Fexinidazole

2023年，孟加拉国成为全球第一个获得世界卫生组织（WHO）消除内脏利什曼病认证的国家。而其他受该疾病严重影响的南亚和东非地区的国家也在朝着消除目标稳步前进——这部分归功于DNDi过去20年的研究工作帮助人们获得了更安全和更简单的治疗。当前， DNDi及其合作伙伴正专注于为内脏利什曼病患者提供全新的口服药物，从而支持全球实现和维持内脏利什曼病的消除。 //认识内脏利什曼病：现状与危害// 利什曼病（Leishmaniasis）可由20多种利什曼虫属原生动物寄生虫引起，目前已知有90多种白蛉可以传播这些利什曼虫属寄生虫。该病有三种主要形式：内脏利什曼病（Visceral leishmaniasis，VL）、皮肤利什曼病（Cutaneous leishmaniasis, CL）和皮肤粘膜利什曼病（Mucocutaneous leishmaniasis）。其中，内脏利什曼病（又名黑热病）是最严重的形式，它可能出现暴发并导致死亡，是继疟疾之后第二致命的寄生虫病。 据估计，全世界有6亿多人面临感染VL的风险，每年新发病例数在5万至9万之间，大约50%的VL患者为儿童群体。研究表明，大多数患者分布在巴西、东非和印度。而在中国，近年来病例报告主要集中于新疆、甘肃和四川等地。VL患者通常会出现发烧、体重下降、肝脾肿大等症状，如果不及时治疗，超过95%的患者会发生死亡。其中，携带艾滋病毒的VL患者尤其难以治愈，具有很高的复发率和死亡率。与其他人群相比，携带艾滋病毒的人群罹患VL的风险高出100倍以上。 [图源：DNDi] //推动进步：内脏利什曼病的治疗创新// 东非的VL患者迫切需要比现有标准治疗更安全、更简单的替代方案，特别是当地占比70%的儿童患者。2003年，DNDi创建了东非利什曼病平台（Leishmaniasis East Africa Platform，LEAP），来自20个机构的60名专家参与研究，并帮助推动了肯尼亚、埃塞俄比亚、乌干达和苏丹抗击VL的进展。 2018年，DNDi与AfriKADIA联盟合作在埃塞俄比亚、肯尼亚、苏丹和乌干达开展了一项III期临床研究，比较米替福辛和帕罗霉素（miltefosine and paromomycin，MF+PM）联合治疗与目前的标准治疗——硬葡萄糖酸钠和帕罗霉素（sodium stibogluconate and paromomycin，SSG+PM）的结局。研究结果显示，MF+PM与SSG+PM一样有效，但所需注射次数较少，治疗周期较短，没有SSG相关毒性风险，并且继发黑热病后皮肤利什曼病（Post-Kala-Azar Dermal Leishmaniasis，PKDL）的风险也更低。为确保MF+PM在儿科用药中的适当剂量，研究团队开展了进一步的工作，研究结果支持在儿童和成人患者中均实施较短的14天治疗方案。 [图源：DNDi] DNDi与第七届利什曼病世界大会和第28届LEAP平台会议的与会专家以及开展研究的区域和社区的利什曼病技术和咨询小组分享了试验结果。与此同时，世卫组织指南制定小组开始审查DNDi的 III期临床试验产生的证据，为东非地区成人和儿童VL患者的治疗指南的修订提供信息。 //打破传播链条：PKDL患者的治疗// 据报告，5-10%的VL患者会继发PKDL。该病症通常表现为面部、上臂和躯干部位出现斑点、丘疹或结节，还可能导致毁容和给患者造成极大的病耻感。此外，PKDL患者仍可以作为VL的传染源，因此，早期和有效的PKDL治疗对于持续减少VL传播至关重要。 基于此前完成的两项II期临床研究——在苏丹开展的旨在测试脂质体两性霉素B (LAmB)+MF和MF+PM的研究，以及在印度和孟加拉国开展的测试LAmB单药疗法和LAmB+MF组合疗法的研究，DNDi及其合作伙伴分别于2023年11月和2024年6月在期刊PLOS Neglected Tropical Diseases上发表了研究结果。由于这些新的科学证据，预计更短期、更安全的治疗方法将在未来被推荐给PKDL患者。 [图源：DNDi] //全新的口服药物：合作与创新// 2023年，DNDi与合作伙伴在开发新的分子实体方面取得了重大进展，这些实体有可能彻底改变VL的治疗方法，并支持其消除目标的实现。 LXE408是一种由DNDi与Novartis联合开发的首创新药化合物。2023年8月，印度的第二个研究点已经启动，并在当年招募了39名患者。与此同时，在埃塞俄比亚进行的一项类似的II期研究已于2024年4月入组了首位受试者。预计到2025年，这两项研究将总共招募140名参与者。 GSK245具有与LXE408相似的作用模式，由DNDi、GSK全球健康部门和邓迪大学药物发现部门合作开发。2023年，针对该化合物的研究继续进行，并完成了健康志愿者单次剂量递增的I期研究。 [图源：DNDi] 此外，DNDi及其合作伙伴也恢复了具有独特的作用机理的化合物DNDI-6899的开发。储存在药明康德的活性药物成分已完成重新加工和配制，以支持2024年启动的多次剂量递增I期研究。在上月举行的第43届DNDi科学咨询委员会会议上，DNDI-6899研发项目从40多个研发项目中脱颖而出，入选“2024年度项目”（2024 Projects of the Year），以表彰该项目在临床前研究中的突出进展。 在DNDi的所有利什曼病药物组合中，DNDI-6174提供了一种全新的作用模式，并且预期具有较低的人用剂量和有前景的安全边际。该化合物由DNDi与GSK和邓迪大学合作发现，并于2019年被提名为VL候选药物，该成果已于2023年12月发表在期刊Science Translational Medicine上。自2019年来，DNDi和Eisai一直在合作开发该化合物，并于2023年继续合作研究以扩大对该化合物非临床特征的了解，从而推进首次人体临床试验。 [图源：DNDi] 我们非常感激这一路同行的合作伙伴们，他们在为被忽视的患者群体推进医学创新方面发挥了重要作用。未来，我们将继续在利用现有药物提供更安全、更短周期的治疗的同时，完成全新药物的长期开发，以拯救生命，减少与内脏利什曼病有关的社会歧视和病耻感，并最终消除内脏利什曼病。 点击“阅读原文”，可了解更多DNDi为最被忽视的病人推动的医学创新。 关于DNDi 被忽视疾病药物研发倡议组织（DNDi）是一个以病患需求为出发点的非营利性药物研发组织。DNDi主要为被忽视的疾病患者研发新的治疗方法，其中包括昏睡病、南美锥虫病、利什曼病、淋巴丝虫病、足菌肿、儿童艾滋病/艾滋病以及丙型肝炎的治疗方法。DNDi同时也在协调ANTICOV临床试验，为非洲的轻度至中度新冠肺炎（COVID-19）患者寻找治疗方法。 自2003年成立以来，DNDi迄今已交付了13种全新的治疗方案，其中包括用于治疗利什曼病的新药物组合、两种固定剂量的抗疟药，首次成功研发的新化学实体药物非昔硝唑（fexinidazole）用于治疗昏睡病，以及通过南南合作研发的丙肝药物拉维达韦（ravidasvir），旨在为全球丙肝患者提供可负担的药物选择。 *点击下方图片，了解更多有关DNDi的介绍。

EMA gives positive opinion to Fexinidazole Winthrop as first oral treatment of acute form of sleeping sickness (rhodesiense) found in East and Southern Africa Paris, Geneva and Nairobi. December 15, 2023. Sanofi, DNDi and the HAT-r-ACC consortium announce the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive scientific opinion of Fexinidazole Winthrop as first oral treatment of acute form of sleeping sickness (rhodesiense). This positive opinion is for the treatment in adults and children six years of age or older and weighing at least 20 kg, of both first-stage (haemo-lymphatic) and second-stage (meningo-encephalitic) Trypanosoma brucei (T.b.) rhodesiense sleeping sickness, an acute and lethal form of this parasitic disease found in Eastern and Southern