Positive Results Revealed for Atopic Dermatitis Investigational Drug Etrasimod

Recently presented clinical trial data on investigational drug candidate etrasimod, a novel investigational therapy, shows promise for treating moderate to severe atopic dermatitis (AD). Executives and researchers say the compound could meet a significant unmet need for new therapies in this inflammatory disease category.

“If approved, etrasimod has the potential to bring a novel, once-daily oral therapy to patients who currently face limited treatment options for this chronic and debilitating disease,” said Paul D. Streck, MD, senior vice president of clinical development and chief medical officer of Arena Pharmaceuticals.

Etrasimod is a highly selective, once-daily, oral sphingosine 1-phosphate (S1P) receptor modulator. It is being studied for various immune-mediated inflammatory diseases in addition to AD, including alopecia areata, eosinophilic esophagitis, Crohn disease, and ulcerative colitis (UC). 

Arena presented clinician- and patient-reported outcomes data from its 12-week, phase 2b ADVISE trial on the AD indication during the American Academy of Dermatology Virual Meeting Experience. Among other things, the study found that the etrasimod 2-mg treatment group achieved numerical improvement in the weekly peak pruritis (PP-NRS), as well as statistically significant change in Dermatology Life Quality Index (DLQI) and Patient-Oriented Eczema Measure (POEM) at week 12; and that the 2-mg treatment was generally well tolerated, consistent with data in previous trials.

A leading AD expert and researcher on the compound presented the results.

“Etrasimod demonstrated clinically meaningful improvements in both clinical signs of [AD] and patient reported outcomes in the etrasimod 2-mg treatment group,” said Emma Guttman-Yassky, MD, PhD, the Waldman Professor and System Chair of Dermatology at the Icahn School of Medicine at Mount Sinai in New York City, NY. She presented the study results at the conference.

Patients in the treatment group saw improvements in their reported outcomes as early as 2 weeks after etrasimod treatment was initiated, she noted. “These results, combined with the fact that etrasimod was generally well-tolerated, are promising for this new mechanism of action for the treatment of AD.”

Etrasimod: An S1P Receptor Modulator
Etrasimod works by modulating receptor type 1, 4, and 5, allowing the agent to decrease trafficking lymphocytes in the plasma. It also works by decreasing trafficking of dendritic cells, which are an important consideration in downregulating inflammation.

Dr Guttman-Yassky explained that etrasimod’s novel mechanism of action does not work by suppressing what is in the skin but rather prevents lymphocytes from entering the skin.

The first S1P receptor modulator, fingolimod, was approved in 2010 to treat relapsing forms of multiple sclerosis (MS).  Etrasimod has demonstrated a better safety profile than the drugs for MS, Dr Guttman-Yassky said. She added that a true test of safety would take longer than the 12 weeks observed in the current trial. “The safety threshold for MS is not the threshold for safety for [AD],” she noted. “It’s a novel mechanism of action, and we still need to see how this works in the long run.”

Dermatologists Want Additional Options
Dermatologists, meanwhile, appear eager for an oral medication option to treat the many patients with AD who do not like taking biologic injections. Dr Guttman-Yassky sees etrasimod as an alternative to biologics, rather than a replacement. “I don’t like to compare apples and oranges,” she said. “I do think it would be welcomed in the dermatology community, as an addition to the toolbox, an oral medication for moderate to severe disease.”

The product also would be a welcome addition to the therapeutic class noted for its many expensive drugs. Existing AD therapy dupilumab, for example, lists for more than $3,200 per carton, and 2% crisaborole costs more than $1,070 for a 60-g tube.

Preparing for Phase 3 Program
Following release of the phase 2b data, there is now consideration of the next steps for etrasimod. Robert Lisicki, executive vice president and chief commercial officer of Arena Pharmaceuticals, said the company is working with the FDA and European Medicines Agency  to establish protocols for the next trial phase.

“Based on that, we then would move to the next stage of drug development,” he said. Mr Lisicki also underscored the significant opportunity for an oral therapy in this class. Currently, dupliumab is the only advanced agent available for treating AD, he said. “[Dupliumab] is an effective medication, however, there are patients and physicians that prefer to use oral medications prior to the introduction of an invasive injection therapy.”

“That supports our belief in the value and need for safe and effective oral-therapy,” he added.

Etrasimod also has potential advantages over current topical solutions. Current options have some limiting factors, such as significant stinging and discomfort when applying the product, and patients with 20% or more of their body covered with AD may find applying the topical to be onerous and sometimes not even possible, explained Mr Lisicki.

Mr Lisicki acknowledged that study did not meet its primary endpoint of percent change in Eczema Area and Severity Index (EASI) from baseline to week 12, followed by a 4-week follow-up observation period. But it did reach statistical significance on secondary endpoints and patient-reported outcomes for the 2-mg dose at week 12, including proportion of participants with a validated Investigator Global Assessment (vIGA) 0 to 1. The study also showed clear dose response for patients, no plateau effect, and resulted in no untoward side effects, Mr Lisicki said.

Addressing Patient and Physician Needs
Mr Lisicki goes back to the unmet need that this product would fill. “There is an opportunity to introduce oral therapy that demonstrates good effect without any onerous labels for monitoring,” he said. “The need within [AD] is so significant today and there are so few agents available for those patients.”

Physicians and patients select drugs based on three factors: Does it work? Is it safe? How likely am I to take it? Today, there is not necessarily a medication that broadly addresses those needs, Mr Lisicki said.

“There are drugs that work, but may be difficult to take, like [dupilumab],” he noted. “And there are drugs that are effective but may have some safety considerations that patients find unappealing, potentially like [Janus kinase] inhibition therapy. So, having an agent that addresses all three of those questions without a greater burden, again, potentially is a significant entrant into the AD market space.”

The company may get an early glimpse of the success of etrasimod in an ongoing trial for another condition. Etrasimod is in phase 3 trials for UC, and initial data is expected in the first quarter of 2022. “That’s an important measurement for the effect of the drug,” Mr Lisicki said. “There’s increasing evidence and data that there’s a bidirectional nature between UC and [AD].”

As many as 30% of patients who have AD may have manifestations of other autoimmune diseases, including UC. “That will be the first entrant that we have into the US and European markets. And it also should give us some signal on [AD],” he added.