A Phase 1, Randomized, Placebo-controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of CC-11050 After Single and Multiple Doses of CC-11050 and Evaluate CC-11050 Pharmacokinetics Under Fasted and Fed Conditions and After Administration of CC-11050 Alone Compared to Co-administration With a Proton Pump Inhibitor in Healthy Adult Subjects

This is a two-part study to be conducted at single study center, (additional center(s) may be selected if needed) to assess the safety, tolerability, PK and PD parameters for a new SDD formulation of CC-11050 in healthy subjects. The effects of a high-fat meal and omeprazole will also be assessed. Blood samples will be collected at prespecified times for PK, clinical laboratory safety assessments, PD (Part 1 only), and/or exploratory analyses. Safety will be monitored throughout the study from the time the ICF is signed through study completion.

开始日期2019-08-28

申办/合作机构

Amgen, Inc.

NCT03807362 / Recruiting临床2期IIT

A Single Center, Open Label Pilot Study to Evaluate the Safety and Efficacy of CC-11050 in Nepalese Patients With Erythema Nodosum Leprosum

This study will be a single center, Phase 2, open-label trial to evaluate the safety and efficacy of 200mg CC-11050 administered twice daily taken with food for patients with moderate to severe ENL. The study will be performed in two steps: 1) to evaluate immediate effect in safety and efficacy of drug in 10 males with new or new recurrent episode ENL and, if found to be safe and effective by the DSMB and 2) if allowed by the DSMB, and approved by relevant study stakeholders, an additional 40 ENL patients will be enrolled for up to 52 weeks of treatment. A safety analysis will be conducted on all patients who have received at least one dose of study drug, and will include the frequency of all adverse events and laboratory abnormalities as well as frequency of dose interruptions, dose reductions and treatment discontinuation.

开始日期2018-01-07

申办/合作机构

The Leprosy Mission International

NCT02968927 / Unknown status临床2期IIT

A Ph2 Randomized Trial to Evaluate the Safety Preliminary Efficacy and Biomarker Response of Host Directed Therapies Added to Rifabutin-modified Standard Therapy in Adults With Drug-Sensitive Smear-Positive Pulmonary TB

To examine the safety and preliminary efficacy of multiple adjunctive host directed TB therapies (TB HDT), to assess their potential to shorten TB treatment and/or prevent permanent lung damage.

开始日期2016-11-01

申办/合作机构

The Aurum Institute

100 项与 Dovramilast 相关的临床结果

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100 项与 Dovramilast 相关的专利（医药）

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项与 Dovramilast 相关的文献（医药）

2023-01-01·Frontiers in immunology

A phosphodiesterase-4 inhibitor reduces lung inflammation and fibrosis in a hamster model of SARS-CoV-2 infection.

Article

作者: Ramasamy, Santhamani ; Kaplan, Gilla ; Kumar, Ranjeet ; Nisa, Annuurun ; Subbian, Selvakumar ; Kolloli, Afsal

Introduction:

The Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infection involves pulmonary inflammation that can progress to acute respiratory distress syndrome, a primary cause of lung damage/fibrosis in patients with Coronavirus Disease-2019 (COVID-19). Currently, there is no efficacious therapy available to alleviate lung fibrosis in COVID-19 cases. In this proof-of-concept study, we evaluated the effect of CC-11050, a small molecule phosphodiesterase-4 inhibitor, in dampening lung inflammation and fibrosis in a hamster model of SARS-CoV-2 infection.

Methods:

Following intranasal inoculation with SARS-CoV-2/WA- 1/2000 strain, hamsters were treated with CC-11050 or placebo by gavage from day-1 until day-16 post-infection (dpi). Animals were monitored for body weight changes, virus titers, histopathology, fibrotic remodeling, cellular composition in the lungs between 2 and 16 dpi.

Results:

We observed significant reduction in lung viral titer with concomitant reduction in inflammation and fibrotic remodeling in CC-11050 treated hamsters compared to untreated animals. The reductions in immunopathologic manifestations were associated with significant downregulation of inflammatory and fibrotic remodeling gene expression, reduced infiltration of activated monocytes, granulocytes, and reticular fibroblasts in CC-11050 treated animals. Cellular studies indicate a link between TNF-α and fibrotic remodeling during CC-11050 therapy.