Africa. This CHMP opinion follows an application by Sanofi under Article 58 and clinical trials in Malawi and Uganda led by the non-profit medical research organization Drugs for Neglected Diseases initiative (DNDi). The CHMP first adopted in 2018, a positive opinion of Fexinidazole Winthrop as the first all-oral treatment , in adults and children six years of age or older and weighing at least 20 kg, of both first-stage (haemo-lymphatic) and second-stage (meningo-encephalitic) of the more common T.b. gambiense form of sleeping sickness found in West and Central Africa. Sleeping sickness, or human African trypanosomiasis (HAT), is usually fatal without treatment. Both forms of sleeping sickness are transmitted by the bite of infected tsetse flies, which are found in 36 African countries. It causes neuropsychiatric symptoms, including aggressiveness, psychosis, a debilitating disruption of sleep patterns that have given this neglected disease its name, and ultimately, death. Dietmar Berger, MD, PhDHead of Development and Chief Medical Officer, Sanofi“The CHMP’s positive opinion is another step forward in Sanofi’s commitment to help deliver innovative treatments to vulnerable patient communities impacted by sleeping sickness, a deadly neglected tropical disease. By working with WHO and DNDi, we have made tremendous progress in improving treatment outcomes and simplifying treatment delivery. This partnership and our donation of Fexinidazole Winthrop through Foundation S, reflect our mission to provide innovative treatments to patients, no matter where they live.” For the T.b. rhodesiense variant, Fexinidazole Winthrop is indicated as a 10-day, once-daily oral treatment. Data from DNDi’s Phase 2/3 clinical trial were recently presented at the European Congress of Tropical Medicine and International Health and showed that Fexinidazole Winthrop was highly effective in treating the T.b. rhodesiense form of sleeping sickness and is a safe alternative to the existing drugs. In periodic follow-up evaluations that continued for 12 months after treatment, only one patient (2.94%) with the advanced form of the disease had relapsed and required treatment with the arsenic derivative that is the standard of care for patients with the most severe stage of the disease. Dr Westain NyirendaPrincipal Investigator and physician at Rumphi Hospital in Malawi“T.b. rhodesiense sleeping sickness is a terrifying disease that progresses more rapidly than T.b. gambiense, killing quickly if untreated. Until now, due to the lack of innovation for this strain of sleeping sickness, old and toxic treatment options have to be administered in a hospital under strict surveillance. Having a simple and safer oral pill to treat this frightening disease will allow doctors to rapidly save lives. It will also help patients to trust the new treatment.” While humans are the main host of T.b. gambiense, T.b. rhodesiense is a zoonotic disease, meaning that the infection can spread from animals to humans. Cattle and wild animals such as bushbucks and zebras are the most common reservoirs for this disease. Movements of these animals – potentially sparked by droughts or changes in climate – could put new populations at risk of T.b. rhodesiense sleeping sickness. In some cases, tourists visiting game reserves have been infected with T.b. rhodesiense. Dr Olaf Valverde MordtClinical Project Leader for sleeping sickness, DNDi“We are already seeing how an all-oral treatment for T.b. gambiense sleeping sickness has simplified the treatment of this variant in countries like the Democratic Republic of Congo. Although there are comparatively few cases of T.b. rhodesiense, last year Ethiopia recorded its first cases since the 1970s. The drought at the time of the infections