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NEWER DRUGS IN ATOPIC DERMATITIS Brief Overview
Abstract
Atopic dermatitis (AD) a chronically relapsing dermatosis characterized by pruritus and a significant impact on the quality of life. Emollient and moisturizers are an integral part of its management and those containing natural moisturizing factors (NMF) and pseudoceramides are known to be efficacious barrier repair agents. Conventionally topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI) are considered as the mainstay of treatment. Systemic medications such as azathioprine, cyclosporine and methotrexate may be associated with substantial side effects, with long-term usage. Novel therapeutic agents such as Janus kinase (JAK) inhibitors, subcutaneous monoclonal antibodies and topical PDE4 inhibitors targeting the complex pathophysiology have been recently developed. Dupilumab is a subcutaneous monoclonal antibody and is FDA approved. Amongst the newer topicals, Crisaborole ointment is found to be potentially effective and is FDA approved. Only dupilumab and crisaborole have been successfully marketed for patients <18 years of age.
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Atopic dermatitis is a chronic inflammatory dermatological condition associated with intense pruritus seen in all age groups and ethnic diversities.
It can have a significant impact on the quality of life. The options for treatment include skincare, topical therapies, systemic therapies, and
phototherapy. Treatment of atopic dermatitis may be associated with several challenges including suboptimal efficacy, risk of adverse events,
and limited patient satisfaction. A better understanding of the pathophysiology of atopic dermatitis has resulted in the evaluation of many
treatment options. Phosphodiesterase 4 plays a role in the pathogenesis of atopic dermatitis and hence can be a target for treatment. Crisaborole
2% ointment is a phosphodiesterase 4 enzyme inhibitor approved for the treatment of mild‑to‑moderate atopic dermatitis in patients above
2 years of age by the USFDA. Currently, it is not approved for use in Indian patients. In this article, the role and potential place of crisaborole
in the management of atopic dermatitis in Indian patients based on global experience and evidence is discussed.
Importance:
Current topical treatment options for seborrheic dermatitis are limited by efficacy and/or safety.
Objective:
To assess safety and efficacy of roflumilast foam, 0.3%, in adult patients with seborrheic dermatitis affecting the scalp, face, and/or trunk.
Design, setting, and participants:
This multicenter (24 sites in the US and Canada) phase 2a, parallel group, double-blind, vehicle-controlled clinical trial was conducted between November 12, 2019, and August 21, 2020. Participants were adult (aged ≥18 years) patients with a clinical diagnosis of seborrheic dermatitis for a 3-month or longer duration and Investigator Global Assessment (IGA) score of 3 or greater (at least moderate), affecting 20% or less body surface area, including scalp, face, trunk, and/or intertriginous areas. Data analysis was performed from September to October 2020.
Interventions:
Once-daily roflumilast foam, 0.3% (n = 154), or vehicle foam (n = 72) for 8 weeks.
Main outcomes and measures:
The main outcome was IGA success, defined as achievement of IGA score of clear or almost clear plus 2-grade improvement from baseline, at week 8. Secondary outcomes included IGA success at weeks 2 and 4; achievement of erythema score of 0 or 1 plus 2-grade improvement from baseline at weeks 2, 4, and 8; achievement of scaling score of 0 or 1 plus 2-grade improvement from baseline at weeks 2, 4, and 8; change in Worst Itch Numeric Rating Scale (WI-NRS) score from baseline; and WI-NRS success, defined as achievement of 4-point or greater WI-NRS score improvement in patients with baseline WI-NRS score of 4 or greater. Safety and tolerability were also assessed.
Results:
A total of 226 patients (mean [SD] age, 44.9 [16.8] years; 116 men, 110 women) were randomized to roflumilast foam (n = 154) or vehicle foam (n = 72). At week 8, 104 (73.8%) roflumilast-treated patients achieved IGA success compared with 27 (40.9%) in the vehicle group (P < .001). Roflumilast-treated patients had statistically significantly higher rates of IGA success vs vehicle at week 2, the first time point assessed. Mean (SD) reductions (improvements) on the WI-NRS at week 8 were 59.3% (52.5%) vs 36.6% (42.2%) in the roflumilast and vehicle groups, respectively (P < .001). Roflumilast was well tolerated, with the rate of adverse events similar to that of the vehicle foam.
Conclusions and relevance:
The results from this phase 2a randomized clinical trial of once-daily roflumilast foam, 0.3%, demonstrated favorable efficacy, safety, and local tolerability in the treatment of erythema, scaling, and itch caused by seborrheic dermatitis, supporting further investigation as a nonsteroidal topical treatment.
Trial registration:
ClinicalTrials.gov Identifier: NCT04091646.
Importance:
Lebrikizumab (LEB), a high-affinity monoclonal antibody targeting interleukin (IL)-13, demonstrated efficacy and safety in patients with moderate-to-severe atopic dermatitis (AD) during 16 weeks of monotherapy in a phase 2b trial, and two 52-week phase 3 trials.
Objective:
To evaluate efficacy and safety of LEB combined with low- to mid-potency topical corticosteroids (TCS) in patients with moderate-to-severe AD.
Design, setting, and participants:
The ADhere trial was a 16-week randomized, double-blinded, placebo (PBO)-controlled, multicenter, phase 3 clinical trial conducted from February 3, 2020, to September 16, 2021. The study was conducted at 54 outpatient sites across Germany, Poland, Canada, and the US and included adolescent (aged ≥12 to <18 years weighing ≥40 kg) and adult patients with moderate-to-severe AD. The treatment allocation ratio was 2:1 (LEB:PBO).
Interventions:
Overall, 211 patients were randomized to subcutaneous LEB (loading dose of 500 mg at baseline and week 2, followed by 250 mg every 2 weeks [Q2W] thereafter) or PBO Q2W in combination with TCS for 16 weeks.
Main outcomes and measures:
Efficacy analyses at week 16 included proportions of patients achieving Investigator's Global Assessment score of 0 or 1 (IGA [0,1]) with 2 or more points improvement from baseline, and 75% improvement in the Eczema Area and Severity Index (EASI-75). Key secondary end points included evaluation of itch, itch interference on sleep, and quality of life. Safety assessments included monitoring adverse events (AEs).
Results:
The mean (SD) age of patients was 37.2 (19.3) years, 103 (48.8%) patients were women, 31 (14.7%) patients were Asian, and 28 (13.3%) patients were Black/African American. At week 16, IGA (0,1) was achieved by 145 (41.2%) patients in the LEB+TCS group vs 66 (22.1%) receiving PBO+TCS (P = .01); corresponding proportions of patients achieving EASI-75 were 69.5% vs 42.2% (P < .001). The LEB+TCS group showed statistically significant improvements in all key secondary end points. Most treatment-emergent adverse events (TEAEs) were nonserious, mild or moderate in severity, and did not lead to study discontinuation. The TEAEs frequently reported in the LEB+TCS group included conjunctivitis (7 [4.8%]), headache (7 [4.8%]), hypertension (4 [2.8%]), injection site reactions (4 [2.8%]), and herpes infection (5 [3.4%]) vs 1.5% or less patient-reported frequencies in the PBO+TCS group. Similar frequencies of patient-reported serious AEs following LEB+TCS (n = 2, 1.4%) and PBO+TCS (n = 1, 1.5%).
Conclusions and relevance:
In this randomized phase 3 clinical trial, LEB+TCS was associated with improved outcomes in adolescents and adults with moderate-to-severe AD compared with TCS alone, and safety was consistent with previously reported AD trials.
Trial registration:
ClinicalTrials.gov Identifier: NCT04250337.
Background:
Most patients with chronic plaque psoriasis receive topical treatment; however, available options lack a balance of efficacy with long-term safety and tolerability. Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 (PDE4) inhibitor approved by the US FDA for treatment of psoriasis.
Objective:
The aim of this study was to define the pharmacokinetic (PK) profile of roflumilast delivered topically from a phase I maximal usage study and data from phase II and phase III studies.
Methods:
PK data for roflumilast and the active metabolite, roflumilast N-oxide, were determined from a phase I PK and safety maximal usage study of roflumilast cream 0.3% applied once daily for 14 days in patients with plaque psoriasis affecting body surface area (BSA) ≥20% (N = 26). Serial plasma samples were obtained on Days 1 and 15 to determine maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC). Plasma concentrations were also assessed at Weeks 3, 4, and 5 for terminal half-life (t½). Concentrations of roflumilast and roflumilast N-oxide in skin were assessed at Day 28 for 14 patients with psoriasis in a phase I/IIa study of once-daily roflumilast cream 0.5% and 0.15% for 28 days. Systemic exposure (Ctrough and AUC) of roflumilast and roflumilast N-oxide in two phase III trials (DERMIS-1, n = 245; DERMIS-2, n = 250) of roflumilast cream 0.3% for 8 weeks was assessed at Weeks 4 and 8.
