Maintenance, withdrawal, and re-treatment with ritlecitinib and brepocitinib in patients with alopecia areata in a single-blind extension of a phase 2a randomized clinical trial

To the Editor: Key findings from a 24-week, double-blind period (DBP) of a phase 2a study (NCT02974868) indicated that the oral Janus kinase (JAK) inhibitors ritlecitinib (inhibits JAK3 and tyrosine kinase expressed in the hepatocellular carcinoma family) and brepocitinib (inhibits tyrosine kinase 2 and JAK1) were efficacious and well tolerated over 24 weeks in patients with alopecia areata and ≥50% scalp hair loss.1King B. Guttman-Yassky E. Peeva E. et al.A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results.J Am Acad Dermatol. 2021; 85: 379-387https://doi.org/10.1016/j.jaad.2021.03.050Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The effects of withdrawing a JAK inhibitor following the treatment of alopecia areata have not been evaluated in a placebo-controlled trial, but uncontrolled studies of the JAK inhibitors ruxolitinib and tofacitinib have reported hair loss 8 weeks after treatment cessation.2Crispin M.K. Ko J.M. Craiglow B.G. et al.Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.JCI Insight. 2016; 1: e89776https://doi.org/10.1172/jci.insight.89776Crossref PubMed Scopus (206) Google Scholar, 3Mackay-Wiggan J. Jabbari A. Nguyen N. et al.Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata.JCI Insight. 2016; 1: e89790https://doi.org/10.1172/jci.insight.89790Crossref PubMed Scopus (171) Google Scholar, 4Jabbari A. Sansaricq F. Cerise J. et al.An open-label pilot study to evaluate the efficacy of tofacitinib in moderate to severe patch-type alopecia areata, totalis, and universalis.J Invest Dermatol. 2018; 138: 1539-1545https://doi.org/10.1016/j.jid.2018.01.032Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 5Park H.S. Kim M.W. Lee J.S. et al.Oral tofacitinib monotherapy in Korean patients with refractory moderate-to-severe alopecia areata: a case series.J Am Acad Dermatol. 2017; 77: 978-980https://doi.org/10.1016/j.jaad.2017.06.027Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar In this phase 2a study, following the DBP and a 4-week washout period, patients continued to be part of a single-blind extension involving the same dosing regimen as that in the DBP: 200 mg of ritlecitinib once daily (for 4 weeks), followed by 50 mg once daily (for 20 weeks); 60 mg of brepocitinib once daily (for 4 weeks), followed by 30 mg once daily (for 20 weeks); or a placebo. The investigators were aware of the treatments. The patients in the single-blind extension were assigned to 1 of 3 groups and blinded to the treatment:1.“Placebo nonresponders” in the DBP: received their preassigned active treatment (ritlecitinib or brepocitinib).2.“Active nonresponders” (those who achieved <30% improvement in their severity of alopecia tool [SALT] score at week 24 compared with that at baseline in the DBP): received the same active treatment.3.“Active responders” (those who achieved ≥30% improvement in their SALT score [SALT30] at week 24 compared with that at baseline in the DBP): received the placebo until they met the re-treatment criterion (>30% loss of hair regrown during the DBP). Patients meeting the re-treatment criterion received 24 weeks of the same active treatment received during the DBP. The primary endpoint was safety. The tertiary endpoints included time to meet the re-treatment criterion and SALT30 (re-treated responders). The most common adverse events were infections and skin or nervous system disorders (Table I). All 26 treatment-related adverse events were mild or moderate. In total, 5 of 17 (29%) versus 8 of 12 DBP placebo nonresponders (67%) achieved SALT30 with ritlecitinib and brepocitinib, respectively, after 24 weeks. For DBP active nonresponders, 2 of 16 (13%) on ritlecitinib and 0 of 5 (0%) on brepocitinib achieved SALT30. For DBP active responders (n = 22 on ritlecitinib and n = 24 on brepocitinib), the median time from the end of DBP to re-treatment was 16.1 and 24.1 weeks, respectively. One patient did not go through withdrawal and directly received re-treatment; 4 of 22 (18%) versus 9 of 23 patients (39%) previously receiving ritlecitinib and brepocitinib, respectively, completed the withdrawal period without meeting the re-treatment criterion; and 14 of 22 (64%) and 14 of 23 patients (61%) who had received ritlecitinib and brepocitinib, respectively, met the re-treatment criterion. For both the treatments, DBP responders showed improved SALT scores during re-treatment following withdrawal (Fig 1). Following re-treatment, 8 of 14 patients (57%) receiving ritlecitinib and 8 of 15 (53%) receiving brepocitinib achieved SALT30.Table ITreatment-emergent AEs and laboratory abnormalitiesn (%)NonrespondersResponders: Re-treatment segmentRitlecitinibBrepocitinibActiven = 16PBOn = 17Activen = 5PBOn = 12Ritlecitinibn = 14Brepocitinibn = 15Treatment-emergent AEs and laboratory abnormalities AEs, n172212322217 Pts with AEs (all cause)8 (50)12 (71)4 (80)10 (83)11 (79)9 (60) Pts with serious AEs∗A serious AE is based on an outcome or action associated with events that pose a threat