Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known

ДЕРЖАВНА ПІДТРИМКА АГАРНОГО СЕКТОРУ ТА ЇЇ ВПЛИВ НА ФОРМУВАННЯ РЕЗУЛЬТАТИВНИХ ПОКАЗНИКІВ ДІЯЛЬНОСТІ ПІДПРИЄМСТВ ГАЛУЗІ

The financial support of agricultural producers at the expense of the state budget according to the of programs and regional peculiarities was analyzed. It was proved that the efficiency of activity at agricultural enterprises under modern conditions of management was impossible without an effective mechanism of state support. In Ukraine, it is implemented through programs financing envisaged by the legislation. The main ones are financial support of measures in the agro-industrial complex by reducing the cost of loans; development of farms; hop growing, laying of young gardens, vineyards and berry plantations and care of them; livestock raising. State support for agricultural producers is not only unstable but also significantly lower than that in Europe. In addition, the complexity and imperfection of the preparation process, the filing of documents and making a decision as to the payment of support led to the fact that not all amounts provided by the Law of Ukraine "About the Budget of Ukraine" are used. Therefore, a very small number of farming entities can use state funds, and farms of population i.e. individuals, are only able to receive a special budget subsidy for young cattle raising. Due to the artificial selection of enterprises that receive budget support, small and medium farms lose the prospect of further development. The above mentioned factors cause distortion in the objectives of state support for agriculture and do not contribute to the dynamic and stable development of the industry.The analysis of the used state support amount in the context of the administrative-territorial regions of Ukraine allowed to reveal a significant variation in its indices value per hectare of agricultural land and one agricultural enterprise that functioned during the research period. In addition, there was an uneven distribution of the state financial support amount concerning the regions with a share ranging from 28,7% to 1,2%. The calculated coefficients of pair correlation allowed us to conclude that the amounts of financial state support and the gross output of agricultural products at constant prices were closely interrelated.Осуществлен анализ финансовой поддержки сельскохозяйственных товаропроизводителей за счет средств государственного бюджета в разрезе программ и региональных особенностей. В Украине она реализуется через финансирование совокупности программ, предусмотренных законодательством. Государственная поддержка сельскохозяйственных товаропроизводителей не только не стабильная, но и значительно ниже по сравнению со странами Европы. Достаточно незначительное количество субъектов хозяйствования могут воспользоваться государственными средствами.Анализ сумм использованной государственной поддержки в разрезе областей Украины позволил выявить значительную вариацию показателей ее величины в расчете на 1 га сельскохозяйственных угодий и 1 сельскохозяйственное предприятие, осуществлявшее свою деятельность в период исследования. Рассчитанные коэффициенты парной корреляции позволили сделать вывод, что суммы финансовой государственной поддержки и валовое производство продукции сельского хозяйства в постоянных ценах находятся в тесной прямой зависимости.Здійснено аналіз фінансової підтримки сільськогосподарських товаровиробників за рахунок коштів державного бюджету в розрізі програм і регіональних особливостей. Доведено, що ефективна діяльність сільськогосподарських підприємств у сучасних умовах господарювання не можлива без дієвого механізму державної підтримки. В Україні він реалізується через фінансування сукупності програм, передбачених законодавством, основними з них є фінансова підтримка: заходів в агропромисловому комплексі шляхом здешевлення кредитів; розвитку фермерських господарств; розвитку хмелярства, закладення молодих садів, виноградників та ягідників і догляд за ними; тваринництва. Державна підтримка сільськогосподарських товаровиробників є не лише нестабільною, а й значно нижчою порівняно з країнами Європи. Крім того, складність і недосконалість процесу підготовки, подання документів та ухвалення рішення щодо виплати підтримки призвела до того, що не всі суми, передбачені Законом України «Про бюджет України», використовуються. Тому досить незначна кількість суб’єктів господарювання мають змогу скористатися державними коштами, а господарства населення, тобто фізичні особи, мають змогу отримати лише спеціальну бюджетну дотацію на вирощування молодняку великої рогатої худоби. Як наслідок, середні й малі господарства перебувають у нерівних умовах із великотоварними виробниками і втрачають перспективу подальшого розвитку.Аналіз сум використаної державної підтримки в розрізі адміністративно-територіальних областей України дозволив виявити значну варіацію показників її величини в розрахунку на 1 га сільськогосподарських угідь та 1 сільськогосподарське підприємство, що здійснювало свою діяльність у період дослідження. Крім того, спостерігається нерівномірність розподілу сум державної фінансової підтримки в розрізі областей, частка яких коливається від 28,7 до 1,2 %. Розраховані коефіцієнти парної кореляції дозволили зробити висновок, що суми фінансової державної підтримки і валове виробництво продукції сільського господарства в постійних цінах перебувають у тісній прямій залежності