Results:
Bioavailability of roflumilast cream 0.3% after topical administration was 1.5%. Unlike after oral dosing, the plasma concentration-time curve was flat, with a peak-to-trough ratio of 1.2. Roflumilast N-oxide concentrations were eightfold higher than roflumilast concentrations. The t½ in adult patients was 4.0 days for roflumilast and 4.6 days for roflumilast N-oxide following the last dose administered. Steady state was reached by Day 15. Concentrations of roflumilast in skin were, on average, 126- and 61.8-fold higher than corresponding mean plasma Ctrough following administration of roflumilast cream 0.15% and 0.5% daily for 28 days. Roflumilast N-oxide was quantifiable in only one skin sample (N = 27). Following 8 weeks of treatment in DERMIS-1, mean plasma Ctrough of roflumilast was 1.78 ng/mL, and 9.86 ng/mL for roflumilast N-oxide. In DERMIS-2, mean plasma Ctrough was 1.72 ng/mL and 10.2 ng/mL, respectively. In the maximal usage study (mean BSA: 27.5%), eight patients (30.8%) experienced adverse events (AEs) and all were mild or moderate, with no reports of diarrhea, headache, insomnia, or application-site pain; no patients discontinued treatment due to an AE.
Conclusion:
Topical administration of roflumilast cream 0.3% results in concentrations in skin 126- and 61.8-fold higher relative to plasma, which are much higher than expected to be achievable with oral dosing. PDE4 inhibition in the skin is likely due to roflumilast as compared with its active metabolite, as there is no significant conversion to roflumilast N-oxide in the skin. Consistent with reservoir formation and retention of drug in the stratum corneum, roflumilast is slowly released from the skin (t½ 4 days) and peak-to-trough ratio is 1.2.
Gov identifiers:
NCT04279119, NCT03392168, NCT04211363, NCT04211389.
The evidence‐ and consensus‐based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty‐nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti‐inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for paediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology.
Atopic dermatitis (AD) is a chronic inflammatory dermatosis with periods of exacerbation and remissions. AD is characterized by intense, persistent pruritus and heterogeneity in clinical symptomatology and severity. Therapeutic goals include the amelioration of cutaneous eruptions, diminishing relapses and eventually the disease burden. To date, topical corticosteroids (TCS) and calcineurin inhibitors (TCI) have yet been deemed the mainstay of topical treatments in AD management. Nevertheless, despite their indisputable efficiency, TCS and TCI are not indicated for continuous long-term use given their safety profile. While research in AD has concentrated predominantly on systemic therapies, more than 30 novel topical compounds are under development. The existing data appear encouraging, with some regimens that are already FDA-approved (ruxolitinib was the most recent in September 2021) and several pharmaceutical pipeline products for mild-to-moderate AD that are in an advanced stage of development, such as tapinarof, difamilast and roflumilast. Larger, long-term studies are still required to evaluate the efficacy and safety of these novel compounds in the long run and weigh their advantages over present treatments. In this review, we aim to provide an overview of the latest knowledge about AD topical treatments, echoing upcoming research trends.
The evidence‐ and consensus‐based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty‐nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for paediatric, adolescent, pregnant and breastfeeding patients.
Tapinarof cream 1% (VTAMA®) is an aryl hydrocarbon receptor (AhR) agonist that is being developed by Dermavant Sciences Inc. (a subsidiary of Roivant Sciences Inc.) as a once-daily topical treatment for plaque psoriasis and atopic dermatitis. AhR is a ligand-dependent transcription factor that has a role in immune-mediated skin responses. In May 2022, tapinarof cream 1% was approved in the USA for the topical treatment of plaque psoriasis in adults. Tapinarof cream 1% is also being investigated for the treatment of atopic dermatitis. This article summarizes the milestones in the development of tapinarof cream 1% leading to this first approval for the topical treatment of plaque psoriasis.
Atopic dermatitis is a prevalent, inflammatory skin disease that presents with an eczematous, itchy rash. As of late, there have been many emerging monoclonal antibody inhibitor and small molecule therapies that have changed the course of eczema treatment. One of the treatments in the pipeline for atopic dermatitis is interleukin 13 monoclonal antibody inhibitor, lebrikizumab. As interleukin 13 has been identified as a pro-inflammatory cytokine in the immunological cascade of eczema, it is thought that lebrikizumab can be a great treatment choice for patients with atopic dermatitis. Lebrikizumab is currently being investigated in several studies. Thus far, lebrikizumab for the treatment of eczema has been found to be efficacious; in particular, a rapid response of pruritus improvement has been demonstrated in as early as 2 days. Additionally, it is well tolerated and has an acceptable safety profile, with reports suggesting that are decreased risks of infection when compared to dupilumab. In this review, we aim to summarize the current understanding of lebrikizumab in terms of the mechanism of action, preclinical pharmacology, pharmacokinetics and metabolism, efficacy and safety, and drug indications.
Previous studies have shown the efficacy of delgocitinib (DEL) ointment, a topical Janus kinase inhibitor, against atopic dermatitis (AD). However, there is no available information regarding the efficacy of DEL ointment in maintaining remission. Data of patients with AD who received remission maintenance therapy twice weekly with DEL or topical corticosteroid (TCS) on the affected skin of each upper limb were extracted from the medical records. Efficacy was assessed based on changes in pruritus Numerical Rating Scale (NRS) score, stratum corneum hydration (SCH), erythema index (EI). Of 25 patients, four patients (16%) had eczema flare‐ups on the TCS side and eight patients (32%) on the DEL side. The extent of change in each parameter between TCS‐ and DEL‐treated areas of the skin did not differ significantly. The mean changes in the NRS and EI showed a slight improvement on the side treated with TCS and were slightly worse on the side treated with DEL. However, the SCH of the DEL group was maintained, while that of the TCS group worsened. TCS is more likely to be effective than DEL in terms of remission maintenance therapy. However, topical delgocitinib is as effective as topical steroid in the maintenance therapy of AD in dry skin patients. This article is protected by copyright. All rights reserved.
Introduction:
Nemolizumab, a new monoclonal antibody that targets the receptor alpha of the neuroimmune cytokine interleukin-31 (IL-31), has shown efficacy in atopic dermatitis (AD) in adults. This study evaluated the pharmacokinetics (PK) and safety of nemolizumab in adolescents with moderate to severe AD as well as the relationship between nemolizumab concentrations and clinical efficacy and the effect of nemolizumab on protein biomarkers.
Methods:
Open-label, 16-week study of nemolizumab in patients aged 12-17 years with moderate to severe AD (baseline EASI ≥ 16, IGA ≥ 3, and BSA ≥ 10%) and associated pruritus with baseline average daily peak pruritus numeric rating scale (PP-NRS) intensity of at least 4. Nemolizumab was administered subcutaneously as a loading dose of 60 mg at baseline, followed by 30 mg every 4 weeks until week 12 with background topical corticosteroids (TCS) or calcineurin inhibitors (TCI). Subsequently patients were followed for 8 weeks more. Stratum corneum (SC) and plasma samples were collected for biomarker assessments.
Results:
Twenty patients participated, with a mean age of 14.8 ± 1.6 years. The PK of nemolizumab was described by a one-compartment model with linear elimination, a first-order absorption, and a mean half-life of 16.7 ± 4.1 days. Mean trough concentrations ranged from 2935 ± 1029 ng/mL to 3292 ± 2018 ng/mL over the 16-week treatment period. There was a marked improvement in rash, itch, and sleep with a decrease from baseline to week 16 in EASI by 66.5 ± 32.5%, in PP-NRS by 43.2 ± 37%, and in sleep disturbance numeric rating scale by 53.5 ± 47.8%. The popPK and PK/PD analyses confirmed that model-predicted exposure and efficacy of nemolizumab were similar in adolescents compared to adults receiving the same dosing regimens. Age did not impact PK parameters, while the main source of PK variability was body weight. Analyses of SC samples identified a panel of AD-related pro-inflammatory biomarkers that were upregulated in lesional skin (compared to non-lesional skin) and correspondingly downregulated in clinical responders to nemolizumab (based on EASI75 and PP-NRS ≥ 4). Four biomarkers (CCL20, CCL22, CCL27, and VEGF) had changes that were 1.9-3.5-fold higher in EASI responders than in EASI non-responders (all p < 0.05). Analysis showed no significant correlation between plasma biomarkers and clinical scores. Adverse events were experienced by 33.3% of subjects (n = 6) and were primarily mild or moderate in severity.
Conclusions:
Nemolizumab PK and safety profiles in adolescents with moderate to severe AD are consistent with previous nemolizumab studies in adults. PK/PD models demonstrate similar exposure-response profiles in 12- to 17-year-old adolescents and adults for three clinical endpoints (EASI, IGA, and PP-NRS). Nemolizumab treatment reversed AD-related pro-inflammatory biomarkers in skin, indicating that the neuroimmune cytokine IL-31 is an important mediator of multiple pathways in AD.
