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.
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.
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.
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.).
Background: Rapid increase in demand for fast, effective and painless cosmetic procedures has inspired the pursue for the ideal method of anesthesia. The aim of the study was to compare the ...effectiveness of different types of topical anesthetics most commonly utilized in dermatological procedures: EMLA cream, BLT cream, infraorbital nerve blocks with 2% lidocaine with epinephrine. Material and Methods: The study involved 12 patients with scheduled painful dermatological procedures intended to improve their facial and neck skin. Pain intensity was measured using 0-10 numeric scale (10 being the worst imaginable pain and 0 no pain). Patients were asked to assess their pain levels during fractionated CO2 laser treatment of the face. Results: Results demonstrated that patients subjected to treatment with the use of anesthetic EMLA and BLT creams still feel a considerable level of pain during the performed dermocosmetic procedures. Similar pain level concerned the group anesthetized with the infraorbital nerve block injection. Conclusion: Finding the ideal topical anesthetic is one of the greatest challenges of present-day cosmetic dermatology. The most desired method of anesthesia in this context would have to be easy to apply, display high clinical effectiveness over a short time period, be able to exert numbing effect on intact skin without systemic effects, cause nominal pain or discomfort during treatment with minimal to no side effects. According to the results of the reported study, the most effective method of anesthesia was proved to be the triple anesthesia involving of a combination of a painkiller drug, EMLA cream and infraorbital nerve block.
The heterogeneous course of moderate-to-severe atopic dermatitis necessitates treatment flexibility.
We evaluated the maintenance of abrocitinib-induced response with continuous abrocitinib ...treatment, dose reduction or withdrawal, and response to treatment reintroduction following flare (JAK1 Atopic Dermatitis Efficacy and Safety JADE REGIMEN: National Clinical Trial 03627767).
Patients with moderate-to-severe atopic dermatitis responding to open-label abrocitinib 200 mg monotherapy for 12 weeks were randomly assigned in a 1:1:1 ratio to blinded abrocitinib (200 or 100 mg) or placebo for 40 weeks. Patients experiencing flare received rescue treatment (abrocitinib 200 mg plus topical therapy).
Of 1233 patients, 798 responders to induction (64.7%) were randomly assigned. The flare probability during maintenance was 18.9%, 42.6%, and 80.9% with abrocitinib 200 mg, abrocitinib 100 mg, and placebo, respectively. Among patients with flare in the abrocitinib 200 mg, abrocitinib 100 mg, and placebo groups, 36.6%, 58.8%, and 81.6% regained investigator global assessment 0/1 response, respectively, and 55.0%, 74.5%, and 91.8% regained eczema area and severity index response, respectively, with rescue treatment. During maintenance, 63.2% and 54.0% of patients receiving abrocitinib 200 and 100 mg, respectively, experienced adverse events.
The definition of protocol-defined flare was not established, limiting the generalizability of findings.
Induction treatment with abrocitinib was effective; most responders continuing abrocitinib did not flare. Rescue treatment with abrocitinib plus topical therapy effectively recaptured response.
Summary Background Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy ...and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis. Methods This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment IGA score 3–4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0–1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434. Findings Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0–1 (23 28% vs three 4%, difference 24% 95% CI 13–34; p<0·0001) and EASI-75 (44 53% vs eight 11%, difference 42% 95% CI 29–55; p<0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 64% of 83 patients) and placebo group (58 74% of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four 5%) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation. Interpretation Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults. Funding Sanofi and Regeneron Pharmaceuticals
Abstract
Introduction/Background
Vitiligo is a chronic autoimmune disease characterized by melanocyte destruction, leading to skin depigmentation. Limited data are available regarding the efficacy of ...long-term topical vitiligo treatment. In 2 randomized, double-blinded, vehicle-controlled phase 3 studies in adults and adolescents (aged ≥12 y) with nonsegmental vitiligo (TRuE-V1 NCT04052425; TRuE-V2 NCT04057573), ruxolitinib cream application resulted in statistically superior improvements in repigmentation versus vehicle in the primary and all key secondary endpoints at Week 24 and was well tolerated. In the open-label period of TRuE-V1/TRuE-V2 (Weeks 24–52) and the TRuE-V long-term extension (LTE; Weeks 52–104) study (NCT04530344), further improvements in facial and body repigmentation (as assessed by Vitiligo Area Scoring Index VASI responses) were observed through Week 104 among patients who continued to apply ruxolitinib cream.
Objectives
In this pooled analysis, we evaluated shifts in facial and total body VASI (F-VASI/T-VASI) responses among patients with vitiligo who had limited or no repigmentation at Week 24 and who continued to apply ruxolitinib cream for an additional 80 weeks.
