A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and Efficacy Study of Investigational Therapeutics for the Treatment of Patients With Ebola Virus Disease

Background:
Ebola virus can cause serious illness or death. No medicines are approved to treat it. Researchers need to test new medicines to see if they help people recover from Ebola and are safe to give. They need to test the drugs and compare them in a controlled way. Researchers want to test 4 drugs with people who have Ebola and are in treatment centers.
Objective:
To study the safety and effectiveness of 4 drugs for people with Ebola virus.
Eligibility:
People of any age with Ebola infection who are in treatment centers
Design:
Participants will be screened with questions, medical history, and blood tests.
Participants will be randomly assigned to get 1 of 3 study drugs:
* ZMapp by IV over about 4 hours. It will be given 3 times, 3 days apart.
* Remdesivir by IV over about 1 hour. It will be given once a day for 10 days.
* Mab114 by IV for 30-60 minutes. It will be given 1 time.
* REGN-EB3 by IV for about 2 hours. It will be given 1 time.
For at least a week, participants will stay in isolation in a clinic. They will:
* Get supportive care and be monitored
* Have a small plastic tube (IV) put in an arm vein for several days to give fluids and collect blood.
* Get their study drug.
* Be monitored for disease signs and drug side effects. They may get medicines for side effects.
* Have blood and urine tests.
Participants will stay in the clinic until they finish the study drug and are well enough to leave.
Participants will have 2 follow-up visits over 2 months. They will answer questions and give blood and semen samples.
...

开始日期2018-11-21

申办/合作机构

National Institute of Allergy & Infectious Diseases

NCT02363322

/ Completed临床1/2期IIT

A Multicenter Randomized Safety and Efficacy Study of Putative Investigational Therapeutics in the Treatment of Patients With Known Ebola Infection

Background:
- Ebola is a viral infection that can spread quickly and causes life-threatening disease. Right now there is an Ebola outbreak in many countries in West Africa. There are no approved treatments for Ebola. But possible treatments are being developed. Researchers need to study these treatments to see if they help people get better.
Objective:
- To identify possible Ebola treatments. Also, to learn if adding 1 or more experimental drugs to advanced Ebola care can reduce the risk of death.
Eligibility:
- People who have recently been diagnosed with Ebola, usually by a test called the Polymerase Chain Reaction (PCR), and have been hospitalized in an isolation unit for treatment.
Design:
* Participants will be randomly assigned to Group A or B. Both groups will get advanced level care. One group will also get an experimental drug.
* Participants may have blood tests. They may have another PCR test.
* Researchers will try to learn how the participant got Ebola.
* Participants put in the experimental drug group may start taking medicine within 24 hours of enrollment. It may be given by mouth or intravenously. Additional doses may be needed.
* Participants may have a series of timed blood tests over the first 24 to 48 hours after they take the medicine.
* Blood will be drawn frequently. Other body fluids (urine, stool, vaginal fluid, etc.) may also be collected.
* Participants will be followed for up to 60 days. They may be evaluated for any long-term effects of the experimental treatment(s). They may be asked to return for 1 or more outpatient visits.
* For consenting participants, follow-up will be extended for up to one full year past Day 58 with contact/visits every 1-3 months to assess for a history of signs or symptoms potentially consistent with late onset of virologic relapse syndrome.

开始日期2015-03-13

申办/合作机构

National Institute of Allergy & Infectious Diseases

[+2]

NCT02389192

/ Withdrawn临床1期IIT

A Phase 1a Open-Label Study to Assess the Safety and Pharmacokinetics of a Single ZMappTM Administration in Healthy Adult Volunteers

Background:
- Ebola is a virus that can spread quickly and causes serious disease. It is currently causing an outbreak in West Africa. There are no approved treatments for Ebola. ZMappTM is a new drug made of natural infection-fighting substances. Researchers want to see if it can treat Ebola.
Objective:
- To assess the safety of ZMappTM and how the body processes it. To measure the immune system response to ZMappTM.
Eligibility:
- Healthy people 18 50 years old.
Design:
* Participants will be screened with a medical history, physical exam, and blood and urine tests. They will have an electrocardiogram (ECG) to measure heart electrical activity. Small pads will be stuck to the arms, legs, and chest.
* Participants will be admitted to the hospital. They will have a physical exam, medication review, and blood samples.
* Two intravenous (IV) lines will be placed into separate arm veins. A needle will be used to guide plastic tubing into the veins. One will be used to take blood samples. The other will be used to give the study drug.
* Participants will be given drugs to help prevent side effects.
* Participants will be given the study drug by IV over 10 12 hours. Participants will be monitored closely and vital signs taken frequently. They may have another ECG.
* Blood samples will be taken before, during, and after the infusion.
* Participants will stay in the hospital 1 or 2 nights after receiving the drug.
* Participants will have several study visits over 90 days after getting the study drug. They will be asked about side effects. They may have a physical exam, and blood may be drawn.

