Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

doi:10.1016/S0140-6736(20)30732-7

The Lancet

Volume 396, Issue 10246, 25–31 July 2020, Pages 255-266

https://doi.org/10.1016/S0140-6736(20)30732-7 Get rights and content

Summary

Background

Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis.

Methods

In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060.

Findings

Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p<0·0001). Of the patients with available data for the coprimary endpoints at week 12, compared with the placebo group, the proportion of patients who had achieved an EASI-75 response was significantly higher in the abrocitinib 100 mg group (62 [40%] of 156 patients vs nine [12%] of 76 patients; p<0·0001) and abrocitinib 200 mg group (96 [63%] of 153 patients vs nine [12%] of 76 patients; p<0·0001). Adverse events were reported in 108 (69%) of 156 patients in the abrocitinib 100 mg group, 120 (78%) of 154 patients in the abrocitinib 200 mg group, and 44 (57%) of 77 patients in the placebo group. Serious adverse events were reported in five (3%) of 156 patients in the abrocitinib 100 mg group, five (3%) of 154 patients in the abrocitinib 200 mg group, and three (4%) of 77 patients in the placebo group. No treatment-related deaths were reported.

Interpretation

Monotherapy with oral abrocitinib once daily was effective and well tolerated in adolescents and adults with moderate-to-severe atopic dermatitis.

Funding

Pfizer.

Introduction

Atopic dermatitis is a chronic and relapsing inflammatory skin condition with a complex pathophysiology that involves the interplay of impaired skin barrier function, immune dysregulation, genetic susceptibility, and environmental factors.¹ Atopic dermatitis is characterised by intense pruritus.² Although estimates vary widely, atopic dermatitis has been reported to affect up to 20% of children and adolescents and up to 10% of adults, and is associated with considerable impairment in quality of life, sleep, depression, anxiety, and work absenteeism.3, 4, 5, 6

Research in context

Evidence before this study

Atopic dermatitis is a chronic and recurrent inflammatory skin condition characterised by intense pruritus. At present, the available systemic treatments for patients with moderate-to-severe atopic dermatitis are limited by their short-term and long-term side-effects. Dupilumab is a subcutaneous systemic drug recently approved in adolescents and adults with moderate-to-severe atopic dermatitis. Not all patients with moderate-to-severe atopic dermatitis respond to dupilumab, and treatment is associated with a risk of conjunctivitis. Furthermore, the use of dupilumab is limited in patients who are unwilling to receive injections. Hence, there is a need for an efficacious, oral treatment with a favourable benefit–risk profile for patients with moderate-to-severe atopic dermatitis. We searched PubMed on June 4, 2020, for studies published in English between 2010 and 2019, using the search terms “atopic dermatitis” or “eczema” AND “treatment” or “moderate to severe” or “moderate-to-severe” AND “phase 3” or “phase III”. Our search yielded nine clinical trials of systemic therapy.

Added value of this study

This phase 3 trial investigated the efficacy and safety of oral abrocitinib in adolescents and adults with moderate-to-severe atopic dermatitis. Abrocitinib 200 mg and 100 mg significantly improved signs and symptoms of moderate-to-severe atopic dermatitis compared with placebo. At week 12, the proportion of patients in the abrocitinib 100 mg and 200 mg groups who had achieved an Investigator Global Assessment response and 75% improvement in Eczema Area and Severity Index score was significantly higher than in the placebo group. Improvements in pruritus were observed at the first post-baseline assessment. Abrocitinib had a favourable safety profile in this 12-week study, and no cases of venous thromboembolism, malignancy, major adverse cardiovascular events, or deaths were observed.

Implications of all the available evidence

Oral abrocitinib 100 mg or 200 mg monotherapy administered once daily was effective in patients with moderate-to-severe atopic dermatitis with a favourable safety profile. Our results suggest that abrocitinib was well tolerated and could present an efficacious oral systemic drug for the treatment of moderate-to-severe atopic dermatitis in patients aged 12 years and older.

Management of moderate-to-severe atopic dermatitis often necessitates systemic therapy; however, few options are available and, of those that are available, most are not approved for atopic dermatitis and can be limited by their risk of adverse effects. Systemic corticosteroids might offer higher efficacy than topical treatments in patients with moderate-to-severe atopic dermatitis, but their effect is often accompanied with short-term and long-term side-effects, and long-term use is not recommended.⁷ Other treatment options include immunosuppressive drugs, such as ciclosporin, methotrexate, azathioprine, and mycophenolate mofetil. None of these drugs are approved for the treatment of moderate-to-severe atopic dermatitis in the USA or Europe; however, ciclosporin is licensed in many European countries for the treatment of severe atopic dermatitis. These drugs have been reported to have a broad adverse event profile and poor tolerability, especially when used long term.⁷

