Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo.

BACKGROUND: Vitiligo is a chronic autoimmune disease that causes skin depigmentation. A cream formulation of ruxolitinib (an inhibitor of Janus kinase 1 and 2) resulted in repigmentation in a phase 2 trial involving adults with vitiligo. METHODS: We conducted two phase 3, double-blind, vehicle-controlled trials (Topical Ruxolitinib Evaluation in Vitiligo Study 1 [TRuE-V1] and 2 [TRuE-V2]) in North America and Europe that involved patients 12 years of age or older who had nonsegmental vitiligo with depigmentation covering 10% or less of total body-surface area. Patients were randomly assigned in a 2:1 ratio to apply 1.5% ruxolitinib cream or vehicle control twice daily for 24 weeks to all vitiligo areas on the face and body, after which all patients could apply 1.5% ruxolitinib cream through week 52. The primary end point was a decrease (improvement) of at least 75% from baseline in the facial Vitiligo Area Scoring Index (F-VASI; range, 0 to 3, with higher scores indicating a greater area of facial depigmentation), or F-VASI75 response, at week 24. There were five key secondary end points, including improved responses on the Vitiligo Noticeability Scale. RESULTS: A total of 674 patients were enrolled, 330 in TRuE-V1 and 344 in TRuE-V2. In TRuE-V1, the percentage of patients with an F-VASI75 response at week 24 was 29.8% in the ruxolitinib-cream group and 7.4% in the vehicle group (relative risk, 4.0; 95% confidence interval [CI], 1.9 to 8.4; P<0.001). In TRuE-V2, the percentages were 30.9% and 11.4%, respectively (relative risk, 2.7; 95% CI, 1.5 to 4.9; P<0.001). The results for key secondary end points showed superiority of ruxolitinib cream over vehicle control. Among patients who applied ruxolitinib cream throughout 52 weeks, adverse events occurred in 54.8% in TRuE-V1 and 62.3% in TRuE-V2; the most common adverse events were application-site acne (6.3% and 6.6%, respectively), nasopharyngitis (5.4% and 6.1%), and application-site pruritus (5.4% and 5.3%). CONCLUSIONS: In two phase 3 trials, application of ruxolitinib cream resulted in greater repigmentation of vitiligo lesions than vehicle control through 52 weeks, but it was associated with acne and pruritus at the application site. Larger and longer trials are required to determine the effect and safety of ruxolitinib cream in patients with vitiligo. (Funded by Incyte; TRuE-V1 and TRuE-V2 ClinicalTrials.gov numbers, NCT04052425 and NCT04057573.).

Ruxolitinib cream for the treatment of patients with alopecia areata: A 2-part, double-blind, randomized, vehicle-controlled phase 2 study.

BACKGROUND: There are currently no treatments for alopecia areata (AA) that are universally effective or approved by the US Food and Drug Administration. Oral ruxolitinib has shown efficacy in extensive AA. Ruxolitinib cream would potentially avoid systemic adverse effects. OBJECTIVE: To assess the efficacy and safety of 1.5% ruxolitinib cream in patients with AA who had at least 25% hair loss by Severity of Alopecia Tool score. METHODS: This was a 2-part study. Part A was an open-label, 24-week study of 1.5% ruxolitinib cream in patients with 25% to 99% hair loss followed by a 24-week extension period. Part B was a double-blind, vehicle-controlled, 24-week study of 1.5% ruxolitinib cream in patients with 25% to 100% hair loss, followed by a crossover to ruxolitinib cream in the vehicle group for 24 weeks and additional treatment time for the ruxolitinib cream group. RESULTS: Although Part A results suggested potential efficacy of 1.5% ruxolitinib cream, there was no significant difference in hair regrowth based on 50% improvement in Severity of Alopecia Tool scores between patients receiving 1.5% ruxolitinib cream and vehicle in part B. There were no significant safety issues with 1.5% ruxolitinib cream. LIMITATIONS: Single strength of ruxolitinib cream. CONCLUSIONS: The 1.5% ruxolitinib cream did not have a significant effect in patients with AA.

Assessing Participants' Experiences with Vitiligo from Patient Interviews.