开始日期2015-03-11

申办/合作机构

National Institute of Allergy & Infectious Diseases

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2024-03-01·The Lancet. Infectious diseases

Effect of anti-Ebola virus monoclonal antibodies on endogenous antibody production in survivors of Ebola virus disease in the Democratic Republic of the Congo: an observational cohort study

Article

作者: Delaporte, Eric ; Mbala-Kingebeni, Placide ; Edidi-Atani, François ; Legand, Anaïs ; Kitenge, Richard ; Peeters, Martine ; Diallo, Mamadou Saliou Kalifa ; Dilu-Keti, Angele ; Ayouba, Ahidjo ; Mukadi-Bamuleka, Daniel ; Tovar-Sanchez, Tamara ; Toure, Abdoulaye ; Ahuka-Mundeke, Steve ; Thaurignac, Guillaume ; Pelloquin, Raphael ; Muyembe-Tamfum, Jean-Jacques ; Formenty, Pierre ; Nkuba-Ndaye, Antoine

BACKGROUND:

The use of specific anti-Ebola virus therapy, especially monoclonal antibodies, has improved survival in patients with Ebola virus disease. We aimed to assess the effect of monoclonal antibodies on anti-Ebola virus antibody responses in survivors of the 2018-20 Ebola outbreak in the Democratic Republic of the Congo.

METHODS:

In this observational prospective cohort study, participants were enrolled at three Ebola survivor clinics in Beni, Mangina, and Butembo (Democratic Republic of the Congo). Eligible children and adults notified as survivors of Ebola virus disease (ie, who had confirmed Ebola virus disease [RT-PCR positive in blood sample] and were subsequently declared recovered from the virus [RT-PCR negative in blood sample] with a certificate of recovery from Ebola virus disease issued by an Ebola treatment centre) during the 2018-20 Ebola virus disease outbreak were invited to participate in the study. Participants were recruited on discharge from Ebola treatment centres and followed up for 12-18 months depending on recruitment date. Routine follow-up assessments were done at 1, 3, 6, and 12-18 months after inclusion. We collected sociodemographic (age, sex, visit site), clinical (anti-Ebola virus drugs), and laboratory data (RT-PCR and Ct values). The primary outcome was the antibody concentrations against Ebola virus glycoprotein, nucleoprotein, and 40-kDa viral protein antigens over time assessed in all participants. Antibody concentrations were measured by the multiplex immunoassay, and the association between anti-Ebola virus antibody levels and the relevant exposures, such as anti-Ebola virus disease drugs (ansuvimab, REGN-EB3, ZMapp, or remdesivir), was assessed using both linear and logistic mixed regression models. This study is registered at ClinicalTrials.gov, NCT04409405.

FINDINGS:

Between April 16, 2020, and Oct 18, 2021, 1168 survivors were invited to participate in the Les Vainqueurs d'Ebola cohort study. 787 survivors were included in the study, of whom 358 had data available for antibody responses. 85 (24%) of 358 were seronegative for at least two Ebola virus antigens on discharge from the Ebola treatment centre. The antibody response over time fluctuated but a continuous decrease in an overall linear evolution was observed. Quantitative modelling showed a decrease in nucleoprotein, glycoprotein, and VP-40 antibody concentrations over time (p<0·0001) with the fastest decrease observed for glycoprotein. The probability of being seropositive for at least two antigens after 36 months was 53·6% (95% CI 51·6-55·6) for participants who received ansuvimab, 73·5% (71·5-75·5) for participants who received REGN-EB3, 76·8% (74·8-78·8) for participants who received remdesivir, and 78·5% (76·5-80·5) for participants who received ZMapp.

INTERPRETATION:

Almost a quarter of survivors were seronegative on discharge from the Ebola treatment centre and antibody concentrations decreased rapidly over time. These results indicate that monoclonal antibodies might negatively affect the production of anti-Ebola virus antibodies in survivors of Ebola virus disease which could increase the risk of reinfection or reactivation.

FUNDING:

The French National Agency for AIDS Research-Emergent Infectious Diseases-The French National Institute of Health and Medical Research, the French National Research Institute for Development, and the European and Developing Countries Clinical Trials Partnership.

TRANSLATION:

For the French translation of the abstract see Supplementary Materials section.

2016-10-13·The New England journal of medicine1区 · 医学

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

1区 · 医学

Article

作者: Dodd, Lori ; Lane, H. Clifford ; Neaton, James ; Massaquoi, Moses B. F. ; Koopmeiners, Joseph S. ; Proschan, Michael A. ; Sahr, Foday ; Davey, Richard T. Jr. ; Nordwall, Jacquie Neuhaus ; Beigel, John ; Fauci, Anthony S. ; Tierney, John ; Malvy, Denis

BACKGROUND:

Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD).

