Signs of Relief From 'Therapeutic Drought' in Atopic Dermatitis

NEW YORK CITY -- A longstanding "therapeutic drought" in atopic dermatitis (AD) could end soon as improved understanding of the pathogenesis and pathophysiology has fueled development of multiple drug candidates, an authority in the field said here.

"We did have treatments like cyclosporine, that are not specific as we know, and they are not treatments we can give our patients for long-term disease control," said Emma Guttman-Yassky, MD, of the Icahn School of Medicine at Mount Sinai in New York City, during the Inflammatory Skin Diseases Summit here.

"[Overcoming the drought] wasn't that easy, largely because we didn't have enough understanding of the disease and its pathogenesis, really preventing therapeutic development for patients with atopic dermatitis," she said.

The path to new therapies for AD followed the trail blazed during therapeutic development in psoriasis, beginning with basic studies that produced insights into pathogenesis, leading to hypotheses that eventually could be tested in clinical trials, she said. Each step forward often followed multiple failures, as occurred during early stages of therapeutic development in psoriasis.

"One failure that I remember very vividly from psoriasis was the failure of interferon-gamma targeting," Guttman-Yassky continued. "In atopic dermatitis, we also had our share of this type of failure, but these failures really helped shape therapeutic directions for all the diseases we are now targeting, including atopic dermatitis."

The combination of failures and successes has led to recognition that AD is a complex disease involving multiple pathogenetic components, including barrier dysfunction, immune abnormalities, disruption of the dermal microbiome, and the peripheral and central nervous systems that play a central role in itch and other disease manifestations.

"Of all the major components involved in AD pathogenesis, immune targeting is the most tractable," said Guttman-Yassky. "Immune abnormalities are the most important because they perpetuate the disease phenotype of atopic dermatitis, from the nonlesional skin to acute disease and chronic lesions."

In contrast to psoriasis, AD is a more heterogeneous disease with multiple clinical phenotypes that correlate with differences in immune polarization and barrier dysfunction. All of the phenotypes exhibit activation of the type 2 inflammatory pathway as a common feature. Across the spectrum of clinical phenotypes, additional cytokine targeting may be required to achieve disease control.

Another relatively recent discovery that has helped further therapeutic development is the recognition that AD arises from systemic inflammation. Several studies have suggested that AD is associated with higher levels of immune activation as compared with psoriasis. Blood samples of patients with AD have showed increased levels of activated T cells, circulatory cytokines, and cardiovascular markers.

The accumulation of new insights into AD pathogenesis added no fewer than a dozen viable therapeutic candidates to the pipeline. Dupilumab (Dupixent) led the way in providing the proof of principle that Th2-specific targeting reverses key pathogenetic factors that drive the disease process in AD.

Guttman-Yassky showed a series of slides illustrating how targeting Th2 inflammation with dupilumab led to reversal of barrier defects and lichenization typical of AD as early as 4 weeks, and that by 16 weeks lesional and nonlesional skin appeared similar. Additionally, markers of epidermal hyperplasia and proliferation were "completely wiped out."

Guttman-Yassky highlighted several key classes of AD drug candidates with potential to build on the success of targeting inflammation.

Interleukin-13 Inhibition

Whether IL-13 inhibition alone provides sufficient control of inflammation remains unclear, as the pathway has two key cytokines, IL-13 and IL-4. Tralokinumab and lebrikizumab both target IL-13. In a phase II trial, lebrikizumab demonstrated dose-dependent efficacy after 16 weeks, including Eczema Area and Severity Index (EASI) 75 and 90 scores as high as 66.9% and 44.0%, respectively. In a long-term evaluation of tralokinumab, most patients achieved EASI75 by week 16 and maintained the improvement at 56 weeks. Both drugs had favorable safety profiles.

OX40 Inhibition

OX40 regulates differentiation of inflammatory Th2 cells, and in laboratory studies, OX40 inhibition blocked Th2-mediated immune responses. The fully human antiOX40 antibody KHK4083/AMG 451 inhibits and depletes activated T cells and inhibits memory T-cell formation.

In a placebo-controlled clinical study, different doses of KHK4083 led to EASI75 responses in more than half of patients by week 16, increasing to about 65% during follow-up to 36 weeks. More than 90% of patients maintained responses to week 56 after discontinuing treatment. Levels of the biomarker thymus- and activation-regulated chemokine were maximally reduced by week 16 and maintained at that level at week 36 and during off-treatment follow-up to week 56. Similar persistence in post-treatment reduction of other pro-inflammatory biomarkers was observed, suggesting the drug may have disease-modifying activity, said Guttman-Yassky.

JAK/STAT Inhibition

A phase III trial of abrocitinib showed rapid improvement in AD, as almost two thirds of patients attained an EASI75 response at 12 weeks, and a majority of EASI75 responses occurred by week 4, said Guttman-Yassky. A phase III trial of different doses of baricitinib (Olumiant) led to EASI75 response rates as high as 36% at 16 weeks. Though somewhat more modest than response rates with some other agents, most EASI75 responses with the drugs were maintained during long-term follow-up, said Guttman-Yassky.

On the other hand, upadacitinib (Rinvoq) had robust activity that led to EASI90 rates as high as 66% at 16 weeks in a trial involving adolescents and adults with moderate-severe AD. About 60% of patients had EASI90 responses by week 8. Additionally 60-70% of patients treated with the JAK inhibitor had at least a four-point reduction in pruritus score from week 4 through week 16. Overall, the treatment was associated with a favorable safety profile that included signals related to acne, nasopharyngitis, and some cases of zoster.

"With these types of response rates, our treatment goals for our patients are evolving," said Guttman-Yassky.

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