Introduction

Alopecia areata (AA) is an autoimmune disorder that causes inflammation of the hair follicle, leading to subsequent nonscarring hair loss. Although AA can develop at any age, the average age of onset is between 25 and 36 years.1 The condition can manifest in several distinct patterns, including patchy alopecia areata with round, well-defined areas of hair loss on the scalp, ophiasis with bands of alopecia along the occipital and temporal regions, alopecia totalis involving complete loss of scalp hair, and alopecia universalis characterized by hair loss across the entire body. Most cases initially present as the patchy subtype, but approximately 25% patients progress to more extensive forms such as alopecia totalis or universalis.2 When more than 50% of the scalp is involved, spontaneous remission rates fall below 10%.2

Ritlecitinib is an oral kinase inhibitor approved for the treatment of severe AA in adults and adolescents aged 12 and older.3 The pathogenesis of AA is thought to involve the activation of T-cell receptors by autoantigens within the hair follicle, activating the Janus kinase (JAK) and TEC kinase pathways to produce and release inflammatory cytokines.4 Ritlecitinib selectively inhibits JAK3 and the TEC kinase family at the adenosine triphosphate (ATP) binding site, reducing cytokine signaling and lymphocyte-mediated inflammation. This article reviews the key findings from the ALLEGRO clinical trial and explores practical considerations for the clinical use of ritlecitinib.

ALLEGRO Trial

Methods

ALLEGRO was a phase 2b/3 randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of ritlecitinib in patients with severe AA.5 Eligible participants were 12 years or older with severe AA, defined as >50% of scalp involvement. Participants were randomized to receive ritlecitinib 50 mg daily (n=130), placebo (n=131), or one of four other ritlecitinib dosing arms (n=457).

Scalp hair loss was assessed using the Severity of Alopecia Tool (SALT), a validated scoring system in which 0 indicates no hair loss and 100 indicates complete scalp hair loss. The primary endpoint was the proportion of participants who achieved a SALT score of l <20 at week 24. Secondary endpoints included SALT <20 at week 48, as well as eyebrow and eyelash improvement at weeks 24 and 48. The eyebrow (EBA) and eyelash assessment (ELA) instruments were used to measure secondary endpoints. Scores ranged from 0, with total hair loss, to 3, with normal hair density.

The average age of participants was 33.7 years, with 85% of individuals over the age of 18. The cohort was 62% female and 68% white. The mean baseline SALT score was 90.4, and 46% of participants had alopecia totalis. At baseline, 83% and 75% had eyebrow and eyelash involvement, respectively.

Results

No significant difference in SALT score was observed between the ritlecitinib and placebo groups at week 12. However, by week 24, 23% of adult patients receiving ritclecitinib 50 mg daily achieved a SALT score <20 compared to only 1.6% in the control group (P<0.001). Efficacy of ritclecitinib in adolescents was consistent with that seen in adults. Placebo was discontinued after 24 weeks. At week 48, 43% of patients in the ritlecitinib group achieved a SALT score <20.

In patients with eyebrow involvement, 29% of those receiving ritlecitinib experienced a ≥2-grade improvement in EBA from baseline or reached a normal score by week 24 compared to 4.7% in the placebo group. Similarly, in patients with eyelash involvement, 28.9% of ritlecitinib patients had a ≥2-grade improvement in ELA or achieved a normal score by 24 weeks compared to 5.2% in the placebo arm.

At the 2-year analysis, 60% of patients on ritlecitinib achieved a SALT score <20. In patients with SALT 50 to <100 at baseline, 61.6% reached SALT <20 after 2 years. Similarly, 59.6% of patients with a baseline SALT 100 score achieved SALT <20 during this timeframe.

Safety analyses included data up to week 24 in the trial. The most common adverse effects in the ritlecitinib group were headache (10.8% vs 8.5%) and diarrhea (10% vs 3.8%). Serious adverse events were infrequent but included serious infections, malignancies, and major cardiovascular events.

Discussion

Clinical Considerations

The ALLEGRO trial supports the efficacy and safety of once daily ritlecitinib 50 in patients aged 12 and older with severe AA.5 Ritlecitinib does not require a dose titration at initiation.3 Combination therapy with other JAK inhibitors, biologics, cyclosporine, or immunosuppressants is not recommended. Patients with active or serious infections (e.g. tuberculosis, hepatitis B or C), history of opportunistic infections, or increased risk of thrombosis are poor candidates for ritlecitinib therapy. Ritlecitinib is also not recommended in individuals with severe hepatic impairment, active malignancy, significant cardiovascular risk factors, or those who smoke.6

The safety of ritlecitinib has not been established in pregnancy or lactation. It is contraindicated during pregnancy, and patients should avoid breastfeeding while on the medication and for at least 14 hours after the last dose.7

Prior to initiating ritlecitinib therapy, patients should be up to date on immunizations and undergo baseline laboratory evaluation, including Quantiferon Gold, hepatitis panel, complete blood count (CBC), and liver function tests.6 Ritlecitinib should not be started in patients with an absolute lymphocyte count (ALC) <500 or a platelet count <100,000. CBC and liver enzymes should be monitored intermittently during treatment. Therapy should be interrupted in cases of serious or opportunistic infections, lymphopenia with ALC <500, signs of thrombosis, elevated liver enzymes, or suspected drug-induced liver injury. Ritlecitinib should be discontinued if platelets fall below 50,000 or if patients experience severe hypersensitivity, myocardial infarction, or stroke.6

Ritlecitinib is CYP3A and CYP1A2 inhibitor and may interact with other drugs that affect these enzymes. Concomitant use of a strong CYP3A inducer such as rifampin may reduce ritlecitinib’s efficacy.8

Conclusion

Ritlecitinib is a selective oral kinase inhibitor approved for the treatment of severe AA in patients aged 12 years and older. In the ALLEGRO trial, 23% of patients reached SALT <20 at 24 weeks and 43% at 48 weeks with once-daily dosing of ritlecitinib 50 mg. Before starting ritlecitinib, patients should undergo appropriate baseline laboratory testing, and clinicians should routinely monitor for hematologic and hepatic adverse effects throughout therapy.