Efficacy and safety of ritlecitinib in adults and adolescents with alopecia areata: a randomised, double-blind, multicentre, phase 2b-3 trial.

BACKGROUND: Alopecia areata is characterised by non-scarring loss of scalp, face, or body hair. We investigated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, in patients with alopecia areata. METHODS: In this randomised, double-blind, multicentre, phase 2b-3 trial done at 118 sites in 18 countries, patients aged 12 years and older with alopecia areata and at least 50% scalp hair loss were randomly assigned to oral ritlecitinib or placebo once-daily for 24 weeks, with or without a 4-week loading dose (50 mg, 30 mg, 10 mg, 200 mg loading dose followed by 50 mg, or 200 mg loading dose followed by 30 mg), followed by a 24-week extension period during which ritlecitinib groups continued their assigned doses and patients initially assigned to placebo switched to ritlecitinib 50 mg or 200 mg loading dose followed by 50 mg. Randomisation was done by use of an interactive response system and was stratified by baseline disease severity and age. The sponsor, patients, and investigators were masked to treatment, and all patients received the same number of tablets to maintain masking. The primary endpoint was Severity of Alopecia Tool (SALT) score 20 or less at week 24. The primary endpoint was assessed in all assigned patients, regardless of whether they received treatment. This study was registered with ClinicalTrials.gov, NCT03732807. FINDINGS: Between Dec 3, 2018, and June 24, 2021, 1097 patients were screened and 718 were randomly assigned to receive ritlecitinib 200 mg + 50 mg (n=132), 200 mg + 30 mg (n=130), 50 mg (n=130), 30 mg (n=132), 10 mg (n=63), placebo to 50 mg (n=66), or placebo to 200 mg + 50 mg (n=65). 446 (62%) of 718 patients were female and 272 (38%) were male. 488 (68%) were White, 186 (26%) were Asian, and 27 (4%) were Black or African American. Of 718 patients randomly assigned, 104 patients discontinued treatment (34 withdrew, 19 adverse events [AEs], 12 physician decision, 12 lack of efficacy, 13 lost to follow up, five rolled over to long-term study transfer, four pregnancies, two protocol deviations, one declined to attend follow-up due to COVID-19, one attended last visit very late due to COVID-19, and one non-compliance). At week 24, 38 (31%) of 124 patients in the ritlecitinib 200 mg + 50 mg group, 27 (22%) of 121 patients in the 200 mg + 30 mg group, 29 (23%) of 124 patients in the 50 mg group, 17 (14%) of 119 patients in the 30 mg group, and two (2%) of 130 patients in the placebo group had a response based on SALT score 20 or less. The difference in response rate based on SALT score 20 or less between the placebo and the ritlecitinib 200 mg + 50 mg group was 29·1% (95% CI 21·2-37·9; p<0·0001), 20·8% (13·7-29·2; p<0·0001) for the 200 mg + 30 mg group, 21·9% (14·7-30·2; p<0·0001) for the 50 mg group, and 12·8% (6·7-20·4; p=0·0002) for the 30 mg group. Up to week 48 and including the follow-up period, AEs had been reported in 108 (82%) of 131 patients in the ritlecitinib 200 mg + 50 mg group, 105 (81%) of 129 patients in the 200 mg + 30 mg group, 110 (85%) of 130 patients in the 50 mg group, 106 (80%) of 132 patients in the 30 mg group, 47 (76%) of 62 patients in the 10 mg group, 54 (83%) of 65 patients placebo to ritlecitinib 200 mg + 50 mg in the extension period, and 57 (86%) of 66 patients in the placebo to 50 mg group. The incidence of each AE was similar between groups, and there were no deaths. INTERPRETATION: Ritlecitinib was effective and well tolerated in patients aged 12 years and older with alopecia areata. Ritlecitinib might be a suitable treatment option for alopecia areata in patients who are candidates for systemic therapy. FUNDING: Pfizer.

