Ritlecitinib 50mg capsules

Background: Alopecia areata (AA) typically presents as round patches of hair loss (e.g., scalp, eyebrow/eyelash, and body), has an unpredictable disease course, and may relapse and remit. AA is a condition with a lifetime risk of approximately 2% in the global population with an annual incidence rate ranging from 2.53 to 26 per 100,000. This comprehensive systematic review and meta-analysis was performed to determine the safety and efficacy of Ritlecitinib in patients with AA. Methods: A systematic search was conducted in PubMed and Cochrane CENTRAL Library for randomized controlled trials (RCTs). We used mean difference with 95% confidence intervals to assess the effectiveness and odds ratio to assess the safety profile. A total of 65 publications were identified through a database search. Following two stages of screening, we included 13 publications. All the studies were parallel and double-blind RCTs and published between 2020 and 2022. Results: Our analysis revealed a significant reduction in SALT score at week 12 and week 24 of (−17.43 [−24.67 to −10.20]; p < 0.0001) and (−20.95 [−29.01 to −12.89]; p < 0.0001), respectively, in patients treated with Ritlecitinib compared to placebo. Furthermore, a significant improvement in PGIC score at week 24 was observed. Additionally, Ritlecitinib revealed a slightly higher reduction in AASIS score compared to placebo; however, this difference was statistically non-significant. Notably, the Ritlecitinib group experienced a higher frequency of headaches, acne and nasopharyngitis compared to placebo, while the placebo group reported a greater occurrence of serious adverse events compared to the Ritlecitinib group. This higher rate of serious events in the placebo arm could be explained by the placebo effect, although these differences were statistically non-significant. Conclusions: These findings suggest that Ritlecitinib holds promise as an effective treatment for AA with an acceptable safety profile, warranting further investigation in larger cohorts and long-term studies.

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Ritlecitinib and baricitinib are recently approved systemic treatments for severe alopecia areata (AA). Both demonstrated superiority over placebo in hair regrowth measured by the Severity of Alopecia Tool (SALT), but they have not been directly compared in randomized controlled trials (RCTs). We conducted a systematic review of RCTs evaluating treatments in AA and estimated the efficacy and safety of ritlecitinib and baricitinib at Week 24 using Bayesian network meta-analysis. To adjust and explore effect modifiers, population-adjusted indirect comparison was performed via multilevel network meta-regression (ML-NMR) using ritlecitinib individual patient data (IPD). Co-primary endpoints were SALT ≤20 and SALT ≤10 at Week 24. Unanchored population adjusted ITCs were also computed to evaluate SALT ≤10 and SALT ≤20 endpoints at Week 48/52. Four RCTs (ALLEGRO 2a [NCT02974868], ALLEGRO 2b/3 [NCT03732807], BRAVE-AA1 [NCT03570749] and BRAVE-AA2 [NCT03899259]) were included. No evidence of a difference between ritlecitinib 50 mg and baricitinib 4 mg on SALT ≤10 (odds ratio, OR: 0.96, 95% credible interval, CrI: 0.18-7.21) and SALT ≤20 (OR: 2.16, 95% CrI: 0.48-16.46) at Week 24 was found. ML-NMR using ALLEGRO IPD adjusted for sex, SALT score at baseline, duration of current episode and disease duration found evidence of effect modification, although relative efficacy between ritlecitinib 50 mg and baricitinib 4 mg remained unchanged. Unanchored population-adjusted ITC at Week 48/52 was consistent with previous results. We found similar efficacy between ritlecitinib 50 mg and baricitinib 4 mg. These ITCs was informed by only four RCTs, uncertainty was considerable, and there was evidence of effect modification, highlighting the need for further quality research in AA.