Dupilumab is a fully human monoclonal immunoglobulin G4 antibody that binds to the shared α chain of interleukin-4 (IL-4) and IL-13 receptors, partly restricting T-helper-2 (Th2) cell-driven inflammatory activity.8, 9 Dupilumab is approved by the US Food and Drug Administration and European Medicines Agency for the treatment of adolescents and adults with moderate-to-severe atopic dermatitis. Some patients do not respond sufficiently to dupilumab, whereas others lose response over time¹⁰ (potentially as a result of drug-neutralising antibodies).¹¹ In clinical trials, conjunctivitis was recorded as an adverse event with dupilumab treatment, which can lead to treatment cessation and the need for ophthalmological care.12, 13 Furthermore, dupilumab is administered subcutaneously, which could prevent use in patients who are unwilling to receive injections.¹⁴ Hence, a need exists for an efficacious oral treatment with a favourable benefit–risk profile for patients with moderate-to-severe atopic dermatitis. The Janus kinase (JAK) family are a group of cytoplasmic tyrosine kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2), which bind cytokine receptor intracellular chains to form functional signalling complexes. JAKs associate with receptor chains, and on receptor activation dimerise (as homodimers or heterodimers) to form receptor complexes. Various cytokines relevant to the pathophysiology of atopic dermatitis, including IL-4, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin15, 16, 17 activate JAK1-containing heterodimeric receptors, thereby mediating Th2 cell differentiation and itch via downstream effects. JAK2 forms homodimeric receptor complexes involved in hematopoiesis.¹⁸ Therefore, selective inhibition of JAK1 is a desirable target to modulate a broad range of cytokines involved in the pathogenesis of atopic dermatitis while avoiding the undesirable effects of JAK2 inhibition, such as neutropenia and anaemia.

Abrocitinib (formerly known as PF-04965842) is an oral, JAK1 selective inhibitor under investigation for the treatment of atopic dermatitis. Monotherapy with oral abrocitinib 100 mg or 200 mg once daily was effective and well tolerated in a dose-ranging phase 2b study in adults with moderate-to-severe atopic dermatitis.¹⁹ At week 12, the proportion of patients who had achieved the primary endpoint of Investigator Global Assessment response (0 [clear] or 1 [almost clear] with ≥2-grade improvement from baseline) was 43·8% for the 200 mg dose and 29·6% for the 100 mg dose compared with 5·8% for placebo (p<0·05 for both). Additionally, reductions in Eczema Area and Severity Index (EASI) score²⁰ and pruritus numeric rating scale were observed in the abrocitinib 200 mg and 100 mg groups. Abrocitinib had a favourable safety profile, with most adverse events being mild and considered unrelated to treatment. On the basis of the positive benefit to risk ratio of the abrocitinib 200 mg and 100 mg doses, a phase 3 trial was designed to assess these doses further.

Here, we report results from the phase 3 trial JADE MONO-1, which investigated monotherapy with oral abrocitinib in adolescent and adult patients with moderate-to-severe atopic dermatitis.

Section snippets

Study design and participants

JADE MONO-1 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done at 69 hospitals and clinics in Australia, Canada, Europe, and the USA. Eligible patients were aged 12 years or older, with a bodyweight of 40 kg or more. Adolescent patients aged younger than 18 years were eligible on a country-by-country basis as approved by the country or regulatory health authority. All eligible patients had a confirmed diagnosis of atopic dermatitis for at least 1 year before

Results

Between Dec 7, 2017, and March 26, 2019, we screened 553 patients, of whom 387 were randomly assigned to receive abrocitinib 100 mg (n=156), abrocitinib 200 mg (n=154), or placebo (n=77). 61 patients in the placebo group, 135 patients in the abrocitinib 100 mg group, and 137 patients in the abrocitinib 200 mg group completed the study (figure 1). The most common reason for discontinuation of the study in the abrocitinib 100 mg and 200 mg groups was adverse events. The proportion of patients who

Discussion

The results of this phase 3 monotherapy trial showed that adolescent and adult patients given abrocitinib 200 mg or 100 mg once daily for 12 weeks had significant improvement in the signs and symptoms of atopic dermatitis when compared with placebo. Clinically meaningful Investigator Global Assessment and EASI-75 responses were observed in the abrocitinib groups as early as week 2 of treatment and continued to increase until week 12. Sensitivity analysis using the per-protocol analysis set and

Data sharing

On request, and subject to certain criteria, conditions and exceptions, Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices for indications that have been approved in the USA or Europe or in programmes that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and

References (31)

