Quabodepistat

Public-private partnership launched a first-of-its-kind phase 2b/c trial to evaluate two novel tuberculosis drug regimens with the potential to treat all forms of active pulmonary TB SEATTLE, Aug. 9, 2023 /PRNewswire/ -- The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) collaboration announced today the start of a phase 2b/c clinical trial, sponsored by the Bill & Melinda Gates Medical Research Institute (Gates MRI). The trial will evaluate whether novel regimens that combine registered products and new chemical entities have the potential to effectively treat drug-sensitive TB (DS-TB) and inform the development of a "pan-TB" regimen capable of treating all forms of active pulmonary TB. Public-private partnership launches first-of-its-kind phase 2b/c trial to evaluate two novel tuberculosis drug regimens The regimens under evaluation are designed to explore shorter treatment durations compared to existing drug regimens, without the need for accompanying drug-resistance testing for individuals. The goal is to identify a candidate regimen suitable for phase 3 development. Trial sites are being hosted in countries with a high burden of TB. The trial has started in South Africa with the first participant screened in the last week of July. Subsequent trial sites are expected to launch in the Philippines in August and in Peru in 2024, pending national approvals. The collaboration is evaluating two novel drug regimens comprising five antibacterial agents—bedaquiline, delamanid, pretomanid, quabodepistat (formerly known as OPC-167832), and sutezolid: DBQS – delamanid, bedaquiline, quabodepistat and sutezolid PBQS – pretomanid, bedaquiline, quabodepistat and sutezolid The trial employs an innovative design that consists of two stages to assess the efficacy of the regimens and evaluate the potential to shorten treatment duration. In the initial stage, the trial will enroll approximately 129 participants. The safety, tolerability, efficacy, and pharmacokinetics of the complete DBQS and PBQS regimens, with each drug administered daily for four months (17 weeks), will be evaluated in participants 18 to 65 years old with DS pulmonary TB. Approximately 43 participants will receive the six-month (26 weeks) standard-of-care treatment for DS-TB1 in the countries where trial sites are located.2 If successful, the second stage will enroll approximately 400 participants to test the selected regimen at shorter treatment durations, ranging from two to four months, across five arms. An additional 30-40 participants will be enrolled in the standard-of-care arm for the second stage of this trial. To support participants during their treatment, the trial integrates a Stop Treatment and Watch (STrAW) Concilium, a group made up of expert clinical consultants that will evaluate trial participants' treatment response, blinded to the specific regimen they receive, and advise trial investigators on patient management. The trial will utilize the best available tools including regular engagement with treatment support workers, direct observation of therapy with video technology, and medication reminder monitors. A novel Biomarkers Strategy will inform promising new biomarkers with the aim of enabling faster access to data to monitor treatment outcomes for future trials. The need for novel TB treatment regimens Despite the introduction of new medicines in recent years, treatment remains a long, complex, and demanding process for people diagnosed