PF-04965842

Expert Opinion on Investigational Drugs

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieid20

Abrocitinib: A potential treatment for moderate- to-severe atopic dermatitis

Novin Nezamololama , Erika L. Crowley , Melinda J. Gooderham & Kim Papp

To cite this article: Novin Nezamololama , Erika L. Crowley , Melinda J. Gooderham & Kim Papp (2020): Abrocitinib: A potential treatment for moderate-to-severe atopic dermatitis, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2020.1804854
To link to this article: https://doi.org/10.1080/13543784.2020.1804854

Accepted author version posted online: 01 Aug 2020.
Submit your article to this journal
Article views: 35
View related articles Image View Crossmark data

Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ieid20

Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group
Journal: Expert Opinion on Investigational Drugs

DOI: 10.1080/13543784.2020.1804854

Abrocitinib: A potential treatment for moderate-to- severe atopic dermatitis

Novin Nezamololama1 Erika L. Crowley2 Melinda J. Gooderham1,3,4 and Kim Papp4,5

1. Skin Centre for Dermatology, 775 Monaghan Road South, Peterborough, ON k9J 5K2
2. International Space University, 1 Rue Jean-Dominique Cassini, 67400 Illkirch-Graffenstaden, France
3. Queen’s University, 99 University Ave, Kingston, ON k7L 3N6
4. Probity Medical Research, 139 Union St E, Waterloo, ON N2J 1C4
5. K Papp Clinical Research, 135 Union St. E., Waterloo, ON N2J 1C4

Corresponding Author:
Melinda J. Gooderham, [email protected]
Skin Centre for Dermatology
775 Monaghan Road South, Peterborough, ON K9J 5K2 Phone number: 705-775-7546

Abstract

Introduction: Atopic dermatitis (AD) is a common and debilitating dermatosis that often impacts the physical and psychological quality of life in children and adults. A limited number of treatment options are available for AD, and often these treatments result in an insufficient response or may be contraindicated for some patients. This treatment gap creates an increasing demand for alternative AD therapies. The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway is known to play a critical role in the dysregulation of immune responses in AD. Inhibition of the JAK enzymes in the JAK-STAT pathway has shown potential for the treatment of this chronic skin condition.
Areas covered: We review the evolving efficacy and safety profile of abrocitinib, an oral JAK1 inhibitor, in the treatment of AD based on the data available from phase I, II, and III clinical trials.
Expert opinion: Evidence supports clinical efficacy, improved pruritus and an acceptable safety profile, making abrocitinib a viable alternative to conventional AD therapies. Pivotal phase III trials included subjects aged 12 years and above, providing a new mechanism of action for future treatment of adolescent and adult AD. Further investigations are required to have a thorough understanding of abrocitinib in the treatment of AD.

Keywords: abrocitinib, PF-04965842, atopic dermatitis, eczema, JAK1, JAK-STAT Pathway

Article Highlights:

⦁ Abrocitinib, an emerging JAK 1 selective inhibitor being investigated for use in atopic dermatitis, is reviewed.
⦁ Clinical trials show a consistent if evolving abrocitinib efficacy and safety profile

⦁ In addition to improving clinical scores, abrocitinib significantly improves the cardinal symptom of atopic dermatitis, pruritus.
⦁ Pivotal trials of abrocitinib include both adults and adolescents providing a potential new option for treatment of those aged 12 years and above
⦁ Additional investigations are required to fully understand the use of abrocitinib for atopic dermatitis including a more complete safety profile

1. Introduction

Atopic dermatitis (AD), commonly referred to as eczema, is a chronic inflammatory skin disease that can be debilitating. AD, characterized by pruritus and eczematous lesions [1], affects primarily children (5-20% globally) but also adults [2,3]. Quality of life of the affected children, adults, and caregivers is a growing concern [2–4] and is compromised as a result of AD. Several domains are impacted including physical, psychological, social, and economic [3]. Emollients and topical therapies are considered the cornerstone of treatments for mild AD; however, topical treatments alone are often insufficient for patients in moderate-to-severe condition [1,5]. Other options include phototherapy, systemic corticosteroids, systemic immunosuppressants, and the monoclonal antibody, dupilumab, all of which have associated limitations and challenges [1]. Taken together, the burden associated with AD, the inadequacy of topical therapies, and the caveats associated with phototherapy and immunosuppressants create a need for alternative therapies for AD.