Clinical trial registration:
Clinicaltrials.gov NCT03921411.
Background/objective:
Patients with moderate-to-severe atopic dermatitis (AD) have increased risk of cutaneous and extracutaneous infections. Dupilumab has previously been associated with reduced risk of serious/severe infections and non-herpetic skin infections in adults with moderate-to-severe AD. This analysis assessed infection rates with dupilumab versus placebo in pediatric patients with moderate-to-severe and severe AD participating in clinical trials.
Methods:
This is a pooled analysis from two 16-week, randomized, placebo-controlled, phase 3 clinical trials of dupilumab: monotherapy in adolescents aged 12-17 years with moderate-to-severe AD (LIBERTY AD ADOL, NCT03054428) and with concomitant topical corticosteroids in children aged 6-11 years with severe AD (LIBERTY AD PEDS, NCT03345914). Data were pooled according to treatment received: placebo/approved dupilumab doses/other studied dupilumab doses/all dupilumab doses. Exposure-adjusted rates (patients with ≥1 event per 100 patient-years [nP/100 PY]) were used to compare treatment groups.
Results:
Overall, 612 patients were included: 205 received placebo and 407 received dupilumab (261 received approved dupilumab doses and 146 received other studied dupilumab doses). Overall infection rates were numerically lower with dupilumab versus placebo (nP/100 PY: placebo, 227; approved dupilumab, 173; other dupilumab, 206; all dupilumab, 184). Total skin infections were numerically less frequent in all dupilumab-treated groups versus placebo (nP/100 PY: placebo, 67; approved dupilumab, 30; other dupilumab, 46; all dupilumab, 36).
Conclusions:
These data suggest that dupilumab treatment in children and adolescents with AD does not increase infection risk overall and is associated with lower rates of skin infections compared with placebo.
BACKGROUND
Safety and tolerability of live-attenuated vaccines in patients administered dupilumab for moderate-to-severe asthma has not been previously evaluated. During the LIBERTY ASTHMA TRAVERSE open-label extension study (NCT02134028), a yellow fever outbreak in Brazil required vaccination with a live-attenuated vaccine of at-risk individuals.
OBJECTIVE
To evaluate immune response to a live-attenuated vaccine in the context of IL-4 receptor blockade (REGN1103, a dupilumab surrogate) in mice and in dupilumab-treated patients with moderate-to-severe asthma who participated in TRAVERSE.
METHODS
In the preclinical study, mice were co-administered REGN1103/isotype control and live-attenuated influenza vaccine/control, followed by influenza virus challenge. During TRAVERSE, 37 patients discontinued dupilumab treatment and were administered 17D live-attenuated yellow fever vaccine (YFV). Safety and tolerability data, dupilumab serum concentrations, and plaque-reduction neutralization titers before and after vaccination were collected.
RESULTS
In the preclinical study, there was no impact of REGN1103 on vaccine efficacy in mice. In TRAVERSE, all 37 patients who received YFV achieved seroprotection despite most having therapeutic levels of dupilumab, with the magnitude of response appearing unrelated to pre-vaccination dupilumab concentrations. No vaccine-related adverse events or vaccine hypersensitivity were reported in 36 patients; 1 patient reported non-serious body ache, malaise, and dizziness 7 days after vaccination and fully recovered.
CONCLUSION
The preclinical model suggested that dupilumab does not impact efficacy of live-attenuated influenza vaccine. The live-attenuated YFV did not raise safety concerns and appeared to be well-tolerated in patients with asthma who recently discontinued dupilumab, and dupilumab concentrations had no apparent impact on the immunologic response to the vaccine.
Background: Atopic dermatitis (AD) is an inflammatory skin disease characterized by a wide phenotypic variety with a very complex pathophysiological mechanism that has led to the identification of new therapeutic targets, such as janus kinasis (JAK) inhibitors. Objectives: To evaluate the efficacy and safety of baricitinib, the first JAK 1 and 2 inhibitor approved in Europe for the treatment of adult patients with moderate-to-severe AD. Methods: The efficacy and safety data available from the Phase III studies belonging to the BREEZE AD program are presented. Results: Results from BREEZE-AD1, AD2, AD4, and AD7 showed the efficacy of Baricitib 4 mg, administered orally, once daily, as monotherapy or in combination with topical corticosteroid (TCS), with a significant proportion of patients achieving primary endpoints IGA 0–1 (16.4% vs. 4.8%; 13.8% vs. 4.5%; 21.7% vs. 9.7%; 30.6% vs. 14.7%) and EASI75 (24.8% vs. 8.8%; 21.1% vs. 6.1%; 31.5% vs. 17.2%; 47.7% vs. 22.9%) at week 16 (W16) compared to placebo, respectively. Baricitinib showed rapid improvement in symptoms, starting from week 1 of treatment at 4 mg dosage, with a good safety profile. Nasopharyngitis, upper respiratory tract infections (URIs), creatine phosphokinase (CPK) elevations, and headache were the most frequently reported adverse events. Conclusions: Following the efficacy and safety data on W 16 from the phase III BREEZE-AD studies, baricitinib has recently been approved in Europe for the treatment of moderate to severe AD in adult patients. Further data to evaluate long-term efficacy and safety in a real-life setting are needed.
Background
Interleukin (IL)-31 affects the inflammatory response, is involved in epidermal barrier disruption in atopic dermatitis (AD), and plays a key role in pruritus. Nemolizumab, a humanized monoclonal antibody against IL-31 receptor A, reduced pruritus in patients with AD after a 16-week administration period.
Objective
To examine the long-term effectiveness and safety of nemolizumab in patients aged ≥13 years with AD and inadequately controlled moderate-to-severe pruritus.
Methods
In two long-term phase III studies, nemolizumab 60 mg every 4 weeks (Q4W) was administered subcutaneously, concomitantly with topical treatments. Study-JP01 patients received double-blind nemolizumab or placebo for 16 weeks, and then entered a 52-week extension period in which all patients received nemolizumab (nemolizumab/nemolizumab and placebo/nemolizumab groups). Study-JP02 patients received nemolizumab for 52 weeks. Both studies included an 8-week follow-up period.
Results
Study-JP01 nemolizumab/nemolizumab and placebo/nemolizumab, and Study-JP02 nemolizumab groups comprised 143, 72, and 88 patients, respectively. In the nemolizumab/nemolizumab group, there were clinically meaningful improvements from the start of treatment to week 68 in the pruritus visual analogue scale (66% decrease) and eczema area and severity index (78% decrease). Quality of life indicators improved after the first nemolizumab dose; improvements were maintained during the follow-up period. The long-term safety profile was consistent with previous studies, with no unexpected late-onset adverse events.
Conclusions
Nemolizumab 60 mg Q4W with concomitant topical treatments in patients with AD and inadequately controlled moderate-to-severe pruritus produced a continuous improvement in pruritus, signs of AD, and quality of life for up to 68 weeks, with a favourable safety profile.
Importance
Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease with an unmet need for treatments that provide rapid and high levels of skin clearance and itch improvement.
Objective
To assess the safety and efficacy of upadacitinib vs dupilumab in adults with moderate-to-severe AD.
Design, Setting, and Participants
Heads Up was a 24-week, head-to-head, phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled clinical trial comparing the safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate-to-severe AD who were candidates for systemic therapy. The study was conducted from February 21, 2019, to December 9, 2020, at 129 centers located in 22 countries across Europe, North and South America, Oceania, and the Asia-Pacific region. Efficacy analyses were conducted in the intent-to-treat population.
Interventions
Patients were randomized 1:1 and treated with oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every other week.
Main Outcomes and Measures
The primary end point was achievement of 75% improvement in the Eczema Area and Severity Index (EASI75) at week 16. Secondary end points were percentage change from baseline in the Worst Pruritus Numerical Rating Scale (NRS) (weekly average), proportion of patients achieving EASI100 and EASI90 at week 16, percentage change from baseline in Worst Pruritus NRS at week 4, proportion of patients achieving EASI75 at week 2, percentage change from baseline in Worst Pruritus NRS (weekly average) at week 1, and Worst Pruritus NRS (weekly average) improvement of 4 points or more at week 16. End points at week 24 included EASI75, EASI90, EASI100, and improvement of 4 points or more in Worst Pruritus NRS from baseline (weekly average). Safety was assessed as treatment-emergent adverse events in all patients receiving 1 or more dose of either drug.
