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31st October 2022
Topical ruxolitinib produces significantly greater re-pigmentation over 52 weeks compared to placebo in patients with non-segmental vitiligo according to the combined results of two randomised, double-blind, placebo-controlled trials by researchers from the TRuE-V study Group.
Vitiligo describes an autoimmune disease in which there is progressive destruction of melanocytes in the skin leading to patchy depigmentation and the condition has an estimated prevalence of 0.5% in the general population. Due to the visible nature of vitiligo, not surprisingly, patients experience a reduction in many aspects of quality of life including feelings of stigmatisation, adjustment disorders, sleep disturbance, relationship difficulties and avoidance or restriction behaviour. Studies suggest that active vitiligo peri-lesional skin is characterised by prominent type 1 and 2 associated immune responses and induces melanocyte dysfunction and an epidermal inflammatory response through Janus Kinase signalling. In fact, in a phase 2 trial, use of topical ruxolitinib was associated with substantial re-pigmentation of vitiligo lesions up to 52 weeks of treatment. Based on these early positive data, in the current study, researchers undertook two identical, randomised, double-blind, placebo-controlled trials, Topical Ruxolitinib Evaluation in Vitiligo Study 1 (TRuE-V1 and 2 (TRuE-V2), using a formulation containing 1.5% ruxolitinib. Individuals 12 years of age and older with non-segmental vitiligo (i.e., where symptoms are bilateral) and depigmentation covering 10% or less of their body surface area and at least 0.5% of the body surface area of the face, were enrolled and randomised, 2:1 to topical ruxolitinib 1.5% or a matching placebo. Treatments were applied twice daily for 24 weeks to all affected areas and after this point, all of the patients were eligible to apply the active treatment up until week 52. The study primary endpoint was a 75% reduction (i.e., improvement) from baseline in the facial vitiligo area scoring index (F-VASI), which ranges from 0 to 3 and where higher scores are indicative of greater facial depigmentation. The primary outcome was assessed at week 24 and secondary endpoints included a F-VASI50 and F-VASI90.
Topical ruxolitinib and improvement of vitiligo
A total of 330 patients with a mean age of 40.2 years (56.4% female) were enrolled in TRuE-V1, of whom, 221 received ruxolitinib. There were 343 participants randomised in TRuE-V2 with a slightly lower mean age (38.9 years, 50.1% female). The baseline mean F-VASI score was 0.95 in TRuE-V1 and 0.88 in TRuE-V2.
In TRuE-V1 the primary outcome was achieved by 29.8% of those receiving ruxolitinib and 7.4% of those using placebo (relative risk, RR = 4, 95% CI 1.9 – 8.4, p < 0.001). Similarly, in TRuE-V2, there was a significant difference between the active and placebo arms (RR = 2.7, 95% CI 1.5 – 4.9, p < 0.001).
For the secondary outcomes, in TRuE-V1, 15.3% of those assigned to ruxolitinib achieved a F-VASI90 (i.e., 90% improvement in score from baseline) compared to only 2.2% of placebo patients.
In terms of safety, mild or moderate adverse events occurred in a similar proportion of ruxolitinib patients in both trials when assessed up to 52 weeks (54.8% and 62.3%). The most common adverse events in ruxolitinib patients were application site acne (6.3%) and application site pruritus (5.4%).
The authors concluded that topical ruxolitinib was superior to placebo for re-pigmentation in vitiligo, adding that longer trials were needed to determine the effect and risks of ruxolitinib in vitiligo.
Citation
Rosemarin D et al. Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo N Eng J Med 2022
28th July 2022
According to a press release by the manufacturer Incyte, ruxolitinib cream has been approved by the US Food and Drug Administration for the treatment of non-segmental vitiligo.
Vitiligo is a common, autoimmune skin disorder, in which there is loss of melanocytes in the epidermis and presents clinically as well-demarcated, white patches on the body. It is estimated that the condition has a worldwide prevalence of 0.5%–2%. Vitiligo has two main types, non-segmental and segmental with the former being symmetrical, whereas the latter is more localised. Non-segmental vitiligo is the more common form and accounts for 85–90% of cases. Ruxolitinib is a Janus kinase inhibitor and the cream has already showed anti-inflammatory and prompt antipruritic effects in the management of patients with atopic eczema.
The FDA decision to approve ruxolitinib (brand name Opzelura™) was based on the findings of two clinical trials, TRuE-V1 and TRuE-V2. Both were similar in design and evaluated the efficacy and safety of ruxolitinib cream in adolescent (12 years and older) and adult participants with non-segmental vitiligo for whom the vitiligo involved area (facial and non-facial) did not exceed 10% of their body surface area (BSA). In each of the trials, participants were randomised received ruxolitinib cream 1.5% or vehicle for 24 weeks which was applied twice daily. Following on from the initial 24 week period, participants were offered the opportunity to continue in the treatment extension arm for up to 52 weeks. The primary endpoint for both trials was the facial Vitiligo Area Scoring Index (F-VASI75) and a 75% improvement from baseline in the F-VASI (F-VASI75) has been identified as within-patient clinically meaningful thresholds.
