Atopic dermatitis: more than skin deep

Dampening down systemic inflammation with targeted
therapies offers new treatment options for AD sufferers

With much of biopharmaceutical development aimed at newsworthy high profile indications (cancer, genetic disease and spinal injury, for example) it’s easy to overlook the advances being made in treating common conditions which, while not life threatening, result in chronic discomfort for millions. 

Eczema (atopic dermatitis- AD), will be a pretty familiar topic to many parents, with up to 20% of children experiencing itchy misery. AD is an immune disorder and associated with other childhood allergic conditions. Skin bacteria and defects in skin permeability also play a part. 

AD in children is generally mild and self-limiting but can persist or reappear in later life. Around 2-5% of adults suffer from AD, of which half consider their condition to be moderate to severe. 

Self-management with emollients and vigilant skin care help, but effective relief may require topical steroid or calcineurin inhibitors (a class of potent immunosuppressant drugs) treatment, although these are not always effective or well tolerated. Oral steroids or immunosuppressant drugs such as cyclosporine are reserved for those failing other treatments and are limited to short-term use. 

Realisation that AD is essentially a systemic (and not topical) inflammatory condition has led to a shift in therapeutic development towards treatments which target key cytokines and enzymes involved in the inflammatory process. 

Two cytokines in particular, IL-13 and IL-4,  are associated with AD (a third, IL-31, is thought to be responsible for the hallmark itchiness of AD) and blocking their corresponding receptors by antibody drugs can effectively damp down inflammation. The first of these, dupilumab (Dupixent®: Sanofi/Regeneron) received regulatory approval in Europe and the US in late 2017.  Several other anti-cytokine antibodies are in the pipeline, including nemolizumab (Chugai/Galderma: Phase II:); tralokinumab (Leo Pharma: Phase III), and lebrikizumab (Dermira: Phase II). 

As the first systemic biologic AD treatment out of the trap, Dupixent® could set a high hurdle for later entrants, with analysts predicting peak global sales of around $3 billion as an AD treatment alone (Dupixent is also under consideration as a treatment for severe asthma). However, at an annual treatment cost of around $37,000 in the US and with UK pricing of close to £1,265 per 2 syringe pack, payers will take some convincing. The UK’s National Institute for Clinical Excellence has already queried Dupixent’s cost effectiveness. 

Small molecule non-steroidal topical and oral treatments will likely further broaden treatment options in AD. Crisaborole (Eucrisa®: Pfizer), a topically applied inhibitor of PDE4, an enzyme involved in cytokine release, was approved in the US in 2016 (and is currently under review in Europe) for the treatment of mild to moderate AD in adults and children. Questions remain over cost-effectiveness (a 60g tube costs around $580) but Eucrisa® does appear to provide some patients with a needed break from topical therapy and is a more acceptable option for facial treatment. Other topical PDE4 inhibitors are in the pipeline, including difamilast (Otsuka Pharmaceutical) and lotamilast (Dermavant). An oral PDE4 inhibitor, apremilast (Otezla®: Celgene, and already approved for the treatment of other immune disorders) has shown some efficacy in AD. 

The enzyme JAK1 (Janus kinase) is central to cytokine action and a number of JAK1 inhibitors are in clinical development as both topical and oral AD treatments, including baricitinib (Eli Lilly: Phase II, already approved as a rheumatoid arthritis treatment); PF-04965842 (Pfizer: Phase II); upadacitinib (AbbVie: Phase II), and the topically administered ruxolitinib (Incyte: Phase II, already approved for other conditions) and delgocitinib (Leo Pharma/Japan Tobacco). The oral anti-histamine ZPL-389 (Ziarco/Novartis), while ineffective in asthma studies, remains in clinical development as a potential AD treatment. 

Establishing the efficacy and safety of novel biologics and small molecules in AD still has some while to go, but it’s a safe bet that Dupixent® and Eucrisa® will eventually be joined by further treatment options for AD sufferers who do not enjoy adequate relief using current therapies. Effective oral therapies that eliminate or substantially reduce topical steroid use have the potential to transform the AD treatment market. 

Photo credit: Jean Beaufort 2017.