Novel immunomodulators expected to usher in new therapeutic era

Emerging treatments are expected to help fill the need for safer and more effective therapies for atopic dermatitis (AD), said Emma Guttman-Yassky, M.D., Ph.D. Speaking at the 2nd Inflammatory Skin Disease Summit (November 2016, New York), she discussed investigational topical and systemic medications for AD that are targeting the immune-mediated pathogenic pathways via novel mechanisms of action.

“Just 10 years ago, research aimed at developing new therapies for AD focused only on correcting the skin barrier abnormalities that are present with the disease. Based on increasing knowledge that AD is an immune-driven disorder and understanding of the inflammatory axes involved in the disease, new disease-specific immunomodulatory therapies have been developed that are showing promise for reversing both the skin barrier and immune abnormalities and with a favorable safety profile that may allow for long-term use,” says Dr. Guttman-Yassky, professor of dermatology and clinical immunology, Icahn School of Medicine at Mount Sinai, New York.
“At the same time, we are seeing translation of advances in understanding of other inflammatory skin diseases into therapeutic developments. Ultimately, bringing better care for patients with these disorders will require bridging academic research with pharma, and the Inflammatory Skin Disease Summit was successful in contributing to that goal.”

Systemic treatment advances

Recognition that AD is a systemic disease and that up to one-third of affected individuals with AD suffers with moderate-to-severe disease underscores the need for systemic treatments.

“Treatment targeting just the lesional skin with topical therapies can be ineffective for maintaining disease control in severe patients because AD is a systemic disease with abnormalities also present in the non-lesional skin that can perpetuate the condition. Treatment with systemic medications is therefore needed to truly reverse the abnormalities in both lesional and nonlesional skin,” Dr. Guttman-Yassky explains.

Of the systemic treatments in development for AD, dupilumab (Dupixent, Regeneron/Sanofi) is the closest to becoming commercially available. Dupilumab is a monoclonal antibody that targets the T_H2-centered inflammatory axis in patients with AD, binding to the shared alpha chain subunit of interleukin-4 (IL-4) and IL-13 receptors to inhibit IL-4 and IL-13 signaling. Analyses of skin biopsy specimens from patients with AD treated with dupilumab show that it suppresses inflammation and also reverses the epidermal hyperplasia and differentiation abnormalities that are present with AD.
“The coupling of the clinical and histological improvement with dupilumab is very important because it provides proof that the immune abnormalities perpetuate AD. In addition, it provides hope that dupilumab may be a safer alternative for systemic treatment because it does not suppress the entire immune system,” Dr. Guttman-Yassky says.

Other systemic treatments in development for AD include agents that target janus kinase (JAK), phosphodiesterase 4 (PDE 4), IL-22, IL-23, and IL-17.

“The fact that several pathways are implicated in the pathogenesis of AD raises the possibility that we may use different targeted therapeutic approaches for disease control,” she says.

“That is an exciting prospect, but we still need to learn which axis or axes will be the best target to successfully control AD and maintain disease remission long-term and whether there are opportunities for a personalized medicine approach to treatment of AD. While it is still very early and there are many questions to be answered, we are very hopeful that we will be able to provide better care for our patients with AD.”

Topical treatments

There is also a huge unmet need for new topical agents considering that local therapy has a role in all patients with AD and the limitations of existing options.
“There is a lot of public phobia about topical corticosteroids and the topical calcineurin inhibitors carry a black box warning,” Dr. Guttman-Yassky says.

Within the topical treatment pipeline, the PDE-4 inhibitor crisaborole 2% ointment (Anacor Pharmaceuticals) showed promising results in trials for AD and is expected to be the first approved based on the positive results from the Phase 3 trials that enrolled patients with mild-to-moderate AD, including children ages two and older. The company’s New Drug Application is under FDA review.

In a Phase 2a vehicle-controlled trial, the topical JAK inhibitor tofacitinib (Pfizer) showed great results when used to treat adults with mild-to-moderate AD.

“In fact, the benefit of topical tofacitinib was much better for AD than for psoriasis,” Dr. Guttman-Yassky says.

“Most ongoing studies with JAK inhibitors involve systemic agents, but hopefully other topical JAK inhibitors will follow the promising study with topical tofacitinib because there is a great need for new topical treatments.”

Disclosure: Dr. Guttman-Yassky is a consultant to most companies that develop medications for AD, including the agents mentioned in this article, but she receives no financial gain from any product.