Crisaborole 2% Ointment for Mild-to-Moderate Atopic Dermatitis

Aryan Riahi, BSc; Joseph M. Lam, MD, FRCPC

Disclosures

Skin Therapy Letter. 2021;26(1) 

In This Article

Completed and Ongoing Studies of Crisaborole

Crisaborole's safety profile and efficacy has been evaluated through 2 double-blind vehicle-controlled controlled phase 3 clinical trials. These studies assigned patients aged 2 years and older with mild or moderate AD as per Investigator's Static Global Assessment (ISGA) scoring for treatment with either 2% crisaborole ointment or vehicle for 28 days. Results collected on day 29 demonstrated that 51.7% of patients receiving crisaborole had an ISGA of clear (0) compared to 40.6% of vehicle-treated patients (P = 0.05) and 48.5% of patients had ISGA of almost clear (1) compared to 29.7% of those treated with vehicle (P < 0.001).[7]

Two randomized, double-blind, vehicle controlled phase 3 studies with 759 and 763 participants demonstrated that crisaborole improves pruritus compared with vehicle (56.6% vs. 39.5%; P < 0.001) as early as day 2 of therapy (34.3% vs. 27.3%; P = 0.013).[31]

TCS are routinely used as therapy for flare-ups in AD.[32] However, only short-term TCS use is recommended to minimize local and systemic adverse effects such as striae, telangiectasia, cutaneous atrophy, and acne.[33] As for TCI, both Health Canada and FDA initially advised against the use of long-term TCI therapy due to the unclear risk of malignancy.[19,20] Health Canada has subsequently removed the black box label for primecrolimus.[34] However, patients may continue to be apprehensive about using TCIs given their previous black box labeling. More research, including investigations on long-term maintenance, is needed to determine optimal topical treatment options for AD with favorable safety profiles. There is a phase 3 randomized, double-blind, vehicle-controlled study being conducted with 700 patients with mild-to-moderate AD.[35] Patients will receive crisaborole twice a day for a maximum of 8 weeks to identify responders, defined as ISGA score of 0 or 1 with 2-grade improvement from baseline or 50% improvement from baseline based on Eczema Area and Severity Index (EASI50) scoring. Non-responders will be discontinued after the 8-week run-in period. Maintenance treatment consists of once daily administration of crisaborole QD. Flares defined as ISGA ≥2 will be treated with twice daily crisaborole for up to 12 weeks. Completion of the trial is anticipated by July 2022.[35]

The efficacy and safety profile of crisaborole is currently being investigated in phase 4 trials. A randomized, double-blind, vehicle-controlled study is evaluating the efficacy and safety of 3 different application rates of crisaborole ointment 2% in adults with mild-to-moderate AD.[36] Each patient will have 4 application areas and receive 1 of 4 treatments ranging from vehicle to 3 different application rates of crisaborole. Patients will be randomly assigned to treatment with topical crisaborole (application rates A, B, or C) or vehicle, once daily, for 2 weeks. The results of this study, with a projected completion of June 2020, may demonstrate whether the efficacy and safety of crisaborole is dose dependent. The results may be compared and contrasted with TCS use, which has a well-known dose dependent effect (e.g., anti-inflammatory effects at lower doses, immunosuppressive activity at higher doses) as well as dose dependent adverse effects (e.g., ecchymosis, parchment-like skin, and sleep disturbances).[36]

Long-term topical treatment is often required for the management of a chronic inflammatory skin conditions like AD. Crisaborole's long-term safety was evaluated in an open-label extension study of 517 patients with mild-to-moderate AD who used crisaborole for 48 additional weeks after the 28-day phase 3 study. The most frequently reported treatment related adverse effect (AE) were AD (3.1%), pain at the site of application (2.3%), and localized infection (1.2%).[27]

The treatment options for patients under 2 years of age with AD are sparse. Pimecrolimus has recently been approved for infants as young as 3 months.[37] However, having a wider array of therapeutic strategies would be ideal for this demographic. A phase 4 multicenter, open-label, single arm investigation called the CrisADe CARE 1 study evaluated the safety, efficacy, and pharmacokinetics of crisaborole 2% ointment applied twice daily on 125 pediatric patients between 3–24 months of age.[38] These patients had extensive AD involving at least 5% of body surface area (BSA) except for the scalp. A total of 29.93% of patients reported non-serious AEs. The most common side effect was pyrexia (9.49%). The study found a total of 1 (0.73%) serious AE involving a febrile convulsion. The study did not comment on whether this AE was related to the use of crisaborole. No deaths occurred. This study is the first to evaluate the safety profile of crisaborole in children less than 24 months of age.

Crisaborole may have the potential of decreasing steroid use in patients with AD. Side effects of TCS can range from cutaneous atrophy to suppression of the hypothalamic-pituitary-axis.[39] Misunderstandings and steroid phobia can interfere with patient compliance, which in turn negatively affect disease control.[40] Currently, a proof-of-concept phase 4 clinical trial with 60 children between 2–18 years with mild-moderate AD is underway to determine whether crisaborole is an effective steroid reducing agent. The trial will be completed by November 2020.[41] Similarly, a single-center observational prospective cohort study aimed to evaluate the efficacy and safety profile of crisaborole ointment 2% and a TCI versus crisaborole alone over 8 weeks. The study included participants aged 2–79 with mild-tomoderate AD and the projected completion was March 2020.[42]

While high-quality phase 3 studies have demonstrated the efficacy of crisaborole compared to vehicle, head-to-head studies comparing crisaborole with TCS or TCI are needed to better define its role in the management of AD. A phase 4 multicenter, randomized, vehicle versus active (TCS and TCI) controlled study is being conducted on 600 patients with mild-to-moderate AD over 4 weeks to evaluate the safety and efficacy of crisaborole 2% ointment, crisaborole vehicle, TCS, and TCI applied BID in patients over 2 years of age.[43] Inclusion criteria include patients with AD involving at least 5% of BSA except for the scalp. The primary efficacy endpoint is change from the patient's baseline in the EASI score by Day 29. The study will be completed by March 2021. This will be the first study to directly compare crisaborole to the current mainstay treatments of mild-to-moderate AD.

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