Benefits of JAK Inhibitors Compared With Existing Therapies for AA Treatment

Patients with alopecia areata showed benefit when treated with deuruxolitinib | Image Credit/ KenamiRyoko - stock.adobe.com

In a systemic review published in Frontiers in Pharmacology, patients with moderate-to-severe alopecia areata (AA) experienced benefits when treated with 12 mg/8 mg deuruxolitinib, 50 mg/30 mg ritlecitinib, and 4 mg/2 mg baricitinib but continuous studies are important to gather new evidence for treatments that can guide clinical decision-making.¹

Patients with moderate-to-severe AA experience low efficacy in common treatment options like topical or systemic corticosteroids, minoxidil, methotrexate, and azathioprine. It is often found that treatments result in high recurrence rates of AA and an increase in adverse events.

Research began to focus on the pathogenesis of the disorder and found Janus kinase (JAK) inhibitors were beneficial for the treatment of AA. Immune dysregulation in various inflammatory disorders, like AA, depicted strong associations to dysregulated JAK activity. The JAK inhibitors are capable of disrupting production of inflamed cytokines by implementing therapeutic effects to treat AA.

In June 2022, the FDA approved baricitinib, the first systemic form of treatment for patients with severe AA. The approval came after trial results that found 40% of patients experienced complete or near complete hair regrowth and 50% had their hair regrow completely in 1 year.²

By June 2023, ritlecitinib was approved to treat both adults and adolescents with AA, marking the only form of treatment for adolescents with severe AA.³

New advancements in JAK inhibitors have continued with the developments of brepocitinib, deuruxolitinib, ivarmacitinib, and ATI-501.¹

A network meta-analysis was conducted to evaluate clinical recommendations for AA treatment. Assessment of outcomes included the change or percentage change in the Severity of Alopecia Tool (SALT) score from baseline to treatment conclusion, the number of patients that achieved a 50% improvement in SALT score (SALT₅₀), the number of patients that achieved a 75% improvement in SALT score (SALT₇₅), and the number of patients that achieved an absolute SALT score of less than or equal to 20. The primary outcome was measured by the incidence of adverse events.

There was a total of 13 randomized control trials that were reviewed and analyzed for the study, all of which were placebo-controlled. The trials included 2 topical JAK inhibitors, delgocitinib ointment and ruxolitinib cream. It also included 6 oral JAK inhibitors: ritlecitinib, brepocitinib, baricitinib, ivarmacitinib, ATI-501, and deuruxolitinib.

Of the total 13 included trials, the median age of participants ranged from 32.1-44.3 years old. The population of participants that were women ranged from 45.5% to 92.6%. At baseline, SALT scores were between 53.7-92.9 for an average of 12-36 weeks.

Only 9 of the 13 trials reported a change in SALT scores with 14 different types of treatment that included 30 mg brepocitinib, 4 mg/2 mg baricitinib, 50 mg/30 mg/10 mg ritlecitinib, 8 mg/4 mg/2 mg ivarmacitinib, 800 mg/600 mg/400 mg ATI-501, delgocitinib ointment, and ruxolitinib cream. All oral formulations showed a reduction in SALT score when compared with the placebo, except for 10 mg ritlecitinib and 2 mg ivarmacitinib.

The greatest changes in SALT scores were ranked as 30 mg brepocitinib, 4 mg baricitinib, 50 mg ritlecitinib, 30 mg ritlecitinib, 4 mg ivarmacitinib, and 8 mg ivarmacitinib. Groups that had higher doses resulted in better performance overall compared with the lower doses.

Percentage changes in SALT scores were observed among 10 trials that included 30 mg brepocitinib, 50 mg ritlecitinib, 8 mg/4 mg/2 mg ivarmacitinib, 12 mg/8 mg deuruxolitinib, 4 mg/2 mg baricitinib, 800 mg/600 mg/400 mg ATI-501, delgocitinib ointment, and ruxolitinib cream.

Participants that reached a SALT₅₀ score were among 9 of the reviewed trials. Patients that were most likely to achieve a SALT₅₀ score were those that received 30 mg brepocitinib, then 50 mg ritlecitinib, 12 mg deuruxolitinib, 600 mg ATI-501, 4 mg baricitinib, and 8 mg deuruxolitinib.

Similarly to SALT₅₀ scores, patients that achieved a SALT₇₅ score were amongst 9 controlled trials. The most effective drug in this area was 12 mg deuruxolitinib, then 8 mg deuruxolitinib, 30 mg brepocitinib, 50 mg ritlecitinib, and 4 mg baricitinib.

There was a total of 8 studies included in the review that resulted in patients with a SALT score of 20 or lower. Patients with severe AA did not find beneficial outcomes with 8 mg/4 mg/2 mg ivarmacitinib or 10 mg ritlecitinib. For more severe cases of AA, 12 mg deuruxolitinib, 50 mg ritlecitinib, 8 mg deuruxolitinib, and 30 mg ritlecitinib were suggested treatment options.

Almost all the trials reviewed (12) had participants who reported adverse events. Higher risks of adverse events were displayed in 4 mg baricitinib, 8 mg deuruxolitinib, and 12 mg deuruxolitinib. The treatment that had the most minimal adverse effects was ruxolitinib cream while 4 mg/8 mg/12 mg deuruxolitinib was ranked with the most adverse effects. Groups with lower doses had expressed higher safety rankings compared with respective higher-dose groups, except for deuruxolitinib.

Adverse effects included folliculitis, conjunctivitis, dry skin, and pruritus. Common effects associated with oral JAK inhibitors were acne, upper respiratory tract infections, headache, urinary tract infection, elevated creatine kinase levels, herpes zoster, and folliculitis. Most adverse effects were of mild to moderate severity.

The network meta-analysis was limited because it only focused on patients with moderate-to-severe AA. Data were restricted due to the study design where some drugs had fewer studies than others, small sample sizes, and insufficient reporting. There may be several inconsistencies within the analysis, potentially impacting the accuracy of the results. The 12-36 weeks timeframe also limited the study outcomes.

Clinical trial data does not suggest a specific form of treatment for patients with AA but instead offers research than can assist physicians and patients with decision making. Between efficacy and acceptability, everyone is different, so ongoing research is necessary to enhance the treatment options available for various patients.

References:

1. Yan T, Wang T, Tang M, Liu N. Comparative efficacy and safety of JAK inhibitors in the treatment of moderate-to-severe alopecia areata: a systematic review and network meta-analysis. Front Pharmacol. 2024;15(1372810)1-16. doi:10.3389/fphar.2024.1372810

2. What we’re reading: FDA approves alopecia drug; AMA opposes abortion restrictions; experimental ALS therapy. AJMC®. June 14, 2022. Accessed June 13, 2024. https://www.ajmc.com/view/what-we-re-reading-fda-approves-alopecia-drug-ama-opposes-abortion-restrictions-experimental-als-therapy

3. FDA approves Pfizer’s LITFULO (ritlecitinib) for adults and adolescents with severe alopecia areata. Pfizer. June 23, 2023. Accessed June 13, 2024. https://www.pfizer.com/news/press-release/press-release-detail/fda-approves-pfizers-litfulotm-ritlecitinib-adults-and