METHODS:

Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days.

RESULTS:

A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups.

CONCLUSIONS:

In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. (Funded by the National Institute of Allergy and Infectious Diseases and others; PREVAIL II ClinicalTrials.gov number, NCT02363322 .).

2015-01-01·Przeglad lekarski

Tobacco against Ebola virus disease.

Review

作者: Budzianowski, Jaromir

The Ebola virus disease (EVD), formerly known as a hemorrhagic fever and discovered in 1976, is dangerous, highly infectious disease with very high mortality. There are no licensed therapeutics against EVD, although a range of medicines and therapies are currently being evaluated. During the 2014 Ebola outbreak, an experimental drug named ZMapp was administered on an emergency basis to seven patients of which five were recovered. Currently, since February 2015, ZMapp is tested in clinical trials. ZMapp is a mixture (named a cocktail) of three chimaeric monoclonal antibodies (mAbs) of IgG class, which bind to three different epitopes on Ebola surface glycoprotein (GP). ZMapp was created by systematic selection of antibodies from two other three-component cocktails--MB-003 and ZMab the components of which were produced by rapid transient expression method in tobacco species of Australian origin--Nicotiana benthamiana. The ZMapp antibodies of pharmaceutical grade are manufactured in green-house grown N.benthamiana according to the cGMP (current Good Manufacturing Practice), using RAMP platform (Rapid Antibody Manufacturing Platform) and MagnICON system, which utilizes transient expression by magnifection method using viral vectors delivered to plant tissue by a bacterium--Agrobacterium tumefaciens. The applied glycosylation mutant of N.benthamiana (delta XTFT) synthesizes human-like, biantennary N-glycans, with terminal N-acetylglucoseamine and without typical of plants, immunogenic sugar epitopes-beta1,2-linked xylose and alpha1,3-linked fucose. Due to an absence of fucose on N-glycans attached to the Fc domains, the plant-produced anti-Ebola mAbs elicited significantly stronger antibody-dependent cellular cytotoxicity (ADCC) than the analogous anti-Ebola mAbs with fucosylated (alpha1,6-linked fucose) N-glycans produced in a mammalian CHO cell line--the basic expression system for the industrial production of recombinant therapeutical glycoproteins. As far as a vaccine against Ebola virus disease is considered, so-called Ebola Immunogenic Complex (EIC) consisting of assembled molecules of a humanized IgG mAb--6D8 specific for Ebola GPI with GP1 fused to the C-terminus of the heavy chains, was obtained by transient expression in N. benthamiana.

