Therapeutics: difamilast for atopic dermatitis

Patients with the chronic inflammatory skin condition atopic dermatitis develop red, swollen patches that are prone to cracking and cause intense itching

It usually starts in the early months of infancy; most of those who are prone to outbreaks will have experienced symptoms before the age of five and only a small minority will have their first symptoms in adulthood.

Although the majority of cases resolve during childhood, it remains a lifelong problem in 10–30% of sufferers.

Topical steroids such as betamethasone are commonly used to alleviate the symptoms, but this can lead to side-effects, notably a thinning of the skin.

A new potential treatment, difamilast, is being developed by Otsuka and licenced to Medimetriks in the US. Difamilast is a non-steroidal topical anti-inflammatory PDE-4 inhibitor.

There is elevated PDE-4 activity in the peripheral leukocytes in patients with atopic dermatitis, which is associated with the production of proinflammatory mediators. The molecule is selective for PDE-4 subtype B, which is thought to be particularly involved in the inflammatory process.

In a double-blind, vehicle-controlled Phase II study, 121 patients aged 10–70 with mild-to-moderate atopic dermatitis were randomised to receive topical treatment with a 0.3% or 1% formulation of the drug or vehicle alone, twice a day for 8 weeks.1

The primary endpoint, an investigator global assessment of disease severity (IGADS) score of 0 or 1, with at least a two-grade reduction, was met at week 4 in the higher dose group, and the improvement was already noticeable in this group after the first week.

The improvement persisted throughout the 8 weeks. Within the first week, the visual analogue scale pruritus scores for this group improved from moderate to mild. There were few adverse events and the majority of these were mild in intensity.

A paediatric Phase II study has also been done.2 A group of 73 children with atopic dermatitis aged 2–14 were treated with an ointment containing 0.3% or 1% of the drug, or vehicle alone, twice a day for 4 weeks.

There were no serious treatment-emergent adverse events. There was an improvement in the IGADS score for both doses of the drug; the treated groups also had improvements in several other scales, including the eczema area and severity index.

Otsuka has recently announced positive results in two multicentre, randomised, double- blind, vehicle-controlled, parallel group Phase III studies, one in adult patients and the second in children. Both studies lasted 4 weeks with twice-daily application; the adults were given 1% difamilast ointment or a vehicle, whereas the children were given a 0.3% or 1% ointment or a vehicle.

In both studies, statistically significant improvements were seen with the active treatment.

References

  1. J.M. Hanifin, et al., J. Am. Acad. Dermatol. 75, 297 (2016).
  2. H. Saeki, et al., J. Dermatol. 47, 17 (2020).