Digital Features for this AdisInsight Report can be found at https://doi.org/10.6084/m9.figshare.23706567.

FormalPara Ritlecitinib (LITFULO™): Key Points

A kinase inhibitor being developed by Pfizer for the treatment of alopecia areata, vitiligo, ulcerative colitis and Crohn’s disease

Received its first approval on 23 June 2023 in the USA

Approved for the treatment of severe alopecia areata in adults and adolescents 12 years and older

1 Introduction

Ritlecitinib (LITFULO™) is a kinase inhibitor that is being developed by Pfizer for the treatment of alopecia areata, vitiligo, ulcerative colitis and Crohn’s disease. Ritlecitinib irreversibly inhibits Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family [1].

On 23 June 2023, ritlecitinib received its first approval in the USA for the treatment of severe alopecia areata in adults and adolescents 12 years and older [1, 2]. Alopecia areata is an autoimmune disease characterized by loss of scalp, face and/or body hair [2]. Ritlecitinib is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, ciclosporin or other potent immunosuppressants [1]. The recommended dosage of ritlecitinib is 50 mg orally once daily, with or without food. Treatment should be interrupted if the absolute lymphocyte count (ALC) is < 500/mm3 and discontinued if the platelet count is < 50,000/mm3. Temporary treatment interruption for < 6 weeks is not expected to result in significant loss of regrown scalp hair. Ritlecitinib carries a boxed warning for serious infections (including tuberculosis), mortality, malignancy, major adverse cardiovascular events (MACE) and thrombosis [1]. Consult local prescribing information for recommendations regarding the use of ritlecitinib in patients at increased risk for these events.

Ritlecitinib was approved in Japan on 26 June 2023 for the treatment of alopecia areata (limited to intractable cases involving widespread hair loss) [3]. Ritlecitinib received a positive opinion in the EU on 20 July 2023 for the treatment of alopecia areata [4] and is under regulatory review in the UK and China for the same indication. Clinical development of ritlecitinib for the treatment of alopecia areata, vitiligo, ulcerative colitis and Crohn’s disease is underway in several countries worldwide. Development of ritlecitinib for the treatment of rheumatoid arthritis has been discontinued.

figure a

2 Scientific Summary

2.1 Pharmacodynamics

Selective dual inhibition of JAK3 and TEC kinase family members by ritlecitinib may block signalling of various cytokines and cytolytic activity of T cells, which is implicated in the pathogenesis of inflammatory and autoimmune diseases [5].

Ritlecitinib inhibits JAK3 with high selectivity over other JAK isoforms; this selectivity is the result of irreversible covalent binding to a cysteine residue at position 909 (Cys-909) in JAK3 which is replaced with a serine residue at the equivalent position in other JAK isoforms [5]. In vitro, ritlecitinib inhibits JAK3 with a half maximal inhibitory concentration (IC50) of 33.1 nM [5, 6]. Ritlecitinib has lower affinity (IC50 > 10,000 nM) against JAK1, JAK2 and tyrosine kinase 2 (TYK2) [6]. In human whole blood, ritlecitinib inhibited cytokine induced signal transducer and activator of transcription (STAT) phosphorylation mediated by JAK3-dependent cytokines including interleukin (IL)-2, IL-4, IL-7, IL-15 and IL-21 [1, 5, 6].

Ritlecitinib also inhibits the TEC kinase family due to a cysteine residue at the equivalent position of Cys-909 in JAK3 [5]. In vitro, ritlecitinib inhibits the TEC kinase family members [resting lymphocyte kinase (RLK), IL-2-inducible T cell kinase (ITK), TEC, Bruton’s tyrosine kinase (BTK) and bone marrow tyrosine kinase on chromosome X (BMX)] with IC50 values of 155, 395, 403, 404 and 666 nM, respectively. Ritlecitinib has been shown to inhibit signalling of immune receptors including B cell receptor (BCR) and T cell receptor (TCR), both dependent on TEC kinase family members. In cellular settings, ritlecitinib inhibits cytolytic activity and production of interferon-γ in natural killer (NK) and CD8+ T cells via inhibition of TEC kinase family members [5].

In patients with alopecia areata, treatment with ritlecitinib was associated with dose-dependent early reductions in ALC, CD3+, CD4+ and CD8+ T cells, and NK cells, but had no effect on CD19+ B cells [1].

Administration of ritlecitinib at 12 times the mean maximum exposure of the 50 mg once daily dose did not prolong the QTc interval to any clinically relevant extent in patients with alopecia areata [1].

