The topical armamentarium for AD is growing

With many studies on novel compounds underway, more options for topical treatments of atopic dermatitis (AD) will soon be within reach.

Limited treatment options for an extensive group of patients

“It’s important to realise that the majority of our patients is still dependent on the topical treatments,” Prof. Marjolein de Bruin-Weller (University Medical Center Utrecht, the Netherlands) stated with regard to AD patients1. Currently, corticosteroids, with their known side-effect profile, and calcineurin inhibitors are the only 2 classes of topical drugs that are available. In the US and Japan, crisaborole is also an option, but not in Europe. “Thus, we have limited treatment options for a very big group of patients,” Prof. de Bruin-Weller explained.

Hopefully, the still unmet need for topical agents in AD will soon be alleviated, as many studies are currently investigating various novel drugs. In her overview, she focussed on the JAK inhibitors ruxolitinib and delgocitinib, the PDE4 inhibitors roflumilast and difamilast, and the AHR modulator tapinarof that has already been approved for psoriasis in the US. “I think the JAK-STAT inhibitors in topical formulation are very interesting,” Prof. de Bruin-Weller commented.

Focus on ruxolitinib and triamcinolone

Ruxolitinib cream that inhibits JAK 1 and 2 is already FDA-approved, and phase 3 is underway in Europe. In a phase 2 trial (NCT03011892), adults were randomised to ruxolitinib cream in various concentrations once (QD) or twice daily (BID), vehicle, or triamcinolone cream 0.1% BID (only for the first 4 weeks)2. At week 4, all regimens of the study drug were superior to vehicle1,2. The highest dose resulted in an Investigator's Global Assessment (IGA) of 0/1 in 38% at week 4, further rising to a rate of 48% at week 8. On the steroid, 25.5% achieved IGA 0/1 response at week 4. Itch responses on the numeric rating scale (NRS) were present within 36 hours.

In phase 3, the identical TRUE-AD1 and 2 trials (NCT03745638, NCT03745651) included adults and about 20% of adolescents ≥12 years, all with an IGA of 2/3. Ruxolitinib cream 1.5% BID and 0.75% BID over 8 weeks were assessed versus vehicle3.

Within both trials, significantly more patients reached an Eczema Area and Severity Index (EASI)75 at both doses of the JAK inhibitor with over 60% on the higher and over 50% on the lower doses (P<0.0001 vs placebo for all comparisons). Also, itch reductions started already after 12 hours and were superior on ruxolitinib at week 8. Apart from nasopharyngitis (3% ruxolitinib vs 1% vehicle), adverse events were overall comparable between groups. Within the long-term extension, the rate of patients with IGA 0/1 was between 74.1% and 77.8% at week 524. Prof. de Bruin-Weller added that no new safety signals were reported, and the drug seems to be rather safe.

Focus on delgocitinib

Delgocitinib ointment (0.5% and 0.25%), another JAK inhibitor, was tested in 2 randomised phase 3 studies in Japanese adults and children over 4 weeks1,5,6. In both populations, delgocitinib was superior to vehicle and demonstrated a fast onset of action as of week 1 in modified EASI and itch, while being well-tolerated. In comparison, the effect in children was somewhat more marked than in adults, the latter achieving rates of 51.9% and 26.4% in modified EASI50 and 75.

Focus on roflumilast and difamilast

Roflumilast is a PDE4 inhibitor with ongoing phase 3 trials1. In a phase 2 study that tested roflumilast cream at dosages of 0.15% and 0.05% over 4 weeks, mean changes in EASI (-6.4 and -6.0) were only numerically superior to vehicle (-4.8; P=0.097 and P=0.356, respectively)7. Secondary endpoints, however, showed significance in comparisons of e.g. EASI75 and IGA 0/1. Safety evaluations found 2.2% of treatment-emergent adverse events in terms of mild rash and moderate application site pain, and only 1 discontinuation due to therapy.

Difamilast ointment, another PDE4 inhibitor, for patients with mild-to-moderate AD was also only studied in phase 3 studies (e.g. NCT03911401) in Japan1,8,9. “There was a significant effect from week 1 that proceeded to week 4 and 58% of participants reached EASI50, and 25% EASI90, so that’s a nice response,” Prof. de Bruin-Weller valued the results in adults1. In children, difamilast also demonstrated a good performance with significant superiority over vehicle in change of EASI and pruritus as of week 1.

Assessing tapinarof

In phase 2b (NCT02564055), the AHR modulator tapinarof cream was assessed at 4 different doses in AD patients from 12–65 years of age with an IGA ≥310. “We observed at week 12 a significantly better performance of all the tapinarof groups compared with the placebo groups, and 4 weeks after the application, the difference is still significant,” Prof. de Bruin-Weller revealed. In terms of body surface area and itch reduction, the highest dose led to the best results1. The investigator-assessed and the patient-reported tolerability scores showed similar results for all study arms.

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References
  1. de Bruin-Weller M. New and emerging topical therapies for AD. D2T02.2B, EADV Congress 2023, 11-14 October, Berlin, Germany.
  2. Kim BS, et al. J Allergy Clin Immunol. 2020;145: 572-82.
  3. Papp K, et al. J Am Acad Dermatol. 2021;85:863-72.
  4. Papp K, et al. J Am Acad Dermatol. 2023 ;88:1008-16.
  5. Nakagawa H, et al. J Am Acad Dermatol. 2020;82:823-31.
  6. Nakagawa H, et al. J Am Acad Dermatol. 2021; 85:854-862.
  7. Gooderham M, et al. J Drugs Dermatol. 2023; 22:139-47.
  8. Saeki H, et al. J Am Acad Dermatol. 2022;86:607-14.
  9. Saeki H, et al. Br J Dermatol. 2022;186:40-9.
  10. Paller AS, et al. J Am Acad Dermatol. 2021;84:632-38.