Ruxolitinib Cream As-Needed Monotherapy Demonstrates Sustained Disease and Symptom Control in Patients with Mild to Moderate Atopic Dermatitis: Pooled Analysis from Two Phase3 Studies.

Standard therapy for patients with mild to moderate atopic dermatitis (AD) typically includes topical therapies; however, patients with more extensive AD and/or AD refractory to topical therapy may benefit from systemic treatment. Ruxolitinib cream monotherapy has demonstrated superior antipruritic and anti-inflammatory effects versus vehicle in patients with mild to moderate AD, and long-term disease control with as-needed use. Here, efficacy/safety of 1.5% ruxolitinib cream through 52weeks was assessed in a subset of patients with moderate and/or more extensive disease. This post hoc analysis of TRuE-AD1/TRuE-AD2 included patients who, at baseline, had Investigator's Global Assessment (IGA) score of 3, Eczema Area and Severity Index (EASI) ≥ 16, and affected body surface area (BSA) ≥ 10% (higher severity of disease threshold subgroup). Disease control and safety were assessed. Of 1249 patients in the overall population, 78 (6.2%) met all higher severity of disease threshold criteria (continuous-use vehicle-controlled period: 1.5% ruxolitinib cream, n = 32; vehicle, n = 13); 28 and 4 of these patients, respectively, continued as-needed 1.5% ruxolitinib cream during the long-term safety (LTS) period. At week8 (continuous-use), IGA-treatment success (IGA0/1, with ≥ 2-grade improvement from baseline) was achieved by 19/32 (59.4%) patients applying 1.5% ruxolitinib cream versus no patients applying vehicle. In the LTS period, those achieving clear/almost clear skin increased from 19/28 patients (67.9%; continuous-use: week8) to 18/23 patients (78.3%; as-needed use: week52) in patients applying ruxolitinib cream from day1. Ruxolitinib cream was well tolerated, with few application site reactions, regardless of disease severity threshold. Efficacy and safety results were similar to the overall study population. Patients with AD who meet standard disease severity eligibility criteria for systemic therapy may achieve IGA-treatment success with clear/almost clear skin with continuous-use ruxolitinib cream, and maintain long term-disease control with as-needed ruxolitinib cream monotherapy. NCT03745638/NCT03745651.

Introduction/Background Atopic dermatitis (AD) is a chronic, inflammatory skin disease with onset usually occurring in childhood. Topical therapy is the mainstay of AD treatment and is typically used prior to systemic therapy in patients with moderate disease. Ruxolitinib (Janus kinase [JAK] 1/JAK2 inhibitor) cream is approved by the US Food and Drug Administration for patients aged ≥12 years with mild to moderate AD, and has demonstrated efficacy and was well tolerated in children (aged 2–11 y) with AD in TRuE-AD3 (NCT04921969), a phase 3, double-blind, randomized, vehicle-controlled study. Objectives Here we investigated the effects of ruxolitinib cream in a subset of patients from TRuE-AD3 with moderate and/or more extensive disease at baseline. Methods TRuE-AD3 included children aged 2–11 years with AD for ≥3 months, an Investigator’s Global Assessment (IGA) score of 2 or 3, and an affected body surface area (BSA) of 3%–20%. Patients were randomized 2:2:1 to apply 1.5% ruxolitinib cream, 0.75% ruxolitinib cream, or vehicle cream twice daily for 8 weeks. Rescue treatment was not permitted. Patients from TRuE-AD3 with moderate and/or more extensive disease at baseline (defined as an IGA score of 3, ≥10% affected BSA, or a combined IGA score of 3 and ≥10% BSA) were included in this analysis. Efficacy was assessed as the proportion of patients in each treatment group who achieved IGA treatment success (IGA-TS; a score of 0 or 1 with a ≥2-grade improvement from baseline), ≥75% improvement from baseline in the Eczema Area and Severity Index (EASI-75), and ≥90% improvement from baseline in the Eczema Area and Severity Index (EASI-90) at Weeks 2, 4, and 8. Statistical significance was assessed at Week 8 using exact logistic regression. Patients with missing post-baseline data were imputed as nonresponders. Results Patients in TRuE-AD3 (N=330) had a median (range) age of 6 (2–11) years, 54.2% were girls, and 54.5% were White. The mean (SD) BSA was 10.5% (5.4%), the mean (SD) EASI was 8.6 (5.4), and 252 patients (76.4%) had a baseline IGA of 3. Among patients with an IGA of 3 at baseline, more patients who applied 1.5% ruxolitinib cream or 0.75% ruxolitinib cream versus vehicle achieved IGA-TS (40.0% and 29.1%, respectively, vs 6.1%), EASI-75 (43.0% and 38.8% vs 8.2%), and EASI-90 (17.0% and 21.4% vs 0%) at Week 2. Improvements were also observed at Week 8 (IGA-TS, 59.0% [P<0.0001] and 37.9% [P=0.004] vs 14.3%; EASI-75, 64.0% [P<0.0001] and 48.5% [P<0.0001] vs 14.3%; EASI-90, 40.0% [P<0.0001] and 33.0% [P=0.001] vs 8.2%), with 1.5% ruxolitinib cream consistently resulting in numerically better improvements than 0.75% ruxolitinib cream. Similar improvements were observed with ruxolitinib cream versus vehicle among patients with ≥10% affected BSA at baseline and a combined baseline IGA of 3 and ≥10% BSA. Both strengths of ruxolitinib cream were well tolerated among patients with an IGA of 3 at baseline; no serious treatment-emergent adverse events (TEAEs) were reported. Conclusions Children with moderate and/or more extensive AD in this study had substantially higher rates of clinical responses with ruxolitinib cream monotherapy versus vehicle as early as Week 2 (first assessment), with further improvement throughout the 8-week treatment period. Ruxolitinib cream was well tolerated with no serious TEAEs.

