JAK1/2: A promising novel treatment target in alopecia areata

In 2 randomised-controlled, phase 3 trials, therapy with the Janus kinase (JAK)1/2 inhibitor baricitinib led to remarkable hair regrowth in a third of patients at week 36. The agent was well tolerated with mostly mild-to-moderate treatment-emergent adverse events.

Alopecia areata (AA) frequently causes significant emotional and psychosocial distress. At present, there is no FDA-approved treatment for AA. In AA, loss of hair follicle immune privilege leads to infiltration by CD8-positive natural killer cells that secrete interferon-γ, which signals through JAK1/2 in the hair follicle epithelial cells [1]. This process is followed by hair follicle damage and hair loss.

Baricitinib is an oral, selective JAK1/2 inhibitor that has demonstrated superiority over placebo in hair regrowth in the phase 2 portion of the BRAVE-AA1 study (NCT03570749) [2]. Prof. Brett King (Yale University School of Medicine, CT, USA) presented the 36-week results of the phase 3 portion of BRAVE-AA1 and the phase 3 trial BRAVE-AA2 (NCT03899259), which were simultaneously published [3].

The participants (BRAVE-AA1, n=654 and BRAVE-AA2, n=546) were adults with severe or very severe AA (defined by Severity of Alopecia Tool [SALT] score 50–94 or 95–100, respectively). The SALT score is a weighted sum of the percentage of hair loss in the 4 quadrants of the scalp, ranging from 0 (i.e. no hair loss) to 100 (i.e. complete hair loss). “We chose an upper age of 60 in men to minimise effects of androgenetic alopecia,” Prof. King explained. The duration of AA was similar between treatment groups. The mean SALT score was 85 across the treatment groups, and 40% to 47% of the participants had alopecia universalis. In both trials, patients with AA were randomised to placebo or baricitinib 2 mg or 4 mg once daily. The primary endpoint was the proportion of patients that achieved a SALT score ≤20 at week 36.

In BRAVE-AA1, the primary endpoint was achieved by 35.2% of participants on 4 mg baricitinib and 21.7% on 2 mg baricitinib. The corresponding numbers in the BRAVE-AA2 trial were 32.5% and 17.3%, respectively (see Figure). Likewise, significant regrowth of brows and lashes were seen in the groups treated with low-dose baricitinib.

Figure: Proportion of patients achieving SALT score ≤20 through week 36 (primary study endpoint) [3]

†Statistically significant compared with placebo after multiplicity adjustment in graphical testing schemes;*P<0.05, **P<0.01, ***P<0.001 versus placebo without adjustment for multiple comparisons.

Baricitinib was well tolerated. No new safety findings were identified compared with the known safety profile. The number of treatment-emergent adverse events were mild to moderate in most cases and there was no death. Common adverse events in both trials included upper respiratory tract infections, nasopharyngitis, headaches, urinary tract infections, and elevated creatine phosphokinase. There was one major adverse cardiovascular event in the baricitinib 2 mg group in a patient with multiple cardiovascular risk factors. Of note, no venous thromboembolic events were reported in either study.

Prof. King concluded that longer periods of observation are required to evaluate the long-term clinical response and safety.

1. 
   
   1. Islam N, et al. Autoimmun Rev. 2015;14:81–89.
   2. King B, et al. J Am Acad Dermatol Venereol. 2021;85:847–53.
   3. King B. Efficacy and safety of baricitinib in adults with alopecia areata: Phase 3 results from two randomized controlled trials (BRAVE-AA1 and BRAVE-AA2). FC02.05, EADV Congress 2021, 29 Sept–2 Oct.

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Posted on 18 November, 202128 March, 2024