Discussion:

These findings suggest that CC-11050 may be a potential host-directed therapy to dampen inflammation and fibrosis in COVID-19 cases.

2021-08-01·The Lancet. Respiratory medicine1区 · 医学

Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial

1区 · 医学

Article

作者: Morongwe Likoti ; Trevor Beattie ; Sibuse Ginindza ; Nishanee Arjun ; Bintou A Ahidjo ; Mboyo D T Vangu ; Khatija Ahmed ; Katherine Fielding ; Robert S Wallis ; Mohammed Rassool ; Gavin Churchyard ; Vinodh A Edward

BACKGROUND:

Current tuberculosis treatments leave patients with clinically significant lung injury and increased all-cause mortality post-cure. Adjunctive host-directed therapies could protect the lungs, improve long-term survival, and shorten treatment duration; however, few have been tested clinically. Therefore, we aimed to assess the safety and preliminary efficacy of four host-directed therapies for tuberculosis.

METHODS:

In this prospective, open-label, phase 2, randomised controlled trial, patients with pulmonary tuberculosis were recruited at three clinical sites in South Africa. Eligible patients were aged 18-65 years, HIV-1-negative, and had rifampicin-susceptible Mycobacterium tuberculosis, a sputum Xpert cycle threshold of less than 20, and moderately advanced or far advanced disease on chest radiography. By use of numbers generated in blocks of ten and stratification by site, eligible patients were randomly assigned (1:1:1:1:1) to receive one of the four oral host-directed treatments plus standard tuberculosis treatment or standard treatment alone (the control group). Host-directed treatments were: CC-11050 (200 mg twice daily, taken with food; day 1-112); everolimus (0·5 mg/day; day 1-112); auranofin (3 mg/day for seven doses, then 6 mg/day; day 1-112); and ergocalciferol (5 mg on day 1, then 2·5 mg on day 28 and day 56). All study participants received oral rifabutin-substituted standard tuberculosis treatment for 180 days. Patients and clinicians were not masked to treatment assignment. Spirometry and sputum culture with solid and liquid media were done at baseline and up to 180 days at specified intervals throughout treatment. The primary endpoint was safety and tolerability up to day 210. Secondary preliminary efficacy endpoints were treatment effects on sputum microbiology (culture status at day 56 and the hazard ratio for stable culture conversion up to day 180) and lung function (FEV₁ and forced vital capacity [FVC]) measured by spirometry at day 56, day 180, and day 540. Safety was analysed in the intention-to-treat population and preliminary efficacy primarily in the per-protocol population. The trial is registered at ClinicalTrials.gov, NCT02968927. Post-treatment follow-up was completed in 2020.

FINDINGS:

Between Nov 18, 2016, and Sept 27, 2018, 200 patients were screened and randomly assigned to different treatment groups (n=40 per group, apart from n=39 in the everolimus group after one patient withdrew consent). 11 treatment-emergent serious adverse events occurred either during treatment or within 30 days after treatment discontinuation, of which three were attributable to a host-directed treatment. Life-threatening thrombocytopenia occurred in an auranofin recipient; apparent intra-abdominal sepsis leading to death occurred in another auranofin recipient and was classified as a suspected unexpected serious adverse reaction. Tuberculous spondylitis occurred as an apparent paradoxical reaction in a patient receiving ergocalciferol. Two patients in the control group had life-threatening, treatment-attributable liver injury. No treatment-emergent, treatment-attributable serious adverse events occurred in patients receiving CC-11050 or everolimus. Mean FEV₁ in the control group was 61·7% of predicted (95% CI 56·3-67·1) at baseline and 69·1% (62·3-75·8) at day 180. Patients treated with CC-11050 and everolimus had increased recovery of FEV₁ at day 180 relative to the control group (mean difference from control group 6·30%, 95% CI 0·06-12·54; p=0·048; and 6·56%, 0·18-12·95; p=0·044, respectively), whereas auranofin and ergocalciferol recipients did not. None of the treatments had an effect on FVC during 180 days of follow-up or on measures of sputum culture status over the course of the study.

INTERPRETATION:

CC-11050 and everolimus were safe and reasonably well tolerated as adjunctive therapies for tuberculosis, and analysis of preliminary efficacy suggests they might also enhance the recovery of FEV₁, a key measure of lung function and predictor of all-cause mortality. Further studies of these candidates are warranted.

