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PARIS -- Patients with moderate to severe alopecia areata had significant new hair growth with either of two drugs that work through the Janus kinase (JAK) pathway, a manufacturer-sponsored randomized trial showed.

After 6 months of treatment, the mean alopecia score improved by more than 50% among patients randomized to the JAK1/tyrosine kinase 2 (TYK2) inhibitor PF-06700841. The mean score on the Severity of Alopecia Tool (SALT) increased by almost 40% in the patients treated with the JAK3 inhibitor PF-06651600.

Patients randomized to placebo had no change in SALT score from baseline, and scores in the two active-treatment groups began to separate from the placebo group as early as 4 weeks after starting treatment, as reported here at the .

"My personal view is that these results represent a paradigm shift in the treatment of alopecia areata," said Rodney Sinclair, MD, of Sinclair Dermatology in Melbourne, Australia. "There is a line in the sand. On one side of the line there are clinical observations and case reports, and on the other side are investigational new drugs seemingly targeting the pathogenesis, tested in prospective, multicenter, double-blind placebo-controlled studies. Perhaps the first instance of evidence-based medicine has arrived in alopecia areata."

Globally, alopecia areata affects an estimated 147 million people. In one third to one half of cases, patients recover the hair loss within a year, although recurrences are common, Sinclair noted. The remaining patients have persistent hair loss, including total or universal hair lose in 15%-25% of cases. No reliable therapies have emerged for alopecia areata, particularly for patients with chronic, extensive disease.

Recently, the literature on new approaches to restore hair loss has increased, including several reports from studies evaluating JAK inhibitors, which have yielded encouraging results, Sinclair continued. The JAK3 inhibitor and the JAK1/TYK2 inhibitor represent the emerging field of precision medicine for alopecia areata.

Sinclair reported initial results from a phase IIa platform study of the two oral JAK-targeted agents. Eligible adult patients had chronic (>6 months' duration) moderate or severe alopecia areata affecting >50% of the scalp. Investigators in the multicenter trial randomized 142 patients to two groups and then further randomized each group 2:1 to the investigational therapy or placebo group.

Treatment began with 4 weeks of induction with 200 mg/day of the JAK3 inhibitor, 60 mg/day of the JAK1/TYK2 inhibitor, or matching placebo groups. Maintenance therapy with reduced doses of the two active drugs continued from week 5 to week 24.

The primary endpoint was the change in mean SALT score from baseline to 24 weeks relative to the combined placebo groups. Secondary endpoints included the proportion of patients achieving 30%, 50%, 75%, 90%, and 100% improvement in SALT score (SALT30 to SALT100); and the proportion of patients achieving at least a one-grade improvement (response) in eyelash and eyebrow status.

The study population had a mean age of 36, and 69% were women. The patients had a baseline mean SALT score of 88.1 and included 62 patients with alopecia totalis, 42 with alopecia universalis, 92 with no or minimal eyelashes, and 94 with no or minimal eyebrows.

Sinclair reported that 115 patients completed the trial: 45 of 48 treated with the JAK3 inhibitor, 36 of 47 treated with the JAK1/TYK2 inhibitor, and 34 of 47 in the placebo groups. Two patients discontinued because of adverse events in the JAK3 inhibitor group, five in the JAK1/TYK2 inhibitor group, and two in the placebo groups.

Analysis of data for the primary endpoint showed that the mean SALT score increased by 33.6 points relative to placebo in patients randomized to the JAK3 inhibitor and by 49.5 points in the group randomized to the JAK1/TYK2 inhibitor (P<0.001 versus placebo for both active-treatment groups).

Patients randomized to the dual inhibitor had more rapid improvement and separation from the placebo group (statistically significant at 4 weeks versus 6 weeks for the JAK3 inhibitor). The proportion of patients meeting SALT improvement 30, 50, 75, 90, and 100 (relative to placebo) were 59.6%, 48.9%, 38.3%, 31.9%, and 12.8% for patients treated with the JAK1/TYK2 inhibitor. Corresponding percentages for patients treated with the JAK3 inhibitor were 47.9%, 37.5%, 27.0%, 25.0%, and 12.5%.

Sinclair reported that 60.7% of the JAK1/TYK2 group qualified as eyelash responders, as did 45.2% of the JAK3 group. Eyebrow response rates were 51.7% in the patients assigned to the JAK1/TYK2 inhibitor and 36.2% treated with the JAK3 inhibitor.

Adverse events occurred in a similar proportion of each group. The most commonly reported adverse events were infections, gastrointestinal disorders, and skin and subcutaneous tissue disorders, all of which were mild in most instances.

The only serious adverse events were two cases of rhabdomyolysis in the JAK1/TYK2 group, leading to discontinuation in both cases. Sinclair said the cases are still being investigated.

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