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Androgenetic alopecia (AGA), the most prevalent clinical hair loss, lacks safe and effective treatments due to downregulated angiogenic genes and insufficient vascularization in the perifollicular microenvironment of the bald scalp in AGA patients. In this study, a hyaluronic acid (HA) based hydrogel-formed microneedle (MN) was designed, referred to as V-R-MNs, which was simultaneously loaded with vascular endothelial growth factor (VEGF) and the novel hair loss drug Ritlecitinib, the latter is encapsulated in slowly biodegradable polyhydroxyalkanoates (PHAs) nanoparticles (R-PHA NPs) for minimally invasive AGA treatment. The integration of HA based hydrogel alongside PHA nanoparticles significantly bolstered the mechanical characteristics of microneedles and enhanced skin penetration efficiency. Due to the biosafety, mechanical strength, and controlled degradation properties of HA hydrogel formed microneedles, V-R-MNs can effectively penetrate the skin's stratum corneum, facilitating the direct delivery of VEGF and Ritlecitinib in a minimally invasive, painless and long-term sustained release manner. V-R-MNs not only promoted angiogenesis and improve the immune microenvironment around the hair follicle to promote the proliferation and development of hair follicle cells, but also the application of MNs to the skin to produce certain mechanical stimulation could also promote angiogenesis. In comparison to the clinical drug minoxidil for AGA treatment, the hair regeneration effect of V-R-MN in AGA model mice is characterized by a rapid onset of the anagen phase, improved hair quality, and greater coverage. This introduces a new, clinically safer, and more efficient strategy for AGA treatment, and serving as a reference for the treatment of other related diseases.

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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).

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BACKGROUND: The ALLEGRO phase IIa and IIb/III (NCT02974868 and NCT03732807) studies have demonstrated that ritlecitinib is effective and well tolerated in adults and adolescents with alopecia areata (AA) up to 48 weeks. OBJECTIVES: To assess the efficacy of ritlecitinib through month 24 and safety through data cutoff in the ALLEGRO phase IIb/III study and the ongoing long-term open-label phase III ALLEGRO-LT study (NCT04006457). METHODS: Patients aged ≥ 12 years with AA and ≥ 50% scalp hair loss from ALLEGRO IIb/III who rolled over to ALLEGRO-LT after up to 48 weeks were included. Proportions of patients with responses based on clinician-reported Severity of Alopecia Tool (SALT) scores of ≤ 20 and ≤ 10, eyebrow assessment (EBA) and eyelash assessment (ELA), patient global impression of change (PGI-C) and patient satisfaction with hair growth were reported through month 24 for patients who received ritlecitinib 50 mg daily with or without a 200-mg 4-week daily loading dose. Observed and imputed data [last observation carried forward (LOCF)] were reported up to 9 December 2022. Safety was assessed throughout. RESULTS: At month 12, a SALT score ≤ 20 was achieved by 45.1% and 45.9% (observed) and 40.3% and 41.8% (LOCF) of the 191 and 194 patients who received ritlecitinib 50 mg and ritlecitinib 200 mg/50 mg, respectively. At month 24, these proportions increased to 60.8% and 63.1% (observed) and 46.1% and 50.8% (LOCF), respectively. Patients with abnormal EBA or ELA scores at baseline achieved responses at month 24 [EBA observed: 57.6% (50 mg), 61.0% (200/50 mg); EBA LOCF: 46.8% (50 mg), 50.9% (200/50 mg); ELA observed: 51.2% (50 mg), 62.7% (200/50 mg); ELA LOCF: 43.2% (50 mg), 51.7% (200/50 mg)]. PGI-C response was achieved by patients at month 24 [observed: 70.0% (50 mg), 76.4% (200/50 mg); LOCF: 56.6% (50 mg), 65.5% (200/50 mg)]. Safety profiles for both treatment groups were consistent with the known safety profile of ritlecitinib. CONCLUSIONS: Ritlecitinib has clinically meaningful and sustained efficacy beyond 1 year with a favourable safety and tolerability profile, supporting its long-term use in patients aged ≥ 12 years with AA.

