Clinically relevant improvements in adults and adolescents with atopic dermatitis who did not achieve Investigator's Global Assessment treatment success following 8 weeks of ruxolitinib cream monotherapy

Ruxolitinib cream is a topical formulation of ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and JAK2. In two phase 3 studies in adults and adolescents (aged ≥12 years) with atopic dermatitis (AD; TRuE‐AD1/TRuE‐AD2), significantly more patients who applied ruxolitinib cream versus vehicle cream achieved Investigator's Global Assessment treatment success (IGA‐TS; IGA score of 0/1 with ≥2‐point improvement from baseline) at week 8 (primary endpoint). This post hoc analysis evaluated the efficacy, safety, and disease control of ruxolitinib cream in patients with AD who did not achieve IGA‐TS at week 8. Patients in TRuE‐AD1/TRuE‐AD2 (N = 1249) were randomized 2:2:1 to apply twice‐daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle cream for 8 weeks followed by a long‐term safety period in which patients applied ruxolitinib cream as needed. In this pooled analysis, clinically meaningful response thresholds included ≥50% improvement in the Eczema Area and Severity Index, ≥2‐point reduction in the Itch Numerical Rating Scale, ≥4‐point improvement in the Dermatology Life Quality Index (DLQI) or ≥6‐point improvement in Children's DLQI, and ≥1‐point reduction in IGA from baseline. Among patients who did not achieve IGA‐TS at week 8 (n = 584), significantly more patients who applied either strength ruxolitinib cream versus vehicle achieved each response threshold at week 8. A response in ≥1 clinically meaningful endpoint was achieved in significantly more patients who applied ruxolitinib cream (93.4%/90.9% for 0.75%/1.5% ruxolitinib cream, respectively) versus vehicle (69.0%, both P < 0.0001). Progressive improvements in disease control were observed, with many patients achieving IGA‐TS by week 52 (55.2%/56.3% for 0.75%/1.5% ruxolitinib cream, respectively). Ruxolitinib cream was well tolerated during the 52‐week study in this patient population. Taken together, these results demonstrate that most patients with AD who did not achieve IGA‐TS at week 8 have clinically meaningful responses to ruxolitinib cream, and continued therapy beyond 8 weeks could result in additional benefit.


| INTRODUC TI ON
Atopic dermatitis (AD) is a chronic, highly pruritic, inflammatory skin disease. 1 In addition to pruritus, other disease features include erythema, lichenification, and xerosis, 1,2 which collectively diminish patient quality of life (QoL). 3Topical therapies are a mainstay of AD treatment, and recent guidelines recommend corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, and Janus kinase (JAK) inhibitors as topical options. 4Efficacy, including speed and duration of response, as well as safety, including short-and long-term adverse events (AEs), are important attributes that influence patient preferences for treatment, and may impact treatment adherence and subsequent outcomes. 57][8] Ruxolitinib cream is a topical formulation of ruxolitinib, a selective inhibitor of JAK1 and JAK2. 9In the phase 3 TRuE-AD1 (NCT03745638) and TRuE-AD2 (NCT03745651) studies, ruxolitinib cream monotherapy demonstrated anti-inflammatory activity with antipruritic action versus vehicle 10 and was well tolerated in adults and adolescents with AD. 11 Significantly more patients who applied 0.75% and 1.5% ruxolitinib cream in TRuE-AD1/TRuE-AD2 achieved the primary endpoint of Investigator's Global Assessment treatment success (IGA-TS [IGA score of 0 or 1 with ≥2-point improvement from baseline]) at week 8 (50.0%/39.0%and 53.8%/51.3%,respectively) versus vehicle (15.1%/7.6%,P < 0.0001 for all comparisons). 10vestigator's Global Assessment responses are typically used as a primary endpoint in AD clinical trials, although there are some limitations to this approach. 12IGA assessments are based on a general physical assessment of AD signs, including erythema, papulation, and oozing/crusting, and do not directly account for body surface area (BSA) affected, location of the disease, and important patientreported outcomes, such as itch, sleep, and QoL.Thus, patients not achieving IGA responses of 0 (clear) or 1 (almost clear) may still have clinically meaningful improvements in AD by other measures.Although regulatory drug approval often defines treatment success as achieving clear or almost clear skin by IGA criteria, several post hoc analyses in trials evaluating systemic AD therapies suggest that this definition of success is too stringent and misses clinically relevant improvements. 13,14Additionally, patients may benefit from longerterm treatment beyond 8 weeks.The objective of this post hoc analysis was to investigate the short-and long-term efficacy, safety, and disease control of ruxolitinib cream in adolescents and adults with AD who did not achieve IGA-TS at week 8, using pooled data from two phase 3 studies.

