Under Development JAK Inhibitors for Dermatologic Diseases

Molecular targeting therapies represent a new exciting era in dermatology. A promising novel drug class, subject of intense research, is Janus kinase (JAK) inhibitors. Multiple cytokine receptors signal through the Janus kinase and signal transducer and activator of transcription (STAT) pathway. The pathway plays a central role in innate and adaptive immunity, and haematopoiesis. The understanding of the contribution of JAKs to the immunologic processes of inflammatory diseases led to the development of JAK inhibitors, initially for rheumatologic and hematologic diseases. Soon, their efficacy in some dermatologic conditions was also demonstrated, and today their role as therapeutic agents is thoroughly researched, mainly in atopic dermatitis, psoriasis, vitiligo, and alopecia areata. JAK inhibitors can be administered orally or used topically. As they are relatively new treatment modalities in dermatology, many questions concerning their efficacy and safety remain unanswered. Data from ongoing trials are eagerly awaited. Here, we summarize under development JAK inhibitors for dermatologic diseases.


INTRODUCTION
Janus kinases (JAKs) is a family of intracellular tyrosine kinases consisting of four members (JAK1, 2, 3, and tyrosine kinase 2 [TYK2]). They are named after the two-faced Roman god because they are comprised of two phosphate-transferring domains with opposite roles.  31 2 2020 SUPPLEMENT I One domain exhibits, and the other inhibits the kinase activity. JAKs, Signal Transducer and Activator of Transcription (STAT) proteins consisting of seven members, STAT-1,-2,-3,-4,-5a,-5b and -6, and trans-membrane receptors are the three main parts of the JAK-STAT pathway, which transmits extracellular information to gene promoters inside the nucleus. 1 A vast array of hormones, interferons, colony-stimulating factors and interleukins exert their actions through the JAK-STAT pathway. 2 Those factors, after binding to their corresponding receptors, activate JAKs, which consequently phosphorylate the receptors, allowing STATs to bind to them and become phosphorylated. Phosphorylated STATs migrate to nucleus where they affect gene expression. 3 The importance of JAKs in human physiology, especially in immunity and haematopoiesis, was revealed quickly after their discovery and they became a field of intense research. The unveiling of their role in inflammatory 4-6 and myeloproliferative 7,8 diseases, identified JAKs as possible therapeutic targets. This led to the development of JAK inhibitors, a new and exciting era in pharmacologic development. Today, five JAK inhibitors are approved in USA and/or Europe, one only in Japan (peficitinib) for the treatment of rheumatoid arthritis (RA) and one (oclacitinib) for canine atopic dermatitis (AD) ( Table 1). Many more are under development for various rheumatologic, dermatologic, neoplastic and other diseases. Here, we summarize under development JAK inhibitors for dermatologic autoimmune/inflammatory conditions.

ATOPIC DERMATITIS
Atopic dermatitis (AD) is a common inflammatory skin disease affecting as much as 25% of children and 10% of adults. 9 Prevalence depends mainly on genetic and socio-economic factors, with developed countries being more affected. As the child ages, the disease improves or totally resolves in more than 50% of the patients over 6 years old, but in some cases, persists or even starts in adulthood. The main characteristics of the disease are pruritus, eczematous lesions usually in age-specific body parts, dry skin and chronic course with relapses and remissions. AD imposes a substantial psychosocial burden on patients and their relatives. Pruritus and the accompanying sleep disturbance are not only distressing but also increase the risk for psychiatric conditions like ADHD, depression, suicidal ideation, autism, and others. 10 Asthma, allergic rhinitis and food allergy are known associations of AD. Multiple other complications and comorbidities have been reported including, but not limited to, growth delay, bacterial and viral infections, ocular abnormalities, aortic stiffness, other allergic, metabolic and autoimmune conditions (Crohn's disease, alopecia areata, vitiligo, etc.). 11,12 Many key processes of AD pathogenesis, such as increased Th2 response, eosinophil activation, suppression of regulatory T-cells and structural factors of the skin, are due to the activation of the JAK-STAT pathway by numerous cytokines. 13