Several pathophysiological mechanisms contribute to AD manifestations, including filaggrin (FLG) mutations, dysbiosis of skin microbiota, and immune dysregulation [6]. FLG is a multifunctional structural protein that is responsible for epidermal barrier function and promoting T-cell infiltration and inflammation. Deficient FLG can lead to AD [7]. Dysbiosis of the skin microbiota has been considered a significant factor in AD pathogenesis, which generally refers predominantly to colonization by Staphylococcus aureus (S. aureus) [8]. AD flares are associated with increased S. aureus colonization that in turn decreases the bacterial diversity on the skin [8].

Perturbations of cutaneous innate immunity, particularly defects in antimicrobial peptides (AMPs) have been associated with a higher susceptibility to AD. It is hypothesized that AD results from increased levels of T-helper 2 (Th2) cytokines, interleukin (IL)-4, and IL- 13 [6,9]. Furthermore, environmental factors such as diet, climate, and microbial exposure are also believed to contribute to the pathogenesis of AD [10].
The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) JAK- STAT pathway play a fundamental role in the pathophysiology of immune-mediated inflammatory skin conditions such as AD, psoriasis, alopecia areata, and vitiligo [11]. The JAK-STAT pathway is the principal signaling mechanism for many growth factors and cytokines. Several critical cellular events, including cell proliferation, migration, differentiation, and apoptosis, are stimulated by JAK activation [12,13]. Abrocitinib (PF-04965842) was developed by Pfizer as an orally administered selective JAK1 inhibitor [14]. According to preclinical studies, abrocitinib has been indicated to possess nanomolar potency with 28-fold selectivity for JAK1 over JAK2, >340-fold selectivity over JAK3 and 43-fold over TYK2 [14]. Therefore, inhibition of JAK1 by abrocitinib could be a novel pharmacological target for the treatment of AD. The purpose of this work is to review the current literature regarding the known efficacy and safety data of abrocitinib for AD.

2. Fundamentals of JAK1

Of the 518 protein kinases in the human body, 90 are protein tyrosine kinases (PTK) [15,16]. These enzymes are responsible for the transfer of γ phosphate of a purine nucleotide triphosphate (ATP, GTP) to the hydroxyl groups of specific protein substrate tyrosine residues.
PTKs can be characterized as receptor PTKs by the presence of transmembrane and extracellular receptor domains that enable them to recognize extracellular ligands [17,18]. Although most are receptor PTKs, some lack these components and are referred to as non-receptor or non- transmembrane PTKs.

The JAK family of enzymes are intracellular, non-receptor PTKs that primarily transduce cytokine-mediated signals via the JAK-STAT pathway. JAK enzymes are comprised of two near- identical phosphate-transferring domains: one with kinase activity and one without. While the pseudokinase lacks kinase activity, it negatively regulates the activity of the other domain [19,20]. There are four members of the JAK family in mammals, including JAK1, JAK2, JAK3, and tyrosine kinase-2 (TYK2). Distributed on three different chromosomes in humans, the genes of TYK2 and JAK3 are located on chromosome 19, at gene p13.2 and p13.1, respectively, whereas the JAK1 genes are located on chromosome 1p31.3 and JAK2 on chromosome 9p24 [21–23]. JAK1, JAK2, and TYK2 are expressed ubiquitously, while JAK3 is expressed primarily in hematopoietic cells [24,25].
The JAK family of enzymes mediate the signal transduction required for leukocyte activation, proliferation, survival, and function through interaction with the Type I and Type II cytokine receptors [19]. Receptors (Type II cytokine receptors) for IL-10, IL-19, IL-20, and IL- 22, along with glycoprotein 130 (gp130) subunit-sharing receptors signal primarily through JAK1 but also associate with JAK2 and TYK2 [19]. Type I interferons (IFNs), including interferon- alpha (IFN-α) and interferon-beta (INF-β) signal through a combination of JAK1 and TYK2 [26]. The Type II interferon-gamma (IFN-γ) receptor activates both JAK1 and JAK2 while common gamma (γc) chain containing receptors (receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) signal with JAK1 and JAK3 [26].Interest in the inhibition of the JAK enzymes, including JAK1, has recently increased dueto the many dermatologically relevant cytokines that rely on the JAK-STAT pathway [29]. AD is one of the dermatologic conditions for which JAK inhibitors have been investigated. As previously mentioned, the complex pathogenesis of AD is driven in part by the Th2 immunity from cytokines signaling the JAK-STAT pathway [30]. Signaling of this pathway occurs as the JAK enzymes act as intracellular secondary messengers bringing the extracellular cytokine signals to the STAT pathway. Signaling cytokines include but are not limited to IL-4, IL-13, Il-31, and IFN-γ, which have signaling mediated by the JAK1 enzyme and are thus inhibited by abrocitinib [31]. Figure 1 shows the structure of JAK1 when in complex with abrocitinib.