Results
Of 924 patients screened, 348 (183 men [52.6%]; mean [SD] age, 36.6 [14.6] years) were randomized to receive upadacitinib and 344 were randomized to receive dupilumab (194 men [56.4%]; mean [SD] age, 36.9 [14.1] years); demographic and disease characteristics were balanced among treatment groups. At week 16, 247 patients receiving upadacitinib (71.0%) and 210 patients receiving dupilumab (61.1%) achieved EASI75 (P = .006). All ranked secondary end points also demonstrated the superiority of upadacitinib vs dupilumab, including improvement in Worst Pruritus NRS as early as week 1 (mean [SE], 31.4% [1.7%] vs 8.8% [1.8%]; P < .001), achievement of EASI75 as early as week 2 (152 [43.7%] vs 60 [17.4%]; P < .001), and achievement of EASI100 at week 16 (97 [27.9%] vs 26 [7.6%]; P < .001). Rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-related adverse events were higher for patients who received upadacitinib, whereas rates of conjunctivitis and injection-site reactions were higher for patients who received dupilumab.
Conclusions and Relevance
During 16 weeks of treatment, upadacitinib demonstrated superior efficacy vs dupilumab in patients with moderate-to-severe AD, with no new safety signals.
Trial Registration
ClinicalTrials.gov Identifier: NCT03738397
Background
Delgocitinib 0.5% ointment, a topical JAK inhibitor, has been approved for adult patients with atopic dermatitis (AD) in Japan.
Objective
To evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD.
Methods
In part 1, a 4-week double-blind period, Japanese patients aged 2 through 15 years were randomized in a 1:1 ratio to delgocitinib 0.25% ointment or vehicle ointment. Eligible patients entered part 2, a 52-week extension period, to receive 0.25% or 0.5% delgocitinib ointment.
Results
At initiation of study, approximately half of the patients had moderate AD. At the end of treatment in part 1, the least-squares mean percent change from baseline in modified Eczema Area and Severity Index score, the primary efficacy endpoint, was significantly greater for delgocitinib ointment than for vehicle (−39.3% vs +10.9%, P < .001). In part 2, the improvements in AD were also seen through week 56. Most adverse events were mild and unrelated to delgocitinib across the study periods.
Limitations
Only Japanese patients were included. In part 2, no control group was included, and rescue therapy was allowed.
Conclusion
Delgocitinib ointment was effective and well tolerated when applied to Japanese pediatric patients with AD for up to 56 weeks.
Background:
Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin-13, a key driver of atopic dermatitis (AD).
Objectives:
To evaluate the efficacy and safety of tralokinumab in combination with TCS in patients with moderate-to-severe AD who were candidates for systemic therapy.
Methods:
This was a double-blind, placebo plus optional TCS-controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator's Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or Q4W, with TCS as needed, for another 16 weeks.
Results:
At week 16, more tralokinumab-treated patients than placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% CI): 12·4% (2·9-21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8-30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve an IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5%, and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events (AEs) was similar across treatment groups.
Conclusions:
Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate-to-severe AD.
Background
Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin‐13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms.
Objectives
To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate‐to‐severe AD who had an inadequate response to topical treatments.
Methods
In two, 52‐week, randomized, double‐blind, placebo‐controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate‐to‐severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W), or placebo. Primary endpoints were IGA score of 0 or 1 at week 16 and EASI 75 at week 16. Patient achieving an IGA score of 0/1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks.
Results
At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0/1: 15·8% vs. 7·1% in ECZTRA 1 [difference (95% CI) 8·6% (4·1–13·1); P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 [11·1% (5·8–16·4); P < 0·001] and EASI 75: 25·0% vs. 12·7% [12·1% (6·5–17·7); P < 0·001] and 33·2% vs. 11·4% [21·6% (15·8–27·3); P < 0·001]. Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient‐Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab‐responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab and in 77·0% and 66·0% of patients receiving placebo in the 16‐week initial period.
Conclusions
Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.
Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. This post hoc analysis pools results from 2 phase 3 studies (ClinicalTrials.gov, NCT02118766 [AD-301]; NCT02118792 [AD-302]) to evaluate crisaborole efficacy in patients ≥ 2 years with mild-to-moderate atopic dermatitis (per Investigator's Static Global Assessment) using the Atopic Dermatitis Severity Index (ADSI) and percentage of treatable body surface area (%BSA). Patients were randomly assigned 2:1 to receive crisaborole (n = 1,016) or vehicle (n = 506) twice daily for 28 days. ADSI scores were the sum of pruritus, erythema, exudation, excoriation, and lichenification severity scores, each graded on a 4-point scale from none (0) to severe (3). Respective mean changes in ADSI score and %BSA at day 29 were (crisaborole vs. vehicle) -3.52 versus -2.42 (p < 0.0001) and -7.43 versus -4.44 (p < 0.0001). Crisaborole was effective in treating mild-to-moderate atopic dermatitis based on ADSI and %BSA.
Atopic dermatitis is a chronic inflammatory condition of the skin affecting a large number of people worldwide. Historically, this condition has been managed by topical corticosteroids and general skincare measures. The inadequacy of these management strategies has always driven efforts to find better drugs. Dupilumab has been recently approved for the management of atopic dermatitis. It is a human monoclonal antibody that inhibits the binding of key interleukins involved in the pathogenesis of atopic dermatitis, thus blocking the signaling mechanisms and disrupting the disease progression. Dupilumab reduces the severity and associated symptoms of atopic dermatitis. It improves the life quality of patients and reduces the anxiety associated with the disease. Combination therapy of dupilumab and topical corticosteroids is more effective than dupilumab monotherapy. The treatment-related adverse events include headache, injection site reaction, conjunctivitis, nasopharyngitis, and herpes viral infections. Moreover, the simultaneous use of live vaccines with dupilumab is contraindicated. It is also beneficial in the management of asthma, chronic rhinosinusitis, and eosinophilic esophagitis. In this review, we have discussed the clinical efficacy and safety profile of dupilumab in the management of atopic dermatitis.
Background
Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD).Objectives
The aim of this study was to evaluate the safety, effectiveness, and pharmacokinetics (PK) of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD in an open-label study.Methods
Infants (3 to < 24 months) with Investigator’s Static Global Assessment (ISGA) of mild (2) or moderate (3) and percentage of treatable body surface area (%BSA) ≥ 5 received crisaborole twice daily for 28 days; a cohort with moderate AD per ISGA and %BSA ≥ 35 were included in a PK analysis. Endpoints included safety (primary), efficacy, and PK (exploratory).ResultsIncluded were 137 infants total (mean age [SD], 13.6 months [6.42]), with 21 in the PK cohort (12.7 months [6.58]). Treatment-emergent adverse events (TEAEs) were reported for 88 (64.2%) patients (98.9% rated as mild/moderate). TEAEs were considered treatment-related for 22 patients (16.1%); most frequently reported were application site pain (3.6%), application site discomfort (2.9%), and erythema (2.9%). ISGA clear/almost clear with ≥ 2-grade improvement at day 29 was achieved by 30.2% of patients. From baseline to day 29, mean percentage change in Eczema Area and Severity Index score was − 57.5%, and mean change in Patient-Oriented Eczema Measure total score was − 8.5. Crisaborole systemic exposures in infants were characterized and, based on nonlinear regression analysis, were comparable with that in patients aged ≥ 2 years.Conclusions
In this open-label study, crisaborole was well tolerated and effective in infants (3 to < 24 months) with mild-to-moderate AD with systemic exposures similar to patients aged ≥ 2 years.Clinical Trial RegistrationNCT03356977.
Importance
Interleukin 13 (IL-13) is a central pathogenic mediator driving multiple features of atopic dermatitis (AD) pathophysiology.
Objective
To evaluate the efficacy and safety of lebrikizumab, a novel, high-affinity, monoclonal antibody targeting IL-13 that selectively prevents formation of the IL-13Rα1/IL-4Rα heterodimer receptor signaling complex, in adults with moderate to severe AD.
Design, Setting, and Participants
A phase 2b, double-blind, placebo-controlled, dose-ranging randomized clinical trial of lebrikizumab injections every 4 weeks or every 2 weeks was conducted from January 23, 2018, to May 23, 2019, at 57 US centers. Participants were adults 18 years or older with moderate to severe AD.
Interventions
Patients were randomized 2:3:3:3 to placebo every 2 weeks or to subcutaneous injections of lebrikizumab at the following doses: 125 mg every 4 weeks (250-mg loading dose [LD]), 250 mg every 4 weeks (500-mg LD), or 250 mg every 2 weeks (500-mg LD at baseline and week 2).
Main Outcomes and Measures
The primary end point was percentage change in the Eczema Area and Severity Index (EASI) (baseline to week 16). Secondary end points for week 16 included proportion of patients achieving Investigator’s Global Assessment score of 0 or 1 (IGA 0/1); EASI improvement of at least 50%, 75%, or 90% from baseline; percentage change in the pruritus numeric rating scale (NRS) score; and pruritus NRS score improvement of at least 4 points. Safety assessments included treatment-emergent adverse events.
