1 Introduction
Atopic dermatitis (AD) is a common, chronic inflammatory skin disease associated with intense pruritus, pain, sleep disturbance, and diminished quality of life [
1‐
4]. Patients with moderate-to-severe disease who do not respond adequately to topical therapies have few effective approved treatment options [
1,
5,
6].
Abrocitinib is an oral, once-daily, Janus kinase-1 (JAK1)-selective inhibitor under investigation for treatment of moderate-to-severe AD. Signaling through JAK1 upregulates production of proinflammatory cytokines proposed to underlie the pathophysiology of AD, including interleukin (IL)-4, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin [
7,
8].
Abrocitinib development was predicated on the hypothesis that JAK1 selectivity would minimize dose-limiting safety findings associated with JAK inhibitor selectivity profiles, thereby allowing dosing to support robust efficacy. Meaningful abrocitinib efficacy at doses of 100 and 200 mg once daily, as monotherapy and in combination with topical therapies, was demonstrated in adolescent and adults with moderate-to-severe AD [
9‐
12]. Although the 100-mg dose has efficacy comparable to dupilumab, abrocitinib 200 mg showed more rapid onset and more profound effect on itch (observed as early as day 2 after treatment initiation) and skin clearance. Abrocitinib also improved measures related to quality of life, depression, and anxiety [
10].
Although efficacy of JAK1 inhibition is clear, safety of long-term JAK1 inhibition in the AD population has not yet been established. To date, JAK inhibitor safety was primarily established in patients with rheumatoid arthritis (RA) [
13,
14]. JAK inhibition in RA is associated with risk of infections (including viral reactivation and opportunistic infections), malignancy, nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), increased low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and various changes in hematologic parameters [
13,
14].
The safety profile of abrocitinib in AD is likely to be impacted, in part, by differences between RA and AD patient populations. JAK1 selectivity is also among the characteristics that may contribute to the overall benefit/risk profile [
7]. For example, increased risk of viral reactivation is likely to occur across JAK inhibitors due to effects on lymphocytes and interferon signaling; however, protection from tuberculosis or other mycobacterial infections might be observed with JAK1 inhibitors because of preserved IL-12 and IL-23 signaling [
15‐
17]. Additionally, effects of JAK inhibition on hematologic physiology is complex, and differences in hematologic profiles might be anticipated based on JAK selectivity. Assessment of these safety aspects in AD patients requires larger data sets than are available from individual randomized controlled studies.
Herein we report an integrated safety analysis in patients with moderate-to-severe AD treated with abrocitinib in the phase II and III clinical trial program, including a long-term extension study. These pooled data provide the opportunity to understand how JAK1 inhibition and patient population influence the safety profile. Objectives of this analysis were to identify dose-related differences for adverse events and laboratory values in abrocitinib-treated patients and, where possible, to identify potential risk factors for adverse events (AEs). Most importantly, these data help determine whether safety and tolerability associated with JAK-1 inhibition support the risk/benefit balance for use of selected doses in the clinic.
4 Discussion
This is the first report of an integrated safety analysis for abrocitinib, a selective JAK1 inhibitor with robust efficacy in adults and adolescents with moderate-to-severe AD. This initial analysis demonstrates that abrocitinib, with appropriate dose and patient selection, has a manageable longer-term safety and tolerability profile that supports its use in patients with moderate-to-severe AD.
Most AEs were mild, self-limited, and infrequently required interruption or permanent discontinuation of abrocitinib therapy. The most common dose-related, drug-related AEs included nausea, vomiting, upper abdominal pain, herpes simplex, headache, dizziness, acne, and creatine phosphokinase increase (without rhabdomyolysis). The most common adverse reactions (nausea and headache) first occurred within 2 weeks of treatment initiation and seldom led to discontinuation. Two phase I studies that examined abrocitinib in fed and fasted states (NCT02163161 and NCT04065633) found that gastrointestinal symptoms, including nausea, occurred only when patients were in the fasted state, suggesting that nausea may be related to local gastric concentration of abrocitinib (Pfizer, data on file), and the effects may be mitigated with food. Acne events are seen across the JAK class; acne occurred in 14% of patients with moderate-to-severe AD treated with upadacitinib 30 mg once daily in a 16-week study [
19]. No acne events in abrocitinib-treated patients were severe, and none led to treatment discontinuation. Further study will be required to understand the nature of the acne and mechanisms involved.