Efficacy and safety of the oral JAK3/TEC family kinase inhibitor ritlecitinib over 24 months: integrated analysis of the ALLEGRO phase 2b/3 and long-term phase 3 clinical studies in alopecia areata.

BACKGROUND: The ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib is efficacious and well tolerated in adult and adolescent patients with alopecia areata (AA) up to 48 weeks. OBJECTIVE: The efficacy of ritlecitinib through Month 24 and safety through data cutoff were assessed in the ALLEGRO phase 2b/3 study and the ongoing long-term, open-label, phase 3 ALLEGRO-LT study. METHODS: Patients aged ≥12 years with AA and ≥50% scalp hair loss from ALLEGRO-2b/3 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) score of ≤20 and ≤10, eyebrow assessment (EBA) and eyelash assessment (ELA), patient global impression of change (PGI-C) and patient satisfaction with hair growth are 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 until December 9, 2022. Safety was assessed throughout. RESULTS: At Month 12, 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 200/50 mg, respectively. At Month 24, 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. CONCLUSION: 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. TRIAL REGISTRIES: ClinicalTrials.gov: NCT03732807, NCT04006457.

A study to understand the effect of ritlecitinib 50 milligrams once daily in people with alopecia areata treated for up to 2 years Alopecia areata (AA) is a condition where the immune system mistakenly attacks hair follicles, causing hair loss. It affects around 2% of people worldwide, including children and adults. AA may involve small patches or complete loss of hair on the scalp and/or body. People with AA may need to use medicines for a long time to manage hair loss. But there are not many options available. Ritlecitinib is a pill taken by mouth daily to treat severe AA. It blocks the steps that cause hair loss. In the ALLEGRO-LT study, we looked at how well ritlecitinib worked over 2 years in people aged 12 years and older with AA who had lost at least half of their scalp hair. We measured hair loss on the scalp, eyebrows and eyelashes, as well as how satisfied people were with their hair regrowth. We also looked at how safe ritlecitinib was when taken for 2 years. A total of 191 people from 17 countries took ritlecitinib 50 milligrams (the approved dose). After 1 year, 74 out of 164 people (45%) had scalp hair regrowth (20% or less scalp hair loss), increasing to 61% after 2 years. For every 8 out of 10 people, their scalp hair regrowth was maintained from 1 to 2 years. Eyebrow and eyelash hair regrowth also increased over 2 years. Around 8 out of 10 people were satisfied with their hair growth after 2 years, and the safety of ritlecitinib was as expected from the studies done before. The results show that ritlecitinib is effective and appropriate for long-term use in people aged 12 years and older with AA.

Sustained hair regrowth with continued ritlecitinib treatment through Week 48 in patients with alopecia areata with or without early target responses: post hoc analysis of the ALLEGRO phase 2b/3 trial.

BACKGROUND: Few treatments for alopecia areata (AA) have demonstrated sustained efficacy. OBJECTIVE: Evaluate the efficacy and safety of continued ritlecitinib treatment to Week 48 in patients with AA with or without target efficacy responses at Week 24. METHODS: Patients aged ≥12 years received daily ritlecitinib (± 4-week loading dose): 200/50 mg, 200/30 mg, 50 mg, or 30 mg. Patients with clinical response at Week 24, based on a Severity of Alopecia Tool (SALT) score ≤20 and ≤10 were evaluated for sustained response through Week 48. Nonresponders at Week 24 were assessed for response through Week 48. RESULTS: Among ritlecitinib-treated patients with SALT score ≤20 and ≤10 responses at Week 24, ≥85% and ≥68%, respectively, sustained these responses through Week 48. Of those with SALT score >20 at Week 24, 22%-34% achieved SALT score ≤20 at Week 48. Of those with a SALT score >10 at Week 24, 20%-26% achieved SALT score ≤10 at Week 48. Safety was similar across subgroups. LIMITATIONS: Small sample size. CONCLUSION: Hair regrowth was sustained through Week 48 in patients with response at Week 24. Up to one-third of patients who did not meet target efficacy at Week 24 achieved response with continued ritlecitinib treatment.

Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants.

AIMS: This clinical study was conducted to evaluate the impact of ritlecitinib on the pharmacokinetics of caffeine, a cytochrome P450 1A2 (CYP1A2) substrate. METHODS: In this single-centre, single-arm, open-label, fixed-sequence study, healthy participants received a single 100-mg dose of caffeine on 2 separate occasions: on Day 1 of Period 1 as monotherapy and on Day 8 of Period 2 after oral administration of ritlecitinib 200 mg once daily for 8 days. Serial blood samples were collected and analysed using a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were estimated by using a noncompartmental method. Safety was monitored by physical examination, vital signs, electrocardiograms and laboratory assessments. RESULTS: Twelve participants were enrolled and completed the study. Coadministration of caffeine 100 mg in the presence of steady-state levels of ritlecitinib (200 mg once daily) increased caffeine exposure compared with caffeine given alone. Area under the curve to infinity and maximum concentration of caffeine increased by approximately 165 and 10%, respectively, when coadministered with ritlecitinib. The ratios of the adjusted geometric means (90% confidence interval) for caffeine area under the curve to infinity and maximum concentration were 265.14% (234.12-300.26%) and 109.74% (103.90-15.91%), respectively, when caffeine was coadministered with steady-state ritlecitinib (test) compared with its administration alone (reference). Multiple doses of ritlecitinib when coadministered with a single dose of caffeine were generally safe and well tolerated in healthy participants. CONCLUSION: Ritlecitinib is a moderate inhibitor of CYP1A2 and can increase systemic exposures of CYP1A2 substrates.

Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and OAT3 Transporter Activity.

PURPOSE: Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. METHODS: In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. RESULTS: In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by ~ 13% and maximum concentration (Cmax) by ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration. CONCLUSION: Ritlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.

Efficacy and safety of ritlecitinib in adolescents with alopecia areata: Results from the ALLEGRO phase 2b/3 randomized, double-blind, placebo-controlled trial.

BACKGROUND/OBJECTIVES: This subgroup analysis of the ALLEGRO phase 2b/3 trial (NCT03732807) evaluated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, for the treatment of alopecia areata (AA) in patients aged 12-17 years. METHODS: In ALLEGRO-2b/3, patients aged ≥12 years with AA and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (±4-week 200-mg loading dose) or 10 mg or placebo for 24 weeks. In a subsequent 24-week extension period, ritlecitinib groups continued their doses, and patients initially assigned to placebo switched to 200/50 or 50 mg daily. Clinician- and patient-reported hair regrowth outcomes and safety were assessed. RESULTS: In total, 105 adolescents were randomized. At Week 24, 17%-28% of adolescents achieved a Severity of Alopecia Tool (SALT) score ≤20 (≤20% scalp without hair) in the ritlecitinib 30 mg and higher treatment groups versus 0% for placebo. At Week 48, 25%-50% of patients had a SALT score ≤20 across ritlecitinib treatment groups (30 mg and higher). Adolescents reporting that their AA "moderately" or "greatly" improved were 45%-61% in the ritlecitinib groups (30 mg and higher) (vs. 10%-22% for placebo) at Week 24 and 44%-80% at Week 48. The most common adverse events in adolescents were headache, acne, and nasopharyngitis. No deaths, major adverse cardiovascular events, malignancies, pulmonary embolisms, opportunistic infections, or herpes zoster infections were reported. CONCLUSION: Ritlecitinib treatment demonstrated clinician-reported efficacy, patient-reported improvement, and an acceptable safety profile through Week 48 in adolescents with AA with ≥50% scalp hair loss.

Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. OBJECTIVE: We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis. METHODS: Twelve patients with plaque psoriasis were randomized (3:1) to receive 10 mg of tofacitinib or placebo twice daily for 12 weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67(+) keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT](+) nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray. RESULTS: In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1 day of tofacitinib (baseline, median of 1290 pSTAT1(+) cells/µm(2); day 1, median of 332 pSTAT1(+) cells/µm(2); and nonlesional, median of 155 pSTAT1(+) cells/µm(2)). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P = .016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/TH17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression. CONCLUSIONS: Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC and T-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/TH17 pathway.

Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.

BACKGROUND: New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population. METHODS: In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3-4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of "clear" or "almost clear" (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591. FINDINGS: Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events. INTERPRETATION: In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis. FUNDING: Pfizer Inc.

Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory condition that is associated with a higher risk of cardiovascular (CV) disease. Tofacitinib is being investigated as a treatment for psoriasis. OBJECTIVE: We sought to evaluate the effects of tofacitinib on CV risk factors and major adverse CV events (MACEs) in patients with plaque psoriasis. METHODS: Changes in select CV risk factors and the incidence rate (IR) of MACEs were evaluated in patients who were treated with tofacitinib. RESULTS: Tofacitinib treatment was associated with small, dose-dependent increases in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, while the total/HDL cholesterol ratio was unchanged. There were no changes in blood pressure and glycated hemoglobin levels; C-reactive protein levels decreased. The IRs of a MACE were low and similar for both tofacitinib doses. Among 3623 subjects treated with tofacitinib, the total patient-years of exposure was 5204, with a median follow-up of 527 days, and the IR of MACEs was 0.37 (95% confidence interval, 0.22-0.57) patients with events per 100 patient-years. LIMITATIONS: There was relatively short follow-up time for patients who had MACEs. CONCLUSIONS: While treatment with tofacitinib is associated with a small increase in cholesterol levels, the total/HDL cholesterol ratio does not change, there are no unfavorable changes in several CV risk factors, and the incidence of MACEs is low.

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. OBJECTIVES: We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis. METHODS: Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. RESULTS: At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. LIMITATIONS: There was no dose comparison beyond week 52. CONCLUSIONS: Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.

Effects of tofacitinib on lymphocyte sub-populations, CMV and EBV viral load in patients with plaque psoriasis.

BACKGROUND: Plaque psoriasis is a debilitating skin condition that affects approximately 2% of the adult population and for which there is currently no cure. Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis. METHODS: The design of this study has been reported previously (NCT00678210). Patients with moderate to severe chronic plaque psoriasis received tofacitinib (2 mg, 5 mg, or 15 mg) or placebo, twice daily, for 12 weeks. Lymphocyte sub-populations, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA were measured at baseline and up to Week 12. RESULTS: Tofacitinib was associated with modest, dose-dependent percentage increases from baseline in median B cell count at Week 4 (24-68%) and Week 12 (18-43%) and percentage reductions from baseline in median natural killer cell count at Week 4 (11-40%). The proportion of patients with detectable CMV and EBV DNA (defined as >0 copies/500 ng total DNA) increased post-baseline in tofacitinib-treated patients. However, multivariate analyses found no relationship between changes in CMV or EBV viral load and changes in lymphocyte sub-populations or tofacitinib treatment. CONCLUSIONS: Twelve weeks of treatment with tofacitinib had no clinically significant effects on CMV or EBV viral load, suggesting that lymphocyte sub-populations critical to the response to chronic viral infections and viral reactivation were not significantly affected. Replication of these findings during long-term use of tofacitinib will allow confirmation of this observation.

Efficacy of tofacitinib, an oral janus kinase inhibitor, on clinical signs of moderate-to-severe plaque psoriasis in different body regions.