| Patients and study design
Pooled data from two phase 3, randomized, double-blinded trials were included in this analysis (TRuE-AD1 [NCT03745638] and TRuE-AD2 [NCT03745651]).Both studies had identical study designs and were reported previously. 10,11Briefly, eligible patients were aged ≥12 years with AD for ≥2 years and had an IGA score of These studies were conducted under the provisions of the Declaration of Helsinki and in accordance with Good Clinical Practice guidelines.Written informed consent/assent was provided by all patients before enrollment.The study protocols were approved by the institutional review board or ethics committee at each study center.

| Assessments
In this analysis, responses were assessed in patients who did not achieve IGA-TS at week 8. IGA-TS, defined as an IGA score of 0 (clear) or 1 (almost clear) and ≥2-grade improvement from baseline, was the primary endpoint in TRuE-AD1 and TRuE-AD2, the results of which were previously reported. 10Responses among patients who did not achieve IGA-TS at week 8 were assessed using thresholds based on minimal clinically important differences published in the literature and included the proportion of patients achieving ≥50% improvement in the Eczema Area and Severity Index (EASI-50), 15 ≥2-point reduction in the Itch Numerical Rating Scale (itch NRS2), 16 ≥4-point improvement in the Dermatology Life Quality Index (DLQI; patients aged ≥16 years) 17 or ≥6-point improvement in Children's DLQI (CDLQI; patients aged 12-15 years), 18 and ≥1-point reduction in IGA from baseline. 19A composite endpoint, defined as achievement of ≥1 of the described efficacy parameters for response, was used to evaluate whether any clinically meaningful outcome occurred during the VC period.
To assess long-term responses in the LTS period, the proportion of patients achieving an IGA-TS as well as the mean percentage of BSA affected by AD at each visit during the VC and LTS periods were evaluated among patients initially randomized to ruxolitinib cream who did not achieve IGA-TS at week 8. Safety was assessed for the full 52-week study period in patients initially randomized to 0.75% or 1.5% ruxolitinib cream who did not achieve IGA-TS at week 8.

| Statistical analyses
Data were pooled from TRuE-AD1 and TRuE-AD2 and analyzed by descriptive statistics.For analyses related to responses in the VC period, data were analyzed by logistic regression.For analyses related to the achievement of IGA-TS and mean BSA with longerterm therapy (i.e., LTS period), data are reported as observed.
Patients from one study site were excluded from the primary efficacy analysis because of quality issues (n = 41). 10

| Patients in the VC period
A total of 1249 patients were randomized in both studies, and 1208 patients were evaluable for efficacy in the VC period.Among these patients, 584 (48.3%) did not achieve IGA-TS at week 8 (vehicle, n = 174; 0.75% ruxolitinib cream, n = 213; 1.5% ruxolitinib cream, n = 197) and were included in this analysis (Supporting Information Figure S1).The median age was 33.0 years (range 12-85 years) and 61.1% of patients were female.Baseline demographics and clinical characteristics among patients who did not achieve IGA-TS at week 8 were generally consistent across treatment arms and with the overall study population (Table 1).However, the proportion of patients with a baseline IGA score of 2, indicating mild disease, was higher among patients who did not achieve IGA-TS by week 8 versus the overall population (37.3% vs 25.8%, respectively).
versus vehicle were also observed at weeks 2 and 4 among patients who did not achieve IGA-TS at these earlier time points (Supporting Information Table S1).
A response in ≥1 of the endpoints (composite endpoint) was achieved in significantly more patients who applied ruxolitinib cream (93.4% and 90.9% for 0.75% and 1.5% ruxolitinib cream, respectively) versus vehicle (69.0%, both P < 0.0001).The same composite endpoint was assessed in all patients who were evaluable for efficacy, including those who achieved IGA-TS at week 8. Significantly more patients who applied ruxolitinib cream achieved ≥1 response at week 8 (96.7% and 96.0% for 0.75% and 1.5% ruxolitinib cream, respectively, vs 73.3% for vehicle, both P < 0.0001).

| Patients in the LTS period
Among patients initially randomized to ruxolitinib cream who did not achieve IGA-TS at week 8, 205 and 184 patients to apply 0.75% and 1.5% ruxolitinib cream, respectively, in the LTS period (Supporting Information Figure S1).Although patients remained on the same strength of ruxolitinib cream, treatment in the LTS period was as needed and was stopped 3 days after lesion clearance (compared with BID application in the VC period, regardless of lesion clearance).