T Werfel et al.
Cellular and molecular immunologic mechanisms in patients with atopic dermatitis
J Allergy Clin Immunol
(2016)
LF Eichenfield et al.
Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis
J Am Acad Dermatol
(2014)
JI Silverberg et al.
Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study
J Allergy Clin Immunol
(2013)
H Williams et al.
Worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood
J Allergy Clin Immunol
(1999)
CL Carroll et al.
The burden of atopic dermatitis: impact on the patient, family, and society
Pediatr Dermatol
(2005)
ATM Ronnstad et al.
Association of atopic dermatitis with depression, anxiety, and suicidal ideation in children and adults: a systematic review and meta-analysis
J Am Acad Dermatol
(2018)
A Wollenberg et al.
Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II
J Eur Acad Dermatol Venereol
(2018)
Highlights of prescribing information
(2018)
Annex I. Summary of product characteristics
(2017)
AJ Hendricks et al.
Management recommendations for dupilumab partial and non-durable responders in atopic dermatitis
Am J Clin Dermatol
(2019)

Cross discipline team leader review, BLA 751055, Dupixent (dupilumab)

B Akinlade et al.

Conjunctivitis in dupilumab clinical trials

Br J Dermatol

(2019)

G Fabbrocini et al.

Treatment of atopic dermatitis with biologic drugs

Dermatol Ther (Heidelb)

(2018)

Y Xu et al.

Patient preferences associated with therapies for psoriatic arthritis: a conjoint analysis

Am Health Drug Benefits

(2018)

L Bao et al.

The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis

JAK-STAT

(2013)