brought humans and cattle in closer proximity to tsetse flies’ habitat. Environmental changes could be one of the reasons behind this resurgence.” The CHMP opinion today paves the way for the update of WHO guidelines on treatment for sleeping sickness, and distribution by WHO of Fexinidazole Winthrop in African countries where T.b. rhodesiense is prevalent. Fexinidazole Winthrop will be donated to WHO by Foundation S, Sanofi’s philanthropic organization. Dr Ibrahima Socé FallDirector of Neglected Tropical Diseases, World Health Organization “The impact of climate change extends to the shifting geographical spread of vector-borne diseases such as sleeping sickness, heightening the likelihood of spillover events where diseases transfer from animals to humans. These shifts disproportionately affect the most vulnerable communities, underscoring the urgency of sustained investment in programs addressing NTDs. This includes the development of innovative tools and improved treatment methods. We extend our gratitude to our partners DNDi for their research for the most neglected and Sanofi for their ongoing support and contribution to these vital efforts.” Fexinidazole Winthrop has already been registered in the Democratic Republic of the Congo and Uganda as a treatment for T.b. gambiense and is recommended for use in a further 10 African countries: (Angola, Burkina Faso, Central African Republic, Chad, Congo, Côte d'Ivoire, Equatorial Guinea, Gabon, Guinea, and South Sudan). Dr Michelle HelinskiSenior Project Officer for Neglected Infectious Diseases at the European and Developing Countries Clinical Trials Partnership Association (EDCTP) “We congratulate the HAT-r-ACC consortium on developing a better treatment option for this truly neglected disease and are thrilled with the positive opinion by CHMP.” The DNDi clinical trial for T.b. rhodesiense was conducted by the HAT-r-ACC Consortium, with funding from the European and Developing Countries Clinical Trials Partnership Association (EDCTP2) programme supported by the European Union; Fundação para a Ciência e a Tecnologia from Portugal; Swiss Agency for Development and Cooperation (SDC), from Switzerland; Médecins Sans Frontières International; and UK International Development, United Kingdom; and other private foundations and individuals. About SanofiWe are an innovative global healthcare company, driven by one purpose: we chase the miracles of science to improve people’s lives. Our team, across some 100 countries, is dedicated to transforming the practice of medicine by working to turn the impossible into the possible. We provide potentially life-changing treatment options and life-saving vaccine protection to millions of people globally, while putting sustainability and social responsibility at the center of our ambitions. Sanofi is listed on EURONEXT: SAN and NASDAQ: SNY About DNDiThe Drugs for Neglected Diseases initiative (DNDi) is a not-for-profit medical research organization that discovers, develops, and delivers safe, effective, and affordable treatments for neglected people. DNDi is developing medicines for sleeping sickness, leishmaniasis, Chagas disease, river blindness, mycetoma, dengue, paediatric HIV, advanced HIV disease, cryptococcal meningitis, and hepatitis C. Its research priorities include children’s health, gender equity and gender-responsive R&D, and diseases impacted by climate change. Since its creation in 2003, DNDi has joined with public and private partners across the globe to deliver twelve new treatments, saving millions of lives. dndi.org About HAT-r-ACCThe HAT-r-ACC consortium brings together a broad range of partners with expertise in sleeping sickness and capacity building in remote health settings. This research, training, and