Summary
Background
ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T ...helper (Th)1, Th2 and Th17/Th22 pathways.
Objectives
The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate‐to‐severe AD.
Methods A total of 36 patients with moderate‐to‐severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28‑day period (20 mg, 40 mg and 80 mg once daily).
Results
ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg −1·3 ± 2·1, P = 0·81; 40 mg −3·1 ± 2·7, P = 0·27; 80 mg −4·7 ± 2·1, P = 0·01; placebo −1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose‐dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis‐associated biomarker E selectin/SELE.
Conclusions
In patients with moderate‐to‐severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.
What's already known about this topic?
Currently available therapeutic options for atopic dermatitis (AD) include topical corticosteroids, calcineurin inhibitors, crisaborole, dupilumab, ciclosporin and phototherapy. However, few oral treatments are available and those are associated with safety concerns.
What does this study add?
ASN002, an oral, dual Janus kinase and spleen tyrosine kinase inhibitor, was well tolerated and showed promising efficacy and rapid onset of action in patients with moderate‐to‐severe AD at daily doses of 40 mg and 80 mg.
The encouraging efficacy, safety and tolerability profile of ASN002 warrant further investigation of ASN002 in patients with moderate‐to‐severe AD.
Linked Comment: Lebwohl. Br J Dermatol 2019; 181:658.
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Summary
Background
Patients with psoriasis value rapid and complete skin clearance. No head‐to‐head studies have focused on early responses to interleukin (IL)‐17 vs. IL‐23 inhibitors.
Objectives
To ...compare early and complete skin clearance by the IL‐17A inhibitor ixekizumab vs. the IL‐23p19 inhibitor guselkumab.
Methods
IXORA‐R, a 24‐week, randomized, double‐blinded study, enrolled adults with moderate‐to‐severe plaque psoriasis static Physician's Global Assessment of Disease (sPGA) score of ≥ 3, Psoriasis Area and Severity Index (PASI) ≥ 12, and ≥ 10% body surface area. Patients were randomized (1 : 1) to receive the approved dose of subcutaneous ixekizumab or guselkumab. Primary end point was 100% improvement in PASI (PASI 100) at week 12. Major secondary end points included other levels of improved PASI and sPGA at different time points. Comparisons were made using the Cochran–Mantel–Haenszel test with a multiple testing strategy. Nonresponder imputation was used for missing data. After the completion of the study, the final secondary end point (PASI 100 at 24 weeks) and safety data through week 24 will be reported.
Results
In total, 1027 patients were randomized. The primary end point PASI 100 at week 12 was met 215/520 ixekizumab (41%); 126/507 guselkumab (25%); P < 0·001. All major secondary end points measured up to week 12 were met, including PASI 50 at week 1 and PASI 75 at week 2. Serious adverse event frequency was 3% for each group; no new safety signals were identified.
Conclusions
Ixekizumab was superior to guselkumab for rapidly improving signs and symptoms in patients with moderate‐to‐severe plaque psoriasis by week 12. Adverse events were similar to previous ixekizumab and guselkumab studies. Compared with the IL‐23 inhibitor guselkumab, ixekizumab can offer complete skin clearance more rapidly to patients with moderate‐to‐severe plaque psoriasis.
What's already known about this topic?
Patients with plaque psoriasis desire both high levels of clearance and rapid onset of treatment effects.
Ixekizumab, a high‐affinity monoclonal antibody that selectively targets interleukin (IL)‐17A, has demonstrated greater and faster skin clearance than etanercept and ustekinumab, with consistent long‐term efficacy, safety and durability of response.
Clinical trial data and systematic reviews have suggested that IL‐17 inhibitors can improve a patient's psoriasis more rapidly than IL‐23 inhibitors.
What does this study add?
The head‐to‐head study design directly compares the efficacy and speed of response of ixekizumab and the IL‐23 inhibitor guselkumab in moderate‐to‐severe plaque psoriasis.
The primary end point was met, showing superiority of ixekizumab over guselkumab for achieving complete skin clearance at week 12.
The safety profile of ixekizumab was consistent with previous studies.
Ixekizumab can deliver patients complete skin clearance and improved quality of life more rapidly than guselkumab.
Linked Comment: Veysey. Br J Dermatol 2020; 182:1321–1322.
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Tapinarof is a topical, aryl‐hydrocarbon receptor agonist that has recently received FDA‐approval for the treatment of psoriasis. This novel therapeutic has also been shown to be effective for atopic ...dermatitis and is currently in phase 3 for this indication. Beyond good efficacy and fast onset of action in patients with psoriasis, the clinical response to tapinarof is notable for durable remission or near remission, maintained for an average of 130 days beyond treatment discontinuation in patients with psoriasis in phase 3 studies. Tapinarof is usually well tolerated but can induce a follicular inflammatory reaction and dermatitis in some patients. This narrative review covers the historical development of this molecule, safety and efficacy data from clinical trials conducted with various topical formulations, and practical considerations derived from our 15 years of clinical trial experience with the drug.