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Use of systemic Janus kinase inhibitors for dermatologic indications in the elderly: A retrospective study of 67 cases
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Abrocitinib efficacy and safety in moderate-to-severe atopic dermatitis by race, ethnicity, and Fitzpatrick skin type
2024, Annals of Allergy, Asthma and Immunology
Response to abrocitinib treatment for moderate-to-severe atopic dermatitis (AD) has not been evaluated across racial and ethnic subpopulations.
To assess the efficacy and safety of abrocitinib on the basis of patient race, ethnicity, and Fitzpatrick skin type (FST).
Data were pooled post hoc from patients treated with abrocitinib 200 mg, 100 mg, or placebo in 3 monotherapy trials (NCT02780167, NCT03349060, and NCT03575871). Race and ethnicity were self-reported; FST was determined by study investigators. Evaluations through Week 12 include the following: (1) Investigator's Global Assessment of clear or almost-clear skin; (2) greater than or equal to 75% improvement in Eczema Area and Severity Index or SCORing AD; (3) a greater-than-or-equal-to 4-point improvement in Peak Pruritus Numerical Rating Scale score; (4) least squares mean changes in Dermatology Life Quality Index and Patient-Oriented Eczema Measure scores; and (5) treatment-emergent adverse events.
The sample comprised 628 White, 204 Asian, and 83 Black patients; 37 were Hispanic or Latino; 624 had FST I to III and 320 had FST IV to VI. Treatment with either abrocitinib dose was associated with greater proportions of patients achieving Investigator's Global Assessment of clear or almost-clear skin, ≥ 75% improvement in Eczema Area and Severity Index, ≥ 75% improvement in SCORing AD, and a ≥ 4-point improvement in Peak Pruritus Numerical Rating Scale, or greater score changes from baseline in Dermatology Life Quality Index and Patient-Oriented Eczema Measure vs placebo regardless of race, ethnicity, or FST. Dose-response was most prominent in White patients. In Black patients, the effects of the 2 doses were similar. Treatment-emergent adverse events were more common in White and Black than in Asian patients.
Abrocitinib was more efficacious than placebo across the racial and ethnic groups and ranges of phototypes analyzed. Studies with increased representation of populations of color are warranted to elucidate potential variations in response across diverse populations.
Clinicaltrials.gov Identifier: NCT02780167 (phase 2b), NCT03349060 (phase 3 MONO-1), and NCT03575871 (phase 3 MONO-2).
Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis
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Telazorlimab is a humanized anti-OX40 monoclonal antibody being studied for treatment of T-cell–mediated diseases.
This randomized, placebo-controlled, phase 2b dose-range finding study investigated efficacy, safety, pharmacokinetics, and immunogenicity of telazorlimab in subjects with atopic dermatitis.
In this 2-part study (NCT03568162), adults (≥18 years) with moderate-to-severe disease were randomized to various regimens of subcutaneous telazorlimab or placebo for 16 weeks’ blinded treatment, followed by 38 weeks’ open-label treatment and 12 weeks’ drug-free follow-up. Telazorlimab treatment groups (following a loading dose) in part 1 were 300 mg every 2 weeks; 300 mg every 4 weeks; or 75 mg every 4 weeks. Part 2 evaluated telazorlimab 600 mg every 2 weeks. The primary end point was percentage change from baseline in Eczema Area and Severity Index (EASI) at week 16. Safety assessments included incidence of treatment-emergent adverse events.
The study randomized 313 subjects in part 1 and 149 in part 2. At 16 weeks, the least squares mean percentage change from baseline in EASI was significantly greater in subjects receiving telazorlimab 300 mg every 2 weeks (part 1) and 600 mg every 2 weeks (part 2) versus placebo (−54.4% vs −34.2% for part 1 and −59.0% vs −41.8% for part 2, P = .008 for both). Telazorlimab was well tolerated, with similar distribution of adverse events between telazorlimab- and placebo-treated subjects in both part 1 and part 2.
Telazorlimab, administered subcutaneously at 300 mg every 2 weeks or 600 mg every 2 weeks following a loading dose, was well tolerated and induced significant and progressive clinical improvement in adults with moderate-to-severe atopic dermatitis.
Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies
2024, Journal of the American Academy of Dermatology
For people with atopic dermatitis (AD) refractory to topical therapies, treatment with phototherapy and systemic therapies can be considered. Multiple biologic therapies and Janus kinase (JAK)inhibitors have been approved since 2014 to treat AD. These guidelines update the 2014 recommendations for management of AD with phototherapy and systemic therapies.
To provide evidence-based recommendations on the use of phototherapy and systemic therapies for AD in adults.
A multidisciplinary workgroup conducted a systematic review and applied the GRADE approach for assessing the certainty of evidence and formulating and grading recommendations.
The workgroup developed 11 recommendations on the management of AD in adults with phototherapy and systemic agents, including biologics, oral JAK inhibitors, and other immunomodulatory medications.
Most randomized controlled trials of phototherapy and systemic therapies for AD are of short duration with subsequent extension studies, limiting comparative long-term efficacy and safety conclusions.
We make strong recommendations for the use of dupilumab, tralokinumab, abrocitinib, baricitinib, and upadacitinib. We make conditional recommendations in favor of using phototherapy, azathioprine, cyclosporine, methotrexate, and mycophenolate, and against the use of systemic corticosteroids.
Sensory neurons promote immune homeostasis in the lung
2024, Cell
Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1^GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1^GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.
Targeted therapy for immune mediated skin diseases. What should a dermatologist know?
2024, Anais Brasileiros de Dermatologia
Molecularly targeted therapies, such as monoclonal antibodies (mAbs) and Janus Kinase inhibitors (JAKis), have emerged as essential tools in the treatment of dermatological diseases. These therapies modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. This review aims to provide an updated summary of targeted immune therapies for inflammatory skin diseases, considering their pathophysiology, efficacy, dosage, and safety profiles.
The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic search was conducted on PubMed over the past 10 years, focusing on randomized clinical trials, case reports, and case series related to targeted immune therapies in dermatology. Eligibility criteria were applied, and data were extracted from each study, including citation data, study design, and results.
We identified 1360 non-duplicate articles with the initial search strategy. Title and abstract review excluded 1150, while a full-text review excluded an additional 50 articles. The review included 143 studies published between 2012 and 2022, highlighting 39 drugs currently under investigation or in use for managing inflammatory skin diseases.
The heterogeneity of summarized information limits this review. Some recommendations originated from data from clinical trials, while others relied on retrospective analyses and small case series. Recommendations will likely be updated as new results emerge.
Targeted therapies have revolutionized the treatment of chronic skin diseases, offering new options for patients unresponsive to standard treatments. Paradoxical reactions are rarely observed. Further studies are needed to fully understand the mechanisms and nature of these therapies. Overall, targeted immune therapies in dermatology represent a promising development, significantly improving the quality of life for patients with chronic inflammatory skin diseases.

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ArticlesEfficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

J Allergy Clin Immunol

J Am Acad Dermatol

J Allergy Clin Immunol

J Allergy Clin Immunol

The burden of atopic dermatitis: impact on the patient, family, and society

Pediatr Dermatol

Association of atopic dermatitis with depression, anxiety, and suicidal ideation in children and adults: a systematic review and meta-analysis

J Am Acad Dermatol

Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II

J Eur Acad Dermatol Venereol

Highlights of prescribing information

Annex I. Summary of product characteristics

Management recommendations for dupilumab partial and non-durable responders in atopic dermatitis

Am J Clin Dermatol

Cross discipline team leader review, BLA 751055, Dupixent (dupilumab)

Conjunctivitis in dupilumab clinical trials

Br J Dermatol

Treatment of atopic dermatitis with biologic drugs

Dermatol Ther (Heidelb)

Patient preferences associated with therapies for psoriatic arthritis: a conjoint analysis

Am Health Drug Benefits

The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis

JAK-STAT

Articles
Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial