Investigational Alopecia Areata Drug Shows Sustained Effect

ORLANDO, FLA. — Janus kinase (JAK) inhibitors have revolutionized the treatment of alopecia areata (AA), and more drugs in this class are still in development for AA. However, a new therapy with a new mechanism of action also appeared to provide major hair regrowth with an effect that persists after treatment is stopped.

The experimental therapy, bempikibart, is a monoclonal antibody that targets the alpha receptor of interleukin-7 and the thymic stromal lymphopoietin (TSLP) pathway, potentially bringing a novel approach to the control of AA, according to Brett King, MD, PhD, associate professor of dermatology, Yale University School of Medicine, New Haven, Connecticut.

Based on animal studies, the effect of this bifunctional therapy is being attributed to the ability of this drug to restore T cell homeostasis, King said at the American Academy of Dermatology (AAD) 2025 Annual Meeting, where he presented the results at a late-breaker session. He believes that the sustained effect and “distinct benefit-risk profile” of bempikibart “could transform AA care” if sustained clinical remission is confirmed in larger trials.

The bempikibart SIGNAL-AA phase 2a study presented by King offered results at least as impressive as those of a separate phase 3 trial conducted with a selective JAK1 inhibitor called ivarmacitinib. Both SIGNAL-AA and the latest phase 3 JAK inhibitor trial were late-breaker presentations on March 8, 2025, at the annual meeting of the AAD.

The phase 2a results were sufficiently positive that they are now being labeled part A in a decision to expand the study before moving to the next phase. While an open-label extension is ongoing for part A, part B will add about 20 more patients to evaluate safety and response in a modified protocol.

In SIGNAL-AA, 33 patients, defined by the Severity of Alopecia Tool (SALT) as having severe alopecia (≥ 50), were randomly assigned to an every-2-week schedule of 200 mg bempikibart administered subcutaneously or a placebo. Entry criteria were typical of AA trials, but this study did permit entry to patients with prior exposure to a JAK inhibitor after washout. The mean baseline SALT score for study participants was 77.7.

Treatment was continued for 24 weeks, but efficacy and safety were monitored for an additional 12 weeks. Extended monitoring was included in the design because the sustained effect that was ultimately seen was anticipated. Prior clinical and experimental studies predicted that the mechanism of the drug, which, again, appears related to resetting T cell activity, might provide benefit after the drug is stopped.

For the primary endpoint of percentage change in SALT at 24 weeks in the per-protocol analysis, separate response data were provided for the 23 patients with severe baseline SALT scores (50-100), 15 patients with very severe baseline SALT scores (50-95), and four patients were randomly assigned to placebo. Relative to the <5% change for placebo, those with very severe AA achieved a mean SALT reduction at 24 weeks of approximately 17%, and those with severe AA reached a reduction of approximately 25%. Both reductions on active treatment were significant relative to placebo (<0.05%).

Over the 12 weeks of monitoring after the end of the 24-week treatment period, “there was some leveling off [in response], but we are still seeing the trend to lower SALT scores after dosing is stopped,” King reported.

Like responses to JAK inhibitors, greater baseline severity and longer duration of AA prior to treatment were predictors of lower rates of benefit, but all patients had sustained benefit after treatment discontinuation. In the small number of patients now followed beyond 36 weeks, persistent hair coverage has been observed.

“After week 36, six patients show continued regrowth,” King said. In one patient with very severe AA (SALT> 95), a SALT of <10 was observed after 52 weeks.

The safety profile was also encouraging. Almost all treatment-emergent adverse events were mild to moderate. No grade 3 or higher adverse event was considered to be drug-related.

In the ongoing part B of SIGNAL-AA, patients will receive a 200 mg dose of bempikibart weekly for 4 weeks in a loading protocol and then a maintenance dose every 2 weeks for an additional 36 weeks. An additional 16 weeks of follow-up of the drug is planned.

Emphasizing that “it is unusual” to see continued hair regrowth after stopping an AA therapy, King is intrigued with the theory that bempikibart might rebalance T cells with the potential that this drug recalibrates the immune response. Such an effect, if validated, might have relevance to other autoimmune disorders.

With three JAK inhibitors now approved for AA in the United States (baricitinib, ritlecitinib, and deuruxolitinib), the efficacy of these drugs for AA is well established, but another phase 3 trial, this one with ivarmacitinib, has reinforced the message. In the randomized trial of 330 patients, conducted in China, the rates of end-of-study SALT scores ≤ 20 were 34.9%, 40.6%, and 9.0% for the daily doses of 4 mg, 8 mg, and placebo, respectively.

“There were no deaths, thromboembolic events, or major cardiovascular events,” reported the principal investigator, Jianzhong Zhang, MD, professor and chairman of dermatology, Peking University’s Peoples Hospital, Beijing, China, who presented the results at the late-breaker session at AAD.

It is not clear whether this drug might have a more favorable side effect profile than the available JAK inhibitors, but Zhang maintained that this drug is at least as effective and well tolerated as approved agents in this class. He expects the “significant efficacy and tolerability” observed in this phase 3 trial to result in regulatory approval in China.

Because of the differences in selectivity for the different JAK subtypes among JAK inhibitors, Zhang suggested that head-to-head trials would be appropriate to evaluate whether these drugs are interchangeable or vary for either safety or efficacy.

King reported financial relationships with more than 25 pharmaceutical companies, including Q32 Bio Inc., which is developing bempikibart and provided the funding for the SIGNAL-AA trial. Zhang reported financial relationships with Jiangsu Hengrui Medicine, which is developing ivarmacitinib.