FUNDING:

The Bill & Melinda Gates Foundation and the South African Medical Research Council.

2019-06-01·Open forum infectious diseases

A Phase I, Randomized, Controlled Clinical Study of CC-11050 in People Living With HIV With Suppressed Plasma Viremia on Antiretroviral Therapy (APHRODITE)

Article

作者: Kibiy, Angela ; Laidlaw, Elizabeth ; Lumbard, Keith ; Poole, April ; Gabriel, Erin ; Arakawa, Ken ; Gorelick, Robert J ; Khetani, Vikram ; Boulougoura, Afroditi ; Sereti, Irini ; Kumar, Princy ; Rupert, Adam ; Pau, Alice ; Higgins, Jeanette

Abstract:

Objective:

Phosphodiesterase 4 inhibitors (PDE4i) are novel anti-inflammatory medications that have been approved for rheumatologic diseases and have been tested as host-directed therapy in tuberculosis. We examined the safety of CC-11050, a potent PDE4i in people living with HIV (PLWH) with suppressed HIV plasma viremia. We hypothesized that CC-11050 could be used to modulate HIV-related inflammation.

Method:

Thirty PLWH on antiretroviral therapy (ART) ≥ 1 year with suppressed HIV viremia were enrolled and randomized 2:1 to 12 weeks of CC-11050 200mg twice daily or placebo with follow-up at weeks 2, 4, 8, 12, and 16. Primary endpoint was safety. Secondary endpoints were the effect of CC-11050 on cytokines, monocyte, and T-cell activation and potential pharmacokinetic interaction between CC-11050 and Efavirenz (EFV).

Results:

At baseline, median age was 49.5 years and CD4 count 459 cells/µL. Most frequent adverse events (grade 1 and 2 only) in CC-11050 group were headache, diarrhea, nausea, cough, nasal congestion, and restlessness. Over a 12-week period, the CC-11050 group had lower level of IL-8, adjusted for baseline level, group, and week (0.72-fold, P = .02), lower percentage of NK cells (0.87-fold, P = .02) and higher IL-6 level (1.48-fold, P = .03) compared to placebo (0.87-fold, P = .02). CC-11050 and EFV co-administration did not reveal any pharmacokinetic interaction.

Conclusions:

CC-11050 was well tolerated in PLWH, without affecting CD4 counts or plasma viremia, and led to a decrease in NK cells and plasma IL-8 level after 12-weeks of administration. Further study will be needed to elucidate the efficacy of CC-11050 as potential anti-inflammatory adjuvant strategy in HIV.