Ruxolitinib
Ruxolitinib is a JAK1/JAK2 inhibitor that, apart from AD, has been trialled for many other dermatologic (psoriasis, vitiligo, alopecia areata) and non-dermatologic diseases. One clinical trial (NCT03011892) comparing mean percentage change from baseline in Eczema Area and Severity Index (EASI) score at Week 4 in subjects treated with 1.5% ruxolitinib BID compared with subjects treated with vehicle cream BID has been completed in March 2018 but the results are not available yet. Another three trials are currently active. NCT03257644 is a pharmacokinetic study in paediatric patients. NCT03745638 and NCT03745651 are phase 3, double-blind, randomized trials to access the efficacy and safety of ruxolitinib cream in adolescents and adults with AD. A total of 1200 patients are estimated to be enrolled in the last two studies.

Delgocitinib
Delgocitinib is a topical pan-JAK inhibitor. Encouraging results firstly published by Nakagawa et al. 14 who conducted a placebo-controlled dose-ranging study on 327 patients. One more, phase 2b, double-blind, randomized, dose ranging trial to evaluate the efficacy and safety of delgocitinib cream in adults with AD started recently

UNDER DEVELOPMENT JAK INHIBITORS FOR DERMATOLOGIC DISEASES
(NCT03725722), and another (NCT03826901) is expected to start soon to evaluate the pharmacokinetics of the substance.

Tofacitinib
Only one phase 2 trial is published on topical administration of tofacitinib, a JAK1/JAK3 inhibitor, for AD, 15 with very promising results. In 69 adults with mild-to-moderate AD, randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily, change from baseline in EASI was 81.7 for tofacitinib vs. 29.9 for vehicle. All relevant scores (EASI, PGA and BSA) were improved by the first week of treatment and pruritus by day 2.

Baricitinib
Baricitinib, as a JAK1/JAK2 inhibitor, modulates cytokines associated with both acute (JAK1: IL-4, -6, -10, -13, -31, IFN-γ / JAK2: IL-5, -6, -23, -31, IFN-γ, GM-CSF) and chronic (JAK2: IL-23) AD lesions. 16 Results of a phase 2 clinical trial have been published. 15 According to those, 61% of the patients under baricitinib 4-mg achieved EASI-50 compared to 37% under placebo. Baricitinib also improved pruritus and sleep loss. A phase 3 trial (NCT03334422) with 750 participants has been completed recently with yet unavailable results and another six phase 3 trials are currently active. Most frequently reported adverse events (AEs) of baricitinib are infections, low neutrophils, and increases in creatinine, transaminases, high-and low-density lipoproteins and creatine phosphokinase levels. Laboratory abnormalities are usually clinically insignificant and rarely lead to discontinuation of treatment. 17,18 Upadacitinib Upadacitinib, a selective JAK1 inhibitor, is one of the most promising new drugs. In total, 35 trials are active or have been completed recently, for various diseases, as Crohn's disease, RA, ankylosing spondylitis, giant-cell arteritis and others. Nine of those trials concern AD. Only one has been completed. In this, patients were randomized to four arms (upadacitinib 7.5 or 15 or 30 mg or placebo) for 16 weeks. Change from baseline EASI was 39.4, 61.7, 74.4 and 23 respectively. Patients in the 30mg arm achieved the best results, EASI 90 in 50% compared to 2.4% in the placebo arm. Drug's effect was fast, decreasing skin lesions by week two of treatment and pruritus by week one. 19 Most frequent AEs were upper respiratory system infections. There was not a difference in severe AEs between the upadacitinib and placebo groups.
Concerning the possible parallel effect of JAK inhibitors on the multiple comorbidities of AD, not many data are available and no safe assumptions can be made at this time point. Nevertheless, a positive action not only on AD but also on some of its comorbidities would not be surprising.
For example, allergic diseases, which are often associated with AD, are primarily characterized by increased levels of IL-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP). All those cytokines induce the JAK/STAT pathway after binding to their respective receptors. 20 There are also reports of positive impact of JAK inhibition on inflammatory-driven comorbidities of myelofibrosis and related neoplasms. 21 JAK inhibitors may provide some benefit to patients with allergic diseases by specifically targeting inflammatory pathways important for disease pathogenesis, but current clinical trials are focused on AD, rather than on its allergic comorbidities or allergic diseases in general.

