Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial

Ezzedine, Khaled; Peeva, Elena; Yamaguchi, Yuji; Cox, Lori Ann; Banerjee, Anindita; Han, George; Hamzavi, Iltefat; Ganesan, Anand K.; Picardo, Mauro; Thaçi, Diamant; Harris, John E.; Bae, Jung Min; Tsukamoto, Katsuhiko; Sinclair, Rodney; Pandya, Amit G.; Sloan, Abigail; Yu, Dao‐Yi; Gandhi, Kavita; Vincent, Michael S.; King, Brett

doi:10.1016/j.jaad.2022.11.005

Cited by 56 publications

(54 citation statements)

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“…19,40 Ritlecitinib is being evaluated in alopecia areata, vitiligo, rheumatoid arthritis, ulcerative colitis, and Crohn's disease, in which its unique mechanism of action could prove to be beneficial, and these studies may help to elucidate how receptor occupancy and the functional effects observed correlate with dosedependent efficacy. [9][10][11][12][13]…”

Section: Discussionmentioning

confidence: 99%

“…As JAK3 is critical for the signaling of IL‐2, IL‐4, IL‐7, and IL‐15, which are involved in B‐ and T‐cell differentiation and activity, combining its inhibition with TEC family kinase inhibition offers an opportunity to develop drugs targeting inflammatory and autoimmune diseases driven by these cells 19,40 . Ritlecitinib is being evaluated in alopecia areata, vitiligo, rheumatoid arthritis, ulcerative colitis, and Crohn's disease, in which its unique mechanism of action could prove to be beneficial, and these studies may help to elucidate how receptor occupancy and the functional effects observed correlate with dose‐dependent efficacy 9–13 …”

Section: Discussionmentioning

confidence: 99%

“…Crohn's disease, and rheumatoid arthritis, and is in late-stage clinical development for alopecia areata. [9][10][11][12][13] Ritlecitinib inhibits JAK3, with high selectivity over the other 3 JAK family isoforms (JAK1, JAK2, and TYK2), as well as the TEC family kinases (BTK, BMX, ITK, TXK, and TEC), with high selectivity over the broader human kinome. 3,[14][15][16][17][18] Ritlecitinib acts by binding covalently and irreversibly to a conserved cysteine residue in the ATP-binding sites of these 6 tyrosine kinases.…”

mentioning

confidence: 99%

“…Ritlecitinib (PF‐06651600) is an oral dual JAK3/TEC family kinase inhibitor that is being developed for the treatment of vitiligo, ulcerative colitis, Crohn's disease, and rheumatoid arthritis, and is in late‐stage clinical development for alopecia areata 9–13 . Ritlecitinib inhibits JAK3, with high selectivity over the other 3 JAK family isoforms (JAK1, JAK2, and TYK2), as well as the TEC family kinases (BTK, BMX, ITK, TXK, and TEC), with high selectivity over the broader human kinome 3,14–18 .…”

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confidence: 99%

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Target Occupancy and Functional Inhibition of JAK3 and TEC Family Kinases by Ritlecitinib in Healthy Adults: An Open‐Label, Phase 1 Study

Martin,

Telliez,

Pleasic‐Williams

et al. 2023

The Journal of Clinical Pharma

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Ritlecitinib is a small molecule in clinical development that covalently and irreversibly inhibits Janus kinase 3 (JAK3) and the TEC family of kinases (BTK, BMX, ITK, TXK, and TEC). This phase 1, open‐label, parallel‐group study assessed target occupancy and functional effects of ritlecitinib on JAK3 and TEC family kinases in healthy participants aged 18‐60 years who received 50 or 200 mg single doses of ritlecitinib on day 1. Blood samples to assess ritlecitinib pharmacokinetics, target occupancy, and pharmacodynamics were collected over 48 hours. Target occupancy was assessed using mass spectroscopy. Functional inhibition of JAK3‐dependent signaling was measured by the inhibition of the phosphorylation of its downstream target signal transducer and activator of transcription 5 (pSTAT5), following activation by interleukin 15 (IL‐15). The functional inhibition of Bruton's tyrosine kinase (BTK)‐dependent signaling was measured by the reduction in the upregulation of cluster of differentiation 69 (CD69), an early marker of B‐cell activation, following treatment with anti‐immunoglobulin D. Eight participants received one 50 mg ritlecitinib dose and 8 participants received one 200 mg dose. Ritlecitinib plasma exposure increased in an approximately dose‐proportional manner from 50 to 200 mg. The maximal median JAK3 target occupancy was 72% for 50 mg and 64% for 200 mg. Ritlecitinib 50 mg had >94% maximal target occupancy of all TEC kinases, except BMX (87%), and 200 mg had >97% for all TEC kinases. For BTK and TEC, ritlecitinib maintained high target occupancy throughout a period of 48 hours. Ritlecitinib reduced pSTAT5 levels following IL‐15‐ and BTK‐dependent signaling in a dose‐dependent manner. These target occupancy and functional assays demonstrate the dual inhibition of the JAK3‐ and BTK‐dependent pathways by ritlecitinib. Further studies are needed to understand the contribution to clinical effects of inhibiting these pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Target Occupancy and Functional Inhibition of JAK3 and TEC Family Kinases by Ritlecitinib in Healthy Adults: An Open‐Label, Phase 1 Study