Results
A total of 280 patients (mean [SD] age, 39.3 [17.5] years; 166 [59.3%] female) were randomized to placebo (n = 52) or to lebrikizumab at doses of 125 mg every 4 weeks (n = 73), 250 mg every 4 weeks (n = 80), or 250 mg every 2 weeks (n = 75). Compared with placebo (EASI least squares mean [SD] percentage change, −41.1% [56.5%]), lebrikizumab groups showed dose-dependent, statistically significant improvement in the primary end point vs placebo at week 16: 125 mg every 4 weeks (−62.3% [37.3%], P = .02), 250 mg every 4 weeks (−69.2% [38.3%], P = .002), and 250 mg every 2 weeks (−72.1% [37.2%], P < .001). Differences vs placebo-treated patients (2 of 44 [4.5%]) in pruritus NRS improvement of at least 4 points were seen as early as day 2 in the high-dose lebrikizumab group (9 of 59 [15.3%]). Treatment-emergent adverse events were reported in 24 of 52 placebo patients (46.2%) and in lebrikizumab patients as follows: 42 of 73 (57.5%) for 125 mg every 4 weeks, 39 of 80 (48.8%) for 250 mg every 4 weeks, and 46 of 75 (61.3%) for 250 mg every 2 weeks; most were mild to moderate and did not lead to discontinuation. Low rates of injection-site reactions (1 of 52 [1.9%] in the placebo group vs 13 of 228 [5.7%] in all lebrikizumab groups), herpesvirus infections (2 [3.8%] vs 8 [3.5%]), and conjunctivitis (0% vs 6 [2.6%]) were reported.
Conclusions and Relevance
During 16 weeks of treatment, lebrikizumab provided rapid, dose-dependent efficacy across a broad range of clinical manifestations in adult patients with moderate to severe AD and demonstrated a favorable safety profile. These data support the central role of IL-13 in AD pathophysiology. If these findings replicate in phase 3 studies, lebrikizumab may meaningfully advance the standard of care for moderate to severe AD.
Trial Registration
ClinicalTrials.gov Identifier: NCT03443024
Background:
Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD).
Objective:
This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment.
Methods:
In part 1, a 4-week double-blind period, Japanese patients aged 16 years or older with moderate or severe AD were randomly assigned in a 2:1 ratio to delgocitinib 0.5% ointment or vehicle ointment. Eligible patients entered part 2, a 24-week extension period, to receive delgocitinib 0.5% ointment.
Results:
At the end of treatment in part 1, the least-squares mean percent changes from baseline in the modified Eczema Area and Severity Index score, the primary efficacy endpoint, were significantly greater in the delgocitinib group than in the vehicle group (-44.3% vs 1.7%, P < .001). The improvement in modified Eczema Area and Severity Index score was maintained in part 2. Most adverse events were mild and unrelated to delgocitinib across the study periods.
Limitations:
Only Japanese patients were included. The vehicle-controlled period lasted only 4 weeks. In part 2, topical corticosteroids were allowed for the treatment of worsening of AD.
Conclusion:
Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks.
Importance
The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD).
Objective
To assess the efficacy and safety of different dupilumab regimens in maintaining response after 16 weeks of initial treatment.
Design, Setting, and Participants
The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received dupilumab treatment and achieved an Investigator’s Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016.
Interventions
High-responding patients treated with dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of dupilumab, 300 mg, weekly or every 2 weeks or to receive dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks.
Main Outcomes and Measures
Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety.
Results
Among the 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] male), continuing dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (−0.06%; P < .001 vs placebo); percent change with the other regimens dose-dependently worsened (dupilumab every 4 weeks, −3.84%; dupilumab every 8 weeks, −6.84%; placebo, −21.67%). More patients taking dupilumab weekly or every 2 weeks (116 of 162 [71.6%]; P < .001 vs placebo) maintained EASI-75 response than those taking dupilumab every 4 weeks (49 of 84 [58.3%]) or every 8 weeks (45 of 82 [54.9%]) or those taking placebo (24 of 79 [30.4%]). Overall adverse event incidences were 70.7% in the weekly or every 2 weeks group, 73.6% in the every 4 weeks group, 75.0% in the every 8 weeks group, and 81.7% in the placebo group. Treatment groups had similar conjunctivitis rates. Treatment-emergent antidrug antibody incidence was lower with more frequent dupilumab dose regimens (11.3% in the placebo group and 11.7%, 6.0%, 4.3%, and 1.2% in the dupilumab every 8 weeks, every 4 weeks, every 2 weeks, and weekly groups, respectively).
Conclusions and Relevance
In this trial, continued response over time was most consistently maintained with dupilumab administered weekly or every 2 weeks. Longer dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of dupilumab every 2 weeks is recommended for long-term treatment.
Trial Registration
ClinicalTrials.gov identifier: NCT02395133
Upadacitinib is a Janus kinase 1 inhibitor developed for treatment of moderate to severe rheumatoid arthritis (RA) and was recently approved by the US Food and Drug Administration for this indication in adults who have had an inadequate response or intolerance to methotrexate. Upadacitinib is currently under regulatory review by other agencies around the world. Ongoing trials are investigating the use of upadacitinib in other inflammatory autoimmune diseases. In this article, we review the clinical pharmacokinetic data available to date for upadacitinib that supported the clinical development program in RA and ultimately regulatory applications for upadacitinib in treatment of patients with moderate to severe RA.
Background:
Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions.
Objective:
This study evaluated the safety and efficacy of multiple doses of the selective Janus kinase 1 inhibitor upadacitinib in patients with moderate-to-severe atopic dermatitis.
Methods:
In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting), adults with moderate-to-severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary endpoint was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment.
Results:
Patients (N=167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n=42; placebo, n=41); 166 were analyzed for safety (each upadacitinib group, n=42; placebo, n=40). The mean (standard error) primary efficacy endpoint was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P=0.03, <0.001, and <0.001). Serious adverse events occurred in 4.8% [2/42], 2.4% [1/42], 0% [0/42] of upadacitinib groups (vs 2.5% [1/40] for placebo).
Conclusion:
A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.
Importance
Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population.
Objective
To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD.
Design, Setting, and Participants
A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included.
Interventions
Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight ≥60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85).
Main Outcomes and Measures
Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator’s Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16.
Results
A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%).
Conclusions and Relevance
In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults.
Trial Registration
ClinicalTrials.gov identifier: NCT03054428
Importance
Atopic dermatitis is associated with substantial patient and caregiver burden. Currently available treatments for atopic dermatitis are inadequate or contraindicated for some patients. Abrocitinib (PF-04965842) is an oral Janus kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis.
Objective
To investigate the efficacy and safety of abrocitinib for patients with moderate to severe atopic dermatitis.
Design, Setting, and Participants
A phase 2b, randomized, double-blinded, placebo-controlled, parallel-group trial was conducted from April 15, 2016, to April 4, 2017, at 58 centers in Australia, Canada, Germany, Hungary, and the United States among 267 patients 18 to 75 years of age with a clinical diagnosis of moderate to severe atopic dermatitis for 1 year or more and inadequate response or contraindication to topical medications for 4 weeks or more within 12 months. Efficacy was assessed in the full analysis set, which was a modified intention-to-treat population that included all patients who received 1 dose or more of the study drug except for 4 patients from 1 site.
Interventions
Participants were randomly assigned 1:1:1:1:1 to receive abrocitinib (200 mg, 100 mg, 30 mg, or 10 mg) or placebo once daily for 12 weeks.
Main Outcomes and Measures
The primary outcome was the proportion of patients achieving an Investigator’s Global Assessment of clear (0) or almost clear (1) with an improvement from baseline of 2 grades or more at week 12. The secondary outcome was the percentage change from baseline in the Eczema Area and Severity Index at week 12.
Results
Of the 267 participants, 144 were women (mean [SD] age, 40.8 [16.1] years). At week 12, 21 of 48 patients receiving 200 mg of abrocitinib (43.8%; P < .001, 2-sided), 16 of 54 patients receiving 100 mg of abrocitinib (29.6%; P < .001), and 3 of 52 patients receiving placebo (5.8%) achieved grades of clear or almost clear on the Investigator’s Global Assessment scale with improvement of 2 grades or more; these rates correspond to maximum effect model-based estimates of 44.5% (95% CI, 26.7%-62.3%) for those receiving 200 mg of abrocitinib, 27.8% (95% CI, 14.8%-40.9%) for those receiving 100 mg of abrocitinib, and 6.3% (95% CI, −0.2% to 12.9%) for those receiving placebo. Reductions in the Eczema Area and Severity Index were 82.6% (90% CI, 72.4%-92.8%; P < .001) for those receiving 200 mg of abrocitinib, 59.0% (90% CI, 48.8%-69.3%; P = .009) for those receiving 100 mg of abrocitinib, and 35.2% (90% CI, 24.4%-46.1%) for those receiving placebo. Adverse events were observed in 184 of 267 patients (68.9%); the most frequently reported adverse events (in ≥3 patients in any group) were dermatitis atopic, upper respiratory tract infection, headache, nausea, and diarrhea. Dose-dependent decreases in platelet count were observed but trended upward toward baseline levels after week 4.