3. Brief overview of the market
JAK inhibition by the targeting of various kinase combinations may be considered a novel treatment for inflammatory diseases such as AD [32]. To date, several JAK inhibitors have been approved by the Food and Drug Administration (FDA) for several conditions, such as tofacitinib (Xelijanz®) for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) and baricitinib (Olumiant®) and upadacitinib (RinvoqTM) for the treatment of RA (Table 1) [33]. Nevertheless, there are currently no approved JAK inhibitors for the treatment of dermatoses [11]. Oral JAK1- selective inhibitors including abrocitinib and upadacitinib, as well as the JAK1/2 inhibitor, baricitinib, are currently under investigation for use in AD [34]. JAK1 plays a fundamental role in the signal transduction of several Type I and II inflammatory cytokine receptors [35]. Selective inhibition of JAK1 may lead to a more favorable safety profile than pan-JAK inhibitors since the effects of JAK2 inhibition are reduced with this class of kinase inhibitors [36]. Currently the market for atopic dermatitis has one approved therapy, a monoclonal antibody dupilumab. However, other monoclonal antibodies under investigation including tralokinumab, lebrikizumab and nemolizumab are also likely to enter the market in the next few years.

4. Clinical efficacy

The safety and efficacy of abrocitinib have to date been evaluated in phase I, II, and III studies. These studies provide promising results for the treatment of AD. Safety, tolerability, and pharmacokinetics of abrocitinib were assessed in a single ascending dose (SAD) study conducted in 79 healthy volunteers randomized to receive placebo or 3, 10, 30, 100, 200, 400, or 800 mg abrocitinib, and a multiple ascending dose (MAD) study, wherein subjects received placebo or 30 mg once daily (QD), 100 mg QD, 200 mg QD, 400 mg QD, 100 mg twice daily (BID), or 200 mg BID abrocitinib for ten consecutive days. These study results supported further evaluation of abrocitinib in patients with inflammatory diseases such as AD [36].
A 12-week phase IIb study was conducted to determine the safety and efficacy of abrocitinib in 267 patients with moderate-to-severe AD. This study assessed AD patients between 18 to 75 years old of age with inadequate response or contraindication to topical medications for at least four weeks within 12 months [31]. There were five treatment arms wherein patients were randomly assigned with an equal chance to receive abrocitinib 200 mg, 100 mg, 30 mg, 10 mg, or placebo [31]. At the end of this trial, 43.8% (21 of 48) of patients receiving 200 mg of abrocitinib, 29.6% (16 of 54) of patients receiving 100 mg of abrocitinib, 5.8% (3 of 52) of patients receiving placebo achieved 0 (clear), or 1 (almost clear) on the Investigator’s Global Assessment (IGA) scale with an improvement of two grades or more [31]. Overall, the 200 mg and 100 mg QD doses of abrocitinib indicated efficacy and acceptable safety in the treatment of moderate-to-severe AD. Recently, results from the phase III JADE MONO-1 and JADE MONO-2 studies were presented. Both studies were 12-week, randomized, double-blinded, placebo-controlled trials that randomized participants into three treatment arms (2:2:1): 200 mg abrocitinib, 100mg abrocitinib, and placebo. Eligible subjects were 12 years of age or greater and had moderate-to-severe AD asdefined as an IGA ≥3, Eczema Area and Severity Index (EASI) score ≥16, affected percentage of body surface area ≥10%, and Peak Pruritus Numerical Rating Scale (PP-NRS) score ≥4 [39,40]. The coprimary endpoints for both studies were the proportion of patients achieving IGA response at week 12 and the proportion of patients achieving an EASI ≥ 75% improvement from baseline (EASI-75) at week 12.

The JADE MONO-1 trial randomized 387 participants and 333 completed the study. The week 12 results showed 43.8 % of patients receiving 200 mg abrocitinib, 23.7% of participants receiving 100 mg abrocitinib, and 7.9 % of those receiving placebo achieved an IGA response [39]. An EASI-75 response was reached in 62.7%, 39.7%, and 11.8% in the abrocitinib 200 mg, 100 mg, and placebo groups, respectively [39].