INTRODUCTION: Tofacitinib is a novel, oral Janus kinase inhibitor currently under investigation for plaque psoriasis. METHODS: This exploratory analysis of a Phase IIb, 12-week, dose-ranging study (clinicaltrials.gov identifier: NCT00678210) evaluated tofacitinib efficacy in four body regions of patients with moderate-to-severe chronic plaque psoriasis. Patients (n=197) were randomized to tofacitinib 2, 5, or 15 mg, or placebo, twice daily (BID). Psoriasis Area and Severity Index (PASI) score, body surface area values and change from baseline to week 12 were measured according to body region (head/neck, upper limbs, trunk and lower limbs). Change in Target Plaque Severity Score (TPSS) from baseline to week 12 was measured according to typically responsive as well as non-responsive treatment areas. RESULTS: At week 12, mean improvements in PASI and body surface area values were significantly greater with tofacitinib doses vs placebo across all four body regions measured (P<0.0001). TPSS in responsive areas decreased (improved) with tofacitinib 2, 5, and 15 mg BID vs placebo: -4.35, -4.79 and -6.32, vs -2.06, respectively (P<0.0001). In non-responsive areas, TPSS decreased with tofacitinib 2, 5, and 15 mg BID vs placebo: -3.74, -4.60 and -6.15, vs -2.23, respectively (P<0.01). CONCLUSION: Short-term (12-week) treatment with oral tofacitinib produced clinical improvement across all body regions assessed in patients with moderate-to-severe plaque psoriasis, including areas typically non-responsive to treatment.

Patient-Reported Hair Loss and Its Impacts as Measured by the Alopecia Areata Patient Priority Outcomes Instrument in Patients Treated with Ritlecitinib: The ALLEGRO Phase 2b/3 Randomized Clinical Trial.

BACKGROUND: The ALLEGRO phase 2b/3 study investigated the efficacy and safety of ritlecitinib in patients with alopecia areata (AA). OBJECTIVE: To describe the impact of ritlecitinib on patient-reported hair loss using the Alopecia Areata Patient Priority Outcomes (AAPPO) instrument and evaluate the relationship between clinically meaningful hair regrowth and improvements in patient-reported impacts. METHODS: In ALLEGRO-2b/3, patients aged ≥ 12 years with AA and ≥ 50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (± 4-week 200-mg daily loading dose), 10 mg, or placebo for 24 weeks and then continued ritlecitinib or switched from placebo to ritlecitinib 200/50 or 50 mg for 24 weeks. The AAPPO instrument evaluated improvement in hair loss, emotional symptoms (ES), and activity limitations (AL) from weeks 4 to 48 (secondary endpoint). Mean changes in ES and AL domain scores and individual items at weeks 24 and 48 were calculated for Severity of Alopecia Tool (SALT) score ≤ 20 responders and nonresponders (exploratory endpoint). RESULTS: Overall, 718 patients were randomized. At week 24, 5-36% of patients receiving ritlecitinib 10-200/50 mg reported improvement in scalp hair loss versus 9% receiving placebo. The results for eyebrow, eyelash, and body hair loss were similar. Mean change from baseline in ES and AL scores at weeks 24 and 48 was small and similar between groups. Mean change was larger for individual hair loss and ES items at weeks 24 and 48 in SALT score ≤ 20 responders versus nonresponders. CONCLUSIONS: The AAPPO instrument demonstrated the beneficial impact of ritlecitinib on patient-reported hair growth, which was consistent with improvements in clinician-reported outcomes. CLINICAL TRIAL REGISTRATION: NCT03732807. INFOGRAPHIC.

The Epidemiology of Hospital-Treated Alopecia Areata in Denmark, 1995-2016.