2.2 Pharmacokinetics

Ritlecitinib area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) increase in an approximately dose-proportional manner up to 200 mg, reaching steady state after ≈ 4 days [1]. Cmax is reached within 1 h following an oral dose. Administration of ritlecitinib 100 mg with a high-fat meal increased AUC∞ by 11% and decreased Cmax by ≈ 32%, indicating that food does not have a clinically meaningful effect on ritlecitinib exposure.

figure b

The absolute oral bioavailability of ritlecitinib is ≈ 64% and only 14% of circulating drug is bound to plasma proteins. Ritlecitinib is metabolized by multiple pathways, including glutathione S-transferase (GST), specifically GST A1/3, M1/3/5, P1, S1, T2, Z1 and microsomal GST 1/2/3, and cytochrome P450 (CYP) enzymes, specifically CYP1A2, CYP2C8, CYP2C9 and CYP3A. Following a radiolabeled dose of ritlecitinib, ≈ 66% and 20% of radioactivity is recovered in urine (≈ 4% as unchanged drug) and faeces, respectively. The mean terminal half-life of ritlecitinib ranges from 1.3 to 2.3 h [1].

The pharmacokinetics of ritlecitinib are not affected to a clinically meaningful extent by age (12–73 years), sex, body weight, race or GST genotype, and are not expected to be affected by mild [estimated glomerular filtration rate (eGFR) 60 to > 90 mL/min] or moderate (eGFR 30 to < 60 mL/min) renal impairment or mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment [1]. Ritlecitinib is not recommended in patients with severe (Child Pugh C) hepatic impairment [1].

In vitro, ritlecitinib is not an inhibitor of CYP2D6, uridine 5’ diphospho glucuronosyltransferase (UGT) 1A1, UGT1A4, UGT1A6, UGT1A9 and UGT2B7, GSTs, sulfotransferases, P-glycoprotein or bile salt export pump [1]. Coadministration of ritlecitinib with CYP1A2 and CYP3A substrates may increase exposure of these substrates and therefore increase the risk of adverse reactions [1, 7]. Monitoring and dose adjustment of CYP1A2 substrates is recommended [1]. Coadministration of ritlecitinib with strong CYP3A inducers (e.g. rifampin) is not recommended, as this may decrease exposure of ritlecitinib and therefore decrease the therapeutic effect. Avoid the use of live attenuated vaccines during or shortly prior to initiating treatment with ritlecitinib [1].

Features and properties of ritlecitinib

Alternative names

LITFULO™; PF 06651600; PF 6651600; ritlecitinib tosylate

Class

Amines, Anti-inflammatories, Antirheumatics, Antiulcers, Heterocyclic bicyclo compounds, Ketones, Piperadines, Pyrimidines, Pyrroles, Skin disorder therapies, Small molecules

Mechanism of action

Emt protein-tyrosine kinase inhibitors; Janus kinase 3 inhibitors

Route of administration

Oral

Pharmacodynamics

Irreversible inhibitor of JAK3 and TEC kinase family

Inhibits cytokine induced STAT phosphorylation mediated by JAK3-dependent cytokines

Inhibits signalling of immune receptors including BCR and TCR, both dependent on dependent on TEC kinase family members

Pharmacokinetics

Absolute oral bioavailability ≈ 64%; time to Cmax 1 h; plasma protein binding ≈ 14%; mean terminal half-life 1.3–2.3 h

Most frequent adverse events

Headache, diarrhoea, acne, rash, urticaria, folliculitis, pyrexia, atopic dermatitis, dizziness, increased blood creatine phosphokinase, herpes zoster, decreased red blood cell count, stomatitis

ATC codes

 WHO ATC code

L04A-F08 (Ritlecitinib)

 EphMRA ATC codes

LX4 (Other Immunosuppressants), D11A (Other Dermatological Preparations)

Chemical name

1-{(2S,5R)-2-methyl-5-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}prop-2-en-1-one 4 methylbenzene-1-sulfonic acid

  1. BCR B cell receptor, Cmax maximum plasma concentration, JAK3 Janus kinase 3, STAT signal transducer and activator of transcription, TCR T cell receptor, TEC tyrosine kinase expressed in hepatocellular carcinoma