Methods
In TRuE-V1/TRuE-V2, patients were randomized 2:1 to apply twice-daily 1.5% ruxolitinib cream or vehicle for 24 weeks, after which all patients could apply 1.5% ruxolitinib cream through Week 52. Patients who completed TRuE-V1/TRuE-V2 were eligible to enroll in the TRuE-V LTE. Patients who did not achieve ≥90% improvement in F-VASI at Week 52 continued to apply open-label 1.5% ruxolitinib cream until Week 104. Patients initially randomized to apply ruxolitinib cream who had <25% improvement from baseline in F-VASI or T-VASI at Week 24 and had non-missing VASI assessments at the evaluated time points were included in this analysis. Shifts in F-VASI and T-VASI were assessed among patients with no facial/body repigmentation or worsening depigmentation (≤0% improvement in F-VASI/T-VASI) and patients with limited facial/body repigmentation (>0%–<25% improvement in F-VASI/T-VASI) at Week 24.
Results
Among patients with no facial repigmentation at Week 24, improvements in F-VASI at Weeks 52 and 104 were observed in 77.8% (49/63) and 97.1% (34/35) of patients, respectively. Among patients with limited facial repigmentation at Week 24, F-VASI improvements at Weeks 52 and 104 were observed in 64.0% (32/50) and 83.3% (30/36) of patients, respectively. Across both groups, 54.9% (39/71) of patients achieved ≥75% improvement from baseline in F-VASI (F-VASI75) at Week 104. Among those with no body repigmentation at Week 24, T-VASI improvements at Weeks 52 and 104 were observed in 79.6% (39/49) and 93.3% (28/30) of patients, respectively. For those with limited body repigmentation at Week 24, T-VASI improvements at Weeks 52 and 104 were observed in 64.5% (80/124) and 81.6% (62/76) of patients, respectively. Across both groups who had <25% improvement in total body repigmentation at Week 24, 50.0% (53/106) of patients achieved ≥50% improvement in T-VASI (T-VASI50) at Week 104.
Conclusions
In the TRuE-V studies, ruxolitinib cream application for an additional 80 weeks resulted in improved repigmentation among patients with nonsegmental vitiligo who had limited or no repigmentation at Week 24. These 2-year TRuE-V results highlight the importance of prolonged treatment in patients with vitiligo, even when minimal or no repigmentation is achieved after 6 months of treatment.
Abstract
There are limited approved systemic treatment options for children with atopic dermatitis (AD). Dupilumab is now approved in the United States for patients 6 months and older with ...moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies. European Medicines Agency is evaluating the use of dupilumab in children aged 6 months through 5 years with severe AD only. To report the efficacy and safety of dupilumab in the subgroup of children aged 6 months to 5 years with severe AD (IGA score = 4) at baseline in the LIBERTY AD PRESCHOOL trial (NCT03346434 part B). Patients aged 6 months to 5 years with inadequately controlled moderate-to-severe AD were enrolled in LIBERTY AD PRESCHOOL (part B), a randomized, double-blind placebo-controlled phase 3 study. Patients were randomized to either dupilumab 200/300 mg every 4 weeks (200 mg if baseline weight 5 to <15 kg, 300 mg if 15 to <30 kg) or placebo for 16 weeks. All patients initiated standardized treatment with low-potency topical corticosteroids (TCS) from day –14. This analysis reports efficacy and quality-of-life endpoints including a 75% reduction from baseline in the Eczema Area and Severity Index (EASI-75), Peak-Pruritus Numerical Rating Scale (PP-NRS), Children’s Dermatology Life Quality Index (CDLQI, for children aged 4 to <6 years), and Infant’s Dermatitis Quality Of Life (IDQOL, for children <4 years) in children with severe AD. Of the total trial population of 162 patients with moderate-to-severe AD, 125 patients with severe AD at baseline were randomized: 63 to the dupilumab + TCS treatment group and 62 to the placebo + TCS treatment group. Baseline demographics were similar. Mean (SD) baseline disease characteristics were also similar between the dupilumab and placebo groups: EASI (38.8 13.7 vs. 35.4 12), body surface area (63.1% 21 vs. 58.9% 21.4), weekly average PP-NRS (7.6 1.4 vs. 7.6 1.6), CDLQI (17.5 5.5 vs. 17.8 6.4) and IDQOL (18.4 5.1 vs. 17.4 5.4). Dupilumab treatment resulted in a rapid and significant increase in the proportion of patients achieving EASI-75 compared with placebo treatment by week 4 (27% vs. 4.8%; P = 0.0009). By week 16, this improvement was further increased compared with the placebo group (46% vs. 7%; P < 0.0001). At week 16, dupilumab-treated patients had a significantly greater percent reduction from