| Disease control in the LTS period
Among patients who did not achieve IGA-TS at week 8 with ruxolitinib cream, the proportion who achieved IGA-TS progressively increased during the LTS period with as-needed use of ruxolitinib cream (Figure 2).At week 52, 55.2% and 56.3% of patients in the 0.75% and 1.5% ruxolitinib cream groups, respectively, achieved IGA-TS.
At baseline, mean affected BSA among patients who did not achieve IGA-TS at week 8 while applying 0.75% and 1.5% ruxolitinib cream was 9.9% and 9.1%, respectively.Mean affected BSA decreased during the VC period, with a mean affected BSA of 5.9% and 5.0% for 0.75% and 1.5% ruxolitinib cream, respectively, at week 8.

| Safety
Ruxolitinib cream was well tolerated during the 52-week study among patients who did not achieve IGA-TS at week 8 (Table 2).

| DISCUSS ION
In this post hoc analysis, adults and adolescents had meaningful improvements in the signs and symptoms of AD as well as healthrelated QoL following treatment with ruxolitinib cream despite for 0.75% and 1.5% ruxolitinib cream, respectively), a significant improvement (both P < 0.0001) compared with vehicle (69.0%).
Despite the known therapeutic benefit of vehicle creams, 20 improvements with ruxolitinib cream compared with its vehicle were statistically significant.
Improvements were also observed among patients who applied ruxolitinib cream as needed in the LTS period, underscoring the benefit with longer-term ruxolitinib cream monotherapy in patients who did not achieve IGA-TS at week 8.More than half of these patients achieved IGA-TS by week 52.Mean affected BSA continued to decrease throughout the LTS period to approximately 2% at week 52, highlighting the continued benefit of ruxolitinib cream, which may be greater in patients with severe disease at baseline.Safety data in this patient population were consistent with the overall population; ruxolitinib cream was well tolerated, with a low incidence of application site reactions. 10vestigator's Global Assessment is often used as an outcome measure in randomized clinical trials. 12More sensitive tools to augment IGA are needed to assess the various domains of disease impact and to identify patients deriving clinical benefit from treatment. 21,22Patient-reported outcomes, such as DLQI and itch NRS, reflect changes in multiple domains of the disease beyond the clinician examination and may be helpful to assess treatment effectiveness and disease burden from the patient perspective. 21Our analysis demonstrates that patients can have meaningful improvement despite failure to achieve an IGA score of 0 or 1 with a 2-point improvement from baseline, similar to findings in other studies. 13,14tably, a greater proportion of patients in this analysis had mild baseline disease (IGA score of 2) versus the overall population.This finding may be attributable to the stringency of IGA-TS criteria, in which patients with mild baseline disease must achieve an IGA score of 0 (clear) to meet the endpoint, a threshold that may be more challenging to achieve than an improvement from an IGA of 3 to an IGA of 1.
As previously reported, application of ruxolitinib cream resulted in early responses, with significant improvement in itch versus vehicle observed within 12 hours of first application, achievement of an itch-free state as early as day 2, and considerable improvement in other endpoints, including IGA-TS, observed at week 2 (first on-treatment study visit). 10,23,24By week 8, more than half of patients achieved an IGA-TS response. 10Among patients who did not achieve IGA-TS by week 8, responses were observed by other criteria, with >90% of patients in the ruxolitinib cream groups achieving a response by ≥1 measure at week 8, as reported in this analysis.
Importantly, a substantial proportion of patients who did not fulfill IGA-TS criteria at week 8 had a significant improvement in QoL versus vehicle as assessed by the DLQI or CDLQI.Among all patients evaluable for efficacy, including those who achieved IGA-TS at week 8, >96% achieved ≥1 response at week 8. Thus, a clinically meaningful response may be achieved within 8 weeks in most patients applying ruxolitinib cream.These findings indicate the importance of incorporating a variety of assessment tools, particularly those assessing benefit from a patient perspective.In addition, the longitudinal improvements observed with ruxolitinib cream over the 52-week study period suggest that as-needed application of ruxolitinib cream monotherapy may provide benefit beyond 8 weeks.F I G U R E 3 Mean affected BSA throughout the 52-week study period among patients who did not achieve IGA-TS † at week 8. ‡ BL, baseline; BSA, body surface area; CI, confidence interval; IGA, Investigator's Global Assessment; IGA-TS, Investigator's Global Assessment treatment success; LTS, long-term safety; RUX, ruxolitinib; VC, vehicle controlled.† IGA-TS was defined as an IGA score of 0 or 1 with ≥2-point improvement from baseline.‡ Among patients randomized on day 1 to RUX cream who continued in the RUX cream groups during the LTS period.These analyses were done post hoc; thus, the results should be interpreted with caution.Although the meaningfulness of the composite endpoint in this study has not been previously assessed and may represent a low threshold for success in this patient population, each individual response threshold used in this analysis has been shown to be clinically relevant.The duration of follow-up was limited to 52 weeks; given that progressive improvements are observed over the 52-week study period, longer follow-up may have identified further incremental improvements in response.
In conclusion, although many patients achieved IGA-TS with ruxolitinib cream monotherapy within 8 weeks, 10 this post hoc analysis demonstrated that significantly more patients who did not achieve this primary endpoint had clinically meaningful improvements by week 8 versus vehicle.Among patients who did not achieve IGA-TS at week 8, progressive improvements in disease control were observed, with the majority of patients achieving IGA-TS by the end of the 52-week study period.Taken together, these results demonstrate that the vast majority of patients have a clinically meaningful response to ruxolitinib cream, and continued therapy beyond 8 weeks can result in additional benefit for patients with mild to moderate AD.

