B. Shumel

Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial

BACKGROUND Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis. METHODS In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigators Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986. FINDINGS Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids. INTERPRETATION Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety. FUNDING Sanofi and Regeneron Pharmaceuticals Inc.

Dupilumab with concomitant topical corticosteroids in adult patients with atopic dermatitis who are not adequately controlled with or are intolerant to ciclosporin A, or when this treatment is medically inadvisable: a placebo-controlled, randomized phase 3 clinical trial (LIBERTY AD CAFÉ)

Atopic dermatitis is a chronic inflammatory skin disease that may require systemic therapy. Ciclosporin A (CsA) is a widely used, potent immunosuppressant but it is not effective in all patients with atopic dermatitis, and side‐effects limit its use. Dupilumab, a fully human anti‐interleukin 4 receptor‐alpha monoclonal antibody, inhibits signaling of IL‐4 and IL‐13, key drivers of Type 2/Th2‐mediated inflammation, and is approved in the U.S.A. and the European Union for the treatment of inadequately‐controlled moderate‐to‐severe atopic dermatitis in adults.

Inhaled Technosphere Insulin Versus Inhaled Technosphere Placebo in Insulin-Naïve Subjects With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetes Agents.

OBJECTIVE To investigate the efficacy and safety of prandial Technosphere inhaled insulin (TI), an inhaled insulin with a distinct time action profile, in insulin-naïve type 2 diabetes (T2D) inadequately controlled on oral antidiabetes agents (OADs). RESEARCH DESIGN AND METHODS Subjects with T2D with HbA1c levels ≥7.5% (58.5 mmol/mol) and ≤10.0% (86.0 mmol/mol) on metformin alone or two or more OADs were randomized to add-on prandial TI (n = 177) or prandial Technosphere inhaled placebo (TP) (n = 176) to their OAD regimen in this double-blind, placebo-controlled trial. Primary end point was change in HbA1c at 24 weeks. RESULTS TI significantly reduced HbA1c by −0.8% (−9.0 mmol/mol) from a baseline of 8.3% (66.8 mmol/mol) compared with TP −0.4% (−4.6 mmol/mol) (treatment difference −0.4% [95% CI −0.57, −0.23]; P < 0.0001). More TI-treated subjects achieved an HbA1c ≤7.0% (53.0 mmol/mol) (38% vs. 19%; P = 0.0005). Mean fasting plasma glucose was similarly reduced in both groups. Postprandial hyperglycemia, based on 7-point glucose profiles, was effectively controlled by TI. Mean weight change was 0.5 kg for TI and −1.1 kg for the TP group (P < 0.0001). Mild, transient dry cough was the most common adverse event, occurring similarly in both groups (TI, 23.7%; TP, 19.9%) and led to discontinuation in only 1.1% of TI-treated and 3.4% of TP-treated subjects. There was a small decline in forced expiratory volume in 1 s in both groups, with a slightly larger decline in the group receiving TI (TI, −0.13 L; TP, −0.04 L). The difference resolved after treatment discontinuation. CONCLUSIONS Prandial TI added to one or more OADs in inadequately controlled T2D is an effective treatment option. Mild, transient dry cough was the most common adverse event.

杜匹鲁单抗结合伴随性局部皮质类固醇治疗对环孢素A应答不充分或不耐受或者在医学上不建议采用环孢素A治疗的过敏性皮肤炎成人患者:安慰剂对照随机阶段III临床试验(LIBERTY AD CAFÉ)

过敏性皮肤炎(又称为AD或湿疹)是一种导致身体大部分皮肤出现瘙痒皮疹的慢性皮肤病,10名成人中就有一名患者。环孢素是常用于AD的口腔治疗药物(口服),药效不稳定,并且有严重的副作用。有时也会使用其他广泛有效的口腔药物,但这些药物未经批准用于AD。杜匹鲁单抗是一种新药物,在很多国家或地区被批准用于控制不足的中度到重度AD成人患者。杜匹鲁单抗专门作用于促进AD的身体通道。欧洲的研究人员评估了杜匹鲁单抗注射对于改善需要环孢素治疗AD,但环孢素无效果、环孢素会导致无法忍受的副作用或者医疗状况不允许使用该药物的患者的皮疹、瘙痒和日常生活的效果。在325名参与者中,110名参与者每周使用一次300 mg杜匹鲁单抗,107名参与者每两周使用一次,其余108名参与者每周使用一次安慰剂(无效药物)。在16周研究期内,所有参与者均使用了局部(用于皮肤)皮质类固醇。杜匹鲁单抗改善了AD皮疹:在第0周,参与者的湿疹面积和严重指数(EASI)分数约为31(范围:0~72),但到了第16周,使用杜匹鲁单抗的参与者中有59%到62%的人的EASI改善了至少75%,而安慰剂组参与者仅改善了29.6%。杜匹鲁单抗还改善了瘙痒、其他症状、情绪和生活质量。结膜炎和注射点反应在使用杜匹鲁单抗的患者中更频繁;皮肤感染(不包括疱疹)和AD恶化则在安慰剂组中更频繁。作者得出结论,杜匹鲁单抗结合局部皮质类固醇可显著改善AD病情,甚至是对于之前治疗失败或者无法使用环孢素的患者。

Could conjunctivitis in patients with atopic dermatitis treated with dupilumab be caused by colonization with Demodex and increased interleukin-17 levels?: reply from the authors

DEAR EDITOR, de Bruin-Weller et al. reported alarmingly high rates of unspecified and allergic conjunctivitis in trial patients with moderate-to-severe atopic dermatitis (AD) who underwent treatment with dupilumab, an antibody that inhibits signalling of interleukin (IL)-4 and IL-13. Importantly, the exact pathogenic mechanism behind incident conjunctivitis in patients treated with dupilumab is unclear. Although all but one case were considered to be of mild or moderate severity, and most resolved after treatment discontinuation, ocular complications may ultimately deprive patients with AD from effective treatment with dupilumab. For this reasons, the medical community needs to identify the pathogenic mechanism rapidly. Normal facial skin is often colonized with harmless arthropods (Demodex folliculorum and Demodex brevis), which reside and consume sebum in the cutaneous and ocular hair follicles. Mite numbers increase with age, but are dramatically elevated in rosacea, where they may contribute to skin and ocular disease through bacteria and toxin release following death. This may in turn result in local inflammation, abnormal lipid composition of the tear film, increased evaporation from the ocular surface, dryness and conjunctivitis. Interestingly, cutaneous and ocular inflammation in rosacea seems to be IL-17 mediated. Useful treatments include eyelid hygiene, lubrication of the ocular surface, topical ciclosporin and oral doxycycline. Dupilumab inhibits T helper (Th) cell 2 signalling through IL-4 receptor alpha blockade, which in turn may comprise the immune response against helminth infections. It is therefore possible that Demodex mites thrive in an IL-4 and IL-13 deprived cytokine milieu. Accordingly, Demodex mites rapidly colonized genetically modified mice (BALB/c-IL13/IL4) with impaired Th 2 response. At least in theory, dupilumab treatment could increase Demodex numbers in hair follicles, cause Meibomian gland dysfunction and ocular rosacea-like disease driven by IL-17 inflammation. Il-17 blocking biologicals should then theoretically benefit these patients. It remains unknown why conjunctivitis is not a similar problem in patients with asthma receiving dupilumab therapy; however, this finding may be explained by AD being a skin condition. Thus, mites preferably colonize skin with low hydration and high pH, which is often the case in AD.