baseline in PP-NRS compared with the placebo group (LS mean (SE)–41.8 5.4 vs. 0.5 5.4; P < 0.0001). Dupilumab also resulted in significant improvement in quality-of-life outcomes compared with placebo (LS mean SE) change from baseline to week 16 in CDLQI (−9.1 1.1 vs. −2.6 1.2; P < 0.0001); IDQOL (−9.1 1.3 vs. −0.6 1.1; P < 0.0001). Treatment-emergent adverse events (TEAEs) were reported in 42 (66.7%) patients in the dupilumab group and 45 (73.8%) patients in the placebo group. Most TEAEs were mild to moderate and deemed unrelated to the study drug by the investigator. The most common TEAE was atopic dermatitis in both the dupilumab group (10 15.9%) and placebo group (16 26.2%). Additionally, TEAEs in the conjunctivitis cluster were reported by 4 (6.4%) patients in the dupilumab group and none in the placebo group. In the placebo group, 3 (4.9%) serious adverse events were reported. No dupilumab-related adverse events were serious or led to treatment discontinuation. Dupilumab significantly improved AD signs, symptoms, and quality of life in children aged 6 months to 5 years with severe AD. The safety profile was consistent with that previously seen in adults, adolescents, and children aged > 6 years of age.
Introduction
Treatment options for children younger than 6 years with severe atopic dermatitis (AD) are limited, as systemic immunosuppressants may present safety concerns in this young age group. ...Dupilumab is the first systemic treatment option approved for infants and young children with severe AD in the European Union. This study reports the efficacy and safety of dupilumab with concomitant low-potency corticosteroids in children aged 6 months to 5 years with severe AD.
Methods
This was a pre-specified subgroup analysis of data for patients aged 6 months to 5 years with severe AD at baseline (Investigator’s Global Assessment IGA = 4) from a randomised, double-blind, placebo-controlled, phase III trial of dupilumab. Patients were randomised to either subcutaneously administered dupilumab (200/300 mg) or matched placebo every 4 weeks, plus low-potency topical corticosteroids for 16 weeks. Co-primary endpoints at week 16 were the proportion of patients with IGA ≤ 1 (clear or almost clear skin) and the proportion of patients with ≥ 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Secondary endpoints at week 16 included mean changes in EASI, pruritus, skin pain, sleep loss and quality of life.
Results
The analysis included 125 patients (63 receiving dupilumab vs. 62 placebo). At week 16, significantly more patients receiving dupilumab vs. placebo had achieved IGA ≤ 1 (14.3% vs. 1.6%;
P
= 0.0085) and EASI-75 (46.0% vs. 6.6%;
P
< 0.0001). Significant improvements with dupilumab were observed in all secondary endpoints, including a least squares mean 44.9% reduction in pruritus. The overall incidence of adverse events (AEs) was similar between the dupilumab and placebo groups (66.7% vs. 73.8%). No dupilumab-related AEs were serious or led to treatment discontinuation.
Conclusion
Dupilumab significantly improved AD signs, symptoms and quality of life in children aged 6 months to 5 years with severe AD with acceptable safety.
Trial Registration
The trial was registered with ClinicalTrials.gov with ID number NCT03346434, part B.
Plain Language Summary
Atopic dermatitis (AD) is a chronic skin disease that is relatively common in infants and young children worldwide. Severe AD causes skin rashes and intense itch that strongly interfere with sleep quality and normal daily activities, thereby affecting the quality of life of patients and their families. When therapies for AD that are applied to the skin do not work, limited options are available to treat severe AD in children younger than 6 years. In this study, we evaluated the efficacy and safety of dupilumab in children aged 6 months to 5 years with severe AD, recruited from various sites in Europe and North America. Patients received 200 or 300 mg of dupilumab (based on the child’s weight) or placebo, together with mild steroids applied to the skin, every 4 weeks for 16 weeks. At the end of treatment, AD severity was greatly improved in patients receiving dupilumab, with 14% of patients achieving almost clear skin. Patients receiving dupilumab also experienced significant improvements in itch intensity, sleep quality, skin pain, and quality of life. Furthermore, dupilumab did not increase the risk of infections. This study demonstrates that dupilumab can be effective at treating severe AD in infants and young children, with important benefits for the quality of life of patients and their families.
