Atopic Dermatitis: Five Promising Targeted Therapies

Promising New Therapies for Atopic Dermatitis

Atopic dermatitis (AD) is a T-cell-driven, chronic inflammatory skin disease with a prevalence of up to 10% in adults and 25% in children.^[1,2] Classic AD presents during infancy with recurrent facial dermatitis, morphing during childhood into chronic inflammatory flexural patches and lichenified plaques. Characteristics include pruritus, associated atopic diathesis (asthma, allergic rhinitis/conjunctivitis, food allergies), impaired epidermal barrier function, and such comorbid conditions as sleep disruption and failure to thrive.

Our understanding of the pathophysiology of another chronic inflammatory skin disease—psoriasis—has undergone a revolution over the past decade, yielding novel and highly effective immune-targeted therapies for this notoriously tough-to-treat chronic skin disease. In a similar vein, researchers are now mapping the immune dysregulation behind AD, which is characterized by chronic activation of the Th2 immune response.^[3]

Systemic T-cell-suppressing therapies, such as azathioprine, methotrexate, mycophenolate mofetil, and cyclosporine, are effective at controlling moderate to severe AD (all as off-label indications). However, these treatments are limited by side effects, including immunosuppression, risk for cancer, and multiorgan toxicity, especially when taken chronically.

In contrast, dupilumab, a human monoclonal antibody targeting the interleukin-4 receptor alpha (IL-4R-alpha), received US Food and Drug Administration (FDA) approval for the treatment of moderate to severe AD in adults, in part on the basis of its remarkable safety profile and efficacy similar to that of some broader and more toxic immunosuppressive agents.^[4]

Far from being a unique "unicorn" drug, dupilumab is the first in a long-line of promising drugs in the developmental pipeline. The following is a brief review of four promising biologics for moderate to severe AD and a fifth category of "small molecules" capable of targeting and inhibiting the atopic Th2 immune response.

Dupilumab: A Human Monoclonal Antibody Against IL-2R-Alpha

Dupilumab inhibits signaling of the proinflammatory Th2 cytokines IL-4 and IL-13. It was the first FDA-approved (March 2017) biologic agent to treat adults with moderate to severe AD that was refractory to topical corticosteroid therapy. The indication for AD was based on randomized, placebo-controlled clinical trials (SOLO 1 and SOLO 2)^[4] involving adults in whom topical corticosteroid treatment had failed.

Adults with moderate to severe AD (SOLO 1, n = 671; SOLO 2, n = 708) were randomly assigned to receive dupilumab (300 mg subcutaneously) or placebo weekly or the same dose of dupilumab every other week alternating with placebo, for 16 weeks.

The primary outcome measure was an Investigator's Global Assessment (IGA) score of 0 or 1 (clear or almost clear) and a score reduction of two or more points from baseline to week 16. Key findings include the following:

• The primary outcome measure was achieved in 38% of patients in SOLO 1 and 36% in SOLO 2 who injected dupilumab every other week versus 10% in the placebo group. Weekly dupilumab dosing did not improve efficacy.

• Dupilumab also improved secondary outcome measures, including > 75% improvement on the Eczema Area and Severity Index (EASI 75), improved pruritus and quality-of-life scores, and reduced symptoms of anxiety and depression.

• Injection-site reactions and conjunctivitis were more frequent in the dupilumab versus placebo groups. Adverse events and laboratory values were otherwise similar in the treatment and placebo arms.

Lebrikizumab: Anti-IL-13 Monoclonal Antibody Targeting Soluble IL-13

IL-13 plays a central role in type 2 (Th2) inflammation, with levels of IL-13 mRNA correlating with AD severity. Lebrikizumab is still in clinical trials, including TREBLE,^[5] a randomized, placebo-controlled 12-week trial of topical corticosteroid plus lebrikizumab every 4 weeks versus placebo involving 209 adults aged 18-75 years with moderate to severe AD. Key findings included the following:

• At week 12, significantly more patients who received lebrikizumab 125 mg by subcutaneous injection every 4 weeks achieved EASI-50 (a 50% improvement) compared with the placebo group (82.4% vs 62.3%, respectively).

• Adverse event rates were similar between the lebrikizumab and placebo groups.

• The benefit of lebrikizumab was probably blunted by protocol-mandated use of topical corticosteroid in the placebo group.

Fezakinumab: An Anti-IL-22 Monoclonal Antibody

IL-22 promotes epidermal hyperplasia, inhibits keratinocyte differentiation, impairs skin barrier formation, and induces proinflammatory cytokines. Hence, IL-22 blockade may have a therapeutic benefit in at least some subsets of AD. Still in early clinical trials, Guttman-Yassky and colleagues^[6] recently concluded a randomized, double-blind, phase 2a trial of fezakinumab, administered intravenously every 2 weeks for 10 weeks, versus placebo. The primary outcome measure was the change in severity scoring of AD (SCORAD), an AD clinical severity index, from baseline to 12 weeks. Findings included the following:

• At 12 weeks, the mean reduction in SCORAD was 13.8 ± 2.7 in the fezakinumab group versus 8.0 ± 3.1 in the placebo group.

• SCORAD improvement was strongest in patients with severe AD treated with fezakinumab versus placebo, measured at 12 and 20 weeks.

• Rates of adverse events were similar in the fezakinumab and placebo groups.

• Because fezakinumab targets a novel inflammatory pathway (IL-22) independent of IL-4 and IL-13, it may help patients with moderate to severe AD that is refractory to dupilumab therapy.

Nemolizumab: An Anti-IL-31 Receptor A Monoclonal Antibody

IL-31 is a pruritogenic cytokine expressed in peripheral nerves and keratinocytes. A pilot placebo-controlled clinical trial^[7] of nemolizumab injected subcutaneously every 4 or 8 weeks for the treatment of moderate to severe AD (n = 264) had the following findings:

• Pruritus, EASI scores, and sleep disruption improved during a 12-week period.

• The greatest improvement was seen in patients who received 0.5 mg/kg nemolizumab every 4 weeks.

• The study included a 52-week double-blind extension, during which improvement in pruritus and EASI scores was maintained or increased.

• No new safety concerns were identified during long-term use.

Small Molecules

Biologics are not the only story when it comes to promising new therapies for AD. The topical phosphodiesterase-4 inhibitor crisaborole received FDA approval in 2016 for the treatment of mild to moderate AD in adults and children aged 2 years or older, with modest efficacy and an excellent safety profile.^[8]

Small molecules that are in clinical trials for AD include a Janus kinase 1/3 inhibitor (tofacitinib); an oral phosphodiesterase-4 inhibitor (apremilast); and drugs targeting the thymic stromal lymphopoietin (TSLP)-OX40 ligand pathway, which is thought to play a key role in Th2 immune activation.^[9]

Viewpoint

Over the past decade, patients with moderate to severe AD had to watch in frustration as one new biologic after another received FDA approval for the treatment of psoriasis. Last spring, AD sufferers finally got their own highly effective biologic with the FDA approval of dupilumab.

Fortunately, this is only the beginning. An improved understanding of the complex immunology of AD has inspired a "gold rush" of targeted therapies to suppress the cytokines and T-cell subsets at the root of AD. Studies are under way to investigate the safety and efficacy of these Th2-axis-inhibiting biologics and small molecules in atopic adults and children. Over the next decade, patients struggling with AD can finally expect some well-deserved and durable relief.