According to the JADE MONO-2 trial of 391 randomized participants, 330 completed the study. At week 12, 38.1 % of patients receiving 200 mg abrocitinib, 28.4% of participants receiving100 mg abrocitinib, and 9.1% of those receiving placebo achieved an IGA response [40]. In addition, 61.0%, 44.5%, and 10.4% of patients receiving 200 mg abrocitinib, 100 mg abrocitinib, and placebo, respectively, achieved an EASI-75 response [40]. These trials demonstrate that abrocitinib met both co-primary endpoints and has an acceptable efficacy in the treatment of moderate-to-severe AD; nevertheless, further investigations are required, particularly if extrapolating to long-term treatment regimens.
The key secondary endpoint of reduction in pruritus, which is a major symptom for AD, was evaluated as PP-NRS score ≥4 in both phase III JADE MONO-1 and JADE MONO-2 trials. According to the results of JADE MONO-1, at week 12, 57.2% of patients receiving 200 mg abrocitinib, 37.7% of those receiving 100 mg abrocitinib, and 15.3% of participants receiving placebo achieved a PP-NRS score ≥4 [39]. At week 12 in the JADE MONO-2 study, 55.3%, 45.2%, and 11.5% of participants receiving 200 mg abrocitinib, 100 mg abrocitinib, and placebo,respectively achieved a PP-NRS score ≥4 [40]. Overall, JADE MONO-1 and JADE MONO-2 indicated that the reduction in pruritus was significantly higher in both the 100 mg and 200 mg abrocitinib treatment arms compared to that of the placebo groups.

5. Safety and tolerability

5.1. Abrocitinib

The first phase I clinical trial with 79 subjects, described previously, had no deaths or serious adverse events. There were 24 patients with treatment-emergent adverse events (TEAE) in the SAD study and 35 in the MAD study [36]. The most frequent TEAEs requiring treatment were headaches (n=13, 16.4%), diarrhea (n=11, 13.9%), and nausea (n=11, 13.9%). Less frequent TEAEs included gastrointestinal disorders (abdominal discomfort, upper abdominal pain, constipation, flatulence, vomiting), infections and infestations (upper respiratory tract infection), musculoskeletal and connective tissue disorders (extremity pain), nervous system disorders (dysgeusia, somnolence), and respiratory, thoracic, and mediastinal disorders (nasal congestion). Although there were no temporary discontinuations or dose reductions because of the adverse events, four (0.5%) subjects discontinued due to these adverse events. Some subjects were noted to have changes in overall lipid levels with elevations of both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol. A total of 25 subjects in the SAD phase and 40 subjects in the MAD phase had laboratory abnormalities, but none were clinically relevant.
The phase II clinical trial with 267 subjects reported overall good tolerance for short-term use [31]. A total of 184 (68.9%) subjects experienced adverse events, with 64 (24.0%) of those considered related to the treatment and there were no deaths. Among these events, dermatitis atopic, upper respiratory tract infection, headache, nausea, and diarrhea were the most frequently reported. Less common TEAEs included nervous system disorders (dizziness) and skin andsubcutaneous disorders (dermatitis contact). In addition, there were two (0.7%) events considered serious, pneumonia in the 200 mg treatment group, and eczema herpeticum in the 100 mg treatment group that were related to the treatment. There were 44 (16.5%) subjects who discontinued treatment because of TEAEs. Dose-dependent changes in the platelet counts were observed, but the dose-dependent decreases trended upward toward baseline after week four despite ongoing therapy.