2.3 Therapeutic Trials

2.3.1 Alopecia Areata

2.3.1.1 ALLEGRO-2b/3

Ritlecitinib was effective in the treatment of alopecia areata in a randomized, double-blind, multinational, phase 2b/3 trial (NCT03732807; ALLEGRO-2b/3) [8]. This trial included adults aged ≥ 18 years and adolescents aged 12–17 years with alopecia areata and ≥ 50% scalp hair loss (including alopecia totalis and alopecia universalis), as measured by the Severity of Alopecia Tool [SALT; scores range from 0 (no scalp hair loss) to 100 (total scalp hair loss)], with maximum duration of current episode of hair loss ≤ 10 years. Key exclusion criteria included other causes of alopecia and previous use of any JAK inhibitor. Patients were randomized to receive ritlecitinib 200 mg for 4 weeks followed by 50 mg (n = 132), ritlecitinib 200 mg for 4 weeks followed by 30 mg (n = 130), ritlecitinib 50 mg (n = 130), ritlecitinib 30 mg (n = 132), ritlecitinib 10 mg (n = 63), placebo for 24 weeks followed by ritlecitinib 200 mg for 4 weeks then 50 mg (n = 65) or placebo for 24 weeks followed by ritlecitinib 50 mg (n = 66). Randomization was stratified by scalp hair loss and age. Study medication was administered orally, once daily, for 24 weeks during the placebo-controlled period and for 24 weeks during the extension period. During the extension period, patients randomized to placebo were switched to ritlecitinib, while patients randomized to ritlecitinib continued their maintenance dosage [8].

At week 24, the proportions of patients achieving the primary endpoint of a SALT score of ≤ 20 (i.e. ≤ 20% scalp hair loss) were 31, 22, 23, 14 and 2% in the ritlecitinib 200 + 50 mg, 200 + 30 mg, 50 mg, 30 mg and 10 mg groups, respectively, compared with 2% in the combined placebo group [8]. The difference between ritlecitinib and placebo was significant (p ≤ 0.0002) in all but the 10 mg group (included for pharmacokinetic, dose-response and safety assessments only). The proportions of patients achieving the more stringent key secondary endpoint of a SALT score of ≤ 10 (i.e. ≤ 10% scalp hair loss) were 22, 13, 14, 11 and 2% in the respective ritlecitinib groups and 2% with placebo. Again, the difference between ritlecitinib and placebo was significant (p ≤ 0.0019) in all but the 10 mg group [8]. The efficacy of ritlecitinib in the treatment of alopecia areata was sustained over the longer term [9]. Through week 48 (i.e. the end of the 24-week extension period), the proportions of patients with a SALT score of ≤ 20 were 40, 34, 43, 31 and 10% in the ritlecitinib 200 + 50 mg, 200 + 30 mg, 50 mg, 30 mg and 10 mg groups, respectively [9].

2.3.1.2 ALLEGRO-LT

Over the longer term, ritlecitinib had sustained clinical efficacy in patients with alopecia areata in an ongoing, open-label, phase 3 trial (NCT04006457; ALLEGRO-LT) [10]. ALLEGRO-LT enrolled both rollover patients from ALLEGRO-2a and ALLEGRO-2b/3 and de novo patients who had not received treatment in other ALLEGRO trials. Eligible patients were aged ≥ 12 years with ≥ 25% scalp hair loss due to alopecia areata, no evidence of terminal hair regrowth within 6 months and maximum duration of current episode of hair loss ≤ 10 years. All patients received ritlecitinib 200 mg once daily for 4 weeks followed by 50 mg once daily [10].

In an interim analysis of de novo patients (n = 447), 62% of patients were categorized as responders; 44% were early responders (SALT score of ≤ 20 at weeks 24, 48 and 96), 11% were middle responders (SALT score of ≤ 20 not by week 24 but by week 48 and at week 96) and 6% were late responders (SALT score of ≤ 20 not by week 48 but by week 96) [10]. Most (> 84%) patients sustained their clinical response through week 96 [10].

2.3.1.3 Integrated Analysis

Ritlecitinib was associated with clinically meaningful and sustained long-term efficacy in patients with alopecia areata, according to pooled data from ALLEGRO-2b/3 and ALLEGRO-LT [11]. The integrated analysis included patients aged ≥ 12 years with ≥ 50% hair loss from ALLEGRO-2b/3 and ALLEGRO-LT (including both rollover and de novo patients). Between months 12 and 24, the proportion of patients with a SALT score of ≤ 20 increased from 52 to 58% in the ritlecitinib 200 + 50 mg group and from 45 to 62% in the ritlecitinib 50 mg group. Likewise, the proportion of patients with a SALT score of ≤ 10 increased from 44 to 47% in the 200 + 50 mg group and from 34 to 51% in the 50 mg group [11].

