Dual ITK/JAK3 Inhibition Shows Strong Preclinical Activity in Severe Alopecia Areata

Alopecia areata (AA) remains a challenging immune-mediated hair disorder, particularly in its most severe forms such as alopecia universalis. While the advent of Janus kinase (JAK) inhibitors has transformed expectations for treatment, durability of response, speed of regrowth, and long-term safety remain active areas of investigation. Recent preclinical data from Aclaris Therapeutics describing the investigational compound ATI-2138 add another layer to this evolving landscape and may be of interest to clinicians familiar with AA pathophysiology and emerging targeted therapies.2

ATI-2138 is an oral small-molecule inhibitor with a dual mechanism of action: inhibition of interleukin-2–inducible T cell kinase (ITK) and JAK3. Both targets play central roles in T cell activation and signaling, processes known to be critical in AA. The new data come from a murine model of severe alopecia areata conducted at Columbia University, whose AA models have been widely used and are often cited as predictive of clinical responses to JAK inhibition in humans.

Study design and key findings

The investigators used a reversal model of alopecia universalis, the most extensive phenotype of AA, in which mice already had established, widespread hair loss before treatment initiation. This is a notable design choice, as it more closely reflects patients with longstanding disease and avoids the confounding effects of spontaneous remission seen in milder or earlier models.

Mice were randomized to receive control chow or chow containing ATI-2138 at 2 concentrations (100 or 300 ppm) or ritlecitinib at 300 ppm. Ritlecitinib, a JAK3/TEC family kinase inhibitor, serves as a relevant comparator given its clinical validation in AA. Hair regrowth was assessed over 6 weeks.

At the higher dose of ATI-2138 (300 ppm), hair regrowth was observed as early as week 2, with a mean regrowth of 37%. By week 4, regrowth reached a mean of 87%, approaching maximal effect, and by week 6, mean regrowth was reported at 93%. In contrast, ritlecitinib-treated mice showed more modest responses at comparable time points (25% at week 2, 48% at week 4, and 78% at week 6). Control animals demonstrated no meaningful regrowth throughout the study.

An additional aspect highlighted by the investigators was the age and disease severity of the mice. Older animals with established alopecia are generally more resistant to treatment, making the rapid and near-complete regrowth observed with ATI-2138 notable within this model.

Mechanistic considerations

From a mechanistic standpoint, ATI-2138 is differentiated from currently approved JAK inhibitors by its combined targeting of ITK and JAK3. ITK sits upstream in T cell receptor signaling, while JAK3 mediates signaling downstream of the common gamma chain cytokine receptor (IL-2Rγc), which includes cytokines such as IL-2, IL-4, and IL-15. These pathways are implicated not only in cytotoxic T cell activity against hair follicles but also in broader immune polarization and maintenance of inflammation.

Preclinical data suggest that ATI-2138 downregulates markers associated with Th1, Th2, and Th17 responses, as well as fibrosis-related pathways, and reduces itch in inflammatory models. For clinicians, this raises the possibility that dual ITK/JAK3 inhibition could provide a more comprehensive modulation of immune activity than JAK inhibition alone, although this remains to be demonstrated clinically in AA.

Importantly, ATI-2138 is reported to be more than 1,000-fold selective for JAK3 over other JAK isoforms, a feature that could theoretically translate into a differentiated safety profile. However, murine selectivity and early human data do not always predict long-term clinical safety, particularly in chronic diseases requiring prolonged treatment.

Clinical relevance and limitations

While murine AA models have shown good correlation with clinical outcomes for JAK inhibitors, clinicians should interpret these findings with appropriate caution. Dose comparisons based on chow concentrations do not directly translate to human dosing, and differences in pharmacokinetics, immune system complexity, and disease chronicity can substantially influence outcomes.

That said, ATI-2138 is not entirely preclinical. The compound has already been evaluated in healthy volunteers and in a phase 2a trial in atopic dermatitis, with reported favorable safety, pharmacokinetic, and pharmacodynamic profiles. These data provide some reassurance as the program advances.

Aclaris has indicated plans to initiate a phase 2b trial in the first half of 2026 and is exploring multiple inflammatory and autoimmune indications, including various forms of alopecia. For clinicians, the key questions moving forward will center on whether the rapid onset and magnitude of regrowth seen in mice translate to patients, how durable responses prove to be, and whether dual ITK/JAK3 inhibition offers meaningful advantages over existing therapies in terms of efficacy, safety, or patient-reported outcomes.

In summary, ATI-2138 represents a mechanistically interesting addition to the AA therapeutic pipeline. While these preclinical results are encouraging, especially in a severe disease model, clinical data will ultimately determine its place among an expanding set of immune-targeted treatments for alopecia areata.

References

1. Townsend J, Godic A. Treatment of alopecia areata with JAK inhibitors: a review of the literature. Acta Dermatovenerol Alp Pannonica Adriat. 2025;34(3):117-120.
2. Aclaris Therapeutics’ novel ITK/JAK3 inhibitor ATI-2138 demonstrates rapid and sustained hair regrowth in validated murine model of alopecia areata (AA). News release. Aclaris Therapeutics. Published January 27, 2026. Accessed January 27, 2026. https://www.globenewswire.com/news-release/2026/01/27/3226283/37216/en/Aclaris-Therapeutics-Novel-ITK-JAK3-Inhibitor-ATI-2138-Demonstrates-Rapid-and-Sustained-Hair-Regrowth-in-Validated-Murine-Model-of-Alopecia-Areata-AA.html