These pooled data allowed for an assessment of the potential impact of JAK1 selectivity on infections and hematologic changes. Serious and opportunistic infections and viral reactivation are associated with JAK inhibition [
20,
21]. This analysis of abrocitinib in patients with AD found no dose-response relationship for serious infections or an excess of events compared with placebo. The most frequent serious infections were herpetic in nature, and a dose-related increase in herpes zoster infections was observed, which is consistent with the viral reactivation seen with other JAK inhibitors [
14]. This was anticipated, as JAK1 inhibitors block signaling of type 1 and type 2 interferons and cytokines via the gamma chain of the IL-2 receptor and are important in lymphocyte development [
22‐
24]. Unlike with tofacitinib and baricitinib [
21,
25], an increased rate of herpes zoster in Asian patients was not observed. There were no opportunistic events of tuberculosis, fungal infections (including invasive fungal infections), mycobacterial infections, or infections with other intracellular bacteria. Differing results may be due to age of enrolled patients, as older patients are more at risk for infections [
7,
26,
27]. Additionally, JAK inhibitor selectivities are different. JAK1-selective inhibitors are expected to preserve signaling of IL-12 and IL-23, cytokines thought to be important in protecting against opportunistic infections [
15‐
17]. Although this suggests preserved protection with JAK1 inhibition, monitoring for tuberculosis prior to the initiation of abrocitinib will be important.
One aspect that may be unique to the AD population is the relationship between herpes simplex and eczema herpeticum. Patients with AD have a propensity to develop herpes simplex, and in a minority of patients, these events may develop into eczema herpeticum [
28]. In this analysis, there was a dose-related increase in herpes simplex events; however, eczema herpeticum events were more frequent in the placebo and abrocitinib 100-mg groups. This suggests that, although herpes simplex is more frequent with abrocitinib 200 mg, these herpes simplex infections do not tend to become disseminated eczema herpeticum. Patients who develop eczema herpeticum have more severe AD, as defined by the Eczema Area and Severity Index, and a more T helper 2-polarized disease, with higher concentrations of immunoglobulin E and eosinophils [
29]. Effects of JAK inhibition on eczema herpeticum may be related to improvement in skin barrier function and immunologic abnormalities [
30,
31].
JAK selectivity may affect the pattern of changes in laboratory values associated with JAK inhibition. Treatment with the JAK1/2 inhibitor baricitinib was shown to increase platelet counts [
32]. In contrast, abrocitinib was associated with an early, dose-related, transient decrease in platelets that recovered toward baseline over the course of treatment. Changes in platelets associated with JAK inhibitors are proposed to occur via mechanisms that affect synthesis and degradation of thrombopoietin (TPO), the primary regulator of platelet homeostasis [
33,
34]. One such mechanism is driven by blockade of JAK2-mediated inhibition of TPO uptake and degradation and is associated with increased platelet production, as observed with baricitinib [
35]. Preclinical studies showed that deletion of JAK2 in the megakaryocyte lineage results in increased platelet production [
36]. Given the in vitro selectivity of abrocitinib targeting JAK1 compared with JAK2 (28-fold) at therapeutic doses [
37], a TPO-driven mechanism is less likely. The other mechanism, which occurs via JAK1-dependent IL-6–mediated hepatic TPO production, is associated with transient decreased platelet production, consistent with effects observed with abrocitinib [
34,
35]. Emerging evidence also points to a direct effect of JAK1-mediated IL-6 signaling on hematopoietic stem and progenitor cell pools [
38‐
40], which could lead to transient reduction of IL-6–dependent hematopoietic progenitors, resulting in low platelet and lymphocyte production [
35]. Although no change in ALC was noted with abrocitinib over time, four patients (0.2%) had confirmed ALC < 0.5 × 10
3/mm
3 in the first 4 weeks of therapy.
Interactions between JAK1- and JAK2-mediated activity are complex. Our data suggest that abrocitinib preserves JAK1 selectivity and that decreased platelet levels associated with abrocitinib may occur via IL-6–mediated decreases in TPO synthesis. This is supported by evidence that IL-6 inhibition with monoclonal antibody tocilizumab is also associated with a decrease in platelet concentration [
41].
Both lymphocyte and platelet effects are more pronounced in older patients. These may be due to age-related decreases in immune function in bone marrow and peripheral blood [
42]. Because effects on platelets and lymphocytes are predictable regarding timing and patient age, they are amenable to monitoring in the clinic. No clinically meaningful changes in neutrophil or hemoglobin levels were noted with abrocitinib treatment; any such changes are manageable with appropriate monitoring early in treatment.
Other events related to JAK inhibition, such as malignancy and VTE, are likely to be managed similarly across this class of agents, either because they occur regardless of selectivity or occur infrequently enough that it is difficult to determine differences based on JAK selectivity. The number of malignancies in the abrocitinib development program was small, limiting IR precision. Because JAK inhibitors may theoretically increase risk of malignancies [
43], including lymphoma and NMSC, this potential risk remains for abrocitinib. Most cases of NMSCs occurred within the first 3 months of abrocitinib treatment, with none accruing thereafter. Identification of cases within 3 months may be due to more frequent assessment by dermatologists in clinical trials or related to skin clearance, and not necessarily to JAK inhibition. Periodic examination of patients for NMSC should be considered, particularly those with risk factors (e.g., older age, history of UV phototherapy).
