reactions and only one patient discontinued therapy due to conjunctivitis. 

More detailed results from SOLO 1 and SOLO 2 will be submitted for presentation at a future medical congress.



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