Pfizer's Next-Gen Oral JAK1 Inhibitor Abrocitinib Shows Significant Efficacy in Phase 3 Trial for Atopic Dermatitis, Anticipated FDA Approval in April

March 28, 2021/BioonBIOON/--PfizerPfizer recently announced that the full results of the Phase 3 JADE COMPARE study (NCT03720470), evaluating once-daily oral JAK1 inhibitor abrocitinib for the treatment of moderate-to-severe atopic dermatitis (AD), have been published in the international medical journal The New England Journal of Medicine (NEJM). The study was conducted in adult patients with moderate-to-severe AD receiving background topical therapy, and assessed the efficacy and safety of two doses of abrocitinib (100 mg and 200 mg) versus placebo. The study also included an active comparator arm, in which patients received subcutaneous injections of Dupixent (dupilumab). The results showed that both doses of abrocitinib met the co-primary endpoints. For detailed study results, see:Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis。

Currently, the New Drug Application (NDA) for abrocitinib (100 mg, 200 mg) for the treatment of patients aged ≥12 years with moderate-to-severe atopic dermatitis (AD) is under review by the U.S.FDApriority review, with the review results expected to be available in April 2021. In addition, the Marketing Authorization Application (MAA) for abrocitinib in the same patient population is also under review by the European Medicines Agency (EMA), with the review results anticipated in the second half of 2021.

Abrocitinib is an oral small molecule that selectively inhibits Janus kinase 1 (JAK1). Inhibition of JAK1 is believed to modulate multiple cytokines involved in the pathophysiology of atopic dermatitis (AD), including interleukin (IL)-4, IL-13, IL-31, IL-22, and thymic stromal lymphopoietin (TSLP). In the United States,FDABreakthrough Therapy Designation (BTD) was granted to abrocitinib for the treatment of moderate-to-severe AD in February 2018.

Atopic Dermatitis (AD) is a chronic skin disease characterized by cutaneous inflammation and skin barrier defects, with clinical manifestations including erythema, pruritus, induration/papule formation, and exudation/crusting. This severe, unpredictable, and often debilitating condition significantly impacts the daily lives of patients and their families. AD is one of the most common chronic, relapsing pediatric skin diseases, affecting up to 10% of adults and up to 20% of children worldwide. Many patients with moderate-to-severe AD experience inadequate disease control and require additional therapeutic options to alleviate the symptoms that matter most to them.

In multipleClinical TrialIn China, abrocitinib demonstrates robust efficacy in alleviating the symptoms and signs of atopic dermatitis (AD), including rapid relief of pruritus. If approved, abrocitinib will bring about meaningful changes in real-world clinical practice.

Molecular structure of abrocitinib (Image source: medchemexpress.cn)

The regulatory application for abrocitinib is based on data from the robust Phase 3 JADE global clinical development program. In this program, abrocitinib demonstrated statistical superiority over placebo in terms of skin clearance, disease extent, and severity, with rapid improvement in pruritus symptoms (as early as Week 2). Abrocitinib also exhibited a consistent safety profile and was generally well tolerated in the trials. The submission includes the following study results from the abrocitinib JADE global development program:

——JADE MONO-1 and JADE MONO-2: These two studies evaluated the efficacy and safety of abrocitinib monotherapy at two doses (100 mg and 200 mg, once daily) versus placebo.

——JADE COMPARE: This study evaluated the efficacy and safety of two doses (100 mg and 200 mg, once daily) of abrocitinib versus placebo in patients receiving background topical therapy. The study also included an active control group receiving subcutaneous biologic therapy with dupilumab, which was compared with placebo.

Atopic Dermatitis (Image source: icresearch.net)

JADE COMPARE was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter Phase 3 study that evaluated the efficacy and safety of two doses of abrocitinib (100 mg and 200 mg, once daily, orally), the active comparator dupilumab (300 mg every 2 weeks subcutaneously, with a 600 mg loading dose at baseline), and placebo in adults with moderate-to-severe atopic dermatitis (AD) receiving background topical therapy. All patients received topical therapy. In the study, 838 patients were randomized in a 2:2:2:1 ratio: (1) 226 patients were assigned to the abrocitinib 200 mg group; (2) 238 patients were assigned to the abrocitinib 100 mg group; (3) 243 patients were assigned to the dupilumab group; and (4) 131 patients were assigned to the placebo group.

The co-primary endpoints of the study were: (1) Investigator’s Global Assessment (IGA) response at Week 12 of treatment, defined as an IGA score (scoring range: 0–4) of 0 (complete clearance of skin lesions) or 1 (almost complete clearance of skin lesions) and an improvement of ≥2 points from baseline; (2) Eczema Area and Severity Index-75 (EASI-75) response at Week 12 of treatment, defined as an improvement of ≥75% in the EASI score (scoring range: 0–72) from baseline. Key secondary endpoints included: itch response at Week 2 of treatment, defined as an improvement of ≥4 points in the Peak Pruritus Numerical Rating Scale (PP-NRS, scoring range: 0–10) from baseline; IGA response and EASI response at Week 16 of treatment. The relative itch relief with abrocitinib was formally compared with dupilumab only at Week 2.

The study met its co-primary endpoints at Week 12: both doses of abrocitinib demonstrated superiority over placebo in the proportion of patients achieving each primary efficacy endpoint. At Week 16, both doses of abrocitinib remained superior to placebo. At Weeks 12 and 16, the active comparator, dupilumab, also demonstrated superiority over placebo for the primary efficacy endpoints.

Primary endpoint data were as follows: (1) IGA response at Week 12 was observed in 48.4%, 36.6%, 36.5%, and 14.0% of patients in the abrocitinib 200 mg, abrocitinib 100 mg, dupilumab, and placebo groups, respectively (p<0.001 for both abrocitinib doses vs. placebo); EASI-75 response at Week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1% of patients in the respective groups (p<0.001 for both abrocitinib doses vs. placebo).

Regarding key secondary endpoints, abrocitinib at the 200 mg dose (but not the 100 mg dose) was superior to dupilumab in terms of itch response at Week 2. In most other key secondary endpoint comparisons at Week 16, there were no significant differences between either dose of abrocitinib and dupilumab. The incidence rates of nausea were 11.1% and 4.2% in the 200 mg and 100 mg abrocitinib groups, respectively, while the incidence rates of acne were 6.6% and 2.9%, respectively.

Conclusion: In this trial, abrocitinib at doses of 200 mg or 100 mg once daily significantly reduced the signs and symptoms of moderate-to-severe atopic dermatitis compared with placebo at Weeks 12 and 16. For itch response at Week 2, abrocitinib 200 mg (but not 100 mg) was superior to dupilumab. In most other key secondary endpoint comparisons at Week 16, there were no significant differences between either dose of abrocitinib and dupilumab. (Bioon.com)

Original Source: Results from Pfizer’s Phase 3 JADE COMPARE Study of Abrocitinib in Moderate-to-Severe Atopic Dermatitis Published in the New England Journal of Medicine