Aclaris Therapeutics Reveals Top-Line Results from Open-Label Phase 2a Trial of ATI-2138; Primary Endpoint Analysis Confirms Favorable Tolerability Profile Of ATI-2138 Without Certain Risks Associated With Other Agents In The Class; Efficacy Results Show Comparable Outcomes To Approved Therapies With Potential For Improved Tolerability, Supporting Exploration Of Higher Doses In Future Clinical Trials

Author: Benzinga Newsdesk | July 29, 2025 03:04pm

WAYNE, Pa., July 29, 2025 (GLOBE NEWSWIRE) -- Aclaris Therapeutics, Inc. (NASDAQ:ACRS), a clinical-stage biopharmaceutical company focused on developing novel product candidates for immuno-inflammatory diseases, today announced positive top-line results from its open-label, single-arm Phase 2a trial of ATI-2138, a potent and selective investigational oral covalent inhibitor of interleukin-2-inducible T cell kinase (ITK) and Janus kinase 3 (JAK3), in 14 patients with moderate-to-severe atopic dermatitis (AD). Based on the growing body of supportive non-clinical and clinical evidence, Aclaris intends to further develop ATI-2138 in alopecia areata and is also exploring other indications relevant to the mechanism of action.

"These Phase 2a trial results represent a significant achievement for our ITK franchise by confirming the mechanism and corroborating our work on next-generation ITK selective compounds," said Dr. Neal Walker, Chief Executive Officer of Aclaris. "The objectives of this trial were to confirm the strong tolerability profile across multiple doses of ATI-2138 over 12 weeks, to test the mechanism in AD before initiating our work in other diseases including alopecia areata, and to further validate ITK as an important therapeutic target; we accomplished each of these. Consistent with prior results, ATI-2138 was shown to be well tolerated. The observed efficacy results across a variety of validated scoring tools – even at this low dose – suggest responses that are in line with, if not better than, that seen with approved therapies. And finally, the PD results confirmed the potential of targeting ITK, including strong downregulation of key ITK-dependent markers and an interesting antifibrotic effect."

The results observed in this trial include a favorable tolerability profile of ATI-2138, clinically meaningful improvements from baseline in assessments of disease severity including extent and severity of AD (Eczema Area and Severity Index (EASI)) and percent of patients experiencing a greater than or equal to four point improvement in worst itch in the last 24 hours (Peak Pruritus Numerical Rating Scale (PP-NRS)) in patients receiving low doses (10mg BID, 12 weeks) of ATI-2138, and PD results that validate ITK as a therapeutic target. Overall, these results provide evidence that the contribution of ITK has the potential to enable ATI-2138, even at low doses, to confer efficacy comparable to that observed in clinical trials of approved JAK and IL-4/13 inhibitors in moderate-to-severe AD, with improved tolerability and without the significant safety risks typically associated with JAK inhibition.

"Although this is a small study, the pharmacodynamic results are quite compelling; I'm excited about the anti-inflammatory activity we observed and the therapeutic potential for ATI-2138, and more broadly, ITK as a potential therapeutic target," said Emma Guttman, M.D., Ph.D., Waldman Professor of Dermatology and Immunology and Health System Chair of the Kimberly and Eric J. Waldman Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York City. "We observed strong downregulation of key inflammatory markers, including those associated with ITK including Th2 and Th1/Th17-related markers, as well as certain ITK pathway- and fibrosis-related markers. Overall, these are important results that define the potential of ATI-2138 and ITK inhibition to address Th2 and Th1/Th17 mediated diseases like alopecia areata, vitiligo, and atopic dermatitis."

Patient Demographics

Twenty-six (26) patients were screened for inclusion in this single-arm Phase 2a trial. Of the 14 that were enrolled, 12 completed treatment. Excluding two protocol violations, 10 patients were available for the per protocol analysis. The enrolled population was split evenly between male and female participants. Consistent with published demographics, half of the enrolled population self-identified as African American. Mean baseline EASI score was 22.7.

