ABSTRACT
Background
Alopecia areata (AA) is an autoimmune disease characterized by hair loss that can negatively impact quality of life. AA has a significant pediatric prevalence; however, no systemic treatments are approved for AA in patients aged < 12 years. Ritlecitinib, a JAK3/TEC family kinase inhibitor, is approved to treat adults and adolescents with severe AA aged ≥ 12 years. This study evaluated ritlecitinib pharmacokinetic (PK) parameters and safety in pediatric patients with AA aged 6 to < 12 years.
Methods
In this single‐group, uncontrolled, open‐label study, participants received ritlecitinib 20 mg once daily for 7 days. PK parameters of ritlecitinib on Day 7 were measured and summarized descriptively. Safety outcomes, including incidence of adverse events (AEs), were evaluated.
Results
Fifteen participants were enrolled and 14 (93.3%) completed the study. The median time to maximum concentration (Tmax) for plasma concentrations of ritlecitinib on Day 7 was ~0.5 h. The mean half‐life of ritlecitinib was ~1.19 h. Geometric means (% coefficient of variation) for area under the curve from 0 to 24 h (AUC24) and maximum concentration (Cmax) were 437.5 ng·h/mL (30%) and 208.7 ng/mL (38%), respectively. Four AEs were experienced by 3 participants, with 1 AE of urticaria resulting in permanent discontinuation. No severe AEs, serious AEs, or clinically meaningful laboratory abnormalities were reported.
Conclusions
Ritlecitinib PK parameters in pediatric patients were successfully characterized in the present study. Ritlecitinib 20 mg once daily was generally well tolerated in pediatric patients with AA.
Trial Registration
Keywords: alopecia areata, children, clinical trial, pediatrics, pharmacokinetics
1. Introduction
Alopecia areata (AA), an autoimmune disease with an underlying immuno‐inflammatory pathogenesis characterized by nonscarring hair loss of the scalp, face, and/or body, can affect children and adults across all ages, races, and sexes [1, 2]. AA is associated with other immune diseases, including asthma, allergic rhinitis, and atopic dermatitis, and autoimmune diseases such as thyroiditis and vitiligo [3].
While AA can develop at any age, 40% of patients first present with symptoms before the age of 20 years [4]. Similarly to the burden of disease observed in adults, pediatric patients also report significant negative impacts to quality of life. A review of 6 studies examining the psychosocial burden and effect of pediatric AA on quality of life found that children with AA experienced an increased prevalence of anxiety, depression, and obsessive‐compulsive disorder compared with age‐matched healthy controls and often reported negative impacts to self‐esteem, academic performance, friendships, and body image [5]. Another study in 33 children with AA and matched healthy controls found that those with AA experienced greater mental and somatic challenges, difficulty in social relations, and worse attention spans [6]. In one study, approximately one‐fifth of all children aged 5–11 years reported bullying and limited participation in activities due to their AA, with the frequency increasing in preteen and teenage patients; nearly 80% of participants aged 5–11 years reported that others would notice or comment on their AA [7].
In the ALLEGRO‐2b/3 pivotal clinical trial, ritlecitinib, an oral JAK3/TEC family kinase inhibitor, showed safety and efficacy vs. placebo in patients aged ≥ 12 years [8, 9]. Ritlecitinib is approved for treatment of severe AA in adults and adolescents aged ≥ 12 years in the US, EU, Japan, China, and several other countries [10]. At this time, there are no systemic treatments approved for the treatment of AA in pediatric patients aged < 12 years. This study was specifically designed to collect data supporting ritlecitinib dose selection for pediatric patients aged 6 to < 12 years.
2. Materials and Methods
2.1. Study Participants
Participants aged 6 to < 12 years who had a diagnosis of severe AA, including alopecia totalis and alopecia universalis, with ≥ 50% scalp hair loss due to AA as determined by a Severity of Alopecia Tool score, and who had no evidence of terminal hair regrowth within the previous 12 months, were eligible for the study.
Exclusion criteria included other etiologies of hair loss, any present malignancies or history of malignancies, history of cytomegalovirus, varicella, herpes zoster (shingles), or disseminated herpes simplex infection, not up to date with all age‐appropriate vaccines (including the 2‐dose vaccination for varicella), and receiving a vaccination with attenuated live vaccine within 6 weeks of the first dose of the study medicine.
At least 12 participants were to be enrolled, including at least 4 participants aged 6–9 years.
2.2. Study Design and Treatment
This was a single‐group, uncontrolled, open‐label, interventional, pharmacokinetic (PK) study to estimate the systemic exposures of ritlecitinib 20 mg once daily (QD) in children with AA.
Participants received oral ritlecitinib 20 mg QD for 7 consecutive days (Figure 1). The first and last doses were administered at the study site, while doses 2 through 6 were administered at home. Ritlecitinib was dispensed to the participants' parents or legal guardians for the duration of the treatment. A follow‐up visit was conducted by phone 28–35 days after the last dose of ritlecitinib.