Summary
Background
Inhibiting interleukin (IL)‐23 in patients with psoriasis has demonstrated high levels of skin clearance.
Objectives
To investigate, in a phase II (AMAF; NCT02899988), multicentre, ...double‐blind trial, the efficacy and safety of three doses of mirikizumab (LY3074828), a p19‐directed IL‐23 antibody, vs. placebo in patients with moderate‐to‐severe plaque psoriasis.
Methods
Adult patients were randomized 1 : 1 : 1 : 1 to receive placebo (n = 52), mirikizumab 30 mg (n = 51), mirikizumab 100 mg (n = 51) or mirikizumab 300 mg (n = 51) subcutaneously at weeks 0 and 8. The primary objective was to evaluate the superiority of mirikizumab over placebo in achieving a 90% improvement in the Psoriasis Area and Severity Index (PASI 90) response at week 16. Comparisons were done using logistic regression analysis with treatment, geographical region and previous biological therapy in the model. Missing data were imputed as nonresponses.
Results
Ninety‐seven per cent of patients completed the first 16 weeks of the study. The primary end point was met for all mirikizumab dose groups vs. placebo, with PASI 90 response rates at week 16 of 0%, 29% (P = 0·009), 59% (P < 0·001) and 67% (P < 0·001) for patients receiving placebo, and mirikizumab 30 mg, 100 mg and 300 mg, respectively. There were two (1%) serious adverse events in mirikizumab‐treated patients vs. one (2%) in a placebo‐group patient.
Conclusions
At week 16, 67% of patients treated with mirikizumab 300 mg at 8‐week intervals achieved PASI 90. The percentage of patients reporting at least one treatment‐emergent adverse event was similar among patients treated with placebo or mirikizumab.
What's already known about this topic?
Interleukin (IL)‐23 is a key cytokine in the pathogenesis of psoriasis.
Inhibiting IL‐23 has shown great promise for psoriasis therapy in clinical trials.
What does this study add?
In this phase II trial of mirikizumab – a p19‐directed IL‐23 antibody – we evaluated three dose regimens of mirikizumab vs. placebo. There was significantly higher efficacy in patients treated with mirikizumab vs. placebo and comparable safety profiles.
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Background
Baricitinib is an oral, selective, reversible Janus kinase 1/2 inhibitor approved in the European Union and Japan and under investigation in the United States for treatment of atopic ...dermatitis (AD).
Objectives
To evaluate the impact of baricitinib plus background topical corticosteroids (TCS) on health‐related quality of life (HRQoL), how AD symptoms impact work productivity and life functioning, and treatment benefit using patient‐reported outcome (PRO) assessments in patients with moderate‐to‐severe AD previously experiencing inadequate response to TCS.
Methods
Adult patients with AD in BREEZE‐AD7, a Phase 3, multicentre, double‐blind trial, were randomised 1 : 1 : 1 to daily oral placebo (control) or baricitinib 4‐ or 2‐mg plus TCS. PROs reported Week 1 through Week 16: Dermatology Life Quality Index (DLQI), Work Productivity and Activity Impairment‐AD (WPAI‐AD); Patient‐Reported Outcomes Measurement Information System (PROMIS) Itch and Sleep measures, and Patient Benefit Index (PBI). Data were analysed using logistic regression (categorical) and mixed model repeated measures (continuous). PBI scores were analysed using analysis of variance.
Results
A total of 329 patients were randomised. Treatment with baricitinib 4‐mg (N = 111) or 2 mg (N = 109) plus TCS led to rapid, statistically significant improvements vs. TCS plus placebo (N = 109) in DLQI ≥4‐point improvement starting at Week 2 (4‐mg plus TCS, P ≤ 0.001; 2‐mg plus TCS P ≤ 0.05), change from baseline in WPAI‐AD presenteeism at Week 1 (4‐mg plus TCS, P ≤ 0.01; 2‐mg plus TCS P ≤ 0.05) and PROMIS itch interference at Week 2 (4‐mg plus TCS P ≤ 0.01). Improvements were sustained through Week 16 for baricitinib 4‐mg. Statistically significant improvements were observed at Week 16 for PBI global score (4‐mg plus TCS, P ≤ 0.001; 2‐mg plus TCS P ≤ 0.05).
Conclusions
Baricitinib plus TCS vs. placebo plus TCS showed significant improvements in treatment benefit at Week 16 and rapid significant improvements in HRQoL and impact of AD symptoms on work productivity and functioning through 16 weeks.
