Topical JAK Inhibitor Offers Promise for Two Skin Diseases
Immune-mediated inflammatory diseases (IMIDs) can cause significant distress for patients. Atopic dermatitis (AD) is one of the most common skin diseases worldwide, affecting an estimated 15% to 20% of children and 1% to 3% of adults.1,2 Vitiligo, a depigmented skin disorder, is characterized by a lack of melanocytes, leading to chalky white skin patches and sometimes loss of pigment in the scalp, hair, and mucous membranes. Vitiligo has a worldwide prevalence of 0.5% to 2%.3 Although it affects all skin colors and types, it is most noticeable in darker skin.4
Both AD and vitiligo can have damaging effect on well-being and quality of life, and therapy options are limited. For vitiligo, treatment offers limited options, including off-label topical corticosteroids or calcineurin inhibitors, or narrowband UV-B, excimer laser, and skin grafting. AD is typically treated first with basic skin care and topical medications, followed by more systemic agents for more refractory or widespread disease.
Research presented during the American Academy of Dermatology Virtual Meeting Experience (AAD VMX), held from April 23-25, 2021, demonstrated the efficacy and tolerability of a topical formulation of ruxolitinib cream, a Janus kinase (JAK) 1 and JAK2 inhibitor. Ruxolitinib cream may be a major advancement in the treatment of both conditions.
Using JAKs for Inflammatory Skin Diseases
JAK inhibitors work by inhibiting the activity of one or more of the JAK family of enzymes. In doing so, the small molecule agent interferes with the JAK and signal transducer and activator of transcription (STAT) signaling pathway. The JAK-STAT pathway plays a role in pathogenesis of cancers and inflammatory diseases, including the destruction of melanocytes in vitiligo and the inflammation and itching of AD.
A variety of oral JAK inhibitors are in development and/or are under FDA consideration for the treatment of IMIDs, including abrocitinib, baricitinib, delgocitinib, deucravacitinib, ruxolitinib, tofacitinib, and upadacitnib. Of them, several have current FDA approvals for dermatologic and nondermatologic conditions: baricitinib (rheumatoid arthritis [RA]), tofacitinib (RA, psoriatic arthritis, ulcerative colitis, juvenile idiopathic arthritis), ruxolitinib (myelofibrosis, polycythemia vera, acute graft-vs-host disease), and upadacitinib (RA). Further, some dermatologists have shared anecdotal stories of compounding JAK inhibitors into a topical formulation, and some of the agents—namely, delgocitinib, ruxolitinib, and tofacitinib–have shown great promise for various diseases.
Clinical Trials for Vitiligo
Ruxolitinib cream has been the focus of several clinical trials. At AAD VMX, Harris et al5 presented recent long-term data from a phase 2 study of 55 patients who completed 104 weeks of treatment. Of these patients, 83.6% had at least 50% improvement in facial vitiligo and 52.7% had 90% improvement at 104 weeks, as scored by a modified Vitiligo Area Scoring Index. Further, 58.2% had at least 50% improvement and 27.3% had 75% improvement in total body vitiligo at the same assessment point. Generally, patients experienced mild treatment-emergent adverse events (eg, acne, upper respiratory tract infection, pruritus, erythema) and no serious treatment-emergent adverse events were reported.
A separate analysis of a smaller group of patients treated with ruxolitinib cream and phototherapy from weeks 52 to 104 showed additional improvement with the addition of narrowband UV-B to ruxolitinib cream.6
The 104-week study showed not only the effectiveness of ruxolitinib cream, but the benefit of continuing treatment past an initial beneficial response, said Jim Lee, MD, PhD, group vice president, inflammation & autoimmunity at Incyte Corporation based in Wilmington, DE. “Traditionally with vitiligo treatment, many patients observe a maximal effect after 6 months or year 1,” said Dr Lee. “And what we wanted to do is show that with continued treatment, with continued dosing, patients actually continue to get better.”
Vitiligo treatment is a two-step process, he explained. In the first step, the immune cells are targeted to reduce the destruction of melanocytes. In the second step, melanocytes begin to repigment affected skin. “But in some individuals, the melanocytes can take a while to come back. I think that supported that hypothesis and just reaffirmed that some patients benefit from long-term treatment.”
