New Therapeutics for Eczema and Atopic Dermatitis, Part 2

Two investigational therapies—the injectable drug dupilumab (Dupixent, Sanofi /Regeneron Pharmaceuticals) and crisaborole (Pfizer/Anacor), a differentiated nonsteroidal topical phosphodiesterase-4 (PDE4) inhibitor with anti-inflammatory properties—are creating excitement in the atopic dermatitis (AD) arena. In part 2 of this series, dupilumab is reviewed. For a look a crisaborole, view part 1 of the series.

Eyes are on the injectable therapy dupilumab, an antibody against the IL-4 receptor, through which both IL-4 and IL-13 signal.

In April 2016, results were released for 2 placebo-controlled phase 3 studies evaluating investigational dupilumab in adult patients with inadequately controlled moderate to severe AD met their primary endpoints. The studies, LIBERTY AD SOLO 1 and SOLO 2 demonstrated that treatment with dupilumab as monotherapy significantly improved measures of overall disease severity, skin clearing, itching, quality of life, and mental health. The results were published online in the New England Journal of Medicine on October 1, 2016.3

A total of 1379 adult patients with moderate to severe AD were enrolled in the identically designed SOLO 1 and SOLO 2 trials. Enrollment included patients who were not adequately controlled with topical medications, or if topical treatment was not medically advisable. Patients were assessed using 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. EASI was also used. Patients were randomized into 1 of 3 treatment groups: dupilumab 300 mg subcutaneously once per week, dupilumab 300 mg subcutaneously every 2 weeks, or placebo for 16 weeks following an initial dupilumab loading dose of 600 mg subcutaneously, or placebo.

For SOLO 1 and SOLO 2, respectively, 37% and 36% of patients who received dupilumab 300 mg weekly, and 38% and 36% of patients who received dupilumab 300 mg every 2 weeks, achieved clearing or near-clearing of skin lesions (IGA 0 or 1), compared with 10% and 8.5% with placebo (P< .0001). This was the primary endpoint of the study in the United States.

For SOLO 1 and SOLO 2, respectively, the improvement in EASI from baseline was 72% and 69% in patients who received the dupilumab 300 mg weekly dose, and 72% and 67% for patients who received dupilumab 300 mg every 2 weeks compared with 38% and 31% for placebo (P<.0001). For SOLO 1 and SOLO 2, respectively, 52.5% and 48% of patients who received dupilumab 300 mg weekly, and 51% and 44% of patients who received dupilumab 300 mg every 2 weeks, achieved EASI-75 compared with 15% and 12% with placebo (P<.0001). This was the key secondary endpoint in the United States and one of the primary endpoints in the European Union.

During the 16-week treatment period, the overall rate of adverse events was comparable between the dupilumab groups and the placebo groups. Adverse events that were noted to have a higher rate with dupilumab treatment across both studies included injection site reactions (10%-20% dupilumab; 7%-8% placebo) and conjunctivitis (7%-12% dupilumab; 2% placebo). No patient discontinued therapy due to injection site reactions and only one patient discontinued therapy due to conjunctivitis.

The LIBERTY AD phase 3 clinical program includes 5 trials of patients with moderate to severe AD at sites around the world. In June 2016, the companies reported data that the 1-year phase 3 study, LIBERTY AD CHRONOS, evaluating investigational dupilumab met its primary and key secondary endpoints. In the study, dupilumab with TCS was compared with TCS alone in moderate to severe AD adult patients. Patients in the study were inadequately controlled by topical TCS with or without TCI. Dupilumab with TCS significantly improved measures of overall disease severity at 16 and 52 weeks, when compared with placebo with TCS, the companies reported.

“This is the first long-term phase 3 data that demonstrated dupilumab with topical corticosteroids was superior to topical corticosteroids alone, and provided sustained efficacy, significantly improving measures of overall disease severity, skin clearing, itching, and quality of life through one year of treatment,” said George D. Yancopoulos, MD, PhD, chief scientific officer of Regeneron and president of Regeneron Laboratories. “Although topical corticosteroids are standard therapies for atopic dermatitis, they are nonspecific anti-inflammatory agents, while dupilumab is a targeted therapy that specifically blocks the IL-4/IL-13 signaling pathway. Our collective clinical data demonstrate that this pathway is a root cause in atopic dermatitis, asthma, and nasal polyposis and we continue to evaluate the potential of this pathway in these atopic and allergic diseases.”

The primary endpoint results at week 16 showed 39% of patients who received either dupilumab 300 mg weekly with TCS or dupilumab 300 mg every 2 weeks with TCS achieved clearing or near-clearing of skin lesions (IGA 0 or 1) compared with 12% of patients receiving placebo with TCS (P<.0001). Sixty-four percent of patients who received dupilumab 300 mg weekly with TCS, and 69% of patients who received dupilumab 300 mg every 2 weeks with TCS achieved EASI-75, a 75% reduction on an index measuring eczema severity, compared with 23% of patients receiving placebo with TCS (P<.0001).

The secondary endpoint 52-week results demonstrated that 40% of patients who received dupilumab 300 mg weekly with TCS, and 36% of patients who received dupilumab 300 mg every 2 weeks with TCS achieved clearing or near-clearing of skin lesions (IGA 0 or 1) compared with 12.5% of patients receiving placebo with TCS (P<.0001). Sixty percent of patients who received 300 mg weekly with TCS, and 65% of patients who received 300 mg every 2 weeks with TCS achieved EASI-75 compared with 22% with placebo with TCS (P<.0001). In addition, the study demonstrated that patients were less likely to discontinue therapy in the dupilumab with TCS groups compared with placebo with TCS group (15% in both dupilumab groups; 33% placebo).

The overall rate of adverse events and serious adverse events were comparable between the dupilumab with TCS groups and the placebo with TCS group. Serious and/or severe infections were numerically higher in the placebo with TCS group. Injection site reactions and conjunctivitis were adverse events that were noted to have a higher rate with dupilumab.

References
1. Nataloni R. Eczema is firmly established as an immunologically-based disease. The Dermatologist. 2016;14(9):41-44.
2. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. [Published online July 11, 2016] J Amer Acad Dermatol. doi:http://dx.doi.org/10.1016/j.jaad.2016.05.046.
3. Simpson EL, Bieber T, Guttman-Yassky E, et al. SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis Published online October 1, 2016. DOI: 10.1056/NEJMoa1610020.