community engagement experience is essential to run the clinical trial in remote settings with a very small target population. The consortium partners include the Malawi Ministry of Health (MMoH), the Uganda National Health Research Organisation (UNHRO), the Makerere University in Uganda, Epicentre (MSF) in France, the Lisbon Institute of Hygiene and Tropical medicine (IHMT) in Portugal, the Institut de Recherche pour le Développement (IRD) in France, the WHO, and the Swiss Tropical and Public Health Institute (Swiss TPH). Sanofi Media RelationsSandrine Guendoul | + 33 6 25 09 14 25 | sandrine.guendoul@sanofi.comEvan Berland | +1 215 432 0234 | evan.berland@sanofi.comNicolas Obrist | + 33 6 77 21 27 55 | nicolas.obrist@sanofi.comVictor Rouault | + 33 6 70 93 71 40 | victor.rouault@sanofi.com Sanofi Investor RelationsEva Schaefer-Jansen | + 33 7 86 80 56 39 | eva.schaefer-jansen@sanofi.comArnaud Delépine | + 33 6 73 69 36 93 | arnaud.delepine@sanofi.comCorentine Driancourt | + 33 6 40 56 92 21 | corentine.driancourt@sanofi.comFelix Lauscher | + 1 908 612 7239 | felix.lauscher@sanofi.comTarik Elgoutni| + 1 617 710 3587 | tarik.elgoutni@sanofi.comNathalie Pham | + 33 7 85 93 30 17 | nathalie.pham@sanofi.com DNDi Media ContactFrédéric Ojardias in Geneva | +41 79 431 62 16 | fojardias@dndi.org Sanofi Forward-Looking StatementsThis press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include projections and estimates and their underlying assumptions, statements regarding plans, objectives, intentions and expectations with respect to future financial results, events, operations, services, product development and potential, and statements regarding future performance. Forward-looking statements are generally identified by the words “expects”, “anticipates”, “believes”, “intends”, “estimates”, “plans” and similar expressions. Although Sanofi’s management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Sanofi, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include among other things, the uncertainties inherent in research and development, future clinical data and analysis, including post marketing, decisions by regulatory authorities, such as the FDA or the EMA, regarding whether and when to approve any drug, device or biological application that may be filed for any such product candidates as well as their decisions regarding labelling and other matters that could affect the availability or commercial potential of such product candidates, the fact that product candidates if approved may not be commercially successful, the future approval and commercial success of therapeutic alternatives, Sanofi’s ability to benefit from external growth opportunities, to complete related transactions and/or obtain regulatory clearances, risks associated with intellectual property and any related pending or future litigation and the ultimate outcome of such litigation,  trends in exchange rates and prevailing interest rates, volatile economic and market conditions, cost containment initiatives and subsequent changes thereto, and the impact that pandemics or other global crises may have on us, our customers, suppliers, vendors, and other business partners, and the financial condition of any one of them, as well as on our employees and on the global economy as a whole. The risks and uncertainties also include the uncertainties discussed or identified in the public filings with the SEC and the AMF made by Sanofi, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-Looking Statements” in Sanofi’s annual report on Form 20-F for the year ended December 31, 2022. Other than as required by applicable law, Sanofi does not undertake any obligation to update or revise any forward-looking information or statements. Attachment Press_Release