Safety, pharmacokinetics, and efficacy of ruxolitinib cream in children and adolescents with atopic dermatitis.

BACKGROUND: Therapies for children with atopic dermatitis (AD) have safety and tolerability concerns that may limit long-term use. Ruxolitinib cream, a Janus kinase (JAK) inhibitor, is effective and well tolerated in adolescents and adults with AD. OBJECTIVE: To analyze the safety and tolerability of ruxolitinib cream in pediatric patients. Pharmacokinetics and efficacy were also evaluated in this phase 1 study (NCT03257644). METHODS: Patients aged 2 to 17 years with AD (affected body surface area 8%-20%; Investigator's Global Assessment score ≥2) were enrolled stepwise in 6 age-descending, strength-increasing cohorts to apply 0.5%, 0.75%, or 1.5% ruxolitinib cream twice daily for 28 days. Safety, pharmacokinetics, and efficacy were analyzed at baseline, week 2 (day 10), and week 4 (day 29). RESULTS: Among 71 patients, 44 (62.0%) had a baseline Investigator's Global Assessment score of 3; median (range) body surface area affected at baseline was 12.2% (1.7%-20.4%). Ruxolitinib cream was well tolerated, with 4 patients (5.6%) experiencing treatment-related adverse events (all grades 1/2). No clinically meaningful changes in mean chemistry or hematology values were observed, and no consistent pattern of change in bone biomarkers was detected. Mean plasma ruxolitinib levels within each cohort (range, 23.1-97.9 nM) were well below the half-maximal inhibitory concentration for thrombopoietin phosphorylation of STAT3 (281 nM). All cohorts experienced improvements in exploratory efficacy end points. CONCLUSION: Ruxolitinib cream was well tolerated in pediatric patients with AD, with no effect on blood counts or bone biomarkers. Mean plasma concentration was low. Efficacy was consistent with data from previous studies in adolescents and adults. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03257644.

Rapid pruritus reduction with ruxolitinib cream treatment in patients with atopic dermatitis.

BACKGROUND: Ruxolitinib cream is a topical formulation of ruxolitinib, a Janus kinase (JAK) 1/JAK2 inhibitor. OBJECTIVES: To report timing and magnitude of effect of ruxolitinib cream on itch in patients with atopic dermatitis (AD), a highly pruritic inflammatory skin disease. METHODS: Two phase 3 trials (TRuE-AD1 [NCT03745638]/TRuE-AD2 [NCT03745651]) enrolled patients aged ≥12 years with AD for ≥2 years, Investigator's Global Assessment score of 2 or 3, and 3%-20% affected body surface area. Patients (total N = 1249; median age, 32 years) were randomised (2:2:1) to twice daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream or vehicle cream for 8 weeks of double-blinded treatment. Worst itch was measured using the numerical rating scale (NRS). RESULTS: Significantly more patients who applied ruxolitinib cream (either strength) achieved a ≥2-point itch reduction (NRS2) within approximately 12 h versus vehicle (0.75%/1.5% ruxolitinib cream, 16.3%/13.1%; vehicle, 6.9%; both P < 0.05), with further improvements through Week 8 (58.3%/65.1% vs 29.4%; both P < 0.0001). A ≥4-point itch reduction (NRS4) was achieved by significantly more patients who applied 0.75%/1.5% ruxolitinib cream versus vehicle by Day 2 (8.9%/11.2% vs 2.1%; P < 0.005); higher rates were observed at Week 8 (41.5%/51.5% vs 15.8%; P < 0.0001). Median time for the 0.75%/1.5% ruxolitinib cream groups to achieve NRS4 from baseline was 15.0/13.0 days; this endpoint was not reached by the vehicle group. CONCLUSIONS: Ruxolitinib cream demonstrated rapid improvement in itch in patients with mild to moderate AD that was sustained for 8 weeks. Significantly more patients applying ruxolitinib cream achieved itch NRS2 within approximately 12 h and itch NRS4 by Day 2 versus vehicle.

Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies.

BACKGROUND: Ruxolitinib (RUX) cream demonstrated potent anti-inflammatory and antipruritic efficacy in a phase 2 study in adults with atopic dermatitis (AD). OBJECTIVE: To evaluate 8-week efficacy and safety in 2 phase 3 studies of RUX cream in patients with AD. METHODS: Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 1 (NCT03745638) and Study 2 (NCT03745651) enrolled patients aged ≥12 years with AD for ≥2 years, an Investigator's Global Assessment score of 2/3, and 3%-20% affected body surface area. Patients were randomized 2:2:1 to twice-daily 0.75% RUX cream, 1.5% RUX cream, or vehicle cream for 8 continuous weeks. The primary endpoint was Investigator's Global Assessment treatment success at week 8 (Investigator's Global Assessment score of 0/1 and ≥2-grade improvement from baseline). RESULTS: In the Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 1 and 2, 631 and 618 patients were randomized (631/577 analyzed for efficacy). Significantly more patients achieved Investigator's Global Assessment treatment success with 0.75% RUX cream (50.0%/39.0%) and 1.5% RUX cream (53.8%/51.3%) versus vehicle (15.1%/7.6%; P < .0001) at week 8. Significant itch reductions versus vehicle were reported within 12 hours of first application of 1.5% RUX (P < .05). Application site reactions were infrequent (<1%) and lower with RUX versus vehicle; none were clinically significant. LIMITATIONS: Longer-term safety data are not yet available. CONCLUSIONS: RUX cream showed anti-inflammatory and prompt antipruritic effects with superior efficacy versus vehicle and was well tolerated.