Background
Preliminary in vitro and in vivo studies have supported the efficacy of the peroxisome proliferator‐activated receptor‐γ (PPARγ) modulator N‐acetyl‐GED‐0507‐34‐LEVO (NAC‐GED) for the ...treatment of acne‐inducing sebocyte differentiation, improving sebum composition and controlling the inflammatory process.
Objectives
To evaluate the efficacy and safety of NAC‐GED (5% and 2%) in patients with moderate‐to‐severe facial acne vulgaris.
Methods
This double‐blind phase II randomized controlled clinical trial was conducted at 36 sites in Germany, Italy and Poland. Patients aged 12–30 years with facial acne, an Investigator Global Assessment (IGA) score of 3–4, and an inflammatory and noninflammatory lesion count of 20–100 were randomized to topical application of the study drug (2% or 5%) or placebo (vehicle), once daily for 12 weeks. The co‐primary efficacy endpoints were percentage change from baseline in total lesion count (TLC) and IGA success at week 12; the safety endpoints were adverse events (AEs) and serious AEs. This study was registered with EudraCT (2018‐003307‐19).
Results
Between Q1 in 2019 and Q1 in 2020 450 patients n = 418 (92·9%) IGA 3; n = 32 (7·1%) IGA 4 were randomly assigned to NAC‐GED 5% (n = 150), NAC‐GED 2% (n = 150) or vehicle (n = 150). The percentage change in TLC reduction was statistically significantly higher in both the NAC‐GED 5% –57·1%, 95% confidence interval (CI) –60·8 to –53·4; P < 0·001 and NAC‐GED 2% (–44·7%, 95% CI –49·1 to –40·1; P < 0·001) groups compared with vehicle (–33·9%, 95% CI –37·6 to –30·2). A higher proportion of patients treated with NAC‐GED 5% experienced IGA success (45%, 95% CI 38–53) vs. the vehicle group (24%, 95% CI 18–31; P < 0·001). The IGA success rate was 33% in the NAC‐GED 2% group (P = not significant vs. vehicle). The percentage of patients who had one or more AEs was 19%, 16% and 19% in the NAC‐GED 5%, NAC‐GED 2% and vehicle groups, respectively.
Conclusions
The topical application of NAC‐GED 5% reduced TLC, increased the IGA success rate and was safe for use in patients with acne vulgaris. Thus, NAC‐GED, a new PPARγ modulator, showed an effective clinical response.
What is already known about this topic?
Acne vulgaris, one of the most common dermatological diseases, affects more than 85% of adolescents.
There is a medical need for innovative and safe treatment of acne vulgaris.
The peroxisome proliferator‐activated receptor‐γ (PPARγ) is involved in lipid metabolism and specifically in cell differentiation, sebum production and the inflammatory reaction.
What does this study add?
N‐acetyl‐GED‐0507‐34‐LEVO (NAC‐GED 5%), a PPARγ modulator, significantly improves acne manifestations in patients with moderate‐to‐severe acne and is safe and well tolerated.
The results suggest that the PPARγ receptor is a novel therapeutic target for acne.
The results provide a basis for a large phase III trial to assess the effectiveness and safety profile of NAC‐GED in combating a disease that afflicts 80–90% of adolescents.
The topical application of NAC‐GED 5% reduced TLC, increased the IGA success rate and was safe for patients with acne vulgaris #10;‐ NAC‐GED, a new PPAR gamma; modulator, showed an effective clinical response.
Linked Comment: C. Dessinioti. Br J Dermatol 2022; 187:455–456.
Plain language summary available online
Atopic dermatitis (AD, also called atopic eczema) is a long-term skin disease that causes intensely itchy, red skin. Healthcare providers can prescribe medicated creams and ointments to reduce the ...signs and symptoms of AD. However, these treatments are not always enough to provide relief. A new medicine called abrocitinib, which is taken every day as a tablet, reduces part of the body's immune response that happens in AD. The clinical study described in this plain language summary, called JADE COMPARE, investigated how well and how safely 16 weeks of treatment with abrocitinib worked in adults with AD compared to placebo ('dummy treatment') and a medicine that is already approved for AD, called dupilumab. The study showed that abrocitinib was better than placebo in improving the signs and symptoms of AD after 16 weeks. In addition, patients who were taking abrocitinib 200 mg for 2 weeks experienced greater relief from itch than patients who were taking abrocitinib 100 mg, placebo, or dupilumab. More people who took abrocitinib 200 mg reported side effects than those taking abrocitinib 100 mg, placebo, or dupilumab, but most of these side effects were mild or moderate. ClinicalTrials.gov NCT number: NCT03720470.
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