Conclusions and Relevance
Once-daily oral abrocitinib was effective and well tolerated for short-term use in adults with moderate to severe atopic dermatitis. Additional trials are necessary to evaluate long-term efficacy and safety.
Trial Registration
ClinicalTrials.gov identifier: NCT02780167
Background:
Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined.
Objective:
This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD.
Methods:
Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15.
Results:
Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10-15) that was sustained until day 15 (92.90% vs 49.59%, P < 10-15). Crisaborole significantly modulated key AD biomarkers versus vehicle, including TH2 and TH17/TH22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function.
Conclusion:
Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD.
Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by pruritus, inflammatory erythematous skin lesions, and skin-barrier defect. Current mainstay treatments of emollients, steroids, calcineurin inhibitors, and immunosuppressants have limited efficacy and potentially serious side effects. Recent advances and understanding of the pathogenesis of AD have resulted in new therapies that target specific pathways with increased efficacy and the potential for less systemic side effects. New FDA-approved therapies for AD are crisaborole and dupilumab. The JAK-STAT inhibitors (baricitinib, upadacitinib, PF-04965842, ASN002, tofacitinib, ruxolitinib, and delgocitinib) have the most promising results of the emerging therapies. Other drugs with potential include the aryl hydrocarbon receptor modulating agent tapinarof, the IL-4/IL-13 antagonists lebrikizumab and tralokinumab, and the IL-31Rα antagonist nemolizumab. In this review, new and emerging AD therapies will be discussed along with their mechanisms of action and their potential based on clinical study data.
Background: Atopic dermatitis (AD) is a common and chronic, pruritic inflammatory skin
condition that affects all age groups. There was a dearth of consensus document on AD for
Indian practitioners. This article aims to provide an evidence‑based consensus statement for
the management of AD with a special reference to the Indian context. This guideline includes
updated definition, etiological factors, classification, and management of atopic dermatitis.
Methodology: The preparation of guidelines was done in multiple phases. Indian Dermatology
Expert Board Members (DEBM), recommended by the Skin Allergy Society of India, prepared 26
evidence‑based recommendations for AD. An extensive literature search was done in MEDLINE,
Google scholar, Cochrane, and other resources. Articles published in the past 10 years were
reviewed and recommendations were graded based on the quality of evidence as per GRADE.
After forming the initial structure, DEBM met in Mumbai and gave their decisions on an agree
and disagree scale with an Indian perspective. Finally, their suggestions were compiled for
preparing the article. After DEBM finalized the draft, a treatment algorithm was formulated
for the management of AD. Results: DEBM suggested a working definition for AD. The panel
agreed that moisturizers should be used as mainstay of therapy and should be continued in
all lines of therapy and in maintenance phase. Topical corticosteroids and topical calcineurin
inhibitors should be considered as the first line of treatment. Among systemic therapies,
cyclosporin should be considered first line, followed by azathioprine, methotrexate, and
mycophenolate mofetil. Phototherapy can be an effecive alternative. Empirical food restriction
was recommended against. Conclusion: These guidelines should form a reference for the
management of patients with AD in an evidence‑based manner.
Background
Two phase 3 trials with identical design, LIBERTY AD SOLO 1 (NCT02277743) and LIBERTY AD SOLO 2 (NCT02277769), confirmed dupilumab efficacy and safety versus placebo in adults with moderate-to-severe atopic dermatitis (AD).
Objectives
To report a pooled analysis of these trials to further explore dupilumab’s effects on AD clinical parameters, patient-reported outcomes (PROs), symptoms of anxiety/depression, health-related quality of life (HRQoL), and safety.
Methods
A pooled analysis of two 16-week phase 3 studies in adults with moderate-to-severe AD (N = 1379) inadequately controlled with/inadvisable for topical medications, randomized to dupilumab 300 mg once weekly (qw), every 2 weeks (q2w), or placebo.
Results
Dupilumab significantly improved all pre-specified efficacy endpoints versus placebo (P < 0.0001), including clinical severity outcomes and PROs, symptoms of anxiety/depression, and HRQoL, consistent with previously published results. In post-hoc analyses, among patients reporting at least some baseline pain/discomfort on the EuroQoL-5D, no pain/discomfort at Week 16 was reported by 43%/46%/14% of dupilumab qw/q2w/placebo-treated patients (P < 0.0001). The distribution of dupilumab-treated patients within pre-defined score categories on the Investigator’s Global Assessment (0–1/2/3/4) and Eczema Area and Severity Index (≥90%/≥75–<90%/≥50–<75%/<50%) steadily and consistently improved over time versus marginal changes with placebo. Dupilumab significantly improved pruritus within 1–3 days of treatment initiation. No new safety signals were observed. Injection-site reactions and conjunctivitis were more common with dupilumab; AD exacerbation and non-herpetic skin infections more frequent with placebo.
Conclusions
Dupilumab versus placebo significantly improved objective AD signs, subjective PROs, symptoms of anxiety/depression, and HRQoL, with a favorable benefit-risk profile in adults with moderate-to-severe AD.
Background
In the US, an Investigator's Global Assessment (IGA) score of ≤ 1 (clear/almost clear skin) has been the regulatory outcome standard measure for registration clinical trials in atopic dermatitis (AD), including those supporting the recent approval of dupilumab.
Objective
To evaluate the treatment effect of dupilumab in patients with IGA>1 at the end of treatment, using other validated outcome measures for AD signs, symptoms and quality of life.
Methods
LIBERTY AD SOLO 1 and 2 were two 16‐week, randomized, double‐blind trials enrolling adult patients with moderate‐to‐severe AD (IGA≥3) inadequately controlled with topical treatment. We performed a post‐hoc analysis in patients receiving dupilumab 300 mg every 2 weeks (q2w) or placebo. Outcome measures in patients with IGA>1 included Eczema Area and Severity Index (EASI), pruritus Numerical Rating Scale (NRS), affected Body Surface Area (BSA), Patient‐Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI).
Results
At Week 16, 278/449 dupilumab q2w‐treated patients (median age 36·0 years) and 396/443 placebo‐treated patients had IGA>1. Among patients with IGA>1 at Week 16, dupilumab significantly improved several outcome measures compared with placebo: EASI (–48·9% vs. –11·3%, P<0·001), pruritus NRS (–35·2% vs. –9·1%, P < 0·001), BSA affected (–23·1% vs. –4·5%, P<0·001), POEM score ≥ 4‐point improvement (57·4% vs. 21·0%, P<0·001), and DLQI score ≥ 4‐point improvement (59·3% vs. 24·4%, P<0·001).
Conclusions
In patients with IGA>1 at Week 16, dupilumab induced statistically significant benefits in multiple validated outcome measures versus placebo. The IGA≤1 endpoint significantly underestimates clinically relevant dupilumab treatment effects.
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Abstract
Background: Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis.
Methods: In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16.
Results: We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups.
Conclusions: In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .).
Background:
Seborrheic dermatitis is a common chronic inflammatory skin disorder that affects the scalp and is characterized by erythema and oily scales. It could perhaps be difficult to control and could seriously degrade one's quality of life. The study's objective is to assess the effectiveness of intradermal administrations of QR678 Neo® hair growth factor therapy for the treatment of scalp seborrheic dermatitis in both men and women.
Method:
Forty male and female patients with clinically diagnosed seborrheic dermatitis of the scalp in the age 18-45 years, not satisfactorily responding to standard therapy for at least 6 months, were included. 1 mL solution of QR678 Neo® was administered in the scalp skin of all patients at 3-week interval till eight sessions. Patients were advised to continue with antifungal shampoo and topical antifungal solution with steroid combination which they had been on during the treatment. Assessment of disease severity, dermoscopic evaluation, and self-assessment were done at baseline and at the end of the fourth and the eighth sessions.
Results:
Improvement was observed in adherent scalp flaking score after eighth session (mean = 12) compared to baseline (mean = 60). The dermoscopic evaluation showed a noticeable difference from baseline (mean = 11) in erythema and scaling with the Seborrheic Dermatitis Scalp Severity Index tool at the end of treatment (mean = 2). A high satisfaction score was given for the efficiency in the self-assessment questionnaire.
Conclusion:
Our study proved that treatment with QR678 Neo® led to an improvement in the overall scalp condition by the resolution of flaking and inflammation.
Background:
Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex.
Methods:
We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [≥18 years of age] and adolescents [12 to <18 years of age, weighing ≥40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed.
Results:
In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation.
Conclusions:
In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocate1 and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.).
Background:
OX40 is crucial for T-cell differentiation and memory induction. The anti-OX40 antibody, rocatinlimab inhibits the OX40 pathway. We evaluated the efficacy and safety of rocatinlimab in adults with moderate-to-severe atopic dermatitis.