Most recently, the phase III clinical trial program, JADE MONO-1 and JADE MONO-2 trials, results have been presented. The JADE MONO-1 trial with 387 participants reported on safety [39]. There were TEAEs in 77.9%, 69.2%, and 57.1% of the abrocitinib 200 mg, 100 mg, and placebo groups, respectively. Rates of SAEs were low with 3.2%, 3.2%, and 3.9% in the abrocitinib 200 mg, 100 mg, and placebo groups, respectively. The rates of discontinuation were higher in the placebo group compared to both abrocitinib groups with 9.1% discontinuation in placebo compared to 5.8% in both abrocitinib groups. The most common TEAEs (>5%) in any group were nausea, nasopharyngitis, headache, upper respiratory tract infection, and dermatitis atopic. There were no cases of venous thromboembolism or any deaths; however, there were two cases of herpes zoster and one case of eczema herpeticum. Many laboratory evaluations, including hemoglobin, neutrophils, and lymphocytes did not show significant changes, but platelet counts decreased with a nadir at four weeks and trended back to baseline with ongoing therapy. Elevations in lipid levels were observed [39].
The JADE MONO-2 trial with 391 patients reported acceptable safety and tolerance [40]. Among these, there were 201 (51.4%) TEAEs, including 42 (53.8%) in the placebo, 99 (62.7%) in the 100 mg abrocitinib, and 102 (65.8%) in the 200 mg abrocitinib groups. The most commonTEAEs (>5% in any group) were nausea, nasopharyngitis, headache, upper respiratory tract infection, dermatitis atopic, acne, and vomiting. There was one death, which was not related to the treatment, and a total of eight SAEs, including 1 (1.3%) subject in the placebo group, 5 (3.2%) in the 100 mg abrocitinib group, and 2 (1.3%) in the 200 mg abrocitinib group. A total of 21 subjects discontinued because of AEs (12.8% placebo group; 3.8% 100 mg abrocitinib; 3.2% 200 mg abrocitinib). Platelet counts decreased but trended towards baseline starting at week 4 similar to what was seen in the phase II program. Dose-related changes in lipid levels were reported (10% increase in both LDL and HDL) as well as increased creatine kinase (CK) levels.
Table 2 contains a summary of the safety and tolerability profile of abrocitinib from the phase I, II, and III clinical trials. From these 1124 patients collectively, headaches, diarrhea, and nausea, as well as dermatitis atopic, upper respiratory tract infection, nasopharyngitis, headache, acne, and vomiting, have been the most common. There were no deaths due to treatment, but there were some discontinuations due to TEAEs and as a result of a few SAEs. Laboratory results were for the most part clinically irrelevant, with some dose-dependent decreases in the platelet counts and increases in lipid and CK levels. Overall, abrocitinib was well tolerated with an acceptable safety profile over the three clinical trials. Information on the long-term safety and tolerability is pending and requires further consideration.

5.2. Comparison to other JAK Inhibitors

There is increasing information regarding JAK inhibitor safety from studies with other inflammatory diseases. Consequently, there have been several reviews discussing JAK inhibitor side effect profiles in relation to AD [41–43]. Generally, the JAK inhibitor AEs are most often mild-to-moderate, while the most common SAEs are serious infections [43]. Consistent with theliterature for JAK inhibitors, an infection was reported in each of the trials for abrocitinib, albeit infrequent and generally lower severity (Table 2). Although malignancies have been reported with other JAK inhibitors for other indications [44,45], there were limited reports in the short-term clinical trials with abrocitinib (Table 2). This is similar to previous reports of thromboembolism in other populations, mainly patients with RA treated with JAK inhibitors. Only one pulmonary embolism was reported in the phase II abrocitinib program [31,46,47].

JAK inhibitors are associated with abnormal laboratory findings, including elevations of liver enzymes, creatine phosphokinase (CK), creatinine, lipids, as well as hematologic abnormalities [43]. Although laboratory abnormalities reported in the abrocitinib clinical trials and were considered clinically irrelevant, there were dose-dependent decreases in platelet counts as well as dose-related increases in CK and lipid levels (Table 2). The increased lipids are a common effect of JAK inhibition while the decreases in platelet counts are associated with JAK1 inhibition [43].
The information regarding the short-term safety of JAK inhibitors for AD patients is increasing, and there has been agreement regarding the current overall acceptability of the safety and tolerability of JAK inhibitors. While there appear to be consistent JAK inhibitor-related laboratory abnormalities and AEs, some of the AEs and laboratory abnormalities seen with other JAK inhibitors were not reported for abrocitinib. Additional clinical trials with larger patient populations and study durations will be useful to understand the long-term safety and tolerability of abrocitinib in AD patients.

6. Development program

Abrocitinib safety and efficacy were analyzed in the phase II and III studies. The phase III trials on the safety and efficacy of abrocitinib for AD are summarized in Table 3.

7. Conclusion

Given the great demand for alternative AD therapies, treatments that inhibit JAK enzymes involved in the JAK-STAT pathway have been studied as potential treatment options for AD. The JAK1 inhibitor, abrocitinib, has shown promise throughout the phase I, II, and III clinical trial studies. Clinical trials have demonstrated the clinical efficacy as well as supporting safety and tolerability of abrocitinib. Further research and studies are ongoing and will provide additional insight into this emerging therapy.