Effects of ruxolitinib cream on pruritus and quality of life in atopic dermatitis: Results from a phase 2, randomized, dose-ranging, vehicle- and active-controlled study.

BACKGROUND: Atopic dermatitis (AD), a chronic, highly pruritic skin disorder, impairs quality of life (QoL). Janus kinase inhibitors suppress inflammatory and pruritus-associated cytokine signaling in AD. OBJECTIVE: To report the effects of ruxolitinib (RUX) cream on itch and QoL in AD. METHODS: A total of 307 adult patients with an Investigator's Global Assessment (score of 2 or 3) and 3% to 20% affected body surface area were randomly assigned for 8 weeks to receive double-blind treatment with RUX (1.5% twice daily, 1.5% once daily, 0.5% once daily, or 0.15% once daily), vehicle twice daily, or triamcinolone cream (0.1% twice daily for 4 weeks then vehicle for 4 weeks). Itch was measured by using the numerical rating scale, and patient QoL was assessed with Skindex-16. RESULTS: Improvements in itch numerical rating scale and Skindex-16 were observed with RUX cream. Overall, 42.5% of patients who applied 1.5% RUX twice daily experienced minimal clinically important difference in itch within 36 hours of treatment (vehicle, 13.6%; P < .01); near-maximal improvement was observed by week 4. Itch reduction was associated with improved QoL burden (Pearson correlation, 0.67; P < .001). Significant improvements in Skindex-16 overall scores were noted at week 2. LIMITATIONS: Facial AD lesions were not treated. CONCLUSION: RUX cream provides a clinically meaningful reduction in itch and QoL burden.

Efficacy, Safety, and Long-Term Disease Control of Ruxolitinib Cream Among Adolescents with Atopic Dermatitis: Pooled Results from Two Randomized Phase 3 Studies.

BACKGROUND: Atopic dermatitis (AD), a highly pruritic, inflammatory skin disease, affects approximately 7% of adolescents globally. A topical formulation of ruxolitinib, a Janus kinase (JAK) 1/JAK2 inhibitor, demonstrated safety and efficacy among adolescents/adults in two phase 3 studies (TRuE-AD1/TRuE-AD2). OBJECTIVE: To describe safety and efficacy of 1.5% ruxolitinib cream versus vehicle and long-term disease control of ruxolitinib cream among adolescents aged 12-17 years from pooled phase 3 study data. METHODS: Patients [≥ 12 years old with AD for ≥ 2 years, Investigator's Global Assessment score (IGA) 2/3, and 3-20% affected body surface area (BSA) at baseline] were randomized 2:2:1 to ruxolitinib cream (0.75%/1.5%) or vehicle for 8 weeks of continuous use followed by a long-term safety (LTS) period up to 52 weeks with as-needed use. Patients originally applying vehicle were rerandomized 1:1 to 0.75%/1.5% ruxolitinib cream. Efficacy measures at week 8 included IGA treatment success (IGA-TS; i.e., score of 0/1 with ≥ 2 grade improvement from baseline), ≥ 75% improvement in Eczema Area and Severity Index (EASI-75), and ≥ 4-point improvement in itch numerical rating scale (NRS4). Measures of disease control during the LTS period included IGA score of 0 (clear) or 1 (almost clear) and percentage affected BSA. Safety was assessed throughout the study. RESULTS: Of 1249 randomized patients, 245 (19.6%) were aged 12-17 years. Of these, 45 patients were randomized to vehicle and 92 patients to 1.5% ruxolitinib cream. A total of 104/137 (75.9%) patients continued on 1.5% ruxolitinib cream in the LTS period [82/92 (89.1%) continued on 1.5% ruxolitinib cream; 22/45 (48.9%) patients on vehicle were reassigned to 1.5% ruxolitinib cream], and 83/104 (79.8%) of these patients completed the LTS period. At week 8, substantially more patients who applied 1.5% ruxolitinib cream versus vehicle achieved IGA-TS (50.6% versus 14.0%), EASI-75 (60.9% versus 34.9%), and NRS4 (52.1% versus 17.4%; P = 0.009). The mean (SD) reduction in itch NRS scores was significantly greater in patients applying 1.5% ruxolitinib cream versus vehicle from day 2 [- 0.9 (1.9) versus -0.2 (1.4); P = 0.03]. During the LTS period, mean (SD) trough steady-state ruxolitinib plasma concentrations at weeks 12/52 were 27.2 (55.7)/15.5 (31.5) nM. The percentage of patients achieving IGA score of 0 or 1 was sustained or further increased with 1.5% ruxolitinib cream; mean affected BSA was generally low (< 3%; i.e., mild disease). Through 52 weeks, application site reactions occurred in 1.8% of adolescent patients applying 1.5% ruxolitinib cream at any time; no patients had serious adverse events. There were no serious infections, malignancies, major adverse cardiovascular events, or thromboembolic events. CONCLUSIONS: Meaningful anti-inflammatory and antipruritic effects were demonstrated with 1.5% ruxolitinib cream in the subset of adolescent patients with AD, comparable with those observed in the overall study population; long-term, as-needed use maintained disease control and was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03745638 (registered 19 November 2018) and NCT03745651 (registered 19 November 2018).