Dataset Information

Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program.

ABSTRACT:

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).

SUBMITTER: King B

PROVIDER: S-EPMC10867086 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program.

King Brett B Soung Jennifer J Tziotzios Christos C Rudnicka Lidia L Joly Pascal P Gooderham Melinda M Sinclair Rodney R Mesinkovska Natasha A NA Paul Carle C Gong Yankun Y Anway Susan D SD Tran Helen H Wolk Robert R Zwillich Samuel H SH Lejeune Alexandre A

American journal of clinical dermatology 20240123 2

<h4>Background</h4>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).<h4>Objective</h4>The objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA.<h4>Methods</h4>Two cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates ...[more]

PMID: 38263353

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Project description:IntroductionPatients with alopecia areata (AA) report high levels of dissatisfaction with commonly used treatments. Patient-reported outcomes are essential to understanding patients' experiences with AA treatments. The objective of this study was to evaluate patient-reported satisfaction with hair growth among patients with AA receiving ritlecitinib or placebo and the correlation between clinician-assessed efficacy and patient-reported satisfaction.MethodsIn the ALLEGRO-2b/3 (NCT03732807) trial, patients with AA and ≥50% scalp hair loss were randomized to daily ritlecitinib or placebo for 24 weeks, with a 24-week extension of continued ritlecitinib or switch from placebo to ritlecitinib. The Patient Satisfaction with Hair Growth (P-Sat) measure evaluated patients' satisfaction with hair growth in 3 domains: amount, quality, and overall satisfaction with hair growth. The prespecified analysis evaluated the proportion of patients who were slightly, moderately, or very satisfied with hair growth. Several post hoc analyses assessed the proportion of patients who were moderately/very satisfied and moderately/very dissatisfied and calculated polyserial correlations between change from baseline (CFB) in Severity of Alopecia Tool (SALT) and P-Sat scores at weeks 24 and 48.ResultsAt week 24, the proportion of patients (N = 718) reporting satisfaction (slightly, moderately, or very satisfied) overall with their hair growth ranged from 36.4% in the ritlecitinib 10-mg group (evaluated for dose ranging only) to 67.5% in the 200/50-mg group versus 22.6% in the placebo groups. In patients randomized to ritlecitinib, the proportion who were satisfied increased or was maintained at week 48. A substantially greater proportion of placebo patients who switched to ritlecitinib reported satisfaction at week 48 than at week 24. Similar results were observed for patient satisfaction with the amount and quality of hair growth. In the post hoc analyses defining satisfaction as moderately/very satisfied and dissatisfaction as moderately/very dissatisfied, the benefit of ritlecitinib was also observed. All P-Sat domain scores strongly correlated with CFB-SALT scores at weeks 24 (range 0.73-0.76; p < 0.05) and 48 (0.74-0.77; p < 0.05).ConclusionsPatients receiving active ritlecitinib doses reported favorable results versus placebo in satisfaction with hair growth up to week 48. High concordance was observed between improvement in scalp hair growth evaluated by clinicians and patient-reported satisfaction.

Project description:IntroductionRitlecitinib demonstrated efficacy in patients with alopecia areata (AA) in the ALLEGRO phase 2b/3 study (NCT03732807). However, hair loss presentation may vary based on location (e.g., scalp, eyebrow/eyelash, body). Here, we sought to identify distinct hair loss profiles at baseline and evaluate whether they affected the efficacy of ritlecitinib.MethodsPatients with AA aged ≥ 12 years with ≥ 50% scalp hair loss were randomized to daily ritlecitinib 10 mg (assessed for dose ranging only), 30 or 50 mg (± 4-week, 200-mg loading dose), or placebo for 24 weeks. Latent class analysis (LCA) identified hair loss profiles based on four baseline measurements: clinician-reported extent of scalp (Severity of Alopecia Tool score), eyebrow hair loss, eyelash hair loss, and patient-reported body hair loss. Logistic regression evaluated ritlecitinib (50 and 30 mg) efficacy vs placebo using Patient Global Impression of Change (PGI-C) and Patient Satisfaction with Hair Growth (P-Sat; amount, quality, and overall satisfaction) responses at Week 24, adjusting for key covariates, including latent class membership.ResultsLCA identified five latent classes: (1) primarily non-alopecia totalis (AT; complete loss of scalp hair); (2) non-AT with moderate non-scalp involvement; (3) extensive scalp, eyebrow, and eyelash involvement; (4) AT with moderate non-scalp involvement; and (5) primarily alopecia universalis (complete scalp, face, and body hair loss). Adjusting for latent class membership, patients receiving ritlecitinib 30 or 50 mg were significantly more likely to achieve PGI-C response (30 mg: odds ratio, 8.62 [95% confidence interval, 4.42-18.08]; 50 mg: 12.29 [6.29-25.85]) and P-Sat quality of hair regrowth (30 mg: 6.71 [3.53-13.51]; 50 mg: 8.17 [4.30-16.46]) vs placebo at Week 24. Results were similar for P-Sat overall satisfaction and amount of hair regrowth.ConclusionDistinct and clinically relevant hair loss profiles were identified in ALLEGRO-2b/3 participants. Ritlecitinib was efficacious compared with placebo, independent of hair loss profile at baseline.Trial registrationClinicalTrials.gov identifier, NCT03732807.

Project description:Ritlecitinib is an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma (JAK3/TEC) family kinase inhibitor approved for the treatment of severe alopecia areata (AA). Benefit-risk profiles of two doses of ritlecitinib (50 mg vs 30 mg once daily) were evaluated by integrating patient preferences and clinical efficacy and safety estimates for ritlecitinib. A discrete-choice experiment (DCE) was utilized to elicit preferences for benefit and safety attributes of systemic AA treatments. Benefits included probabilities of ≥80% scalp hair coverage and achieving moderate to normal eyebrows and eyelashes. Potential risks included 3-year probabilities of serious infection, cancer, and blood clots. Preference estimates were used to calculate the maximum acceptable risk (MAR) that patients would accept for expected increases in benefit from choosing a higher ritlecitinib dose over a lower dose. Ritlecitinib benefits were calculated from the ALLEGRO-2b/3 clinical trial. MARs were calculated separately for each risk and jointly for all possible combinations. Adults (n = 201) with physician-confirmed ≥50% scalp hair loss from AA participated. To achieve expected increases in the probabilities of ≥80% scalp hair coverage or moderate to normal eyebrows and eyelashes when choosing 50 mg over 30 mg of ritlecitinib, patients would be willing to accept increases in each 3-year risk up to a mean of 3.88 absolute percentage points (95% confidence interval [CI], 2.86-4.90) for serious infection, 1.63 (95% CI, 1.08-2.18) for cancer, and 5.30 (95% CI, 3.60-7.00) for blood clots. These results, combined with the estimated differences in risks between the two doses, indicate that patients with AA value increases in the probabilities of scalp, eyebrow, and eyelash hair regrowth, with the average patient accepting increases in potential treatment-related risks for the 50-mg dose in exchange for higher efficacy than 30 mg. The DCE approach to measuring risk tolerance, combined with comparisons to expected benefit and risk differences, can be used to optimize AA treatment dose selection.

Dataset Information

Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program.

Background

Objective

Methods

Results

Conclusions

Trial registries

Publications

Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program.

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