Dose-related events of VTE occurred in patients treated with abrocitinib and other JAK inhibitors [
44,
45]. A population-based cohort study in a Danish health care registry found VTE IR of 0.14 (95% CI 0.12–0.16) per 100 PY in individuals with AD compared with 0.12 (95% CI 0.11–0.12) per 100 PY for an age- and sex-matched general population control group (Pfizer, data on file). In our analysis, adjudicated IR for VTE in the all-abrocitinib cohort was 0.3/100 PY (95% CI 0.1–0.7), with all five events occurring in patients receiving abrocitinib 200 mg. This suggests that appropriate patient selection (e.g., excluding patients with high risk of VTE such as previous PE or recent hospitalization) to minimize this risk may need to be considered. Note that exclusion criteria for VTE risk were added later in the abrocitinib development program as the class risk for VTE became clearer.
There were three adjudicated MACE with abrocitinib (IR 0.18/100 PY [95% CI 0.04–0.52]). In a population-based cohort study of patients in a Danish health care registry, IRs for patients with AD and matched controls were 0.26 (95% CI 0.24–0.29) per 100 PY and 0.22 (95% CI 0.21–0.23) per 100 PY, respectively (Pfizer, data on file).
Appropriate dose selection can minimize risk related to abrocitinib. The more robust efficacy of abrocitinib 200 mg, both its rapidity and depth of effect, suggests that this dose may be preferred for many patients. The safety and tolerability profile described here supports this dose for most patients, including adolescents. However, the 100-mg dose may be a more appropriate starting dose for patients with higher risk for or lower tolerance for adverse reactions. Although most patients aged ≥ 65 years tolerated abrocitinib 200 mg well, many dose-related effects, such as hematologic changes and herpes zoster, occurred at higher rates in this age group. Vaccination for herpes zoster should be given to eligible patients prior to initiating abrocitinib [
21]. Most abrocitinib-treated patients did not have characteristics traditionally associated with cardiovascular risk (i.e., older age, smoking, history of cardiovascular disease, and diabetes). Although most patients with moderate-to-severe AD are unlikely to need lipid monitoring and management, patients with those risk factors may need closer attention.
Declarations
Conflicts of interest and financial disclosures
E. L. Simpson reports grants from Pfizer Inc., Eli Lilly, Kyowa Kirin, LEO Pharma, Merck, and Regeneron and personal fees from Pfizer Inc., Bausch Health (Valeant), Dermira, Eli Lilly, Galderma, LEO Pharma, Menlo Therapeutics, Novartis, Regeneron, and Sanofi Genzyme. J. I. Silverberg is an investigator for AbbVie, Celgene, Eli Lilly, GSK, Kiniksa, LEO Pharma, Menlo Therapeutics, Realm Therapeutics, Regeneron, Roche, and Sanofi; a consultant for Pfizer Inc., AbbVie, Anacor, AnaptysBio, Arena Pharmaceuticals, Asana Biosciences, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Glenmark, Incyte, Kiniksa, LEO Pharma, MedImmune, Menlo Therapeutics, Novartis, Realm Therapeutics, Regeneron, and Sanofi; a speaker for Regeneron and Sanofi; and is on advisory boards for Pfizer Inc., Dermira, LEO Pharma, and Menlo Therapeutics. A. Nosbaum is an investigator for AbbVie, Eli Lilly, Incyte, LEO Pharma, Novartis, and Sanofi; a consultant for Pfizer Inc., AbbVie, Eli Lilly, Galderma, LEO Pharma, Novartis, and Sanofi; a speaker for AbbVie, Regeneron, and Sanofi; and is on advisory boards for Pfizer Inc., AbbVie, LEO Pharma, and Sanofi. K. L. Winthrop reports research grants from Bristol Myers Squibb and consultant honorarium from Pfizer, Eli Lilly, Bristol Myers Squibb, UCB, AbbVie, Gilead, Roche, Novartis, Regeneron, and Sanofi. E. Guttman-Yassky is an advisory board member for Celgene, Dermira, Galderma, Glenmark, Medimmune, Novartis, Pfizer, Regeneron, Sanofi, Stiefel/GlaxoSmithKline, Vitae, and Asana Biosciences (honorarium); consultant for AbbVie, Anacor, Celgene, Dermira, Galderma, Glenmark, LEO Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi, Stiefel/GlaxoSmithKline, Vitae, Mitsubishi Tanabe, Eli Lilly, Asana Biosciences, Kiowa Kirin, and Almirall (honorarium); and investigator for Celgene, LEO Pharma, Medimmune, Regeneron, and Eli Lilly (grants to institution). K. M. Hoffmeister has received honoraria as consultant from Pfizer. A. Egeberg has received research funding from Pfizer, Eli Lilly, Novartis, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the Simon Spies Foundation, and the Kgl Hofbundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker from AbbVie, Almirall, LEO Pharma, Galápagos NV, Samsung Bioepis Co., Ltd., Pfizer, Eli Lilly and Company, Novartis, Galderma, Dermavant, UCB, Mylan, Bristol Myers Squibb, and Janssen Pharmaceuticals. H. Valdez, M. Zhang, S. A. Farooqui, W. Romero, A. J. Thorpe, R. Rojo, and S. Johnson are employees of and shareholders in Pfizer.