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

Long-term safety and disease control with ruxolitinib cream in atopic dermatitis: Results from two phase 3 studies

Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream

Efficacy and safety of ruxolitinib cream in children aged 2 to 11 years with atopic dermatitis: Results from TRuE-AD3, a phase 3, randomized double-blind study.

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

BackgroundRuxolitinib cream is a topical formulation of ruxolitinib, a Janus kinase (JAK) 1/JAK2 inhibitor.ObjectivesTo report timing and magnitude of effect of ruxolitinib cream on itch in patients with atopic dermatitis (AD), a highly pruritic inflammatory skin disease.MethodsTwo 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).ResultsSignificantly 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.ConclusionsRuxolitinib 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.

The 2021 US approval of ruxolitinib cream for treatment of atopic dermatitis (AD) in patients aged ≥ 12years was based on the results of two pivotal phase 3 studies. Currently, real-world data to describe effectiveness of ruxolitinib cream and physician satisfaction with treatment remain limited. Our objective is to describe disease control among adults with mild to moderate AD prescribed ruxolitinib cream and physician satisfaction with treatment. Data were from the Adelphi AD Disease Specific Programme™, a US real-world, cross-sectional survey of physician-reported data, undertaken between August 2022 and March 2023. For patients aged ≥ 18years, physicians reported patient demographics, clinical characteristics, treatment patterns, and physician satisfaction with disease control. Descriptive analysis of data for patients with mild to moderate AD prior to the initiation of ruxolitinib cream and treated with ruxolitinib cream for ≥ 1month was undertaken. Among physician-reported data from 1360 patients with AD, 149 patients had received ruxolitinib cream (in combination or as monotherapy) for ≥ 1month, including 59 patients receiving monotherapy. Prior to treatment with ruxolitinib cream, 84.6% of patients had moderate AD (Investigator's Global Assessment, IGA of 3), whereas after treatment (median duration, 26weeks), only 21.5% had an IGA of 3, with 48.3% of patients having clear or almost clear skin (IGA of 0/1). For these patients, 81.2% were not currently experiencing a flare, and physicians were satisfied with disease control for 87.3%. Results were similar in patients receiving monotherapy. The most frequent physician-reported reasons for prescribing ruxolitinib cream included relieving itch, improving lesion redness/thickness, achieving disease control, and reducing/controlling flares. These real-world findings demonstrate effective disease control and physician satisfaction with ruxolitinib cream for the treatment of AD in adults in a clinical practice setting. Outcomes were similar whether ruxolitinib cream was prescribed as monotherapy or in combination regimens, suggesting a role for ruxolitinib cream across the spectrum of disease.

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

Ruxolitinib cream demonstrated rapid reductions in itch and atopic dermatitis signs that correlated with biomarkers.