INTRODUCTION: Alopecia areata (AA) is an autoimmune skin disease presenting as nonscarring hair loss. Information on the epidemiology of AA, especially the occurrence of AA and its subtypes within the general population, is scarce. The study aimed to estimate the incidence rates and prevalence of hospital-treated AA and its subtypes in Denmark and to examine the demographic and clinical characteristics of patients with AA, including comorbidities and use of prescription medications. METHODS: This was a cohort study based on data from administrative and health registers in Denmark in 1995-2016. The study included individuals who were (1) registered with a hospital inpatient or hospital-based outpatient clinic diagnosis of AA between 1995 and 2016 in the Danish National Patient Registry covering encounters at all Danish hospitals, (2) alive and resided in Denmark anytime between 1995 and 2016, (3) aged ≥ 12 years, and (4) resided uninterrupted in Denmark during the 12 months before the first AA diagnosis during the study period. RESULTS: During the study period, 2778 individuals with an incident hospital-based diagnosis of AA were identified; 63.1% were female and 28.7% of the patients were aged ≥ 50 years. Over the study period, the overall incidence rate for any hospital-treated AA per 100,000 person-years was 2.62 (95% confidence interval [CI], 2.53-2.72), and the overall prevalence in 2016 was 71.7 (95% CI 69.4-74.1) per 100,000 persons. Both incidence rate and prevalence increased over time. Prevalence of most hospital-treated comorbidities or history of medication use was below 10% and was similar in the alopecia totalis (AT)/alopecia universalis (AU) and non-AT/AU subtypes of AA. CONCLUSION: This cohort study reported incidence rates and prevalence over time and characteristics of individuals with hospital-treated AA in Denmark, which are in agreement with those previously reported in this population.

Impact of Previous Alopecia Areata Treatment on Efficacy Responses up to Week 48 Following Ritlecitinib Treatment: A Post Hoc Analysis.

INTRODUCTION: Patients with alopecia areata (AA) may have received several therapies for management of AA during their lives. In the ALLEGRO phase 2b/3 (NCT03732807) study, the oral JAK3/TEC family kinase inhibitor ritlecitinib demonstrated efficacy and an acceptable safety profile in patients aged ≥ 12 years with AA and ≥ 50% scalp hair loss. This post hoc analysis investigated associations between prior use of AA therapies and Severity of Alopecia Tool (SALT) responses in patients receiving ritlecitinib for AA. METHODS: Patients receiving ritlecitinib 30 mg or 50 mg once daily with or without an initial 4-week 200-mg daily loading dose were grouped by previous exposure to AA treatments, including topicals, intralesional corticosteroids (ILCS), topical immunotherapy, and systemic immunosuppressants or any prior AA treatment. Multivariable logistic regression analyses evaluated the association between response based on a SALT score of ≤ 20 and any prior treatment for AA at weeks 24 and 48. RESULTS: Of 522 patients, 360 (69.0%) had previous exposure to any AA treatment. At Week 24, SALT ≤ 20 response was positively associated with prior use of ILCS (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.23-3.65; P < 0.05) and negatively associated with prior use of systemic immunosuppressants (OR 0.50; 95% CI 0.28-0.88; P < 0.05). Prior use of topicals or topical immunotherapy was not associated with SALT ≤ 20 response at Week 24. By Week 48, no association was identified between SALT ≤ 20 response and prior use of topicals, ILCS, topical immunosuppressants, or systemic immunosuppressants (all P > 0.05). Previous exposure to any AA therapy was not associated with SALT ≤ 20 response at weeks 24 or 48 (all P > 0.05). CONCLUSIONS: Prior AA treatment history had no effect on longer-term treatment response to ritlecitinib. TRIAL REGISTRATION NUMBER: NCT03732807.

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: 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).

Efficacy and safety of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, in adolescent and adult patients with alopecia totalis and alopecia universalis.