2.3.1.4 ALLEGRO-2a

Ritlecitinib and brepocitinib were effective in the treatment of alopecia areata in a randomized, double-blind, multinational, phase 2a trial (NCT02974868; ALLEGRO-2a) [12]. This trial included adults aged ≥ 18 years with alopecia areata with ≥ 50% scalp hair loss, no hair regrowth within 6 months of the screening and baseline visits, and a current episode of fixed hair loss of ≤ 7 years in duration. Key exclusion criteria included another type of alopecia or active inflammatory disease involving the scalp and use of JAK inhibitors within 12 weeks of the first dose of study medication. Patients were randomized to receive ritlecitinib 200 mg once daily for 4 weeks followed by 50 mg once daily for 20 weeks or matching placebo, or brepocitinib 60 mg once daily for 4 weeks followed by 30 mg once daily for 20 weeks or matching placebo. Randomization was stratified by agreement to participate in an optional biopsy substudy and the presence or absence of alopecia totalis or alopecia universalis. The primary endpoint was the change from baseline in SALT score at week 24 [12].

At week 24, the least-squares mean difference from placebo in the change from baseline in SALT score was 31.1 with ritlecitinib and 49.2 with brepocitinib (both p < 0.001) [12]. Similar results were seen in a sensitivity analysis excluding patients with a current episode of fixed hair loss of > 7 years (31.7 and 49.0; both p < 0.001). The proportion of patients achieving ≥ 30% improvement in SALT score at week 24 (key secondary endpoint) was 50% with ritlecitinib and 64% with brepocitinib versus with 2% with placebo [12].

The initial 24-week treatment period was followed by a 24-week single-blind extension [13]. Patients who did not achieve ≥ 30% improvement in SALT score at the end of the single-blind extension entered a 24-week crossover open-label extension, during which the ritlecitinib group switched to brepocitinib and the brepocitinib group switched to ritlecitinib [14]. After 24 weeks of treatment in the single-blind extension, the proportion of placebo non-responders who achieved ≥ 30% improvement in SALT score was 29% with ritlecitinib and 67% with brepocitinib, while the proportion of active non-responders who achieved ≥ 30% improvement in SALT score was 13% with ritlecitinib and 0% with brepocitinib [13]. None of the patients who switched to ritlecitinib and four of 16 patients who switched to brepocitinib achieved ≥ 30% improvement in SALT score at week 24 of the crossover open-label extension [14]. This analysis was limited by the open-label study design, the small number of patients and the single-dose regimen of each study drug [14].

2.3.2 Vitiligo

Ritlecitinib was effective in the treatment of active non-segmental vitiligo in a phase 2b, randomized, double-blind, multinational, dose-ranging trial (NCT03715829) [15]. This trial enrolled adults aged 18–65 years with a clinical diagnosis of non-segmental vitiligo for ≥ 3 months. Patients were required to have the following: body surface area (BSA) involvement of 4–50% excluding palms, soles and feet; BSA facial involvement of ≥ 0.25% excluding vermilions; and ≥ 1 active lesion, defined as new/extending lesion(s) in the previous 3 months confirmed by photographs/medical record, confetti-like lesion(s), trichrome lesion(s) or Koebner phenomenon/phenomena excluding history-based isomorphic reaction. Key exclusion criteria included other types of vitiligo and other disorders causing hyperpigmentation. In the 24-week dose-ranging period, patients were randomized to receive ritlecitinib 100 mg for 4 weeks followed by 50 mg (n = 65), ritlecitinib 200 mg for 4 weeks followed by 50 mg (n = 67), ritlecitinib 50 mg (n = 67), ritlecitinib 30 mg (n = 50), ritlecitinib 10 mg (n = 49) or placebo (n = 66). Study medication was administered orally, once daily. During the 24-week extension period, non-responders at week 16 of the dose-ranging period received open-label brepocitinib, open-label ritlecitinib plus narrow-brand ultraviolet B therapy or blinded treatment with ritlecitinib 200 mg + 50 mg [15].