PSORIASIS
Psoriasis is another common inflammatory pruritic skin disease, characterized by abnormal epidermal growth, usually presenting as red, scaly patches, papules or plaques (psoriasis vulgaris) with a prevalence of approximately 2-3%. Other phenotypes of the disease include guttate, inverse, pustular, generalized pustular, palmoplantar and erythrodermic psoriasis. 22 27 There were also two similarly designed, phase 3 RCTs (OPT Pivotal 1 and 2) in which 745 patients received tofacitinib 5mg, 741 received 10mg, and 373 received placebo b.i.d. PASI 75 achievement rates were: OPT Pivotal 1 -39.9%, 59.2% and 6.2% for tofacitinib 5 and 10 mg twice daily and placebo; OPT Pivotal 2 -46%, 59.6% and 11.4% respectively. 28 In general, AEs were similar across studies with infections being the most common. Rates were also similar, with around 80% of patients developing an AE and 10% discontinuing treatment because of them. The short and long-term safety profile of tofacitinib was stable over time and consistent between phase 3 studies. Regarding the different dosage regimens, tofacitinib 10 mg did not appear to be associated with higher rates of AEs or discontinuations due to AEs than the 5mg dosage.

Ruxolitinib
Three phase 2 studies have been completed for topical ruxolitinib in psoriasis. In the first one, the drug showed better results than placebo and comparable to topical calcipotriene and betamethasone. 29 Owing to the small population of 29 patients, statistically significant conclusions could not be reached. The same group of investigators conducted a bigger study with 200 patients where ruxolitinib 1% induced 40% mean PASI improvement compared to 1% with placebo. 30 The most frequent AE of topical ruxolitinib was irritation in the site of application. No phase 3 trials of the drug are currently active.

Other JAK Inhibitors
Baricitinib showed encouraging results in the only phase 2 study of the drug in moderate-to-severe psoriasis. 271 patients were randomized in five groups (baricitinib 2, 4, 8, 10mg and placebo). 43% of the patients in the 8mg group and 54% in the 10mg group achieved PASI 75 compared to 17% in the placebo group. 31 Peficitinib also showed good dose-dependent results without serious AEs. 32 Finally, no results have been published from the only trial of itacitinib in psoriasis.

VITILIGO
Vitiligo is the most common acquired chronic pigmentation disorder. It is characterized by progressive epidermal melanocyte destruction, presenting as white patches, with a prevalence of approximately 1%. 33 Vitiligo has devastating psychological effects to the patients, especially to women and people with dark skin in whom it is more easily noticeable. 34 Common comorbidities include thyroid dysfunction, diabetes mellitus, alopecia areata and more. Contrary to psoriasis and AD, existing therapies for vitiligo have limited efficacy and the course of the disease is highly unpredictable, although spontaneous repigmentation rarely occurs. Melanocytes are destroyed by CD8 T cells. Those cells produce Interferon-γ (IFN-γ) which plays a crucial role in the disease pathogenesis, accumulating more T cells in vitiligo lesions. 23 Since IFN-γ signalling utilizes the JAK-STAT pathway, JAK inhibitors may be a step in the direction of much needed, new, safe and effective vitiligo treatments. Currently, only ruxolitinib has been trialled for vitiligo. 11 patients applied 1.5% cream twice daily for 20 weeks. In facial lesions, Vitiligo Area Scoring Index was improved by 76%, but in other areas, the response was minimal. AEs were minor (erythema, hyperpigmentation, transient acne). 35 It is unknown if better response in facial lesions was due to thinner epidermis of the face, or if light is important for topical JAK inhibitors. A subsequent report of two cases suggested the later. 36 Three large trials, including the phase 3 TRuE-V1 and TRuE-V2 with 300 participants each, are expected to end in 2021.