Currently, there is no medicine approved by the FDA for repigmenting vitiligo, said David Rosmarin, MD, FAAD, vice chair of research and education in the dermatology department at Tufts Medical Center in Boston, MA. For patients who want even skin tones, there are bleaching agents to make them white, but ruxolitinib cream, he hoped, will be the first medication to restore pigment.
“These results are very promising and provide hope for the hundreds of thousands of patients with vitiligo,” said Kim Papp, MD, PhD, founder and president at Probity Medical Research in Waterloo, Ontario, Canada.
Clinical Trials for AD
As previously mentioned, ruxolitinib cream also has been studied for AD. In pooled results from a pair of phase 3 clinical trials involving a total of 1249 patients, 245 of whom were aged 12 and 17 years, ruxolitinib cream was associated with a significant mean patient change from baseline in Patient-Oriented Eczema Measure after 8 weeks.7 Dermatology Life Quality Index scores were significantly improved in patients using either the ruxolitinib 1.5% or 0.75% formulation compared with placebo. Patient ratings of skin pain were significantly improved within 12 hours of the first application of ruxolitinib cream and were furthered reduced by week 8. In addition, the topical agent demonstrated reductions in itch 12 hours after application, with rapid, clinically meaningful, and sustained improvement over 8 weeks.8
“The mean reduction occurs very quickly. You see that actually within a day or two where you see statistically significant reduction in itch reported by the patients,” said Dr Lee.
“One of the most striking differences between emollients and the JAK inhibitor cream is how quickly the cream works,” said Dr Papp. He added that 1.5% works a bit better than 0.75%, but both are “very competent.”
Safety of a Topical JAK Inhibitor
The trial results5-8 suggest that ruxolitinib cream was well tolerated. “The main two side effects that we are seeing are some application site reactions or acne, which in most cases is mild,” said Dr Rosmarin. “So, this seems to be overall very well tolerated.”
Although oral JAK inhibitors must carry a black box warning concerning an increased risk of thrombosis, many researchers believe the data from ruxolitinib cream’s clinical studies do not warrant such warnings. “I believe we need to assess each drug and each mode of delivery on its own merits. Extending class labels to topical therapies is entirely unwarranted unless serum drug levels are comparable to those treated orally,” stated Dr Papp.
In tests of people using the topical JAK inhibitor, blood levels of the drug were “miniscule,” Dr Rosmarin said. “So that helps prevent systemic effects of the medication. When we are looking at platelet abnormalities, we are not seeing those when the medicine is used topically.”
Dr Lee concurred. “When we look at our data, we do not see any systemic [adverse events] related to high systemic exposure.”
Conclusion
The researchers believe the topical JAK inhibitor may provide new benefits over current options for both diseases. Further studies are planned for both skin conditions, including trials with children.
References
1. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66(suppl 1):8-16. doi:10.1159/000370220
2. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: section 1. diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. doi:10.1016/j.jaad.2013.10.010
3. Krüger C, Schallreuter KU. A review of the worldwide prevalence of vitiligo in children/adolescents and adults. Int J Dermatol. 2012;51(10):1206-1212. doi:10.1111
/j.1365-4632.2011.05377
4. Grimes PE, Miller MM. Vitiligo: patient stories, self-esteem, and the psychological burden of disease. Int J Womens Dermatol. 2018;4(1):32-37. doi:10.1016/j.ijwd.2017.11.005
5. Harris JE, Pandya AG, Lebwohl M, et al. Safety and efficacy of ruxolitinib cream for the treatment of vitiligo: 104-week data from a phase 2 study. Presented at: American Academy of Dermatology Virtual Meeting Experience; April 23-25, 2021; virtual.
6. Pandya AG, Harris JE, Lebwohl M, et al. Addition of narrow-band ultraviolet light B phototherapy to ruxolitinib cream in patients with vitiligo. Presented at: American Academy of Dermatology Virtual Meeting Experience; April 23-25, 2021; virtual.
7. Simpson EL, Augustin M, Thaçi D, et al. Patient-reported outcomes of ruxolitinib cream for the treatment of atopic dermatitis: pooled results from two phase 3 studies. Presented at: American Academy of Dermatology Virtual Meeting
Experience; April 23-25, 2021; virtual.
8. Blauvelt A, Szepietowski JC, Papp K, et al. Ruxolitinib cream rapidly decreases pruritus in atopic dermatitis: pooled results from two phase 3 studies. Presented at: American Academy of Dermatology Virtual Meeting Experience; April 23-25, 2021; virtual.
