New Therapeutics for Eczema and Atopic Dermatitis, Part 1

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 1 of this series, crisaborole is reviewed; part 2 of the series will discuss dupilumab.

 

In a recent Q&A interview with The Dermatologist,1 Emma Guttman-Yassky, MD, PhD, professor, dermatology and medicine, clinical immunology, The Mount Sinai Hospital in New York, spoke of new therapeutics for AD.

“In AD, there are major developments in several fields. One field is the development of biologic therapeutics that target the specific cytokines. An example here is dupilumab, which targets both TH2 cytokines IL-4 and IL-13. Dupilumab is [potentially] the first biologic that will be approved for AD. It finalized its phase 3 study with very promising results and a very good safety profile. It is pending FDA approval, and we are hoping for approval in the beginning of 2017,” she said.

“Crisaborole is another exciting treatment in the pipeline. It is a topical that targets PDE4. …We hope it will gain FDA approval by the end of 2016 or beginning of 2017. We’re excited about crisaborole because we haven’t had anything new to give our patients topically since 2002 when the calcineurin antagonists were brought to the market,” she said.

Dr Guttman-Yassky added that other biologic therapies are in the pipeline targeting IL-31, the itch cytokine, IL-22, and others. “There are also small molecules such as PDE4 antagonists (apremilast [Otzela] that is approved for psoriasis) and Janus kinase inhibitors that are being actively tested as oral agents. It is important to have availability of oral treatments as well for moderate to severe patients as some patients will prefer an oral to an injectable, and we are aiming to have all options,” she explained.

Emerging Therapies

In May 2016, Pfizer entered an agreement to purchase Anacor Pharmaceuticals, which develops novel small-molecule therapeutics including crisaborole, for $5.2 billion. Crisaborole is under review by the FDA for the treatment of mild to moderate AD in children and adults. In both of its phase 3 pivotal studies, crisaborole achieved statistically significant results on all primary and secondary endpoints and in March 2016, the FDA accepted for review Anacor’s new drug application. The Prescription Drug User Fee Act goal date for the completion of the FDA’s review is January 7, 2017. If approved, peak year sales for crisaborole have the potential to reach or exceed $2 billion, according to Pfizer.

The ointment demonstrated a favorable safety profile and improvement in all measures of efficacy for the topical treatment of AD in children and adults, according to a recent study published online in the Journal of the American Academy of Dermatology2 in July 2016.

For the study, researchers tested safety and efficacy of crisaborole ointment in 2 phase 3 AD studies. Patients 2 years of age or older were randomly assigned (2:1, crisaborole:vehicle) in 2 identically designed, vehicle-controlled, double-blind studies with an Investigator’s Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary goal of the study was ISGA score at day 29 was clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus.  

Treatment-related adverse events were infrequent and mild to moderate in severity. Patients treated with crisaborole then the vehicle treatment achieved successful ISGA scores (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%; P=.038; AD-302: 31.4% vs 18.0%; P< .001).

Crisaborole-treated patients experienced a greater percentage score with clear/almost clear (51.7% vs 40.6%; P=.005; 48.5% vs 29.7%; P<.001). Patients experienced improvements in pruritus earlier when treated with crisaborole than those treated with vehicle (both P≤.001).

The researchers concluded that future analysis using the Eczema Area and Severity Index (EASI) would provide insight into site-specific efficacy of crisaborole ointment for comparison with topical corticosteroids (TCS), and topical calcineurin inhibitors (TCI).

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.