Regulatory Decision Summary for Litfulo

This New Drug Submission (NDS) for a New Active Substance (NAS) was filed to obtain market authorization for Litfulo (ritlecitinib tosylate capsules) for the treatment of adults and adolescents 12 years and older with all types of alopecia areata (including alopecia totalis and alopecia universalis) for hair regrowth, including scalp, eyebrow and eyelash in patients who are candidates for systemic therapy. Upon review, an indication for the treatment of adults and adolescents 12 years and older with severe alopecia areata was approved.

The proposed indication was supported by the results of a pivotal and dose ranging Phase 2b/3 randomized, double-blind, placebo-controlled, parallel-group, multicenter study (Study B7981015) in adults and adolescents ≥12 years of age with alopecia areata (AA). The study was conducted worldwide, including sites in Canada, in 718 adults and adolescents with AA with ≥50% scalp hair loss, including alopecia totalis (AT) and alopecia universalis (AU). Participants were randomized to one of the following treatment regimens for 4 weeks: 200 mg once daily (QD) for 4 weeks followed by 50 mg QD, 200 mg QD for 4 weeks followed by 30 mg QD, 50 mg QD, 30 mg QD, 10 mg QD, and placebo for 24 weeks followed by 50 mg QD. The recommended dose of Litfulo is 50 mg QD; therefore, the results for this dose are presented below.

The primary efficacy endpoint investigated was a greater proportion of subjects with a Severity of Alopecia Tool (SALT) score ≤20 (i.e., 20% or less scalp hair loss) compared to placebo at week 24. The primary efficacy endpoint was achieved: at Week 24, the proportion of responders who reached SALT≤20 was significantly higher in ritlecitinib 50 mg compared to placebo with at an overall significance level (of 0.00125 (i.e., 23.39% and 1.54% for ritlecitinib 50 mg QD and placebo, respectively). The efficacy of Litfulo was further supported by the study’s key secondary endpoint, which was the proportion of responders who reached SALT≤10 score at Week 24. The treatment effect was observed as early as Week 18. Other important secondary endpoints were supportive of the key efficacy results.

The safety review was based on data from three randomized studies and one long-term study in patients with AA. There is limited long-term data to support the chronic use of ritlecitinib. In total, there were 1,011 patients with at least 1 year of exposure to ritlecitinib. In the placebo-controlled period of clinical trials in alopecia areata, a total of 668 patients were exposed to ritlecitinib, with 130 receiving 50 mg once daily for up to 24 weeks. In this population , the most frequent adverse events (AEs) (≥2% in any treatment group) that occurred more commonly in the Litfulo group than placebo were headache (Litfulo 50 mg QD: 9.2% vs. placebo 8.0%), diarrhea (9.2% vs. 3.8%), acne (6.2% vs. 4.7%), urticaria (4.6% vs. 1.4%), rash (3.8% vs. 0.9%), abdominal pain upper (3.1% vs. 0.9%), pyrexia (3.1% vs. 0), folliculitis (3.1% vs. 1.9%), dermatitis atopic (2.3% vs. 0.5%), and dizziness (2.3% vs. 1.4%). 1.5% of participants permanently discontinued from study or study drug due to AEs; the AE leading to permanent discontinuation from study or study drug that occurred in more than 1 participant was urticaria (occurring in 2 participants).

Ritlecitinib is a covalent, irreversible inhibitor of the Janus Kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family. Adverse events of special interest associated with JAK inhibitors were identified in the clinical program, including serious infection, herpes zoster, herpes simplex, major cardiovascular and thrombolytic events, malignancies, rhabdomyolysis, and elevated creatinine phosphokinase (CPK). Additionally, neurological and audiological events were observed at higher rates in participants administered Litfulo compared to placebo. The Product Monograph (PM) is sufficiently labelled to mitigate these risks.

The safety profile in adolescent patients was generally similar to that of adults. However, the proportion of geriatric participants experiencing severe AEs, serious AEs, and AEs leading to permanent discontinuations was higher than in adults. Therefore, caution is recommended when treating subjects ≥65 years of age. A contraindication for patients with severe hepatic impairment was added to the PM due to increased liver enzymes observed across the clinical program and because no study was conducted in this population. A contraindication for use in pregnant and lactating women was added to the PM. Adverse effects on embryo-fetal development and pre- and post-natal development were observed in rats and rabbits at 12-fold the recommended human dose. Since ritlecitinib is known to be excreted in the milk of lactating rats, there is a possibility of peri-natal toxicity in nursing women.

In addition to the PM, risk mitigation measures are outlined in the Risk Management Plan (RMP) for Litfulo that will include educational materials for patients and physicians (patient card and health care professional guide) to enhance awareness and knowledge of the risk of serious and opportunistic infections including herpes zoster, thromboembolic events including major adverse cardiovascular events, malignancy, neurological events, effect on pregnancy and the foetus and use during breastfeeding.

Overall, the anticipated benefits of Litfulo are expected to outweigh its risks under the conditions of use recommended in the Litfulo PM at this time and with post-market requirements outlined in the RMP.