with TB and can place significant costs on households and the health system. The most used drug regimen for the treatment of DS-TB requires people to take multiple drugs for at least six months, often with routine monitoring. TB treatment can place unmanageable financial strain on individuals and their households. The World Health Organization (WHO) estimates that nearly half of TB-affected households face catastrophic total costs associated with treatment, including costs of travel to clinics, loss of income during treatment, and more, fueling cycles of poverty in vulnerable communities. Further, accurate, rapid drug resistance testing is essential for early diagnosis of both drug-sensitive and drug-resistant TB, but access to testing can be limited due to high costs, technical challenges, and other barriers. Emilio Emini, PhD, CEO, the Bill & Melinda Gates Medical Research Institute, said: "The Bill & Melinda Gates Medical Research Institute is committed to developing biomedical interventions that address global health concerns for those in the greatest need. The team at the Gates MRI looks forward to working with our partners across the PAN-TB collaboration, to evaluate the potential of these novel TB treatment regimens, in the hope that it may offer a potentially easier pathway for all people diagnosed with pulmonary TB by offering well-tolerated, shorter and simpler treatment options." Masanori Kawasaki, Global TB Project Leader, Otsuka Pharmaceutical Co. Ltd, said: "We are immensely proud to be part of this remarkable, trailblazing, collaboration which is now launching a clinical trial for a new, and shorter, pan-TB treatment regimen. We are excited too to be working closely with key partners to bring new treatment options to patients. Otsuka is dedicated to life-saving research and development as demonstrated by our sustained hard work and investment in developing a new chemical entity called quabodepistat. We are most grateful to the Bill & Melinda Gates Medical Research Institute for bringing together leaders in the field of TB, towards the goal of ending TB for good." Ruxandra Draghia-Akli, MD, PhD, Global Head of Global Public Health R&D, Janssen Research & Development, LLC, said: "Our medicine for multidrug-resistant TB has reshaped TB treatment regimens over the past decade, but more must be done to develop the even shorter, simpler regimens needed to treat all forms of the disease and end TB once and for all. Today's milestone is another step in this direction, and we look forward to seeing the results of this important study." Mel Spigelman, MD, President and CEO of TB Alliance, said: "Sincere thanks and congratulations to all who have made this innovative and exciting new journey a reality. Bringing revolutionary, highly impactful new treatments to all TB patients around the world is a goal that deserves and requires all our concerted dedicated efforts." About the Project to Accelerate New Treatments for Tuberculosis The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) is a first-of-its-kind collaboration among philanthropic, non-profit and private sectors that aims to accelerate the development of an investigational drug regimen capable of treating all forms of tuberculosis. The PAN-TB collaboration leverages members' collective assets, resources and scientific expertise to identify and evaluate new drug regimens with an acceptable safety profile, that have the potential to treat both drug-sensitive and drug-resistant