The percent change from baseline on the Facial-Vitiligo Area Scoring Index (F-VASI) at week 24 (primary endpoint) was – 21.2, – 21.2, – 18.5, – 14.6 and – 3.0 in the ritlecitinib 200 + 50 mg, 100 + 50 mg, 50 mg, 30 mg and 10 mg groups, respectively, compared with 2.1 in the placebo group [15]. The difference between ritlecitinib and placebo was significant in all 50 mg groups (p < 0.001) and in the 30 mg group (p = 0.01). The proportions of patients achieving the key secondary endpoint of ≥ 75% improvement on the F-VASI at week 24 were 12, 9, 8, 3 and 2% in the respective ritlecitinib groups and 0% in the placebo group. The difference between ritlecitinib and placebo was significant in all 50 mg groups (p ≤ 0.04). Patients who received ritlecitinib 200 + 50 mg in the extension period demonstrated accelerated improvement on the F-VASI after week 28, regardless of initial treatment allocation [15].

2.3.3 Ulcerative Colitis

Ritlecitinib and brepocitinib were effective in the treatment of moderate to severe active ulcerative colitis in a phase 2b, randomized, double-blind, multinational, dose-ranging, umbrella study (NCT02958865; VIBRATO) [16]. This trial enrolled patients aged 18–75 years with a diagnosis of ulcerative colitis for ≥ 3 months. All patients had moderate to severe active disease, as defined by a total Mayo Score (TMS) of ≥ 6, a rectal bleeding subscore of ≥ 1 and a Mayo endoscopic subscore of ≥ 2, with active disease > 15 cm from the anal verge. A total of 319 patients were randomized to receive oral once-daily ritlecitinib (20, 70 or 200 mg) or matched placebo, or once-daily brepocitinib (10, 30 or 60 mg) or matched placebo. The study comprised an 8-week double-blind induction period, a 24-week chronic dosing period and a 4-week follow-up period. The primary endpoint was TMS at week 8 (scores range from 0 to 12) [16].

The placebo-adjusted mean TMS at week 8 was – 2.0 (p = 0.003), – 3.9 (p < 0.001) and – 4.6 (p < 0.001) for ritlecitinib 20, 70 and 200 mg, respectively, and – 1.8 (p = 0.009), – 2.3 (p = 0.001) and – 3.2 (p < 0.001) for brepocitinib 10, 30 and 60 mg, respectively [16]. The estimated placebo-adjusted proportions of patients with modified clinical remission at week 8 were 14, 33 and 36% for ritlecitinib 20, 70 and 200 mg, respectively, and 15, 26 and 26% for brepocitinib 10, 30 and 60 mg, respectively [16].

Key clinical trials of ritlecitinib (Pfizer)

Drug(s)

Indication

Phase

Status

Location(s)

Identifier

Ritlecitinib, brepocitinib

Alopecia areata

2a

Completed

Multinational

ALLEGRO-2a; NCT02974868; EudraCT2016-004048-13

Ritlecitinib

Alopecia areata

2a

Active, no longer recruiting

Multinational

ALLEGRO-2a safety study; NCT04517864; EudraCT2020-001509-21

Ritlecitinib

Alopecia areata

2b/3

Completed

Multinational

ALLEGRO-2b/3; NCT03732807; EudraCT2018-001714-14; JapicCTI194699

Ritlecitinib

Alopecia areata

3

Active, no longer recruiting

Multinational

ALLEGRO-LT; NCT04006457; EudraCT2019-001084-71; JapicCTI195004

Ritlecitinib

Alopecia areata

EAP

Recruiting

Unknown

NCT05522556

Ritlecitinib, brepocitinib

Vitiligo

2b

Completed

Multinational

NCT03715829; EudraCT2018-001271-20; JapicCTI194671

Ritlecitinib

Vitiligo

3

Recruiting

Multinational

Tranquilo; NCT05583526; EudraCT2022-501668-16-00

Ritlecitinib, brepocitinib

Ulcerative colitis

2b

Completed

Multinational

VIBRATO; NCT02958865; EudraCT2016-003708-29

Ritlecitinib

Ulcerative colitis

3

Discontinued

Multinational

EudraCT2021-003702-42

Ritlecitinib, brepocitinib

Crohn’s disease

2a

Active, no longer recruiting

Multinational

NCT03395184; EudraCT2017-003359-43

  1. EAP expanded access program

2.4 Adverse Events

2.4.1 Alopecia Areata

Ritlecitinib was well tolerated in patients with alopecia areata, according to an integrated safety analysis of data from ALLEGRO-2a, ALLEGRO-2a safety study, ALLEGRO-2b/3 and ALLEGRO-LT [17]. Two cohorts were analyzed: a placebo-controlled cohort from three trials (n = 881) and an all-exposure pool of patients who received ≥ 1 dose of ritlecitinib in any of the four trials [n = 1294; 2092 total patient-years (PY) of exposure]. Most adverse events (AEs) were mild in severity, self-limiting, and did not require dose interruption or permanent discontinuation of treatment. In the placebo-controlled cohort, 345 patients were treated with ritlecitinib 50 mg once daily (i.e. the recommended dosage) for up to 24 weeks. AEs occurring in ≥ 10% of these patients and at a higher rate than placebo included nasopharyngitis (23% vs 15% with placebo), headache (21% vs 19%), upper respiratory tract infection (20% vs 17%) and acne (13% vs 10%). In the all-exposure cohort, AEs of special interest in patients treated with ritlecitinib 50 mg (n = 1228) included herpes simplex (adjusted incidence rate 1.3/100 PY), herpes zoster (1.0/100 PY), serious infections (0.7/100 PY) and malignancies excluding non-melanoma skin cancer (0.4/100 PY). Six percent of patients discontinued treatment with ritlecitinib 50 mg due to AEs [17].

Another integrated safety analysis also found that long-term ritlecitinib was well tolerated in adolescents with alopecia areata, with no new safety signals identified [18]. Data were obtained from a cohort of adolescents from the 24-week placebo-controlled period of ALLEGRO-2b/3 (n = 105) and an any-ritlecitinib cohort of adolescents who received ≥ 1 dose of ritlecitinib in ALLEGRO-2b/3 and/or ALLEGRO-LT (n = 181). In the placebo-controlled cohort, AEs occurred in 67–83% of ritlecitinib recipients and 79% of placebo recipients. Two patients reported serious AEs (suicidal behaviour and eczema) and two patients discontinued ritlecitinib due to AEs. In the any-ritlecitinib cohort, the incidence of AEs was 83% (160.6/100 PY) and the incidence of serious AEs was 4% (2.3/100 PY). The most frequent AEs were acne (13.7/100 PY) and headache (13.3/100 PY) [18].

Long-term (up to 36 months) treatment with ritlecitinib was generally safe and well tolerated in patients with alopecia areata, according to interim results from ALLEGRO-LT [19]. Treatment-emergent AEs (TEAEs) occurred in 78% of patients in the de novo arm. Most TEAEs were mild or moderate in severity. The most common TEAE was headache (16%). Serious AEs occurred in 4% of patients and 5% of patients discontinued treatment due to AEs [19].

2.4.2 Other Indications

Ritlecitinib was well tolerated in patients with active non-segmental vitiligo [15]. Most TEAEs during the dose-ranging period were of mild or moderate severity. There were no dose-dependent trends in TEAEs, serious AEs or AEs leading to treatment discontinuation. During the entire 48-week study period, the most common TEAEs were nasopharyngitis, upper respiratory tract infection and headache [15].

Ritlecitinib had an acceptable short-term safety profile in patients with ulcerative colitis [16]. The majority of AEs were mild in severity. The most common (incidence ≥ 5%) all-cause AEs were anaemia, headache, nasopharyngitis, abdominal pain, pyrexia and arthralgia. Infections and infestations, most of which were mild or moderate in severity, occurred in 9% of ritlecitinib recipients, 17% of brepocitinib recipients and 4% of placebo recipients [16].

2.5 Ongoing Clinical Trials

The ongoing ALLEGRO-LT trial (NCT04006457) is investigating the safety and efficacy of ritlecitinib in rollover patients with alopecia areata from ALLEGRO-2a and ALLEGRO-2b/3, as well as de novo patients who had not received treatment in either trial. An expanded access study (NCT05522556) is currently recruiting patients with alopecia areata.

A randomized, double-blind, multicentre, phase 3 trial (NCT05583526; Tranquilo) is currently recruiting patients. The study plans to investigate the efficacy, safety and tolerability of ritlecitinib in adults and adolescent patients with non-segmental vitiligo. A randomized, double-blind, multicentre, phase 2a trial (NCT03395184) is underway to evaluate the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of ritlecitinib in patients with moderate to severe Crohn’s disease.

3 Current Status

Ritlecitinib received its first approval on 23 June 2023 for severe alopecia areata in the USA [2]. Ritlecitinib was approved in Japan on 26 June 2023 for the treatment of alopecia areata (limited to intractable cases involving widespread hair loss) [3]. Ritlecitinib received a positive opinion in the EU on 20 July 2023 for the treatment of alopecia areata [4] and is under regulatory review in the UK and China for the same indication.