Atopic dermatitis (AD) is a chronic, recurring, highly pruritic inflammatory skin disease. The mechanical injury from scratching contributes to skin inflammation and barrier disruption, exacerbating the itch–scratch cycle, which perpetuates the disease. Ruxolitinib cream is a topical formulation of ruxolitinib, a selective Janus kinase (JAK) 1/JAK2 inhibitor, approved in the USA for the short-term and noncontinuous chronic treatment of mild to moderate AD in patients ≥12 years old whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. In two pivotal phase 3 trials (TRuE-AD1 and TRuE-AD2) in adolescents and adults with AD, ruxolitinib cream 1.5% demonstrated significant improvement in itch vs. vehicle cream, as early as 12 h after initial application. A phase 2, open-label, single-site study (SCRATCH-AD; NCT04839380) was undertaken to further understand the short-term clinical benefits of ruxolitinib cream to control pruritus and reduce disease severity in participants with AD. Participants enrolled in the study were aged 18–65 years with AD for ≥6 months, with chronic itch related to AD for ≥3 months, 1–20% affected body surface area (BSA), Investigator’s Global Assessment (IGA) of ≥2 and a peak pruritus numerical rating scale (PP-NRS) score ≥4 at baseline. Participants applied ruxolitinib cream 1.5% twice daily to all lesions identified at baseline and any new lesions for 28 days. The primary endpoint was change from baseline in PP-NRS at Day 2 (24 h after the first application of ruxolitinib cream). Secondary endpoints included change from baseline in modified PP-NRS (mPP-NRS; current itch intensity) at 15 and 30 min and at 1, 2, 4, 6 and 12 h post-treatment on Day 1, as well as change from baseline in PP-NRS from Days 3 through 29, change from baseline in IGA at Days 8, 15 and 29, and safety. The primary analysis included 46 participants in the modified intent-to-treat population. Median age (range) was 30 (18–64) years; 69.6% were female, and 89.1% were White. At baseline, mean (SD) affected BSA was 9.5% (4.94%), mean (SD) 7-day average PP-NRS score was 6.7 (1.36), mean (SD) pretreatment mPP-NRS score was 6.4 (1.72) and 89.1% had an IGA score of 3. The mean (SD) change from baseline in PP-NRS on Day 2 was –3.4 (1.85). The mean (SD) change from baseline in mPP-NRS at 15 min post-treatment was –2.3 (2.34), peaking at –4.2 (2.12) at 4 h post-treatment and was –3.1 (2.00) at 12 h post-treatment. The mean (SD) change from baseline PP-NRS continued to increase through Day 29 [–5.7 (1.60)]. The mean (SD) changes from baseline in IGA score on Days 8, 15 and 29 were –1.4 (0.73), –2.0 (0.87) and –2.2 (0.90), respectively. Treatment-emergent adverse events (TEAEs) were reported in 15/49 (30.6%) participants (none were serious); one participant had a treatment-related TEAE [grade 1 application site reaction (acne)]. No participant discontinued treatment due to TEAE. Lesional skin treated with ruxolitinib cream 1.5% twice daily showed substantial decrease in transepidermal water loss from a baseline mean (SD) score of 35.0 (17.47) to 13.1 (4.42) over 4 weeks, thus reaching similar levels to the nonlesional skin score of 12.7 (4.56) at Day 29. Participants with AD applying ruxolitinib cream 1.5% experienced rapid, substantial improvement in itch, which was sustained and further improved through 28 days of treatment. Itch reduction was observed as early as 15 min, and peak reduction was observed at 4 h after first cream application. These results further demonstrate the clinical benefits and are consistent with the established data on ruxolitinib cream as an effective, well-tolerated topical treatment for AD.

Ruxolitinib cream has demonstrated anti-inflammatory and antipruritic activity and was well tolerated in a phase 3 study in patients aged 2-11 years with mildtomoderate atopic dermatitis (AD). This study examined the safety, tolerability, pharmacokinetics, efficacy, and quality of life (QoL) with ruxolitinib cream under maximum-use conditions and with longer-term use. Eligible patients were aged 2-11 years with moderate to severe AD [Investigator's Global Assessment (IGA) score 3-4], and ≥ 35% affected body surface area (BSA). Patients applied 1.5% ruxolitinib cream twice daily to all baseline-identified lesions during the 4-week maximum-use period, then to active lesions only up to week 52 (patients with ≤ 20% affected BSA from week 8). Safety was assessed by frequency and severity of adverse events. Pharmacokinetic parameters were assessed as secondary endpoints, and efficacy and QoL were exploratory endpoints. Overall, 29 patients (median age 5years) were enrolled. Treatment-emergent adverse events were reported in 9/29patients (31.0%); there were no adverse events of special interest (i.e., no serious infections, malignancies, major adverse cardiovascular events, or thromboses) during the study period. Mean steady-state plasma concentration during the maximum-use period was below the known half-maximal inhibitory concentration of Janus kinase-mediated myelosuppression in adults. Reductions in affected BSA and IGA observed at week 4 were sustained with as-needed use through 52weeks. Improvements in patient-reported outcomes and QoL measures were consistent with efficacy results. These results support the safety of ruxolitinib cream in children (2-11years) with AD, including those with extensive disease, and are consistent with previous efficacy findings. NCT05034822, first registered 30 August 2021.

