Aclaris announces ATI-2138 trial meets primary, secondary endpoints

Aclaris Therapeutics (ACRS) announced top-line results from its open-label, single-arm Phase 2a trial of ATI-2138 in 14 patients with moderate-to-severe atopic dermatitis. 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. 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 and percent of patients experiencing a greater than or equal to four point improvement in worst itch in the last 24 hours in patients receiving low doses 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. Twenty-six 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. ATI-2138 was very well tolerated in this Phase 2a trial. No severe adverse events or treatment-emergent adverse events 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; all but one were mild, transient, and resolved during treatment. No safety signal over the extent of the trial was observed in chemistry, creatine phosphokinase, hematology, lipids, electrocardiogram, ECG with corrected QT, or vital signs. 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 or very severe disease. At week 12, the mean improvement in EASI score in patients receiving 10mg BID of ATI-2138 was 60.5%. Patients in the trial experienced a rapid and sustained response, with measurable improvements observed starting at the first office visit. At week 4, the mean improvement in EASI score was 70.5%. At week 8, the mean improvement in EASI score was 70.7%. 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 was 77.1%. At week 4, the mean improvement in EASI score was 77.3%, and at week 8, the mean improvement in EASI score was 81%. All other assessed efficacy response curves showed similar mean and median improvements from baseline, starting at the first office visit. The PP-NRS assesses the severity of itch at the worst moment during the previous 24 hours on a scale of 0 to 10. A 4-point improvement in PP-NRS score is considered a clinically meaningful reduction in itch intensity and severity. At week 12, 62.5% of patients experienced a 4-point improvement in PP-NRS. 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 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 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. 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.