Efficacy and safety of ingenol disoxate gel in field treatment of actinic keratosis on full face, scalp or large area (250 cm2) on the chest: results of four phase 3 randomized controlled trials

Introduction: Actinic keratosis (AK) is a skin condition arising from chronic exposure to ultraviolet light and may lead to the development of malignancies. This trial aimed to evaluate efficacy and safety of ingenol disoxate gel (IngDsx, 0.018% for face/chest [FC]; 0.037% for scalp [S]), versus vehicle. Methods: Four identical phase 3 trials in patients with AK on the full face/up to 250cm2 of chest or full balding scalp, with an initial 8-week period and 12-month follow-up, were conducted. FC and S trials were pooled for analysis. The primary endpoint was complete clearance at Week 8. Results: Across trials, 616 patients were randomized to FC and 626 to S, with 410 and 420 assigned to receive IngDsx, respectively. In the FC and S trials, 25.9% and 24.5% of patients in the IngDsx group, respectively, achieved the primary endpoint. IngDsx was relatively well tolerated. During extended follow-up, there were more identified non-melanoma skin malignancies in the IngDsx group than vehicle group; HR: 2.38 (95% CI: 1.28, 4.41). Conclusion: Treatment with IngDsx was superior to vehicle on all clinical endpoints, patient-reported and cosmetic outcomes. During the 12-month follow-up, slightly increased skin malignancies in the treatment area were identified, potentially due to unintentional detection bias

Usability of a novel disposable autoinjector device for ixekizumab: results from a qualitative study and an open-label clinical trial, including patient-reported experience

Kristina Callis Duffin,1 Michael Bukhalo,2 Margaret A Bobonich,3 David Shrom,4 Fangyi Zhao,4 James R Kershner,4 Anne Gill,4 Beth Pangallo,4 Catherine L Shuler,4 Jerry Bagel5 1Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, 2Arlington Dermatology, Arlington Heights, IL, 3CWRU Schools of Medicine and Nursing, Case Western Reserve University Cleveland, OH, 4Lilly Research Labs, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 5Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ, USA Background: Most biologic therapies for psoriasis are delivered via subcutaneous injection. Ixekizumab, an anti-interleukin 17A monoclonal antibody approved for patients with moderate-to-severe plaque psoriasis, is delivered subcutaneously via prefilled syringe or autoinjector. Here we report the results of an ixekizumab autoinjector usability study as well as the patient-reported experience with the autoinjector in a clinical trial. Methods: The usability study enrolled 49 subjects (patients with a range of autoimmune conditions or their caregivers). Subjects were randomized to a trained or untrained group and were evaluated for their ability to perform an injection successfully when provided the device and the instructions for use. In the clinical trial, 102 subjects (patients with psoriasis or their caregivers) used the autoinjector to deliver injections of ixekizumab (80 mg every 2 weeks after a starting dose of 160 mg). At weeks 0, 4, and 8, subjects completed the subcutaneous administration assessment questionnaire, which assesses the ease of use and confidence with using an injection device. Results: In the usability study, all subjects in the untrained arm performed successful injections, while two subjects in the trained arm had an injection failure. These incidences were not consistent with any pattern of issues with the device or the instructions for use. In the clinical trial, there were two injection failures of 674 total self-injections performed over 12 weeks. At the first use of the device, 95% of subjects either agreed or strongly agreed that the device was &ldquo;overall easy to use&rdquo;, and they felt &ldquo;confident the dose was complete&rdquo; according to the subcutaneous administration assessment questionnaire. Conclusion: The ixekizumab autoinjector was used successfully by patients and caregivers with or without training. Subjects using the autoinjector in a clinical trial felt it was easy to use and felt confident while using it. Trial Registration: NCT01777191. Keywords: ixekizumab, autoinjector, ease of use, usability, confidenc

Efficacy of Roflumilast Foam, 0.3%, in Patients With Seborrheic Dermatitis: A Double-blind, Vehicle-Controlled Phase 2a Randomized Clinical Trial

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 \u3c .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 \u3c .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