This post-hoc analysis of the ALLEGRO phase 2b/3 study (NCT03732807) evaluated the efficacy and safety of ritlecitinib, an oral Janus kinase 3/TEC family kinase inhibitor, in patients with alopecia totalis (AT) and alopecia universalis (AU). Patients aged ≥ 12 years with alopecia areata (AA) and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (± 4-week 200-mg loading dose) or placebo for 24 weeks. In a subsequent 24-week extension period, the ritlecitinib groups continued their doses and patients initially assigned to placebo switched to ritlecitinib (200/50 or 50 mg daily). In this analysis, clinician- and patient-reported hair regrowth outcomes were assessed at weeks 24 and 48 in four AA subgroups: AT/AU, AT, AU, and non-AT/AU. Safety was monitored throughout. Of the 718 randomized patients, 151 (21%) and 147 (20%) were defined as having AT or AU, respectively. At week 24, Severity of Alopecia Tool (SALT) score ≤20 (≤20% scalp hair loss) response rates were higher in the ritlecitinib-treated AT/AU, AT, and AU groups (7%-14%, 7%-21%, and 4%-10%, respectively) vs the placebo group (0% in the AT/AU, AT, and AU groups). The proportions of patients with a SALT score of ≤20 increased through week 48 (AT/AU, 13%-31%; AT, 11%-27%; AU, 6%-41%). Additionally, at week 24, 25%-43%, 32%-42%, and 12%-50% of patients with AT/AU, AT, and AU, respectively, who received ritlecitinib achieved a moderately or greatly improved response based on the Patient Global Impression of Change scale. Response rates generally increased through week 48 and were similar across AA subgroups. In patients with AT/AU, ritlecitinib was well tolerated with a safety profile consistent with that of the overall AA population. Ritlecitinib demonstrated clinical efficacy, patient-reported improvement, and an acceptable safety profile in patients with AT and AU through week 48. A plain language summary of this study is available at https://doi.org/10.25454/pfizer.figshare.26879161. Clinicaltrials.gov: NCT03732807.

A phase 2a study investigating the effects of ritlecitinib on brainstem auditory evoked potentials and intraepidermal nerve fiber histology in adults with alopecia areata.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9-month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50-mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double-blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4-week loading dose of 200 mg QD or placebo for 9 months (placebo-controlled phase); they then entered the active-therapy extension and received ritlecitinib 50 mg QD (with a 4-week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I-V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.

Hair Loss Profiles and Ritlecitinib Efficacy in Patients with Alopecia Areata: Post Hoc Analysis of the ALLEGRO Phase 2b/3 Study.

INTRODUCTION: Ritlecitinib 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. METHODS: Patients 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. RESULTS: LCA 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. CONCLUSION: Distinct 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 REGISTRATION: ClinicalTrials.gov identifier, NCT03732807.

Prevalence of autoimmune and inflammatory diseases and mental health conditions among an alopecia areata cohort from a US administrative claims database.

Alopecia areata (AA) is associated with an increased burden of autoimmune and inflammatory disease and mental health conditions that may have a negative impact on quality of life. However, the exact burden of comorbidities on US patients with AA and the clinical subtypes alopecia totalis (AT) and alopecia universalis (AU) compared with those without AA is not well understood. This retrospective cohort study aimed to assess the incidence rates and prevalence of AA and its clinical subtypes and examine the autoimmune and inflammatory disease and mental health condition diagnosis burden in US patients with AA and a matched cohort without AA. The Optum Clinformatics Data Mart database was used to select patients aged ≥12 years enrolled between October 1, 2016, and September 30, 2020, who had two or more AA diagnosis codes for the AA cohort. Three patients without AA were age-, sex-, and race-matched to each patient with AA. Autoimmune and inflammatory diseases and mental health conditions were evaluated at baseline and up to 2 years after the index date. In total, 8784 patients with AA (599 with AT/AU) and 26 352 matched patients without AA were included. The incidence rate of AA was 17.5 per 100 000 person-years (PY; AT/AU: 1.1 per 100 000 PY; non-AT/AU: 16.3 per 100 000 PY), and the prevalence was 54.9 per 100 000 persons (AT/AU: 3.8; non-AT/AU: 51.2). Patients with AA had a higher prevalence of autoimmune and inflammatory diseases than the matched non-AA cohort, including allergic rhinitis (24.0% vs 14.5%), asthma (12.8% vs 8.8%), atopic dermatitis (8.3% vs 1.8%), and psoriasis (5.0% vs. 1.6%). The proportions of anxiety (30.7% vs 21.6%) and major depressive disorder (17.5% vs 14.0%) were higher in patients with AA than those without AA. Patients with AT/AU generally had a greater prevalence of autoimmune and inflammatory disease and mental health conditions than patients with non-AT/AU AA.