Methods:
This multicentre, double-blind, placebo-controlled phase 2b study was done at 65 secondary and tertiary sites in the USA, Canada, Japan, and Germany. Eligible patients were adults (aged 18 years or older) with confirmed atopic dermatitis (American Academy of Dermatology Consensus Criteria or local diagnostic criteria) with moderate-to-severe disease activity, as defined by an Eczema Area and Severity Index (EASI) score of 16 or more, validated Investigator's Global Assessment for Atopic Dermatitis score of 3 (moderate) or 4 (severe), and affected body surface area 10% or higher at both screening and baseline, with documented history (within 1 year) of inadequate response to topical medications or if topical treatments were medically inadvisable. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous rocatinlimab every 4 weeks (150 mg or 600 mg) or every 2 weeks (300 mg or 600 mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up. Percentage change from baseline in EASI score was assessed as the primary endpoint at week 16 and during the active extension and follow-up in all randomly assigned patients exposed to study drug with a post-baseline EASI score at week 16 or earlier according to the group they were randomly assigned to. Safety was assessed in all randomly assigned patients exposed to study drug; patients were analysed according to the group they were randomly assigned to. The study is registered with ClinicalTrials.gov, NCT03703102.
Findings:
Between Oct 22, 2018, and Oct 21, 2019, 274 patients (114 [42%] women, 160 [58%] men; mean age 38·0 years [SD 14·5]) were randomly assigned to one of the rocatinlimab groups (217 [79%] patients) or to the placebo group (57 [21%] patients). Compared with placebo (-15·0 [95% CI -28·6 to -1·4]), significant least-squares mean percent reductions in EASI score at week 16 were observed in all rocatinlimab groups (rocatinlimab 150 mg every 4 weeks -48·3 [-62·2 to -34·0], p=0·0003; rocatinlimab 600 mg every 4 weeks -49·7 [-64·3 to -35·2], p=0·0002; rocatinlimab 300 mg every 2 weeks -61·1 [-75·2 to -47·0], p<0·0001; and rocatinlimab 600 mg every 2 weeks -57·4 [-71·3 to -43·4], p<0·0001). The most common adverse events during the double-blind period in patients receiving rocatinlimab (adverse events ≥5% of patients in the total rocatinlimab group and more common than the placebo group) were pyrexia (36 [17%] patients), nasopharyngitis (30 [14%] patients), chills (24 [11%] patients), headache (19 [9%] patients), aphthous ulcer (15 [7%] patients), and nausea (13 [6%] patients). There were no deaths.
Interpretation:
Patients treated with rocatinlimab had progressive improvements in atopic dermatitis, which was maintained in most patients after treatment discontinuation. Treatment was well tolerated.
Funding:
Kyowa Kirin.
Atopic dermatitis (AD) is a common inflammatory skin disease that has emerging treatments targeting the underlying immunological mechanism. Interleukin-31 (IL-31) is associated with the pathobiological mechanism of AD, contributing to symptoms such as dermatitis and pruritus. Nemolizumab is an anti-IL-31 receptor α-chain (IL-31RA) monoclonal antibody agent that is efficacious in improving symptoms of AD in several phase II and phase III studies in recent years. Nemolizumab demonstrates great efficacy in reducing pruritus and to a lesser degree, dermatitis associated with AD. Additionally, one advantage of nemolizumab is its quick speed of action. Adverse effects are mild and transient in nature, including exacerbation of AD, nasopharyngitis, upper respiratory tract infections, elevated creatine kinase and peripheral edema. Severe adverse effects were not common and consisted of exacerbation of AD and asthma exacerbation. Therefore, nemolizumab has the potential to be an important treatment of choice for AD given its efficacy, mild side effect profile and rapid time of onset. In this review, we examine the preclinical and clinical studies of the novel drug nemolizumab for the treatment of AD with a focus on its mechanism of action, pharmacokinetics, safety, efficacy, indications and drug interactions.
Tralokinumab (tralokinumab-ldrm) [Adbry™ (USA); Adtralza® (EU)], a human IgG4 monoclonal antibody that binds specifically to interleukin (IL)-13, is an effective and generally well tolerated treatment option for adult patients with moderate to severe atopic dermatitis who are candidates for systemic therapy. In pivotal phase III trials, subcutaneous tralokinumab improved the clinical signs and symptoms of atopic dermatitis as well as quality of life (QOL). In ECZTRA 1 and 2, tralokinumab monotherapy was superior to placebo in the first 16 weeks of treatment, with improvements in pruritus and sleep scores seen as early as week 1. Many patients who met the criteria for clinical response at week 16 maintained this response at week 52. Tralokinumab was also more effective than placebo when used in combination with 'as needed' topical corticosteroids (TCS) in ECZTRA 3 and 7; most tralokinumab recipients used no or very little amounts of TCS. In an open-label extension trial, tralokinumab provided consistent symptom control over the longer term (up to 2 years). The majority of adverse events with tralokinumab, including injection-site reactions and conjunctivitis, were of mild to moderate severity. The tolerability profile of tralokinumab longer term was consistent with that in the phase III trials.
The skin microbiome is a key component of pathogenesis in atopic dermatitis (AD). The skin of AD patients is characterized by microbial dysbiosis, with a reduction of microbial diversity and overrepresentation of pathogenic Staphylococcus aureus (S. aureus). Recent exciting studies have elucidated an importance of establishing an appropriate immune response to microbes in early life and uncovered the new mechanisms of microbial community dynamics in modulating our skin microbiome. Several microbes are associated with AD pathogenesis, with proposed pathogenic effects from S. aureus and Malassezia. The complex relationships between microbes within the skin microbiome consortia includes various species, such as Staphylococcal, Roseomonas and Cutibacterium strains, that can inhibit S. aureus and are potential probiotics for AD skin. Numerous microbes are now also reported to modulate host response via communication with keratinocytes, specialized immune cells and adipocytes to improve skin health and barrier function. This increased understanding of skin microbiota bioactives has led to new biotherapeutic approaches that target the skin surface microenvironment for AD treatment.
Background
Difamilast is a selective phosphodiesterase 4 (PDE4) inhibitor. PDE4 is involved in cytokine production linked with inflammatory disorders, including atopic dermatitis (AD).
Objectives
To demonstrate the superiority of difamilast 1% ointment to vehicle in Japanese adult AD patients.
Methods
In this phase 3, randomized, double-blind trial, patients (15-70 years) with an Investigator Global Assessment (IGA) score of 2/3 received topical difamilast 1% (n = 182) ointment or vehicle (n = 182) twice daily for 4 weeks.
Results
The success rate in IGA score at week 4 (primary endpoint), percentage of patients achieving IGA score of 0/1 with ≥2-grade improvement, was significantly higher with difamilast 1% than vehicle (38.46% vs 12.64%, P < .0001). The success rate in ≥ 50%, ≥ 75%, and ≥ 90% improvement in overall Eczema Area and Severity Index (EASI) score at week 4 followed the same trend. Difamilast 1% provided significant mean percent improvement from baseline in overall EASI score versus vehicle from week 1 to week 4. Treatment-emergent adverse events were mostly mild or moderate and less frequent with difamilast.
Limitations
Study treatment was limited to four weeks.
Conclusion
Difamilast 1% ointment demonstrates superiority to vehicle and favorable safety in Japanese adult AD patients.
An enhanced understanding of the importance of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signalling in multiple disease states has led to an increasing applicability of therapeutic intervention with JAK inhibitors. These agents have revolutionised treatments for a heterogeneous group of disorders, such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven dermatological diseases, exemplifying rapid bench-to-bedside translation. In this Therapeutics paper, we summarise the currently available data concerning the successes and safety of an array of JAK inhibitors and hypothesise on how these fields could develop.
Background:
Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
Methods:
In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting.
Findings:
Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group.
Interpretation:
Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis.
Funding:
AbbVie.
Background:
Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
Methods:
Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12-17 years) and adults (aged 18-75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis [vIGA-AD] score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting.