TB and are well-tolerated, shorter in duration and simpler to use than existing options. The collaboration focuses on advancing research through phase 2 clinical efficacy studies to identify promising regimens for further development. The PAN-TB collaboration plans to work closely and transparently with the European Regimen Accelerator for Tuberculosis (ERA4TB), which was launched in January 2020. New molecular entities identified by ERA4TB that show promise in initial human studies could later be incorporated into the PAN-TB collaboration's later-stage, clinical research. Several organizations, including Evotec, GSK, TB Alliance and Janssen Pharmaceutica NV, are members of both projects, which will help to ensure coordination across collaborations toward the common goal of advancing TB drug and regimen development. The members of the PAN-TB collaboration are Evotec, GSK, Janssen Pharmaceutica NV, Otsuka Pharmaceutical Co., Ltd., based in Japan, TB Alliance, the Bill & Melinda Gates Medical Research Institute and the Bill & Melinda Gates Foundation. Additional members may be announced in the future. Find out more at: . About Evotec SE Evotec is a life science company with a unique business model that delivers on its mission to discover and develop highly effective therapeutics and make them available to the patients. The Company's multimodality platform comprises a unique combination of innovative technologies, data and science for the discovery, development, and production of first-in-class and best-in-class pharmaceutical products. Evotec leverages this "Data-driven R&D Autobahn to Cures" for proprietary projects and within a network of partners including all Top 20 Pharma and over 800 biotechnology companies, academic institutions, as well as other healthcare stakeholders. Evotec has strategic activities in a broad range of currently underserved therapeutic areas, including e.g., neurology, oncology, as well as metabolic and infectious diseases. Within these areas of expertise, Evotec aims to create the world-leading co-owned pipeline for innovative therapeutics and has to-date established a portfolio of more than 200 proprietary and co-owned R&D projects from early discovery to clinical development. Evotec operates globally with more than 4,900 highly qualified people. The Company's 17 sites offer highly synergistic technologies and services and operate as complementary clusters of excellence. For additional information please go to and follow us on Twitter @Evotec and LinkedIn. About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com/company. About the Janssen Pharmaceutical Companies of Johnson & Johnson At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension. Learn more at . Follow us at . Janssen Research & Development, LLC and Janssen Pharmaceutica NV are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. About Otsuka Pharmaceutical Co., Ltd. Otsuka is a global healthcare company with the corporate philosophy, Otsuka-people creating new products for better health worldwide. Otsuka researches, develops, manufactures and markets innovative products, focusing on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health. In pharmaceuticals, Otsuka is a leader in the challenging area of mental health and also has research programs in several under-addressed diseases including tuberculosis, a significant global public health issue. About The Global Alliance for TB Drug Development, Inc. (TB Alliance) TB Alliance