Ruxolitinib cream: clinical efficacy
A dose ranging Phase II randomised trial did provide evidence for the effectiveness of the treatment. In the trial, 157 patients (mean age, 48·3 years, 46% male), with depigmentation of 0·5% or more of their facial body surface area (BSA) and 3% or more of their non-facial BSA, were randomised 1:1:1:1 to receive ruxolitinib cream (1·5% twice daily, 1·5% once daily, 0·5% once daily, or 0·15% once daily) or vehicle twice daily. The primary endpoint was a F-VASI50 after 24 weeks and this was achieved after 24 weeks by 45% of patients using the 1.5% cream twice daily and 50% of those using the same strength once daily compared to only 3% receiving placebo.
Although the results of TRuE-V1 and V2 are not yet published, the manufacturer’s press release reports that after 24 weeks, approximately 30% of patients using ruxolitinib cream achieved the primary endpoint compared with approximately 8% of those using the vehicle in TRuE-V1 and 13% in TRuE-V2. Additionally, after 24 weeks, more than 15% of those receiving ruxolitinib cream achieved a F-VASI90 (i.e., 90% improvement from baseline), compared to approximately 2% of patients treated with vehicle. At week 52, approximately 50% of ruxolitinib cream patients achieved the primary endpoint and 30% had achieved a F-VASI90.
Although ruxolitinib cream has yet to be approved by the European Medicines Agency, it is currently under review by the organisation.
26th October 2021
Biopharmaceutical company Incyte has been granted approval by the FDA for Opzelura™ (ruxolitinib) cream, the first, topical janus kinase (JAK) inhibitor used in the treatment of mild to moderate atopic dermatitis (AD). More specifically, Opzelura™ can be used for the short-term and non-continuous, chronic treatment of AD in non-immunocompromised patients, 12 years of age and older whose disease is not adequately controlled with topical prescription therapies. The importance of inhibition of JAK is based on the fact that the janus kinase (JAK)-signal transducer and activator of transcription (STAT), or JAK-STAT pathway, has been shown to play an essential role in the dysregulation of immune responses in AD. Although there are four separate JAK-STAT pathways, ruxolitinib, is a selective inhibitor of only JAK1 and JAK2, effectively suppressing the cytokine signalling involved in AD pathogenesis.
Clinical efficacy
The efficacy of ruxolitinib was examined in a 2020 study among adult patients with mild to moderate AD. Participants were randomised for 8 weeks to three different strengths of ruxolitinib; 1.5% cream, applied twice daily or once daily, a 0.5% and 0.15% cream, vehicle or triamcinolone cream 0.1% applied twice daily for 4 weeks, then vehicle for 4 weeks.
The results showed that all concentrations of ruxolitinib were more effective after 4 weeks than placebo, the greatest improvement occurred with the 1.5% strength, based on an improvement in the Eczema Area and Severity Index (71.6% vs 15.5%; ruxolitinib vs placebo, p < .0001). Interestingly, the authors of the study reported that use of ruxolitinib 1.5% both once a twice daily produced a numerically greater improvements compared with triamcinolone after 4 weeks but that the difference was not statistically significant.
Based on these early finding, the company conducted two phase 3, randomised, placebo-controlled trials comparing topical ruxolitinib 0.75% and 1.5% in patients 12 years and over with mild to moderate AD. The primary outcome was Investigator’s Global Assessment treatment success at week 8 (i.e., an investigator’s Global Assessment score of 0/1 and ≥2-grade improvement from baseline). The results were published in May 2021 and showed that significantly more patients achieved the primary outcome at week 8 with 0.75% ruxolitinib (50.0% vs 15.1%, ruxolitinib vs placebo) and 1.5% ruxolitinib (53.8% and 7.6%), both with p < 0.001.
The company have now released data on the trial’s secondary outcomes which included the proportion of participants with at least a 4-point improvement in the itch Numerical Rating Scale (NRS), and the proportion of participants with at least a 6-point improvement in the Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form. The latest data release show that 20.9% and 23.8% of patients using 0.75% and 1.5% topical ruxolitinib achieved a greater than 6-point improvement in sleep scores. Similarly, 41.5% and 51.5% using the 0.75% and 1.5% creams had at least a 4-point improvement in NRS.
Now that ruxolitinib has been approved by the FDA, the company intends to seek EMA approval.
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