项与 Dovramilast 相关的新闻（医药）

2023-08-13

·医药观澜

华东医药、信达生物、安进等看好，PDE4抑制剂有何治疗潜力？

▎药明康德内容团队报道磷酸二酯酶-4（PDE4）是一种细胞内酶，可增加促炎介质的生成并减少抗炎介质的生成，抑制它可减轻炎症反应。因此，PDE4抑制剂具有治疗多种炎症性疾病的潜力，包括银屑病、神经炎症、慢性阻塞性肺病、哮喘、强直性脊柱炎、炎症性肠病、特应性皮炎、类风湿关节炎、系统性红斑狼疮等。PDE4抑制剂的治疗潜力也得到了行业的青睐。近年来，已有多家公司就PDE4抑制剂达成收购或合作。就在8月10日，华东医药全资子公司中美华东与Arcutis Biotherapeutics宣布签署许可协议，中美华东获得了后者PDE4抑制剂罗氟司特外用制剂在大中华区及东南亚的独家许可。而在此之前，安进（Amgen）、辉瑞（Pfizer）、阿斯利康（AstraZeneca）、信达生物等公司也已通过合作或收购开发PDE4抑制剂。本文将根据公开资料分享8款PDE4抑制剂的授权合作或收购信息，看看这些药物都具有治疗哪些疾病的潜力。图片来源：123RF引进方：华东医药授权方：Arcutis Biotherapeutics产品：罗氟司特2023年8月，华东医药全资子公司中美华东与Arcutis Biotherapeutics宣布签署产品独家许可协议。中美华东将获得新一代PDE4抑制剂罗氟司特2种外用制剂在大中华区及东南亚的独家许可。其中，Zoryve乳膏（0.3%）已于2022年7月获得美国FDA批准，用于治疗12岁及以上患者的斑块状银屑病。ARQ-154泡沫剂（0.3%）的新药上市申请已于2023年4月获FDA受理，用于治疗9岁及以上患者的脂溢性皮炎。根据协议条款，Arcutis公司将获得3000万美元的首付款，不超过6425万美元的注册及销售里程碑付款和分级两位数的净销售额提成费。引进方：济川药业授权方：恒翼生物产品：口服PDE4抑制剂2022年11月，济川药业宣布与恒翼生物签署合作协议，就后者口服PDE4抑制剂等2款创新药在中国大陆地区达成商业化战略合作，涉及总金额约为4亿元。根据济川药业当时发布的新闻稿，此次引进的PDE4抑制剂具有对PDE4靶点特异选择性和低中枢神经系统渗透性的特点和优势，即将进入临床3期阶段。根据中国药物临床试验登记与信息公示平台，目前恒翼生物正在开展一项多中心、随机、双盲、安慰剂对照3期临床试验，以评价PDE4抑制剂HPP737治疗中重度斑块型银屑病成人患者的有效性和安全性。引进方：信达生物授权方：UNION therapeutics产品：orismilast2021年9月，信达生物与UNION therapeutics宣布就后者用于治疗炎症性皮肤病的PDE4抑制剂orismilast达成在中国的独家授权协议。为此，UNION公司将收到2000万美元的首付款，并有权获得累计不超过2.47亿美元的里程碑付款等。公开资料显示，orismilast是一种强效和高选择性的下一代PDE4抑制剂，具有广泛的抗炎特性。它对PDE4亚型B和D的高选择性和创新的缓释方法带来的优异的治疗窗口，预计会带来更好的抗炎效果和耐受性。根据中国药物临床试验登记与信息公示平台，一项评估IBI353在中国健康受试者中多次口服给药的1期研究已完成。引进方：优锐医药授权方：Verona Pharma产品：ensifentrine2021年6月，优锐医药通过一项2.19亿美元的战略合作，获得了在大中华区开发和商业化Verona Pharma在研的一款吸入式PDE3/4双抑制剂新药ensifentrine（RPL554）的独家权利。该产品的双重抑制机理使其能够凭借单个化合物同时实现支气管扩张和抗炎效果。Ensifentrine还能激活囊状纤维化跨膜转导调节子（CFTR），这有利于降低粘液粘度和改善粘膜纤毛清除。根据中国药物临床试验登记与信息公示平台，目前一项随机、双盲、安慰剂对照3期临床研究正在进行中，以评价该产品在中度至重度慢性阻塞性肺疾病患者中给药24周的有效性和安全性。图片来源：123RF引进方：安进授权方：新基（Celgene）产品：阿普米司特2019年8月，安进宣布以134亿美元的价格收购口服小分子PDE4抑制剂阿普米司特（Otezla）。阿普米司特最初由百时美施贵宝旗下新基研发，通过剂量依赖性抑制人类滑膜细胞释放肿瘤坏死因子（TNF）-α而发挥作用。该药已在海外获批多项适应症，包括中度至重度斑块型银屑病、活动性银屑病关节炎、与白塞病相关的口腔溃疡等。在中国，阿普米司特已被纳入第一批临床急需境外新药名单，并曾被纳入优先审评。2021年8月，该药也在中国获批治疗银屑病。值得一提的是，2022年6月，复星医药与安进宣布已就阿普米司特片在中国大陆的商业化授权许可达成合作。引进方：MDGH公司授权方：安进产品：AMG 634AMG 634是安进从新基收购的一款PDE4抑制剂。2020年12月，安进和Medicines Development for Global Health（MDGH）宣布就PDE4抑制剂AMG 634（CC-11050）签订许可协议。该项合作后，MDGH公司将全权负责AMG 634的进一步开发和商业化。目前，该产品正在被开发用于治疗结核病（TB）和麻风结节性红斑（ENL），这是麻风的一种炎症性皮肤和全身并发症。根据ClinicalTrials网站，目前AMG 634已进入2期临床试验阶段。引进方：辉瑞授权方：Anacor公司产品：克立硼罗软膏2016年5月，辉瑞以52亿美元收购了Anacor公司，从而获得后者PDE4抑制剂局部外用克立硼罗软膏（Eucrisa，crisaborole）。克立硼罗是一款新型的小分子、非激素、非甾体类抗炎的PDE4抑制剂，该药曾被列入中国《第二批临床急需境外新药》。2020年7月，克立硼罗2%软膏剂在中国获批，用于2岁及以上轻度至中度特应性皮炎患者的局部外用治疗。今年8月，该产品在中国获批扩大适应症至3月龄及以上轻度至中度特应性皮炎患者的局部治疗。