FIGURE 1.
Study design.
The study was conducted in accordance with the ethical principles derived from international guidelines, including the Declaration of Helsinki Council and Council for International Organizations of Medical Sciences international ethical guidelines, applicable International Council of Harmonization Good Clinical Practice guidelines, and other applicable laws and regulations, including privacy laws. Participants or their legally authorized representatives were informed that participation was voluntary and signed a statement of informed consent/assent that met the requirements of 21 Code of Federal Regulations 50 (21 CFR Part 50), local regulations, International Council of Harmonization guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the institutional review board or study center.
2.3. Collection and Analysis of Plasma and Urine Samples
Blood samples for PK analysis were collected on Day 7 at 0 (pre‐dose), 0.5, 1, 3, and 8 h post dosing. Urine and plasma samples were also collected for clinical chemistry, hematology, and urinalysis. Blood and urine samples were analyzed by a central laboratory, ICON Laboratory Services Inc.
2.4. Assessments
The primary objective was to characterize the PK of ritlecitinib in children with AA aged 6 to < 12 years. The primary PK measure was the area under the concentration‐time curve from 0 to 24 h (AUC24) of ritlecitinib on Day 7. Secondary PK endpoints included maximum concentration (Cmax), time to reach Cmax (Tmax), apparent clearance and volume of distribution (CL/F, Vz/F), and terminal half‐life (t1/2) of ritlecitinib on Day 7.
Secondary objectives also included evaluating the safety and tolerability of ritlecitinib, including treatment‐emergent adverse events (TEAEs), treatment‐related AEs, serious AEs (SAEs), AEs leading to discontinuation, and clinically significant abnormalities in vital signs and clinical laboratory values.
2.5. Statistical Analysis
All participants with evaluable PK data were included in the PK analysis population. Participants who were not able to provide a full set of evaluable PK data or missed > 1 dose could be replaced at the discretion of the sponsor. Plasma concentrations were summarized descriptively by nominal PK sampling time. Samples below the lower limit of quantification were set to 0 ng/mL for analysis. Individual participant and median profiles of the plasma concentration‐time data were plotted using actual and nominal times, respectively. Median profiles were presented on both linear‐linear and log‐linear scales.
3. Results
3.1. Patient Disposition and Demographics
A total of 16 participants were screened and 15 were assigned to receive ritlecitinib; 14 participants (93.3%) completed treatment. One participant (6.7%) discontinued ritlecitinib due to an AE of urticaria on Day 3. All 15 participants completed the follow‐up phase of the study.
Mean (SD) participant age was 8.5 (1.6) years, with 9 participants (60%) aged 6 to < 9 years (Table 1). A total of 12 participants (80%) were female, 13 (86.7%) were White, and 8 (53.3%) were Hispanic or Latino. Median (range) body mass index (BMI) was 17.1 kg/m2 (13.1–22.3 kg/m2).
TABLE 1.
Demographic characteristics of the study population.
| Characteristic | Ritlecitinib 20 mg QD (N = 15) |
|---|---|
| Age, years | |
| 6–8, n (%) | 9 (60.0) |
| 9–11, n (%) | 6 (40.0) |
| Median (range) | 8.0 (6–11) |
| Mean (SD) | 8.5 (1.60) |
| Sex, n (%) | |
| Male | 3 (20.0) |
| Female | 12 (80.0) |
| Race, n (%) | |
| White | 13 (86.7) |
| Black or African American | 2 (13.3) |
| Ethnicity, n (%) | |
| Hispanic or Latino | 8 (53.3) |
| Not Hispanic or Latino | 7 (46.7) |
| Weight, kg | |
| Mean (SD) | 32.3 (8.3) |
| Median (range) | 33.4 (21.0–50.6) |
| BMI, kg/m2 | |
| Mean (SD) | 17.4 (2.7) |
| Median (range) | 17.1 (13.1–22.3) |
Abbreviations: BMI, body mass index; QD, once daily.
3.2. Pharmacokinetics
A total of 13 participants were included in the PK analysis population. Two participants were excluded as they did not have evaluable PK data (1 participant discontinued and the other had no PK samples collected on Day 7). Following multiple doses of ritlecitinib 20 mg, plasma concentrations of ritlecitinib on Day 7 had a median Tmax of ~0.5 h (Table 2). Ritlecitinib mean terminal t1/2 was ~1.19 h (Figure 2A,B). Geometric mean values for ritlecitinib exposure parameters AUC24 and Cmax were 437.5 ng∙h/mL and 208.7 ng/mL, respectively. The geometric mean CL/F was 45.7 L/h and mean Vz/F was ~74.9 L. The variability (geometric % coefficient of variation) for AUC24 and Cmax was 30% and 38%, respectively.
TABLE 2.