Findings:
Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 [70%] of 281 patients) and upadacitinib 30 mg (227 [80%] of 285 patients) groups than the placebo group (46 [16%] of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% [95% CI 46·4-60·2] for the upadacitinib 15 mg group; 63·4% [57·1-69·8] for the upadacitinib 30 mg group) and Measure Up 2 (166 [60%] of 276 patients in the upadacitinib 15 mg group and 206 [73%] of 282 patients in the upadacitinib 30 mg group vs 37 [13%] of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% [39·9-53·9] for the upadacitinib 15 mg group; 59·6% [53·1-66·2] for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 [48%] patients) and upadacitinib 30 mg (177 [62%] patients) groups than the placebo group (24 [8%] patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% [33·2-46·4] for the upadacitinib 15 mg group; 53·6% [47·2-60·0] for the upadacitinib 30 mg group) and Measure Up 2 (107 [39%] patients in the upadacitinib 15 mg group and 147 [52%] patients in the upadacitinib 30 mg group vs 13 [5%] patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% [27·8-40·2] for the upadacitinib 15 mg group; 47·4% [41·0-53·7] for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 [7%] of 281 patients in the upadacitinib 15 mg group, 49 [17%] of 285 patients in the upadacitinib 30 mg group, and six [2%] of 281 patients in the placebo group in Measure Up 1; 35 [13%] of 276 patients in the upadacitinib 15 mg group, 41 [15%] of 282 patients in the upadacitinib 30 mg group, and six [2%] of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 [9%] patients, 38 [13%] patients, and 20 [7%] patients; 19 [7%] patients, 17 [16%] patients, and 12 [4%] patients), nasopharyngitis (22 [8%] patients, 33 [12%] patients, and 16 [6%] patients; 16 [6%] patients, 18 [6%] patients, and 13 [5%] patients), headache (14 [5%] patients, 19 [7%] patients, and 12 [4%] patients; 18 [7%] patients, 20 [7%] patients, and 11 [4%] patients), elevation in creatine phosphokinase levels (16 [6%] patients, 16 [6%] patients, and seven [3%] patients; nine [3%] patients, 12 [4%] patients, and five [2%] patients), and atopic dermatitis (nine [3%] patients, four [1%] patients, and 26 [9%] patients; eight [3%] patients, four [1%] patients, and 26 [9%] patients).
Interpretation:
Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit-risk profile in adolescents and adults with moderate-to-severe atopic dermatitis.
Funding:
AbbVie.
Background
The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited.
Methods
In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator’s Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index–75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16.
Results
A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively.
Conclusions
In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.)
VISUAL ABSTRACT
Abrocitinib vs. Placebo or Dupilumab for Atopic Dermatitis
Background:
Atopic dermatitis (AD) is a widely acquired, relapsing inflammatory skin disease. Biologics are now widely used in patients with moderate-to-severe AD.
Objective:
This work aims to summarize both label and off-label biologics on AD treatment in phase II and phase III stages, and compile evidence on the efficacy of the most-studied biologics.
Methods:
We conducted a comprehensive literature search through PubMed, EMBASE, and ClinicalTrials.gov to identify all documented biological therapies for AD. The criteria were further refined to focus on those treatments with the highest evidence level for AD with at least one randomized clinical trial supporting their use. Only studies or articles published in English were enrolled in this study.
Findings:
Primary searches identified 525 relevant articles and 27 trials. Duplicated articles and papers without a full text were excluded. Only completed trials were enrolled. We included 28 randomized controlled trials, 4 unpublished trials, 2 observational studies, and 1 meta-analysis. Eight kinds of biologics, including IL-4/IL-13 inhibitors, JAK inhibitors, anti-IL-13 antibodies, anti-IL-22 antibodies, anti-IL-33 antibodies, thymic stromal lymphopoietin inhibitor (TSLP), OX40 antibodies, and H4R-antagonists were included in this work. Dupliumab, as the most widely used and investigated biologic, was reported in 1 meta-analysis and 4 trials exploring its long-term use and application in both adults and pediatric patients. Besides dupilumab, four other IL-4/IL-13 inhibitors recruited were all randomized, clinical trials at phase 2-3 stage. Six different kinds of JAK inhibitors were summarized with strong evidence revealing their significant therapeutic effects on AD. There were 3 trials for nemolizumab, an anti-IL-13 antibody, all of which were in the phase 2 clinical trial stage. Results showed nemolizumab could be another alternative therapy for moderate-to-severe AD with long-term efficiency and safety.
Conclusion:
The biological therapies with the most robust evidence on efficacy and long-term safety for AD treatment include dupilumab, barcitinib, abrocitinib, and delgocitinib. Most of the biologics mentioned in this review were still at the exploratory stage. This review will help practitioners advise patients seeking suitable biological therapies and offer experimental study directions for treatment.
Background
Baricitinib, an oral, selective Janus kinase (JAK)1/JAK2 inhibitor, is being studied for moderate-to-severe atopic dermatitis (AD) in adults.
Objective
To evaluate the efficacy and safety of baricitinib monotherapy in a North American Phase 3 trial (BREEZE-AD5/NCT03435081) of adults with moderate-to-severe AD who responded inadequately or were intolerant to topical therapy.
Methods
Patients (N=440) were randomized 1:1:1 to once-daily placebo or baricitinib (1 mg or 2 mg). The primary endpoint was the proportion of patients achieving ≥75% reduction in the Eczema Area and Severity Index (EASI75) at Week 16. A key secondary endpoint was the proportion of patients achieving a validated Investigator Global Assessment for AD (vIGA-AD™) score of 0 (clear)/1(almost clear) with ≥2-point improvement.
Results
At Week 16, the proportion of patients achieving EASI75 was 8%, 13%, and 30% (P <.001, 2 mg vs. placebo) and those with a vIGA-AD 0/1 were 5%, 13%, and 24% (P <.001, 2 mg vs. placebo), for placebo, baricitinib 1 mg, and 2 mg, respectively. Safety findings were similar to other baricitinib AD studies.
Limitations
Short-term clinical trial results may not be generalizable to real-world settings.
Conclusion
Baricitinib was efficacious for patients with moderate-to-severe AD with no new safety findings over 16 weeks.
Background:
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a Phase 2 study with concomitant topical corticosteroids.
Objectives:
To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD and an inadequate response to topical therapies.
Methods:
In two independent, multicentre, double-blind, Phase 3 monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomised 2:1:1:1 to once-daily placebo, baricitinib 1-mg, 2-mg or 4-mg for 16 weeks.
Results:
At Week 16, more patients achieved the primary endpoint of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4-mg and 2-mg compared with placebo in BREEZE-AD1 (N=624; 4-mg 16.8%, 2-mg 11.4%, 1-mg 11.8%, placebo 4.8%; P<0.001, P<0.05, P<0.05), and BREEZE-AD2 (N=615; 4-mg 13.8%, 2-mg 10.6%, 1-mg 8.8%, placebo 4.5%; P=0.001, P<0.05, P=0.085). Improvement in itch was achieved as early as Week 1 for 4-mg and Week 2 for 2-mg. Improvements in night-time awakenings, skin pain, and quality-of-life measures were observed by Week 1 for both 4-mg and 2-mg (P≤0.05, all comparisons). The most common adverse events in baricitinib-treated patients were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dose.
Conclusions:
Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.
Importance
Topical medication is the central treatment for patients with atopic dermatitis (AD), but the options are limited. Phosphodiesterase 4 (PDE4) inhibitors are a new candidate for AD therapy.
Objective
To evaluate the efficacy and safety of topical PDE4 inhibitors in mild to moderate AD.
Data Sources
Clinical trials were identified from MEDLINE, Embase, Cochrane Controlled Register of Trials, Chinese medical databases (Wanfang, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, and China Science and Technology Journal Database), ClinicalTrials.gov, and other trial registries from inception to August 15, 2018. No restrictions on languages were placed.
Study Selection
Only double-blind randomized clinical trials with topical PDE4 inhibitors vs topical vehicle treatment for patients with mild to moderate AD were included.
Data Extraction and Synthesis
Two reviewers independently extracted study features, intervention details, and outcomes. A meta-analysis was performed using the random-effects model. The Cochrane Collaboration’s risk of bias assessment tool was used to assess the risk of bias. Funnel plots and Egger tests were used to assess the publication bias.
Main Outcomes and Measures
Changes from baseline in target lesion score were expressed in terms of standardized mean differences (SMDs) with 95% CIs. Outcomes of investigators’ assessment and safety were expressed in terms of relative risk with 95% CIs.
Results
Seven studies were identified, which included 1869 patients with mild to moderate AD. Overall, compared with the topical vehicle control, topical application of PDE4 inhibitors was associated with a significant decrease in target lesion score (SMD −0.40; 95% CI, −0.61 to −0.18; P < .001) and a higher response rate in investigators’ assessment of clear or almost clear skin (relative risk, 1.50; 95% CI, 1.33-1.70; P < .001). There was no difference in treatment-related adverse events or in adverse events that required discontinuation of therapy. Subgroup analyses indicated that after 14 and 28 days of therapy with PDE4 inhibitors, target lesion score was significantly decreased. However, these beneficial effects were displayed only for the PDE4 inhibitors crisaborole and AN2898 (crisaborole at day 14: SMD, −0.59; 95% CI, −1.15 to −0.02; P = .04; AN2898 at day 14: SMD, −0.76; 95% CI, −1.38 to −0.13; P = .02; crisaborole at day 28: SMD, −0.86; 95% CI, −1.44 to −0.28; P = .004; AN2898 at day 28: SMD, −0.68; 95% CI, −1.30 to −0.05; P = .03). Heterogeneity was not significant across studies.
Conclusions and Relevance
This meta-analysis suggests that topical PDE4 inhibitors are a safe and effective treatment for mild to moderate AD. Current evidence supports the use of crisaborole or AN2898 as the choice of maintenance or sequential therapy for mild to moderate AD.