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BACKGROUND: Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, demonstrated efficacy over 48 weeks in patients with alopecia areata (AA) in the ALLEGRO phase 2b/3 study. OBJECTIVES: This post hoc analysis evaluated individual Severity of Alopecia Tool (SALT) score trajectories in patients who received ritlecitinib 50 mg and rolled over from Phase 2b/3 into the ongoing, open-label, Phase 3 ALLEGRO-LT study to describe long-term response patterns and associated baseline disease characteristics. METHODS: Patients aged ≥12 years with ≥50% scalp hair loss received ritlecitinib 50 mg once daily in both studies. SALT score trajectories from baseline to Month 24 were used to categorise patients as early (SALT score ≤20 at Week 24 and Months 12 and 24), middle (≤20 at Months 12 and 24) or late responders (≤20 by Month 24) or as partial responders (maintained 30% improvement), relapsers (achieved but did not maintain 30% improvement) or non-responders (did not achieve 30% improvement). The proportions of patients achieving sustained response (achieved and maintained SALT score ≤20 at all subsequent available time points through Month 24) and complete response (SALT score 0 at ≥1 time point through Month 24) were evaluated. Multivariable logistic regression assessed variables associated with response. RESULTS: Of 191 patients treated with ritlecitinib 50 mg, 87 (45.5%) were responders (SALT score ≤20), 24 (12.6%) were partial responders, 24 (12.6%) were relapsers and 56 (29.3%) were non-responders. Of 87 patients categorised as responders, 81 (93.1%) sustained their clinical response and 47 (46.0%) achieved complete response. Factors associated with treatment response included female sex and less extensive and shorter duration of hair loss. CONCLUSIONS: Approximately 45% of patients were SALT score responders, with up to 11% requiring >1 year of ritlecitinib treatment to achieve response, highlighting the importance of extended treatment duration. GOV REGISTRATION: ALLEGRO phase 2b/3 study (NCT03732807); ALLEGRO-LT study (NCT04006457).

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BACKGROUND: ALLEGRO-LT is an ongoing, long-term, open-label, multicentre, phase 3 study of ritlecitinib in adults and adolescents with alopecia areata (AA). OBJECTIVES: To evaluate ritlecitinib safety and efficacy through Month 24 in patients with AA and ≥25% scalp hair loss. METHODS: ALLEGRO-LT enrolled rollover patients who previously received study intervention in either ALLEGRO phase 2a or 2b/3 studies and de novo patients who had not received treatment in either study. The de novo cohort results are reported here. Patients aged ≥12 years with AA and ≥25% scalp hair loss received a daily, 4-week 200-mg ritlecitinib loading dose, followed by daily 50-mg ritlecitinib. Analyses are based on data up to the cut-off (December 2022). Efficacy outcomes included proportions of patients achieving Severity of Alopecia Tool (SALT) scores ≤20 and ≤10, Patient Global Impression of Change (PGI-C) score of 'moderately improved' or 'greatly improved' and eyebrow assessment (EBA) and eyelash assessment (ELA) response (≥2-grade improvement from baseline or normal score in patients with abnormal baseline EBA/ELA). RESULTS: Mean (SD) ritlecitinib exposure among the 449 de novo patients enrolled was 728.7 (273.81) days. At Month 24 (as observed), 73.5% and 66.4% of patients achieved SALT score ≤20 and ≤10; 82.4% had PGI-C response; 60.8% and 65.7% had EBA and ELA response. 86.1% of patients reported treatment-emergent adverse events (AEs); most were mild or moderate in severity, with the most frequent being positive SARS-CoV-2 test (24.2%), headache (20.8%) and pyrexia (13.0%). Rates of serious AEs, severe AEs and treatment discontinuations were 4.9%, 6.0% and 6.5%, respectively. Herpes zoster infection occurred in six patients, serious infections in four, malignancies (excluding nonmelanoma skin cancer) in three and major adverse cardiovascular events in three. CONCLUSIONS: In patients with AA and ≥25% scalp hair loss, ritlecitinib demonstrated clinical efficacy and had an acceptable safety profile with long-term treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04006457.

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Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.

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