ALOPECIA AREATA
Alopecia Areata (AA) is another immune-mediated dermatological disease. It affects nearly 2% of the population and it is the second most common non-scarring alopecia after male and female pattern alopecia. 37 It usually manifests as solitary, round, small patches of hair loss. At the other end of the disease spectrum, all hair in the scalp (alopecia totalis -AT) or whole body (alopecia universalis -AU) may be affected. Usually, treatment-resistance depends on the extent of the disease. IFN-γ and Interleukin-15 (IL-15) signalling play a crucial role in AA development and maintenance. The first signals through JAK1/2 and the second mostly through JAK1/3. 38 Thus, blocking the activation of these receptors may be a treatment option for AA.

Tofacitinib
The largest published report is a retrospective study of 90 patients 39 with severe disease (AA with more than 40% of scalp hair lost, AT or AU). Analysis of response rates yielded a critical period of over than 10 years duration of AT or AU to be the point at which patients were much less likely to respond to treatment. Patients not belonging in this group (n=65) were considered potential responders (AA independent of disease duration or AT/AU with duration of less than 10 years). 28 received tofacitinib 5mg b.i.d. and 37 adjuvant therapy (5mg b.i.d. with prednisolone, >5mg b.i.d, alone or with prednisolone) for 4 to 18 months. The clinical response rate was 77%. Response was better in patients with AA than those with AT/AU. No serious AEs were reported, In the group with more than 10 years duration of AT/AU, 68% showed no response to tofacitinib.

UNDER DEVELOPMENT JAK INHIBITORS FOR DERMATOLOGIC DISEASES
In an additional study with 66 patients, 40 32% achieved 50% or more improvement in the severity of alopecia with 5mg tofacitinib b.i.d. Again, AEs were minimal, mainly infections, and notably drug cessation resulted in disease relapse in two months. In a Korean retrospective study, 41 43 where topical clobetasol dipropionate was compared with topical JAK inhibitors, 5 out of 16 patients had partial regrowth in the areas treated with ruxolitinib 1% ointment.

Baricitinib
The efficacy of oral baricitinib in AA has been demonstrated only in two case reports, 47 Cost of treatment is high, response is usually lost after treatment is stopped, optimal dosage, target and treatment duration are not precisely known and, most importantly, long-term safety results in dermatologic conditions are non-existent. Since JAK inhibitors are relatively new, real-life long-term safety data have just begun to emerge, although they concern non-dermatologic conditions, in which their usage has begun earlier.
Future research of JAK inhibitors in dermatology, beyond the above concerns, has clear directions in which it needs to move. As our understanding of the kinase family broadens, targeting will thankfully become more specific, increasing the precision of therapy, and thus lowering off-target activity and AEs. Finally, the easy accessibility of skin should be taken advantage of. As most topical treatments, future efficient topical JAK inhibitors will provide their benefits to the patients with lower cost and increased safety. Concerning the already established biologics agents and the reasonable question as to how they compare to JAK inhibitors in the treatment of dermatologic disorders, we believe it is too early for a sensible answer. From the very limited existing data concerning non-dermatologic conditions, mainly RA, it seems that JAK inhibitors have comparable efficacy to biologics. Small (or, less likely, big) differences in efficacy will appear in future studies and answer this question. Until then, we can point out that, compared to biologics, JAK inhibitors are not proteins, so they do not trigger antidrug immune response, have wider blockade spectrum, are administered topically or orally, and are small molecules that are more easily made, hence, are more economical. Therefore, in our opinion, at this time, the important point is that we will soon have a different, new, promising weapon in our armamentarium against chronic, life-altering diseases. 2020