Summary of plasma ritlecitinib PK parameters.
| Parameter | Ritlecitinib 20 mg QD (N = 13) a |
|---|---|
| AUC24, geometric mean (geometric % coefficient of variation), ng.h/mL | 437.5 (30) |
| CL/F, geometric mean (geometric % coefficient of variation), L/h | 45.7 (30) |
| Cmax, geometric mean (geometric % coefficient of variation), ng/mL | 208.7 (38) |
| t1/2, arithmetic mean ± SD, h | 1.19 ± 0.11 |
| Tmax, median (range), h | 0.50 (0.45–1.00) |
| Vz/F, geometric mean (geometric % coefficient of variation), L | 74.9 (23) |
Abbreviations: AUC24, area under the curve from 0 to 24 h; CL/F, clearance; Cmax, maximum concentration; PK, pharmacokinetics; QD, once daily; t1/2, half‐life; Tmax, time to maximum concentration; Vz/F, volume of distribution.
n = 8 for t1/2 and Vz/F.
FIGURE 2.
(A) Linear median plasma ritlecitinib concentration‐time curve (ng/mL) and (B) Semi‐log median plasma ritlecitinib concentration‐time curve (ng/mL). QD, once daily.
3.3. Safety
Of the 15 participants in the safety population, 3 participants experienced a total of 4 AEs. One participant experienced vomiting and nausea, and a second participant experienced myalgia; these AEs were considered mild and not treatment related, and neither participant experienced a dose interruption or modification. A third participant experienced urticaria (investigator term: acute urticaria on both legs), which was considered moderate and treatment related by the investigator. The urticaria began on study Day 1, lasted for 3 days, and resulted in permanent discontinuation from the study. The case of urticaria was reported. No SAEs, severe AEs, dose reductions, temporary discontinuations due to AEs, or deaths were reported. No clinically significant changes were observed in vital signs or clinical laboratory assessments.
4. Discussion
This phase 1 study characterized the PK and safety of ritlecitinib in pediatric patients with AA aged 6 to < 12 years. PK results will be used to update the population PK model established based on prior studies in adults and adolescents [11], and subsequently to guide the dosing selection in pediatric phase 3 studies.
Among pediatric patients with AA in this study, ritlecitinib 20 mg QD was generally well tolerated. No serious AEs or SAEs were reported. Of 15 participants, 3 (20%) reported AEs, with 1 participant permanently discontinuing from treatment. The safety profile of ritlecitinib was previously characterized in adults and adolescents aged ≥ 12 years for doses up to 200 mg [8, 9, 12]. No new or unique safety findings were reported in this study of younger pediatric patients aged 6 to < 12 years.
In conclusion, after 7 days of ritlecitinib 20 mg QD, geometric mean values for ritlecitinib exposure parameters AUC24 and Cmax were 437.5 ng.h/mL and 208.7 ng/mL, respectively, with a median Tmax of ~0.5 h and a mean t1/2 value of ~1.2 h. These observed PK data will be used to inform the dose selection for pediatric phase 3 studies. Ritlecitinib was generally well tolerated among children with AA aged 6 to < 12 years. Future studies will assess the efficacy and safety of ritlecitinib in pediatric patients with AA.
Ethics Statement
This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines, including the Declaration of Helsinki Council and Council for International Organizations of Medical Sciences international ethical guidelines, applicable International Council of Harmonization Good Clinical Practice guidelines, and other applicable laws and regulations, including privacy laws.
Consent
Participants and their legally authorized representatives were informed that their participation was voluntary and signed a statement of informed consent that met the requirements of 21 Code of Federal Regulations 50 (21 CFR Part 50), local regulations, International Council for Harmonization guidelines, Health Insurance Portability and Accountability Act (HIPPA) requirements, where applicable, and the institutional review board or study center.
Conflicts of Interest
M.E.G. declares being an investigator for AbbVie, Arcutis Biotherapeutics, Amgen, Anterogen, Dermavant, Eli Lilly, Incyte, Krystal Biotech, Neilsen Biosciences, Novartis, Pfizer, Regeneron, and Sanofi; being a consultant for Abeona Therapeutics, Arcutis Biotherapeutics, Alphyn Biologics, Dermavant, Eli Lilly, Incyte, Krystal Biotech, and Verrica Pharmaceuticals; and being on speakers bureaus for AbbVie, Arcutis, Eli Lilly, Krystal Biotech, Pfizer, Regeneron, Sanofi, and Verrica Pharmaceuticals. J.B. declares no conflicts. S.S. has received research grants from Teoxane SA. At the time of the study, A.P., J.Z., S.P., Y.H., and R.W. were employees of and may own shares/stock options in Pfizer.
Acknowledgments
Editorial support was provided by Carolyn Maskin, PhD, of Nucleus Global, and was funded by Pfizer Inc.
Gonzalez M. E., Browning J., Smith S., et al., “A Phase 1, Open‐Label Study of the Pharmacokinetics of Ritlecitinib in Children Aged 6–12 Years With Alopecia Areata,” Pediatric Dermatology 42, no. 4 (2025): 742–746, 10.1111/pde.15895.
Funding: This work was supported by Pfizer Inc.
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.