INTRODUCTION: Vitiligo is an autoimmune disease, causing skin depigmentation. Individuals with vitiligo incur substantial psychosocial burden and have expressed frustration with their treatments. Here, we describe the burden of vitiligo and opinions on what constitutes meaningful change among participants of two qualitative interview studies. METHODS: Qualitative interviews were conducted with a subgroup of adolescent and adult participants with vitiligo from two pivotal phase 3 clinical trials of ruxolitinib cream (Study 1) and a real-world panel (Study 2). Participants were asked about their disease burden, treatment goals, importance of facial/body improvement (treatment satisfaction: scale range 0-10), and meaningfulness of change (yes/no). RESULTS: A total of 36 participants from Study 1 and 23 from Study 2 were interviewed. In Study 1, the highest degree of impact was on reduced self-esteem (facial lesions, 62.5%; body lesions, 55.6%), social inhibition (facial lesions, 65.6%; body lesions, 61.1%), and sun sensitivity (facial lesions, 31.3%; body lesions, 55.6%). Most participants (83.3%) reported that facial improvement was equally (36.1%) or more important (47.2%) than body improvement, with mean treatment satisfaction of 8.1 and 6.9, respectively. Meaningful change was reported by 83.3% and 92.9% of participants with 50-74% and ≥ 75% improvement per the facial Vitiligo Area Scoring Index, respectively, and by 82.6% of participants with ≥ 25% improvement per the total Vitiligo Area Scoring Index per Study 1 outcomes at Week 24. In Study 2, most (82.6%) participants felt that the noticeability of their vitiligo affected their behavior. Nearly all (87.0%) said that an ideal treatment would repigment or return natural color to their facial skin; 56.5% considered ≥ 50% facial repigmentation to be the smallest meaningful improvement. CONCLUSIONS: Participants from both qualitative interviews expressed substantial psychosocial burden. Repigmentation in both facial and body vitiligo were important, with meaningful change determined to be ≥ 50% facial repigmentation and ≥ 25% body repigmentation.

Vitiligo is an autoimmune disease that causes white patches to appear on the skin, affecting about 2% of people worldwide. People with vitiligo often have poor quality of life due to their disease and frequently do not believe that treatments work. We explored how people with vitiligo felt about their disease, and asked what hopes they had for treatment. Individual telephone interviews were conducted with 36 adolescents and adults with vitiligo from two clinical studies (Study 1) and 23 adolescents and adults with vitiligo from a real-world panel (Study 2) in the USA and Canada. Those from Study 1 said that their vitiligo caused them to have low self-esteem and to feel lonely. Most said that it was as important or more important to restore color to white patches on their face (i.e., repigmentation) than the body. Most achieving repigmentation of more than 50% on the face or more than 25% on the body were pleased with their treatment. In Study 2, most people said that their disease affected their behavior, and nearly all said that completely restoring color to their facial skin (i.e., 100% repigmentation) was important. Over half said that the smallest change they thought was important was more than 50% facial repigmentation. In short, people with vitiligo in two interview studies said that their vitiligo affected their quality of life. Most people with vitiligo in these studies reported that it was important to repigment more than 50% on the face and more than 25% on the body.

Target Product Profile for Cutaneous Neurofibromas: Clinical Trials to Prevent, Arrest, or Regress Cutaneous Neurofibromas.

Cutaneous neurofibromas (cNFs) are benign tumors of the skin that affect >95% of adults with neurofibromatosis type 1. Despite their benign histology, cNFs can significantly impact QOL due to disfigurement, pain, and pruritus. There are no approved therapies for cNFs. Existing treatments are limited to surgery or laser-based treatments that have had mixed success and cannot be readily applied to a large number of tumors. We review cNF treatment options that are currently available and under investigation, discuss the regulatory considerations specific to cNFs, and propose strategies to improve cNF clinical trial design and standardize clinical trial endpoints.

Safety and Efficacy of Ruxolitinib in Patients with Myelofibrosis and Low Platelet Counts (50 - 100 × 109/L): Final Analysis of an Open-Label Phase 2 Study.

INTRODUCTION: Treatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50 - 100 × 109/L) are reported. PATIENTS AND METHODS: Patients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 109/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety. RESULTS: Of 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were -20.5% (-55.8% to 38.5%, n=51) and -39.8% (-98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3). CONCLUSION: A starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.

Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial.

BACKGROUND: The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib-the first myelofibrosis-approved therapy-reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results. METHODS: Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment. RESULTS: Patients were randomized (September 2009-April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50-0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%). CONCLUSION: The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00952289.