is a not-for-profit organization dedicated to finding faster-acting and affordable drug regimens to fight TB. Through innovative science and with partners around the globe, we aim to ensure equitable access to faster, better TB cures that will advance global health and prosperity. TB Alliance operates with support from Australia's Department of Foreign Affairs and Trade, Bill & Melinda Gates Foundation, Cystic Fibrosis Foundation, Foreign, Commonwealth and Development Office (United Kingdom), Germany's Federal Ministry of Education and Research through KfW, Global Disease Eradication Fund (Korea), Global Health Innovative Technology Fund, Indonesia Health Fund, Irish Aid, Korea International Cooperation Agency, Medical Research Council (United Kingdom), National Institute of Allergy and Infectious Diseases, Republic of Korea's Ministry of Foreign Affairs, and the United States Agency for International Development. For more information, visit . About the Bill & Melinda Gates Medical Research Institute (Gates MRI) The Bill & Melinda Gates Medical Research Institute is a non-profit medical research organization dedicated to the development and effective use of novel biomedical interventions addressing substantial global health concerns, for which investment incentives are limited, including malaria, tuberculosis, enteric and diarrheal diseases, and diseases that impact maternal, newborn, and child health. For further information please visit . About the Bill & Melinda Gates Foundation Guided by the belief that every life has equal value, the Bill & Melinda Gates Foundation works to help all people lead healthy, productive lives. In developing countries, it focuses on improving people's health and giving them the chance to lift themselves out of hunger and extreme poverty. In the United States, it seeks to ensure that all people—especially those with the fewest resources—have access to the opportunities they need to succeed in school and life. Based in Seattle, Washington, the foundation is led by CEO Mark Suzman, under the direction of Co-chairs Bill Gates and Melinda French Gates and the board of trustees. For further information please visit . About Bedaquiline Bedaquiline, developed by Janssen Pharmaceutica NV, part of the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen), was the first targeted medicine for TB with a novel mechanism of action to be introduced in over 40 years when it received accelerated approval by the U.S. Food and Drug Administration in 2012. Today, it is recommended by the World Health Organization (WHO) as a core component of all-oral treatment regimens for nearly all DR-TB patients and is included on the WHO Model List of Essential Medicines. It is indicated in the U.S. and European Union for use as part of combination therapy in the treatment of adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary multidrug-resistant tuberculosis (MDR TB). To date, 159 countries are accessing the medicine today, including the 30 countries with the highest burdens of TB, and three out of every four patients with MDR-TB on treatment receive an all-oral bedaquiline-containing regimen. Janssen provided the exclusive rights for developing and marketing bedaquiline for drug-sensitive TB to TB Alliance in 2009. To learn more about how Johnson & Johnson is working to enable access to this medicine, visit JNJ.com/TB. About Delamanid (Deltyba) Delamanid is a compound created by Otsuka Pharmaceutical with a mechanism of action showing anti-mycobacterial activity that occurs through inhibition of the synthesis of mycolic acid, an essential component of mycobacterial cell walls. 