to a patient's life or functioning and the need to fulfill an additional reporting process (reported to regulatory agencies, corporate pharmacovigilance group, or institutional review boards). The US Food and Drug Administration defines a serious AE as an event with one of the following outcomes: death, life-threatening, hospitalization, disability, which is characterized by a significant, persistent, or permanent change, impairment, damage, or disruption in the patient's body function or structure, physical activities, or quality of life; a congenital anomaly; or a condition that requires intervention to prevent permanent impairment or damage.000001 (7)†Same patient with AE of lower limb fracture, considered unrelated to the study drug. Pts with severe AEs‡A severe AE is a class of AEs based on intensity (severity) and is medically significant but not immediately life-threatening, limiting self-care or activities of daily living.001 (20)001 (7)†Same patient with AE of lower limb fracture, considered unrelated to the study drug. DC from study because of AEs1 (6)00001 (7) DC from study because of laboratory values00001 (7)§Alanine aminotransferase >2.5 × upper limit of normal, confirmed on retesting.0 Pts with treatment-related AEs5 (31)1 (6)01 (8)2 (14)2 (13) Pts with serious treatment-related AEs000000 Pts with severe treatment-related AEs000000 DC from study because of treatment-related AEs1 (6)00000 DC from study because of laboratory values00001 (7)0Treatment-emergent AEs in ≥3 patients in any group Infections or infestations6 (38)5 (29)2 (40)7 (58)8 (57)3 (20) Nasopharyngitis02 (12)02 (17)3 (21)1 (7) Skin or SC tissue2 (13)3 (18)1 (20)5 (42)1 (7)0 Nervous system3 (19)2 (12)02 (17)3 (21)2 (13) Investigations (SOC)ǁSOC investigations covered laboratory test results.1 (6)1 (6)1 (20)4 (33)2 (14)2 (13) Gastrointestinal1 (6)2 (12)1 (20)3 (25)1 (7)2 (13) Musculoskeletal or connective tissue03 (18)0001 (7)AE, Adverse event; DC, discontinued; PBO, placebo; Pts, patients; SC, subcutaneous; SOC, system organ class.∗ A serious AE is based on an outcome or action associated with events that pose a threat to a patient's life or functioning and the need to fulfill an additional reporting process (reported to regulatory agencies, corporate pharmacovigilance group, or institutional review boards). The US Food and Drug Administration defines a serious AE as an event with one of the following outcomes: death, life-threatening, hospitalization, disability, which is characterized by a significant, persistent, or permanent change, impairment, damage, or disruption in the patient's body function or structure, physical activities, or quality of life; a congenital anomaly; or a condition that requires intervention to prevent permanent impairment or damage.† Same patient with AE of lower limb fracture, considered unrelated to the study drug.‡ A severe AE is a class of AEs based on intensity (severity) and is medically significant but not immediately life-threatening, limiting self-care or activities of daily living.§ Alanine aminotransferase >2.5 × upper limit of normal, confirmed on retesting.ǁ SOC investigations covered laboratory test results. Open table in a new tab AE, Adverse event; DC, discontinued; PBO, placebo; Pts, patients; SC, subcutaneous; SOC, system organ class. No new safety signals during withdrawal or re-treatment were observed. Efficacy appeared to decrease after re-treatment following withdrawal compared with that with the initial response, although the study was not statistically powered to confirm this. The results suggest that to maintain hair regrowth, continuous treatment should be considered in patients with alopecia areata who tolerate and respond to ritlecitinib or brepocitinib. Dr Guttman-Yassky has received institutional grants from AbbVie, Celgene, Eli Lilly, Janssen, Dermavant, DS Biopharma, Novartis, Pfizer, Regeneron, Glenmark, Galderma, Asana Biosciences, Innovaderm, Dermira, LEO Pharma, Novan, Kyowa Kirin, Concert, Union Therapeutics, and Ralexar and serves as a consultant for Sanofi, Regeneron, Celgene, Dermira, Galderma, Glenmark, Novartis, Pfizer, LEO Pharma, AbbVie, Eli Lilly, Kyowa Kirin, Mitsubishi Tanabe, Asana Biosciences, Union Therapeutics, Allergan, Amgen, Concert, DS Biopharma, EMD Serono, Escalier, and FLX Bio. Dr Sinclair provided professional services to Novartis, Merck & Co, Janssen, Samson Clinical, Pfizer, Eli Lilly and Company, Arena, Dermira, Astra Zeneca, Sanofi, AbbVie, Galderma, Principia, Reistone Pharma, Aclaris, and Sun Pharma. Dr Cox is a paid consultant to Pfizer. Dr King has served on advisory boards and/or is a consultant and/or a clinical trial investigator for AbbVie, Aclaris Therapeutics Inc, AltruBio Inc, Almirall, Arena Pharmaceuticals, Bioniz Therapeutics, Bristol-Meyers Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences Inc, Eli Lilly and Company, Incyte Corp, LEO Pharma, Otsuka/Visterra Inc, Pfizer Inc, Regeneron, Sanofi Genzyme, TWi Biotechnology Inc, and Viela Bio. He is on speaker bureaus for Pfizer Inc, Regeneron, and Sanofi Genzyme. Drs Peeva, Banerjee, L. Zhu, H. Zhu, and Vincent are employees and stockholders of Pfizer.