ACK N OWLED G M ENTS
The authors thank the patients, investigators, and investigational sites whose participation made the study possible.This study was funded by Incyte Corporation (Wilmington, DE, USA).Medical writing support was provided by Valerie Kinchen, PhD, of The Curry Rockefeller Group, LLC (Tarrytown, NY, USA), and was funded by Incyte Corporation.a IGA-TS was defined as an IGA score of 0 or 1 with ≥2-point improvement from baseline.

CO N FLI C T O F I NTE R E S T S TATE M E NT
b Patients randomized on day 1 to ruxolitinib cream who continued in the ruxolitinib cream groups during the LTS period.c Occurring in >2% of total patients in this analysis.
d Reported terms may include atopic dermatitis exacerbation, atopic dermatitis worse from baseline, exacerbation of atopic dermatitis on the neck, flare of atopic dermatitis, worsening of atopic dermatitis, worsening of left periorbital atopic dermatitis, atopic skin changes on the thighs, worsening of atopic dermatitis on eyelids, worsening of atopic dermatitis on hands and legs, atopic dermatitis outbreak, and itching in atopic dermatitis.
TA B L E 2 Adverse events during the 52-week study period.

2 or 3
and 3% to 20% affected BSA, excluding scalp.Key exclusion criteria included an unstable disease course, other types of eczema or skin disorders, immunocompromised status, and the use of systemic or topical AD therapies (except bland emollients) during the washout period and during the study.Patients were randomized (2:2:1) to either of two ruxolitinib cream strength regimens (0.75% twice daily [BID], 1.5% BID) or vehicle cream BID for 8 weeks of double-blinded continuous treatment (vehicle-controlled [VC] period); patients were instructed to continue treating lesions even if they improved.Patients who applied ruxolitinib cream during the VC period subsequently continued treatment for 44 weeks (long-term safety [LTS] period); patients initially randomized to vehicle who applied ruxolitinib cream in the LTS period were not included in this analysis.During the LTS period, patients were instructed to treat skin areas with active AD only and to stop treatment 3 days after clearance of lesions; patients were to restart treatment with ruxolitinib cream at the first sign of recurrence.Rescue treatment was not permitted at any time during the study.

TA B L E 1
Patient demographics and baseline clinical characteristics.Characteristic Patients who did not achieve IGA-TS a at week Age, median (range), years 34.
Responses in the VC period among patients who did not achieve IGA-TS † at week 8 by individual response criteria and composite response.CDLQI, Children's Dermatology Life Quality Index; DLQI, Dermatology Life Quality Index; EASI-50, ≥50% improvement in Eczema Area Severity Index; IGA, Investigator's Global Assessment; IGA1, 1-point improvement in Investigator's Global Assessment; IGA-TS, Investigator's Global Assessment treatment success; itch NRS2, ≥2-point reduction in Numerical Rating Scale score; RUX, ruxolitinib; SE, standard error; VC, vehicle controlled.**P<0.01vs vehicle, ***P < 0.001 vs. vehicle, ****P < 0.0001 vs. vehicle.†IGA-TSwasdefined as an IGA score of 0 or 1 with ≥2-point improvement from baseline.‡Definedasa ≥4-point reduction in DLQI or ≥6-point reduction in CDLQI.§Defined as patients who achieved ≥1 of the following responses: EASI-50, itch NRS2, ≥4-point reduction in DLQI or ≥6-point reduction in CDLQI, or a 1-point reduction in IGA from baseline.notachievingIGA-TS by the end of the VC period (week 8).The majority of these patients achieved clinically meaningful responses in ≥1 validated measure by week 8 (93.4% and 90.9% Proportion of patients achieving IGA-TS † during the LTS period among patients who did not achieve IGA-TS † at week 8. ‡ IGA, Investigator's Global Assessment; IGA-TS, Investigator's Global Assessment treatment success; LTS, long-term safety; RUX, ruxolitinib; SE, standard error; VC, vehicle controlled.† IGA-TS was defined as an IGA score of 0 or 1 with ≥2-point improvement from baseline.‡ Among patients randomized on day 1 to RUX cream who continued in the RUX cream groups during the LTS period.§ End of the VC period.