Summary
Background
Long‐term efficacy and safety of ixekizumab 160 mg at week 0, then 80 mg every 2 weeks (Q2W) for 12 weeks, followed by every 4 weeks (Q4W) thereafter (i.e. Q2W/Q4W), which is the ...labelled psoriasis dosing where approved, except in Japan have been established for the treatment of adults with moderate‐to‐severe plaque psoriasis. However, some patients may benefit from remaining on Q2W dosing beyond 12 weeks.
Methods
Among patients who had static Physician's Global Assessment (sPGA) > 1 at week 12, efficacy through week 52 of continuous Q2W dosing in the IXORA‐P study was compared indirectly with Q2W/Q4W in the integrated data from the UNCOVER‐1, UNCOVER‐2 and UNCOVER‐3 studies. The continuous Q4W dose group, which had comparable results across studies, was used as the common comparator.
Results
In the IXORA‐P study, among patients with sPGA > 1 at week 12, 64% of patients in the continuous Q2W group achieved sPGA ≤ 1 at week 52, which was statistically significantly higher than the 36% of patients with sPGA > 1 in the Q2W/Q4W group based on the integrated data from the UNCOVER studies (P = 0·0007). There were no clinically meaningful differences in frequencies of safety events between patients with sPGA ≤ 1 and patients with sPGA > 1 at week 12 in the IXORA‐P study.
Conclusions
Among patients who did not have clear or almost clear skin at week 12, nearly 30% more patients who were treated continuously with ixekizumab Q2W in IXORA‐P had clear or almost clear skin at week 52 when compared indirectly with those who were treated using the labelled psoriasis dosing in integrated UNCOVER studies.
What's already known about this topic?
Most patients with moderate‐to‐severe psoriasis who were given the labelled psoriasis dosing of ixekizumab 160‐mg loading dose at week 0, 80 mg every 2 weeks (Q2W) through week 12, and 80 mg every 4 weeks (QW4) thereafter respond quickly with a high percentage of skin clearance.
Additionally, patients who achieve static Physician's Global Assessment (sPGA) ≤ 1 by week 12 tend to maintain this response, even after switching to Q4W.
What does this study add?
Here, we assessed whether patients with sPGA > 1 at week 12 benefited from receiving more frequent dosing beyond the first 12 weeks.
The results showed that Q2W dosing beyond 12 weeks resulted in more patients achieving sPGA ≤ 1 by week 52 than the labelled psoriasis dosing among patients with sPGA > 1 at week 12.
Linked Comment: Kim. Br J Dermatol 2020; 183:6.
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Coronavirus disease 2019 (COVID‐19) is caused by SARS‐CoV‐2, a novel RNA virus that was declared a global pandemic on 11 March 2020. The efficiency of infection with SARS‐CoV‐2 is reflected by its ...rapid global spread. The SARS‐CoV‐2 pandemic has implications for patients with inflammatory skin diseases on systemic immunotherapy who may be at increased risk of infection or more severe infection. This position paper is a focused examination of current evidence considering the mechanisms of action of immunotherapeutic drugs in relation to immune response to SARS‐CoV‐2. We aim to provide practical guidance for dermatologists managing patients with inflammatory skin conditions on systemic therapies during the current pandemic and beyond. Considering the limited and rapidly evolving evidence, mechanisms of action of therapies, and current knowledge of SARS‐CoV‐2 infection, we propose that systemic immunotherapy can be continued, with special considerations for at risk patients or those presenting with symptoms.
Background There is a need for the development of novel non‐steroidal topical drugs for the treatment of psoriasis.
Objective To assess the efficacy and safety of topical 1.0% WBI‐1001 in patients ...with mild to moderate plaque psoriasis.
Methods A total of 61 patients with 1–10% body surface area (BSA) covered with plaque psoriasis and a physician’s global assessment score (PGA) of 2–4 were randomized (2 : 1) to receive either 1% WBI‐1001 in a cream formulation or placebo, applied twice daily for 12 weeks. Efficacy was evaluated using PGA, BSA and Psoriasis Area and Severity Index (PASI). The primary endpoint was the change from baseline (Day 0) in PGA at week 12.
Results The improvement in PGA at week 12 was 62.8% for patients randomized to WBI‐1001 when compared with 13.0% for patients randomized to placebo (P < 0.0001). At week 12, the proportion of patients who achieved a PGA of clear or almost clear and the mean improvement in BSA were 67.5% and 79.1%, respectively, for patients randomized to WBI‐1001, when compared with 4.8% (P < 0.0001) and an increase of 9.4% (P < 0.0001), respectively, for patients randomized to placebo. More application site adverse drug reactions were observed in patients randomized to WBI‐1001 than in those randomized to placebo. These adverse drug reactions were all mild or moderate in intensity.
Conclusion Topical WBI‐1001 induces rapid and significant improvement in patients with plaque psoriasis.
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