Martin,

Telliez,

Pleasic‐Williams

et al. 2023

The Journal of Clinical Pharma

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“…An autoimmune disease called vitiligo causes spontaneous loss of skin pigmentation as a result of the immune system. It affects quality of life significantly, has an erratic clinical course, and has an incidence of between 0.5% and 1.0% globally [1,2] . Segmental and nonsegmental vitiligo are the 2 most prevalent forms.…”

mentioning

confidence: 99%

Advancements in vitiligo treatment: the Food and Drug Administration approval of the RECELL system and its impact on repigmentation and quality of life

Khan,

Rohail,

Fareed

et al. 2023

International Journal of Surgery: Global Health

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Short-Term Cardiovascular Complications in Dermatology Patients Receiving JAK-STAT Inhibitors

Ireland,

Jansson,

Spencer

et al. 2024

JAMA Dermatol

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ImportanceEvolving evidence suggests that patients receiving Janus kinase–signal transducer and activator of transcription inhibitors (JAK-STATi) may be at higher risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). Most existing literature has focused on indications that may confer a higher MACE and VTE risk than that among patients with isolated dermatological indications.ObjectiveTo evaluate risk of MACE, VTE, serious adverse events (SAEs), and tolerability of systemic JAK-STATi compared with placebo, in those with a dermatologic indication.Data SourcesA systematic review of the literature was carried out to June 2023, using databases Embase, MEDLINE, SCOPUS, Cochrane Library of Registered Trials, and registered Clinical Trials. The analysis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The analysis itself took place in June 2023.Study SelectionPlacebo-controlled randomized clinical trials that compared systemic JAK-STATi with placebo, and investigated the safety in patients with alopecia areata, psoriasis, vitiligo, atopic dermatitis, lichen planus or hidradenitis suppurativa.Data Extraction and SynthesisStudy selection and data extraction by 2 authors working independently using a standardized template. Crude numbers for MACE, VTE, SAEs, and study discontinuation due to treatment emergent adverse events (TEAEs) were pooled and underwent meta-analysis.Main Outcomes and MeasuresIncidence of MACE, VTE, SAE, and study discontinuation due to TEAEs. Analysis of these values against person exposure years to determine the incidence rate (IR). Risk ratios (RRs) compared incidence rates among treatment and placebo comparator arms.ResultsForty-five randomized clinical trials were eligible for inclusion, with 12 996 patients receiving active JAK-STATi therapy and 4925 allocated to placebo treatment. Meta-analysis found no significant increase in MACE (I2 = 0.00%; RR, 0.47; 95% CI, 0.28-0.80) or VTE (I2 = 0.00%; RR, 0.46; 95% CI, 0.26-0.80) between placebo and JAK-STATi comparator arms. There was also no significant difference in SAEs (I2 = 12.38%; RR, 0.92; 95% CI, 0.72-1.20) and discontinuations between JAK-STATi and placebo (I2 = 23.55%; RR, 0.94; 95% CI, 0.76-1.19).Conclusions and RelevanceThis meta-analysis did not identify a significant increase in the risk of MACE and VTE in dermatology patients receiving JAK-STATi for median duration of 16 weeks. The results of this review suggest there is insufficient evidence that JAK-STATi confer an increased risk of cardiovascular complications in dermatological patients, especially when used for short time frames.

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Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial

Cited by 56 publications

References 37 publications

Target Occupancy and Functional Inhibition of JAK3 and TEC Family Kinases by Ritlecitinib in Healthy Adults: An Open‐Label, Phase 1 Study

Target Occupancy and Functional Inhibition of JAK3 and TEC Family Kinases by Ritlecitinib in Healthy Adults: An Open‐Label, Phase 1 Study

Advancements in vitiligo treatment: the Food and Drug Administration approval of the RECELL system and its impact on repigmentation and quality of life

Short-Term Cardiovascular Complications in Dermatology Patients Receiving JAK-STAT Inhibitors

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