8. Expert opinion

Once approved for use in AD, abrocitinib will provide a welcome addition to the basket of therapeutic options. Traditional treatments for AD, many of which are used off label — methotrexate, cyclosporine, azathioprine, mycophenolate mofetil, and systemic steroids — are burdened by AEs and predictable end-organ toxicity [49]. Monitoring of abrocitinib will likely be similar to what is already required of these agents, with no apparent risk of end- organ toxicity and, for the most part, only minor issues surrounding tolerability. However, monitoring may also pose a burden to therapy, which is not required with newer monoclonal antibodies for the treatment of AD. Dupilumab, currently approved since 2017, does not require any screening investigations or monitoring with therapy. Other agents in the pipeline, such as tralokinumab and nemolizumab, will likely have a similar label. However, increasing the options for patients with AD may lead to improved diagnosis and treatment of this population, which has largely been undertreated. Inclusion of subjects aged 12 years and older in the phase III pivotal trails may provide treatment options for both adolescents and adults. There are currently no trials registered for the pediatric population under the age of 11. It is not clear whether abrocitinib will be considered second- or third- line therapy after topical treatment in patients with moderate-to-severe AD. Treatment hierarchy depends upon several factors including cost, access, and safety data. If cost is less than the biologics, abrocitinib could be placed as second line after topical therapy.
With efficacy comparable to that of dupilumab (which has an IGA response rate of approximately 36-39%) [50], 200 mg abrocitinib (which has an IGA response rate of 38-44%) should be seen as a viable treatment alternative to dupilumab.
It will offer the option of oral therapy over injectable therapy, which may be preferred by some patients. The results from the phase II and phase III studies suggest that the higher dose of 200 mg will achieve higher levels of response with minimal or incremental increases in tolerability concerns. We anticipate that the rates of all levels of response will increase with greater exposure to abrocitinib.
Our clinical impression, backed by results of the clinical trials, is that the pruritic component responds quickly compared to other traditional therapies, with improvement in pruritus noted within days of starting treatment [39]. As pruritus probably has the most significant impact on the quality of life, this is a strong positive in support of abrocitinib as a therapeutic option. Improvement in pruritus can lead to improved sleep and overall wellbeing.

Missing from the literature to date are studies regarding long-term efficacy and maintenance of response, but with ongoing long-term extension studies, these gaps should be filled. The short-term 12-week responses are insufficient to establish clinical expectations of the long-term response. We do not yet know if efficacy is sustained over years of continuous treatment, nor do we yet know the impact of interruptions in treatment. We can anticipate that lack of adherence may produce a loss of response, as is observed with other chronic treatments, and a concern with this patient population. Also missing is more information on the safety of JAK inhibitors as a class. Many unanswered questions remain, such as the true risk of venous thromboembolism, infection rates, and impact on malignancy. With regards to abrocitinib, furtherinformation is required on the mechanism of the decrease in platelets. Although there have been no clinical sequalae related to changes in platelets, a better understanding is required. The long- term results from clinical studies of abrocitinib are important when considering abrocitinib for the treatment of AD.

Funding
This paper was not funded.

Declaration of interest
M Gooderham has been an investigator, speaker, consultant or advisory board member for AbbVie, Amgen, Akros, Arcutis, Boehring Ingelheim, BMS, Celgene, Dermira, Dermavant, Galderma, GSK, Eli Lilly, Janssen, Kyowa Kirin, Leo Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, UCB, and Valeant/Bausch.

K Papp has been an investigator, speaker, consultant or advisory board member for AbbVie, Amgen, Akros, Arcutis, Boehring Ingelheim, BMS, Celgene, Dermira, Dermavant, Galderma, GSK, Eli Lilly, Janssen, Kyowa Kirin, Leo Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sandoz, Sun Pharma, Takeda, UCB, and Valeant/Bausch. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers

[1] 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;70:338–351.

[2] Birdi G, Cooke R, Knibb RC. Impact of atopic dermatitis on quality of life in adults: a systematic review and meta-analysis. Int. J. Dermatol. 2020;59:e75–e91.

[3] Carroll CL, Balkrishnan R, Feldman SR, et al. The Burden of Atopic Dermatitis: Impact on the Patient, Family, and Society. Pediatric Dermatology. 2005;22:192–199.

[4] Clarke S-A, Eiser C. The measurement of health-related quality of life (QOL) in paediatric clinical trials: a systematic review. Health Qual Life Outcomes. 2004;2:66.