1 To date, delamanid (50 mg film-coated tablets) is approved in 47 countries for treatment of patients with MDR-TB. It was added to the WHO Model List of Essential Medicines in 2015 and to date has been used to treat patients with MDR-TB in more than 122 countries. In 2020, in the European Union, approval was granted for Deltyba 50 mg film-coated tablets to be used in children and adolescents weighing at least 30 kg.2 In 2021, a 25 mg dispersible tablet formulation was approved in the European Union for children with pulmonary MDR-TB weighing at least 10 and below 30 kg as part of an appropriate combination regimen, when an effective treatment regimen cannot otherwise be composed for reasons of resistance and tolerability.2 About Quabodepistat Quabodepistat, previously known as OPC-167832, is an anti-TB compound discovered and currently under investigation by Otsuka. It inhibits the enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1), which is connected to synthesis involving mycobacterial cell walls. This is a different mechanism of action from other currently available anti-TB drugs. In vivo studies in mice suggest that quabodepistat plus delamanid-containing regimens have the potential to shorten therapy and improve outcomes in drug-susceptible TB and multidrug-resistant TB (MDR-TB).1 About Pretomanid Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. Pretomanid was developed by TB Alliance as an oral tablet formulation for the treatment of tuberculosis in combination with other anti-tuberculosis agents. Pretomanid is recommended by the WHO as part of a combination regimen with bedaquiline and linezolid, with or without moxifloxacin, for the treatment of patients ≥14 years old with MDR-TB or rifampicin-resistant tuberculosis (RR-TB). It is also included in the WHO List of Essential Medicines for MDR-TB. Pretomanid received its first regulatory approval from the US FDA in 2019 followed by EMA approval in 2020. About Sutezolid In January 2017, the Medicines Patent Pool (MPP) and Johns Hopkins University (JHU) entered into a license agreement which granted MPP rights to sublicense to third parties the patents owned by JHU relating to sutezolid. In March 2017, MPP and TB Alliance signed a sublicense agreement wherein JHU granted TB Alliance a sublicense to those rights. In October 2019, MPP and Pfizer entered into a license agreement which granted MPP rights to sublicense to third parties the patents and information relating to sutezolid. In December 2020, MPP and Gates MRI signed an agreement to advance the development of this investigational drug from the oxazolidinone class, for use in low- and middle-income countries. Since acquiring rights to develop sutezolid, TB Alliance and Gates MRI have been working together to advance the development of that drug. 1 The current global and national six-month standard of care treatment regimen for DS-TB consists of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). 2 For example, Philippines National Tuberculosis Control Program Manual of Procedures 6th Edition, Republic of South Africa Department of Health National Tuberculosis Management Guidelines.

