Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis

Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis

Bieber T, Simpson EL, Silverberg JI, et al. N Engl J Med. 2021;384:1101-12. doi:10.1056/NEJMoa2019380

• The first-line treatment for atopic dermatitis is topical therapies, but when these prove insufficient, systemic therapies are recommended. Dupilumab, a monoclonal antibody, is an approved systemic treatment, and immunosuppressants have also been recommended
• Janus kinase (JAK) inhibitors target cytokines involved in the pathogenesis of atopic dermatitis and are being investigated as alternative systemic treatments
• Abrocitinib, a small-molecule JAK1 inhibitor administered orally once daily, has shown promise as a treatment for atopic dermatitis in previous trials^1,2

This paper reports the findings of the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) COMPARE trial, which evaluated the safety and efficacy of abrocitinib in patients with moderate-to-severe atopic dermatitis who were receiving background topical therapy. The trial also compared the efficacy of abrocitinib with dupilumab.

How was the trial conducted?

• In this phase 3, double-blind trial, 838 adult patients with atopic dermatitis unresponsive to topical agents or that warranted systemic therapy were randomised to four treatment groups:
  • 200 mg abrocitinib orally once daily (226 patients)
  • 100 mg abrocitinib orally once daily (238 patients)
  • 300 mg dupilumab subcutaneously on alternate weeks (after 600 mg loading dose) (243 patients)
  • placebo (131 patients)

 All patients received topical background therapy

• The primary endpoints at week 12 were:
  • Investigator’s Global Assessment (IGA) response, defined as a score of 0 (clear) or 1 (almost clear) on the IGA (scores range from 0 to 4), with an improvement of ≥2 points from baseline
  • Eczema Area and Severity Index-75 (EASI-75) response, defined as ≥75% improvement from baseline in EASI score (scores range from 0 to 72)
• The key secondary end points were:
  • Itch response, defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale (scores range from 0 to 10) at week 2
  • IGA response at week 16
  • EASI-75 response at week 16

A range of additional secondary end points at week 16 were also included.

• Adverse events were recorded

What were the findings of the trial?

For the primary end points for efficacy of abrocitinib vs placebo:

• The IGA response at week 12 differed significantly from placebo (P <0.001) for both doses of abrocitinib (Figure 1)
• The EASI-75 response at week 12 differed significantly from placebo (P <0.001) for both doses of abrocitinib (Figure 1)

Figure 1. Primary end point results. A: Patients with an Investigator’s Global Assessment (IGA) response during the trial. B: Patients with an Eczema Area and Severity Index-75 (EASI-75) response during the trial. P values are shown for between-group comparisons that were controlled for multiplicity. Note: The trial was not formally designed to compare the efficacy of abrocitinib and dupilumab for the two primary end points.

For the secondary end points comparing efficacy of abrocitinib vs dupilumab:

• The 200 mg dose of abrocitinib, but not the 100 mg dose, was superior to dupilumab for itch response at 2 weeks
• Both doses of abrocitinib produced significant (P <0.001) IGA and EASI-75 responses at 16 weeks, but neither dose of abrocitinib differed significantly from dupilumab in most end-point comparisons at 16 weeks

Adverse events:

• The main adverse events with abrocitinib were nausea, acne, nasopharyngitis and headache
• Adverse events were more frequent in the 200-mg abrocitinib group
• Nausea: 11.1% of patients in the 200-mg abrocitinib group experienced nausea, compared with 7% in the dupilumab group and 1.5% in the placebo group
• Mild-to-moderate acne: 6.6% of patients in the 200-mg abrocitinib group developed acne, compared with 1.2% in the dupilumab group and 0% in the placebo group
• The frequency of most adverse events was similar in the dupilumab and 100 mg abrocitinib groups
• Conjunctivitis occurred more frequently in the dupilumab group (6.2% of patients), as found in previous trials

Note: Herpes zoster infections occurred in 6 patients given abrocitinib and serious infections occurred in 2 patients (serious and opportunistic infections are considered a risk with JAK inhibitors in patients with rheumatoid arthritis)

What can we conclude from the trial?

• As measured by IGA or EASI-75 responses, 100 mg or 200 mg of abrocitinib once daily reduced signs and symptoms of moderate-to-severe atopic dermatitis significantly better than placebo at weeks 12 and 16 in patients receiving background topical therapy
• The 200-mg dose of abrocitinib was superior to dupilumab for itch response at week 2, but neither abrocitinib dose differed significantly from dupilumab in most measures at 16 weeks
• Abrocitinib was effective against atopic dermatitis in this trial. However, because atopic dermatitis is a lifelong disease, the long-term efficacy and safety of abrocitinib should be established

Access the full paper here

References

1. Simpson EL, Sinclair R, Forman S, Wollenberg A, Aschoff R, Cork M, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet (London, England). 2020;396(10246):255–266.
2. Silverberg JI, Simpson EL, Thyssen JP, Gooderham M, Chan G, Feeney C, et al. Efficacy and Safety of Abrocitinib in Patients with Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatology. 2020;156(8):863–873.