引进方：阿斯利康授权方：武田（Takeda）产品：roflumilast2016年5月，阿斯利康宣布已完成对武田呼吸系统核心业务的收购，以扩大包括口服PDE4抑制剂roflumilast的权利。根据此前协议条款，阿斯利康将支付5.75亿美元。此前，罗氟司特已在海外被批准用于治疗慢性阻塞性肺疾病。自2015年第一季度收购Actavis公司以来，阿斯利康一直在美国销售roflumilast（美国商品名Daliresp）。希望科学家在PDE4抑制剂研发领域取得更多突破，早日为更多炎症性疾病患者带来新的治疗选择。参考资料：（可上下滑动查看） [1]华东医药宣布与美国Arcutis公司就罗氟司特外用制剂在大中华区和东南亚国家签署独家战略合作协议. Retrieved Aug 11, 2023. From https://mp.weixin.qq.com/s/uU_rcqixIvPTDVT6J9aNbg[2]Verona Pharma 和优锐医药宣布开展2.19亿美元的战略合作，在大中华区开发和商业化Ensifentrine. Retrieved Jun 10 , 2021. From https://www.prnasia.com/story/321878-1.shtml[3] 信达生物与UNION therapeutics达成战略合作，引进用于治疗炎症性皮肤病的下一代PDE4抑制剂. Retrieved Sep 28，2020, from https://www.prnasia.com/story/334369-1.shtml[4]复星医药与安进达成合作以加速两款创新药物惠及中国患者. Retrieved Jun 27, 2022. From https://mp.weixin.qq.com/s/HolomUMYK36UVYtoeSLpXg[5]剑指千亿市场！济川药业与恒翼生物达成4亿元项目合作. Retrieved Nov 07, 2022. From https://mp.weixin.qq.com/s/Fixf206I3qZlXlEr7tB_qA[6] Amgen To Acquire Otezla® For $13.4 Billion In Cash, Or Approximately $11.2 Billion Net Of Anticipated Future Cash Tax Benefits. received Aug, 26th from http://investors.amgen.com/news-releases/news-release-details/amgen-acquire-otezlar-134-billion-cash-or-approximately-112[7]Pfizer adds eczema drug with $5.2bn Anacor acquisition.Retrieved May 17,2016.from http://www.pmlive.com/pharma_news/pfizer_adds_eczema_drug_with_$5.2bn_anacor_acquisition_1023628[8]AstraZeneca to strengthen therapy area franchise through acquisition of Takeda’s respiratory business. Retrieved Dec 16, 2015. From https://www.astrazeneca.com/media-centre/press-releases/2015/AstraZeneca-to-strengthen-therapy-area-franchise-through-acquisition-of-Takedas-respiratory-business-16122015.html#[9]AstraZeneca completes acquisition of Takeda’s respiratory business. Retrieved May 16, 2016. From https://www.astrazeneca.com/media-centre/press-releases/2016/astrazeneca-completes-acquisition-of-takedas-respiratory-business.html#[10]Amgen Licenses AMG 634, An Investigational Treatment For Tuberculosis And Leprosy, To Medicines Development for Global Health. Retrieved Dec 12, 2020. From本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
麻风	临床2期	澳大利亚	Medicines Development for Global Health Ltd	2022-08-09
类圆线虫病	临床2期	澳大利亚	Medicines Development for Global Health Ltd	2022-08-09
结核	临床2期	澳大利亚	Medicines Development for Global Health Ltd	2022-08-09
盘状红斑狼疮	临床2期	美国	Amgen, Inc.	2010-10-01
皮肤红斑狼疮	临床2期	-	Celgene Corp.	-
HIV感染	临床1期	美国	National Institute of Allergy & Infectious Diseases	2018-01-01
HIV感染	临床1期	美国	Leidos, Inc.	2018-01-01
虱病	临床前	澳大利亚	Medicines Development for Global Health Ltd	2022-08-09