导语2023年3月24日是第28个世界防治结核病日。世界卫生组织（WHO）发布的主题为：“是的！我们可以终止结核病（YES! WE CAN END TB）！”，旨在呼吁各国广泛参与，共同终结结核病的流行。我国疾病预防控制局最新发布的宣传主题“你我共同努力，终止结核流行”。正文感染结核病的人大多脸色苍白，身形消瘦，咳嗽严重，故西方称之为“白色瘟疫”。历史上三国著名军事家诸葛亮就是脊椎结核，所以年纪轻轻就是扶杖而行，最后死于吐血。红楼梦中的女主角林黛玉是肺结核，最后吐血而亡。波兰著名作曲家肖邦，俄国批判现实主义作家契诃夫，德国著名文学家席勒，美国诗人梭罗，以及英国诗人雪莱——他曾向世人呼喊“冬天来了，春天还会远吗”，自己却未能看到人类战胜肺结核的春天。中国近代文学大家鲁迅先生，也是身患肺结核最后早逝。今天，我们一起来了解下什么是结核病，如何预防、诊断和治疗这种疾病，以及关于它的最新研究进展。1.结核病和结核杆菌结核杆菌(Mycobacterium Tuberculosis,MTB))是德国细菌学家Robert Koch于1882年3月24日发现的，它是引起人和动物结核病的病原菌。并将其分为人型、牛型、鸟型和鼠型4型，其中人型菌是人类结核病的主要病原体。图1.结核病常见临床表现肺结核(Tuberculosis，TB)就是主要由人型结核杆菌侵入肺脏后引起的一种具有强烈传染性的慢性消耗性疾病。常见临床表现为咳嗽、咯痰、咯血、胸痛、发热、乏力、食欲减退等局部及全身症状。肺结核90％以上是通过呼吸道传染的，病人通过咳嗽、打喷嚏、高声喧哗等将带菌液体喷出体外，健康人吸入后就会被感染。据WHO的《2022年全球结核病报告》显示：2021年全球约有1060万结核病患者，比2020年增加4.5%；有160万人死于结核病，我国2021年估算的结核病新发患者数为78.0万。受新冠肺炎疫情的影响，预计2020年和2021年结核病作为单一传染源的死亡原因将降至第2位。2.结核杆菌与宿主免疫系统MTB是一种非常成功的细胞内病原体，与宿主共同进化。宿主免疫细胞被触发成不杀灭MTB，导致MTB的潜伏感染，其通过形成肉芽肿在宿主和病原体之间保持平衡。患者体内的潜伏期肺结核的再激活率从5到10%。宿主细胞不能抑制MTB生长导致肉芽肿病变，坏死的巨噬细胞死亡和炎性细胞募集增。这种宿主免疫力的退避反映了致病性分枝杆菌在宿主细胞内存活、存留的高度进化和多因子能力。MTB开发的逃避宿主天然免疫的复杂机制包括细胞溶质逃逸，抗菌肽的限制性生成，吞噬体成熟的阻断，细胞凋亡，炎性体激活和自噬的调节。3.结核病的预防图2.如何预防结核病1.控制传染源。早期发现传染源和彻底治愈涂阳肺结核病人是控制传染源的关键。对确诊的结核病人，应及时转至结核病防治机构，进行统一管理，并实行全程督导短程化学治疗(DOTS)。2.切断传播途径。结核菌主要通过呼吸道传播，患者和家属应佩戴一次性外科口罩；开窗通风，保持空气新鲜，可有效降低结核病传播；餐具煮沸消毒或用消毒液浸泡毒，同桌共餐时使用公筷；衣物、寝具、书籍等污染物可在烈日下暴晒进行杀菌。3.保护易感人群。进行卡介苗(BCG)接种：可使未受过结核菌感染者获得对结核病的特异免疫力；化学药物预防：对于高危人群，可以遵医嘱预防服用抗结核的化学药物；生活有规律：避免长期过劳和精神紧张，戒烟、饮食均衡，适当进行锻炼，增强抵抗力。4. 结核病的诊断及治疗1.体外诊断IVD世界卫生组织(WHO)推荐使用快速分子检测技术作为结核病的初始诊断方法，分子检测技术准确可靠，在早期发现结核病和耐药结核病方面发挥着重要作用，是终止结核病流行（END TB）策略中加强结核病实验室工作的重要内容。2021年，WHO推荐分子诊断技术的原则由特定技术类型推荐改为基于类别进行推荐，依据操作复杂程度和自动化水平对诊断技术进行分类，共批准6项用于结核病诊断和抗结核药物耐药性检测的分子诊断技术：l 低复杂程度自动化检测平台：赛沛Xpert MTB/XDRl 中等复杂程度自动化检测平台：雅培Abbott RealTime MTB &MTB RIF/INH、碧迪BD Max MDR-TB、罗氏cobas MTB & MTB-RIF/INH、海恩/布鲁克FluroType MTB & MTBDRl 高复杂程度尼：普洛Genoscholar PZA-TB检测 2.化学药物治疗临床上针对敏感结核分歧杆菌广泛采用的标准治疗方案由利福平、异烟肼、吡嗪酰胺和乙胺丁醇组成，其机理为杀菌和抑菌作用，具有较好的治疗效果。但目前，耐多药和广泛耐药结核分枝杆菌感染在世界范围内广泛流行。针对这一现象，WHO推荐用药不断推陈出新，从以往的注射药物治疗转为短程口服治疗，以缩短药物疗程，防止细菌耐药。 此外，结核新药研发也取得很大的进展。抗结核新药(贝达喹啉、普瑞玛尼、德拉马尼等)已进入临床使用，对于耐药结核治疗及缩短疗程具有良好的效果。包括 TBA-7371、 GSK-656、 OPC-167832、Telacebec、Delpazolid、Sutezolid、SQ-109等候选药物已经进入Ⅱ期临床试验。3.免疫治疗耐药结核病的治疗，除了开发新型抗结核药物外，提高宿主免疫应答水平和减轻宿主免疫炎性损伤的免疫治疗逐渐受到重视。● 细胞因子治疗  通过注射或者雾化吸入的方式提高宿主体内特定细胞因子的含量，对宿主进行免疫干预来激发宿主的抗结核免疫应答。例如γ－干扰素、粒细胞－巨噬细胞集落刺激因子、、白细胞介素１/2等。● 免疫细胞治疗  通过体内激活自体免疫效应细胞，或体外扩增自体或异体免疫效应细胞，然后回输给患者纠正免疫失衡和改善免疫功能，提高宿主抗感染应答水平。例如Ｖγ２Ｖδ２Ｔ细胞、固有自然杀伤Ｔ细胞等。4.治疗性疫苗实验性疫苗ID93+GLA-SE是由西雅图的Christopher B. Fox博士和Access to Advanced Health Institute（前身为传染病研究所）的科学家开发的。它是一种重组亚单位疫苗，由结核分枝杆菌的4种蛋白质与GLA-SE（一种免疫刺激佐剂）结合而成。这种冻干配方不需要冷藏，在注射前与无菌水混合。对于偏远地区来说，不需要冷链运输的高效疫苗将成为结束这一流行病的重要工具。5. 最新研究进展自新型冠状病毒全球大流行以来，结核分枝杆菌已成为仅次于SARS-CoV-2的第二大单一感染致死病原，同时感染结核分枝杆菌和艾滋病病毒的患者更是高危人群。近期，北京协和医院医院李永哲教授、石家庄市第五医院戴二黑教授团队发表于《感染杂志》（Journal of Infection）一项横断面研究，对成年结核病患者新冠灭活疫苗加强针的安全性和免疫原性进行分析。临床数据表明：尽管灭活疫苗加强针提高了结核病患者的SARS-CoV-2特异性抗体水平和中和活性，但结核病患者的体液免疫差于健康人群，可进行动态血清抗体监测以推断接种加强针的最佳时机，从而发挥疫苗的最大优势。同时，相对于第2剂灭活疫苗，加强接种可实现结核病患者广泛的体液免疫，尽管仍低于健康人群。而相对于野生毒株，Omicron BA.4/5的中和活性仍然较低，虽然两组人群均已接种第3剂COVID-19疫苗。Omicron亚变种的刺突蛋白RBD突变使其获得了突破性感染，并且能够逃避由COVID-19疫苗构建的免疫保护。因此，为Omicron变异株定制疫苗必不可少。让我们一起努力，对抗结核，守护健康!❒ 第七届宁波生物产业论坛暨BioDeveloper药研者大会大会名称丨第七届宁波生物产业论坛暨BioDeveloper药研者大会大会主题丨潮起甬南 · 破浪笃行大会时间丨2023年4月26-27日大会地点 | 浙江 · 宁海（喜来登酒店-桃源街道天明中路108号）大会规模 | 200+主办单位 | 中共宁海县委组织部、宁海县生物产业园管理中心承办单位 | 甲贝医药支持单位 | 中国生物工程学会、宁波市经信局、宁波市科技局、宁波市投资促进署、中共宁海县委统战部、宁波市医药行业协会、宁波体外诊断联盟、宁波股权交易中心、“科创中国”生物医药产业科技服务团、美国华人生物医药科技协会(CBA)媒体支持 | 佰傲谷BioValley、动脉网扫码报名（免费参会需审核）▽邀请辞本届论坛将以“潮起甬南，破浪笃行”为主题，汇聚政产学研等各路行业领袖专家。于暮春日，游宁海，凭栏远眺，闲谈些许求药故事。第七届宁波生物产业论坛暨BioDeveloper药研者大会将于4月26日-27日在浙江宁海举办。我们期待药物研发者们暂时放下严肃的“奋斗者”姿态，换一种风格、换一种情绪，在严谨的工作之余，重新认识一下并肩作战的朋友们，好好的交流一下当前与未来？风景几许？岂不美哉？推荐阅读：最新议程发布 | 第七届宁波生物产业论坛4月宁海召开！点击“阅读原文”，立即报名~