Primary Endpoint: Safety Results

ATI-2138 was very well tolerated in this Phase 2a trial. No severe adverse events (SAEs) or treatment-emergent adverse events (TEAEs) were observed. A majority of the adverse events were mild and resolved spontaneously during treatment; there were no discontinuations due to adverse events. Three patients experienced a combined total of four adverse events determined to be related to study drug (TRAE); all but one (moderate myalgia; starting on day 24 with no elevation in CPK) were mild, transient, and resolved during treatment. No safety signal over the extent of the trial was observed in chemistry, creatine phosphokinase (CPK), hematology (e.g., leukocytes, lymphocytes, neutrophils), lipids, electrocardiogram (ECG), ECG with corrected QT (ECG-QTcF), or vital signs.

Secondary Endpoints: Efficacy Results

Mean and median change from baseline in Eczema Area and Severity Score (EASI) over time:

The EASI score is a validated tool used to assess the severity of AD. It measures the extent and severity of lesional skin associated with AD across different body regions and assigns a composite score from 0 to 72, with higher scores indicating severe (21.1 to 50.0) or very severe (50.1 to 72.0) disease.

• At week 12 (end of treatment), the mean improvement in EASI score in patients receiving 10mg BID of ATI-2138 (n=10) was 60.5% (median improvement = 76.8%).
• Patients in the trial experienced a rapid and sustained response, with measurable improvements observed starting at the first (week 1) office visit. At week 4, the mean improvement in EASI score (n=10) was 70.5% (median improvement = 71.9%). At week 8, the mean improvement in EASI score (n=10) was 70.7% (median improvement = 76.3%).
• The week 12 results were skewed by a single patient who was identified by an independent lab as being a statistical molecular outlier by more than four standard deviations compared to others. This patient demonstrated systemic findings inconsistent with AD alone including significant non-lesional inflammation, based on various PD measures. In addition, this patient was not fully compliant with study drug administration. Excluding this patient, the mean improvement in EASI score at week 12 (end of treatment) was 77.1% (median improvement = 82.1%). At week 4, the mean improvement in EASI score was 77.3% (median improvement = 72.9%), and at week 8, the mean improvement in EASI score was 81.0% (median improvement = 77.1%).
  
   

All other assessed efficacy response curves showed similar mean and median improvements from baseline, starting at the first (week 1) office visit.

Percent of patients with a greater than or equal to four-point improvement in Peak Pruritus Numerical Rating Scale (PP-NRS):

The PP-NRS assesses the severity of itch at the worst moment during the previous 24 hours on a scale of 0 ("no itch") to 10 ("worst itch imaginable"). A ≥4-point improvement in PP-NRS score is considered a clinically meaningful reduction in itch intensity and severity.

• At week 12 (n=8), 62.5% of patients experienced a ≥4-point improvement in PP-NRS.
  
   

Secondary Endpoint: Pharmacodynamic Results

The clinical activity was supported by pharmacodynamic analyses clearly demonstrating modulation of both the ITK and JAK3 pathways as evidenced by inhibition of ex vivo pathway-specific stimulation of patient whole blood. Near complete and sustained ITK target occupancy was observed across the dosing interval ranging from ~90% at peak to 60-70% at trough. Proteome and transcriptome lesional skin tape strip analyses (minimally invasive methods to study changes in gene expression in affected skin) measured at trough levels to better represent steady state showed significant ATI-2138-dependent reduction of multiple inflammatory pathways associated with ITK. Strong downregulation of key ITK-dependent markers including Th2, Th17, and TCR (ITK) pathways along with the Th1 pathway were observed at week 8 and week 12. Fibrosis-related markers were also shown to be strongly downregulated by ATI-2138. These tape strip data were confirmed with skin biopsies from a subset of patients.

Next Steps for ITK Franchise

Positive results from this Phase 2a single-arm, open-label trial help validate Aclaris' ITK franchise. The Company intends to further develop ATI-2138 in alopecia areata and is also exploring other indications relevant to the mechanism of action. In addition, preclinical work is ongoing for next-generation ITK inhibitors, which Aclaris expects to provide the basis for new INDs starting in 2026.

Posted In: ACRS