[5] Boguniewicz M, Alexis AF, Beck LA, et al. Expert Perspectives on Management of Moderate-to- Severe Atopic Dermatitis: A Multidisciplinary Consensus Addressing Current and Emerging Therapies. J Allergy Clin Immunol Pract. 2017;5:1519–1531.

[6] Napolitano M, Marasca C, Fabbrocini G, et al. Adult atopic dermatitis: new and emerging therapies. Expert Rev Clin Pharmacol. 2018;11:867–878.

[7] Čepelak I, Dodig S, Pavić I. Filaggrin and atopic march. Biochemia Medica. 2019;29:1–14.

[8] Wan P, Chen J. A Calm, Dispassionate Look at Skin Microbiota in Atopic Dermatitis: An Integrative Literature Review. Dermatology & Therapy. 2020;10:53–61.

[9] Afshar M, Gallo RL. Innate immune defense system of the skin. Veterinary Dermatology. 2013;24:32-e9.

[10] Egawa G, Weninger W. Pathogenesis of atopic dermatitis: A short review. Ginhoux F, editor. Cogent Biology [Internet]. 2015 [cited 2020 Apr 15];1. Available from: https://www.cogentoa.com/article/10.1080/23312025.2015.1103459.

[11] Montilla AM, Gómez-García F, Gómez-Arias PJ, et al. Scoping Review on the Use of Drugs Targeting JAK/STAT Pathway in Atopic Dermatitis, Vitiligo, and Alopecia Areata. Dermatology & Therapy. 2019;9:655–683.

[12] Harrison DA. The JAK/STAT Pathway. Cold Spring Harb Perspect Biol [Internet]. 2012 [cited 2020 Mar 29];4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282412/.

[13] Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAK-STAT. 2013;2:e24137.

[14] Xu P, Shen P, Yu B, et al. Janus kinases (JAKs): The efficient therapeutic targets for autoimmune diseases and myeloproliferative disorders. European Journal of Medicinal Chemistry. 2020;192:112155.

[15] Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291:1304–1351.

[16] Manning G, Whyte DB, Martinez R, et al. The protein kinase complement of the human genome. Science. 2002;298:1912–1934.

[17] Tsygankov AY. Non-receptor protein tyrosine kinases. Front. Biosci. 2003;8:s595-635.

[18] Gocek E, Moulas AN, Studzinski GP. Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells. Crit Rev Clin Lab Sci. 2014;51:125–137.

[19] Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol. Rev. 2009;228:273–287.

[20] Raivola J, Haikarainen T, Silvennoinen O. Characterization of JAK1 Pseudokinase Domain in Cytokine Signaling. Cancers (Basel). 2019;12.

[21] Firmbach-Kraft I, Byers M, Shows T, et al. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene. 1990;5:1329–1336.

[22] Riedy MC, Dutra AS, Blake TB, et al. Genomic sequence, organization, and chromosomal localization of human JAK3. Genomics. 1996;37:57–61.

[23] Pritchard MA, Baker E, Callen DF, et al. Two members of the JAK family of protein tyrosine kinases map to Chromosomes 1p31.3 and 9p24. Mammalian Genome. 1992;3:36–38.

[24] Yamaoka K, Saharinen P, Pesu M, et al. The Janus kinases (Jaks). Genome Biol. 2004;5:253.

[25] Rane SG, Reddy EP. JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells. Oncogene. 1994;9:2415–2423.

[26] Müller M, Briscoe J, Laxton C, et al. The protein tyrosine kinase JAK1 complements defects in interferon-α/β and -γ signal transduction. Nature. 1993;366:129–135.

[27] Rodig SJ, Meraz MA, White JM, et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998;93:373–383.

[28] Kleppe M, Spitzer MH, Li S, et al. Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis. Cell Stem Cell. 2017;21:489-501.e7.

[29] Damsky W, King BA. JAK inhibitors in dermatology: The promise of a new drug class. J. Am. Acad. Dermatol. 2017;76:736–744.

[30] Leung DYM, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J. Allergy Clin. Immunol. 2014;134:769–779.

[31] Gooderham MJ, Forman SB, Bissonnette R, et al. Efficacy and Safety of Oral Janus Kinase 1 Inhibitor Abrocitinib for Patients With Atopic Dermatitis: A Phase 2 Randomized Clinical Trial. JAMA Dermatol. 2019;155:1371–1379.
**This study indicates abrocitinib resulted in significant improvement in the symptoms of AD.