SummaryBackgroundIn the U.S.A., an Investigator's Global Assessment (IGA) score of ≤ 1 (clear or almost clear skin) has been the standard measure in regulatory outcomes for registration clinical trials in atopic dermatitis (AD), including those supporting the recent approval of dupilumab.ObjectivesTo evaluate the treatment effect of dupilumab in patients with IGA > 1 at the end of treatment, using other validated outcome measures for AD signs, symptoms and quality of life.MethodsLIBERTY AD SOLO 1 and 2 were two 16‐week, randomized, double‐blind trials enrolling adult patients with moderate‐to‐severe AD (IGA ≥ 3) inadequately controlled with topical treatment. We performed a post hoc analysis in patients receiving dupilumab 300 mg every 2 weeks (q2w) or placebo. Outcome measures in patients with IGA > 1 included Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), affected body surface area (BSA), Patient‐Oriented Eczema Measure (POEM) and Dermatology Life Quality Index (DLQI). The trials were registered at ClinicalTrials.gov: NCT02277743 and NCT02277769.ResultsAt week 16, 278 of 449 dupilumab q2w‐treated patients (median age 36·0 years) and 396 of 443 placebo‐treated patients had IGA > 1. Among patients with IGA > 1 at week 16, dupilumab significantly improved several outcome measures compared with placebo: EASI (−48·9% vs. −11·3%, P < 0·001), pruritus NRS (−35·2% vs. −9·1%, P < 0·001), affected BSA (−23·1% vs. −4·5%, P < 0·001), POEM score ≥ 4‐point improvement (57·4% vs. 21·0%, P < 0·001) and DLQI score ≥ 4‐point improvement (59·3% vs. 24·4%, P < 0·001).ConclusionsIn patients with IGA > 1 at week 16, dupilumab induced statistically significant benefits in multiple validated outcome measures compared with placebo. The IGA ≤ 1 end point significantly underestimates clinically relevant dupilumab treatment effects.

In the TRuE-AD1/2 studies, patients aged ≥12 years with atopic dermatitis (Investigator’s Global Assessment [IGA] 2/3; 3%–20% affected body surface area) were randomized (2:2:1) to twice-daily 0.75%/1.5% ruxolitinib cream or vehicle for an 8-week, double-blind period followed by a 44-week long-term safety (LTS) period of as-needed ruxolitinib cream. This analysis examines associations between Week 8 responder status to 1.5% ruxolitinib cream with LTS outcomes. At Week 8, 57.0% (244/428) of LTS-evaluable patients applying 1.5% ruxolitinib cream achieved IGA–Treatment Success (IGA-TS; IGA 0/1 with ≥2-grade improvement from baseline); 66.6% (285/428) achieved ≥75% improvement in Eczema Area and Severity Index from baseline (EASI-75); 45.8% (196/428) achieved Itch numerical rating scale 0/1 (NRS 0/1). For patients with ≥2 visits (every 4 weeks) during LTS, mean percentages of visits with clear/almost clear skin were 83.2% vs 59.7%, 82.2% vs 54.9%, and 77.3% vs 70.1% for Week 8 IGA-TS, EASI-75, and Itch NRS 0/1 responders vs nonresponders, respectively. Mean percentages of visits with clear/almost clear skin were similar regardless of time to achieve IGA-TS (83.4%/77.4%/81.9% for those achieving at Week 2/4/8), EASI-75 (80.7%/78.8%/81.6%), and Itch NRS 0/1 (75.8%/70.7%/72.8%). During LTS, mean (SD) cumulative treatment-free days due to complete clearance were 149.2 (86.43) vs 104.0 (89.10), 146.4 (88.43) vs 95.9 (83.55), and 142.6 (87.58) vs 124.4 (91.47) for Week 8 IGA-TS, EASI-75, and Itch NRS 0/1 responders vs nonresponders, respectively. Percentage of treatment-free days between study visits (between Weeks 8 and 12 vs Weeks 48 and 52) among Week 8 responders and nonresponders increased from 44.1% to 50.2% and from 16.3% to 42.3% for IGA-TS; from 41.2% to 49.9% and from 14.9% to 40.6% for EASI-75; from 39.8% to 49.4% and from 29.9% to 46.0% for itch NRS 0/1. In summary, efficacy responses achieved with 8-week ruxolitinib cream treatment are associated with higher disease control in LTS; however, nonresponders approach similar disease control with continued treatment. As-needed ruxolitinib cream monotherapy demonstrated substantial long-term disease control regardless of time to first response achievement.