PMID- 38263353 OWN - NLM STAT- MEDLINE DCOM- 20240216 LR - 20240312 IS - 1179-1888 (Electronic) IS - 1175-0561 (Print) IS - 1175-0561 (Linking) VI - 25 IP - 2 DP - 2024 Mar TI - Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program. PG - 299-314 LID - 10.1007/s40257-024-00846-3 [doi] AB - BACKGROUND: The ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib, an oral JAK3/TEC family kinase inhibitor, is efficacious at doses of >/= 30 mg in patients aged >/= 12 years with alopecia areata (AA). OBJECTIVE: The objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA. METHODS: Two cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates (IRs) of adverse events (AEs) of interest and laboratory abnormalities are reported. RESULTS: In the placebo-controlled cohort (n = 881; median exposure: 169 days), the proportion of ritlecitinib-treated patients with AEs was 70.2-75.4% across doses versus 69.5% in the placebo group; serious AEs occurred in 0-3.2% versus 1.9% for the placebo. A total of 19 patients permanently discontinued due to AEs (5 while receiving the placebo). In the all-exposure cohort (n = 1294), median ritlecitinib exposure was 624 days [2091.7 total patient-years (PY)]. AEs were reported in 1094 patients (84.5%) and serious AEs in 57 (4.4%); 78 (6.0%) permanently discontinued due to AEs. The most common AEs were headache (17.7%; 11.9/100 PY), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (15.5%; 9.8/100 PY), and nasopharyngitis (12.4%; 8.2/100 PY). There were two deaths (breast cancer and acute respiratory failure/cardiorespiratory arrest). Proportions (IRs) were < 0.1% (0.05/100 PY) for opportunistic infections, 1.5% (0.9/100 PY) for herpes zoster, 0.5% (0.3/100 PY) for malignancies (excluding nonmelanoma skin cancer), and 0.2% (0.1/100 PY) for major adverse cardiovascular events. CONCLUSIONS: Ritlecitinib is well tolerated with an acceptable safety profile up to 24 months in patients aged >/= 12 years with AA (video abstract and graphical plain language summary available). TRIAL REGISTRIES: ClinicalTrials.gov: NCT02974868 (date of registration: 11/29/2016), NCT04517864 (08/18/2020), NCT03732807 (11/07/2018), and NCT04006457 (07/05/2019). CI - (c) 2024. The Author(s). FAU - King, Brett AU - King B AD - Yale School of Medicine, New Haven, CT, USA. FAU - Soung, Jennifer AU - Soung J AD - Southern California Dermatology, Santa Ana, CA, USA. FAU - Tziotzios, Christos AU - Tziotzios C AD - St John's Institute of Dermatology, King's College London, London, UK. FAU - Rudnicka, Lidia AU - Rudnicka L AD - Department of Dermatology, Medical University of Warsaw, Warsaw, Poland. FAU - Joly, Pascal AU - Joly P AD - Rouen University Hospital, INSERM 1234, Normandie University, Rouen, France. FAU - Gooderham, Melinda AU - Gooderham M AD - Skin Centre for Dermatology, Canada Probity Medical Research, Waterloo, ON, Canada. FAU - Sinclair, Rodney AU - Sinclair R AD - Sinclair Dermatology, Melbourne, VIC, Australia. FAU - Mesinkovska, Natasha A AU - Mesinkovska NA AD - Department of Dermatology and Dermatopathology, School of Medicine, University of California, Irvine, CA, USA. FAU - Paul, Carle AU - Paul C AD - Department of Dermatology, Toulouse University and INSERM infinity U1291, Toulouse, France. FAU - Gong, Yankun AU - Gong Y AD - Pfizer Inc, New York, NY, USA. FAU - Anway, Susan D AU - Anway SD AD - Pfizer Inc, Groton, CT, USA. FAU - Tran, Helen AU - Tran H AD - Pfizer Inc, New York, NY, USA. FAU - Wolk, Robert AU - Wolk R AD - Pfizer Inc, Groton, CT, USA. FAU - Zwillich, Samuel H AU - Zwillich SH AD - Pfizer Inc, Groton, CT, USA. FAU - Lejeune, Alexandre AU - Lejeune A AD - Pfizer Inc, 23 Av. du Dr Lannelongue, 75014, Paris, France. alexandre.lejeune@pfizer.com. LA - eng SI - ClinicalTrials.gov/NCT02974868 SI - ClinicalTrials.gov/NCT04517864 SI - ClinicalTrials.gov/NCT03732807 SI - ClinicalTrials.gov/NCT04006457 GR - UL1 TR001863/TR/NCATS NIH HHS/United States PT - Clinical Trial PT - Journal Article PT - Video-Audio Media DEP - 20240123 PL - New Zealand TA - Am J Clin Dermatol JT - American journal of clinical dermatology JID - 100895290 RN - 0 (Antineoplastic Agents) RN - 0 (Carbazoles) RN - H82Q2D5WA7 (frovatriptan) RN - EC 2.7.10.2 (JAK3 protein, human) RN - EC 2.7.10.2 (Janus Kinase 3) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Tryptamines) RN - Diffuse alopecia SB - IM MH - Humans MH - *Alopecia Areata/drug therapy/epidemiology MH - *Antineoplastic Agents MH - Carbazoles MH - Janus Kinase 3 MH - Protein Kinase Inhibitors/adverse effects MH - SARS-CoV-2 MH - Treatment Outcome MH - *Tryptamines PMC - PMC10867086 COIS- Brett King: AbbVie, AltruBio, Almirall, AnaptysBio, Arena Pharmaceuticals, Bioniz Therapeutics, Bristol Myers Squibb, Concert Pharmaceuticals, Equillium, Horizon Therapeutics, Eli Lilly, Incyte, Janssen Pharmaceuticals, LEO Pharma, Otsuka/Visterra, Pfizer, Regeneron, Sanofi Genzyme, TWi Biotechnology, and Viela Bio. He has served on speaker bureaus for Pfizer. Jennifer Soung: speaker for Regeneron/Sanofi and Ortho Dermatologics; speaker and investigator for Amgen, AbbVie, and Pfizer; speaker, investigator, and advisor for Eli Lilly; investigator and advisor for LEO Pharma; investigator, speaker, and consultant for Novartis; investigator for UCB, Janssen, Kyowa Kirin, KoBio Labs, and Castel Biosciences; investigator and consultant for Dermavant; speaker and consultant for Bristol Myers Squibb, speaker, investigator and consultant for Arcutis. Christos Tziotzios: speaker for LEO Pharma; principal and chief investigator for Pfizer; consultant for Pfizer. Lidia Rudnicka: speaker for AbbVie, L'Oreal, LEO Pharma, Novartis, Pierre Fabre, and Pfizer; advisory board member for LEO Pharma, Janssen, L'Oreal, Novartis, Pfizer, Sanofi, and UCB. Pascal Joly: consultant for Amgen, Argenx, AstraZeneca, Innovaderm, Principia Biopharma, Roche, Sanofi-Regeneron Pharmaceuticals, Thermo Fisher Scientific, Novartis, Pfizer, Lilly, AbbVie, and Janssen Cilag. Melinda Gooderham: investigator, speaker, and/or advisor for AbbVie, Amgen, Akros, AnaptysBio, Arcutis, Bausch Health, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi Genzyme, Sun Pharma, and UCB. Rodney Sinclair: professional services to Aerotech, AbbVie, AstraZeneca, Akesobio, Amgen, Arcutis, Arena, Ascend, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Coherus Biosciences, Connect, Cutanea, Demira, Eli Lilly, Galderma, GSK, Janssen, LEO Pharma, MedImmune, Merck, MSD, Novartis, Oncobiologics, Pfizer, Regeneron, Reistone, Roche, Samson Clinical, Sanofi, Sun Pharma, and UCB. Natasha A. Mesinkovska: professional services to AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Concert Pharmaceuticals, Eli Lilly, La Roche Posay, and Pfizer. Carle Paul: consulting fees and/or grants from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Celgene, GSK, Janssen Cilag, LEO Pharma, Eli Lilly, Novartis, Pierre Fabre, Pfizer, Sanofi, and UCB Pharma. Yankun Gong, Helen Tran, Robert Wolk, Samuel H. Zwillich, and Alexandre Lejeune are employees of, and hold stock or stock options in, Pfizer. Susan D. Anway was an employee of Pfizer at the time of the study and holds stock or stock options in Pfizer. EDAT- 2024/01/24 00:42 MHDA- 2024/02/16 06:42 PMCR- 2024/01/23 CRDT- 2024/01/23 23:55 PHST- 2024/01/16 00:00 [accepted] PHST- 2024/02/16 06:42 [medline] PHST- 2024/01/24 00:42 [pubmed] PHST- 2024/01/23 23:55 [entrez] PHST- 2024/01/23 00:00 [pmc-release] AID - 10.1007/s40257-024-00846-3 [pii] AID - 846 [pii] AID - 10.1007/s40257-024-00846-3 [doi] PST - ppublish SO - Am J Clin Dermatol. 2024 Mar;25(2):299-314. doi: 10.1007/s40257-024-00846-3. Epub 2024 Jan 23.