[32] Clarysse K, Pfaff CM, Marquardt Y, et al. JAK1/3 inhibition preserves epidermal morphology in full thickness 3D skin models of atopic dermatitis and psoriasis. Journal of the European Academy of Dermatology and Venereology. 2019;33:367–375.

[33] Mogul A, Corsi K, McAuliffe L. Baricitinib: The Second FDA-Approved JAK Inhibitor for the Treatment of Rheumatoid Arthritis. Ann Pharmacother. 2019;53:947–953.

[34] Rodrigues MA, Torres T. JAK/STAT inhibitors for the treatment of atopic dermatitis.

Journal of Dermatological Treatment. 2020;31:33–40.

[35] Rompaey LV, Galien R, Aar EM van der, et al. Preclinical Characterization of GLPG0634, a Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases. The Journal of Immunology. 2013; 1201348.

[36] Peeva E, Hodge MR, Kieras E, et al. Evaluation of a Janus kinase 1 inhibitor, PF-04965842, in healthy subjects: A phase 1, randomized, placebo-controlled, dose-escalation study. British Journal of Clinical Pharmacology. 2018;84:1776–1788.
*This study establishes that abrocitinib safety in healthy participants.

[37] Guttman-Yassky E, Thaçi D, Pangan AL, et al. Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. J. Allergy Clin. Immunol. 2020;145:877–884.

[38] Mobasher P, Seradj MH, Raffi J, et al. Oral small molecules for the treatment of atopic dermatitis: a systematic review. Journal of Dermatological Treatment. 2019;30:550–557.

[39] Simpson EL, Sinclair R, Forman S, et al. Efficacy and Safety of Abrocitinib in Patients With Moderate-to-Severe Atopic Dermatitis: Results From the Phase 3 JADE MONO-1 Study. Chicago, Illinois; 2020.
**This study establishes significant safety and efficacy results for abrocitinib in AD patients.

[40] Silverberg JI, Simpson EL, Thyssen JP, et al. Efficacy and Safety of Abrocitinib in Patients With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatology. 2020: E1-E11.
**This study establishes significant safety and efficacy results for abrocitinib in AD patients.

[41] Shreberk-Hassidim R, Ramot Y, Zlotogorski A. Janus kinase inhibitors in dermatology: A systematic review. J. Am. Acad. Dermatol. 2017;76:745-753.e19.

[42] Cotter DG, Schairer D, Eichenfield L. Emerging therapies for atopic dermatitis: JAK inhibitors. J. Am. Acad. Dermatol. 2018;78:S53–S62.

[43] He H, Guttman-Yassky E. JAK Inhibitors for Atopic Dermatitis: An Update. Am J Clin Dermatol. 2019;20:181–192.

[44] Maneiro JR, Souto A, Gomez-Reino JJ. Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta-analysis, and network meta-analysis. Semin. Arthritis Rheum. 2017;47:149–156.

[45] Curtis JR, Lee EB, Kaplan IV, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann. Rheum. Dis. 2016;75:831–841.

[46] Scott IC, Hider SL, Scott DL. Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is the Risk? Drug Saf. 2018;41:645–653.

[47] Risk of Thromboembolism with Janus Kinase Inhibitors: A Systematic Review and Meta- Analysis of Randomized Placebo Controlled Trials [Internet]. ACR Meeting Abstracts. [cited 2020 Jul 3]. Available from: https://acrabstracts.org/abstract/risk-of-thromboembolism-with- janus-kinase-inhibitors-a-systematic-review-and-meta-analysis-of-randomized-placebo-
controlled-trials/.

[48] ClinicalTrials.gov [Internet].
[cited 2020 Apr 24].
Availablefromhttps://clinicaltrials.gov/ct2/results?cond=Abrocitinib+for+atopic+dermatitis&age_v=&gndr=&typ e=&rslt=&phase=2&Search=Apply.

[49] Gooderham M, Lynde CW, Papp K, et al. Review of Systemic Treatment Options for Adult Atopic Dermatitis. J Cutan Med Surg. 2017;21:31–39.

[50] Gooderham MJ, Hong HC-H, Eshtiaghi P, et al. Dupilumab: A review of its PF-04965842 use in the treatment of atopic dermatitis. J. Am. Acad. Dermatol. 2018;78:S28–S36.

[51] O’Shea JJ, Schwarts DM, Villarino A V., et al. The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention. Annu Rev Med. 2015;66:311-328.