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当一片烟草田，开始“长”出救命的抗体

如果，救命的疫苗，不是来自冰冷的针管，而是来自一片你随口吃下的生菜沙拉？如果，你昂贵的抗衰老面霜中，最核心的“生长因子”，不是在十亿美元的钢铁发酵罐中合成，而是在一片烟草的叶片中“收获”？这，不是科幻小说的畅想。这，是正在全球悄然引爆的“植物分子农业”革命。它背后的逻辑，简单、粗暴，却又无比优雅：为什么还要建造昂贵、复杂、笨重的“生物反应器”工厂？当这个星球上，本就存在着一种以太阳为能源、以二氧化碳为原料、可以自我复制和无限扩展的“生物反应器”——植物。 📌 阅读导航昂贵的围墙：传统生物反应器之困绿色工厂：植物的“光合”超能力烟草“洗白”：从健康杀手到救命恩人生菜疫苗：一口吃下的“免疫防线” “基因漂移”：田野中的安全与伦理新农人：从“农民”到“生物工程师” “绿金”赛道：万亿级的分子农业蓝图 2014年，埃博拉病毒在西非肆虐，死亡率高达90%。时间，就是生命。在传统疫苗和抗体研发“远水救不了近火”的绝望时刻，一个名为ZMapp的“神秘血清”被紧急投入使用，奇迹般地治愈了两名美国援助人员。这个“救命药”的来源，震惊了世界：它既不是来自辉瑞或默沙克的巨型钢铁发酵罐，也不是来自仓鼠的卵巢细胞。它，来自肯塔基州一个戒备森严的温室里，一片正在生长的、不起眼的烟草。通过一种“瞬时表达”技术，科学家将抗体的“蓝图”注入烟草叶片，仅仅几周后，这些叶片就“长”满了救命的抗体。这，就是“植物分子农业”（PMF）的惊世首秀。它向世界宣告：农田，不再只是生产食物的土地。它，即将成为21世纪最廉价、最快、最具扩展性的“生物反应器”。 🏭 昂贵的围墙：传统生物反应器之困要理解这场“绿色革命”为何如此迫切，必须先看懂传统生物制药业的“昂贵”困局。我们今天使用的大多数生物药物（如胰岛素、抗体、疫苗），都依赖于一种技术：哺乳动物细胞培养。简而言之，就是在一个价值数十亿美元、需要极致无菌环境的巨型不锈钢“发酵罐”中，“喂养”经过基因改造的仓鼠卵巢（CHO）细胞，让它们缓慢地“分泌”出我们想要的蛋白质。这个系统的痛点，显而易见：贵：建造一个符合GMP（药品生产质量管理规范）标准的生物反应器设施，动辄投资10亿美金。慢：培养这些“娇气”的哺乳动物细胞，周期极长，动辄数月。风险高：由于使用动物细胞，系统始终存在被动物源病毒（如朊病毒）污染的潜在风险。规模有限：当全球性大流行（如COVID-19）爆发时，这些钢铁巨兽的产能，根本无法在短时间内满足数十亿剂量的需求。我们，急需一个更便宜、更快、更具弹性的“生产平台”。 🌿 绿色工厂：植物的“光合”超能力答案，就在我们脚下。植物，就是大自然演化了数亿年的、以光合作用为能源的“生产车间”。“植物分子农业”的逻辑，就是“黑”入植物的操作系统，让它为我们“代工”。实现“代工”的路径，主要有两条：稳定转化：这就像是“建一座永久工厂”。科学家通过基因工程，将目标蛋白质（如胰岛素）的基因，永久地“写入”作物的DNA（如玉米、水稻、红花）中。从此，这株作物和它的所有后代，都会在它们的种子或叶片中，稳定地生产这种蛋白质。其优点是稳定、可传代；缺点是研发周期长，通常需要数年。瞬时表达：这就像是“租一个快闪工厂”。这是目前PMF领域最火热、最迅猛的技术，埃博拉抗体ZMapp就诞生于此。科学家利用一种经过“解除武装”的植物病毒（如烟草花叶病毒, TMV）作为“信使”，将目标基因的“指令”带入植物叶片。植物的细胞防御系统被“欺骗”，误以为自己被感染了，于是疯狂地调动所有资源，在短短几天内，大量“复刻”这份指令——也就是我们想要的蛋白质。这种“瞬时”系统，将蛋白质的生产周期，从“年”压缩到了“周”。 🚬 烟草“洗白”：从健康杀手到救命恩人在这场革命中，被选中的“天选之子”，出人意料，正是烟草——但不是我们用来抽的普通烟草，而是它的一个“表亲”，本氏烟草（Nicotiana benthamiana）。本氏烟草，是植物学界的“小白鼠”。它在进化中丢失了大部分的免疫系统，这使其对病毒“信使”的“入侵”，几乎“毫不设防”，因此成为了“瞬时表达”系统最完美的“宿主”。与大流行赛跑的“烟草速度”当2020年COVID-19大流行爆发时，传统疫苗研发正以“月”为单位艰难推进。而加拿大一家名为Medicago的生物技术公司，利用其烟草瞬时表达平台，上演了真正的“速度与激情”：在拿到新冠病毒的基因序列后，他们仅仅用了20天，就在本氏烟草的叶片中，生产出了第一批“病毒样颗粒”（VLP）疫苗候选物。其后续获批的疫苗Covifenz，成为了全球首款获批上市的、完全在植物中生产的人用疫苗。烟草，这个背负了百年“健康杀手”骂名的植物，在分子生物学家的手中，奇迹般地“洗白”，摇身一变，成为了“救命恩人”。 🥬 生菜疫苗：一口吃下的“免疫防线” 清明节兼具自然与人文两大内涵，既是自然节气点，也是传统节日。扫墓祭祖与踏青郊游是清明节的两大礼俗主题。如果说烟草解决的是“生产”问题，那么，以生菜、番茄为代表的食用作物，则指向了一个更具颠覆性的未来——“可食用疫苗”。一个“可以吃”的疫苗梦亚利桑那大学的查尔斯·阿恩特森（Charles Arntzen）博士，是这个领域的“教父”。他毕生的梦想，是在那些缺乏冷链、医疗资源和无菌针头的贫困地区，消灭霍乱和乙型肝炎。他的方案是：让当地人，像吃沙拉一样，吃下含有疫苗的“转基因生菜”或“转基因香蕉”。这个构想的精妙之处在于：常温储运：疫苗被植物坚韧的细胞壁包裹，使其在常温下也能保持活性，彻底摆脱了对昂贵“冷链”的依赖。口服免疫：当生菜被食用，疫苗蛋白在肠道中被缓慢释放，精准地激活了肠道黏膜的免疫系统——这正是大多数病原体入侵人体的“第一道防线”。无需针头：消除了注射的痛苦、成本和医疗垃圾。尽管“可食用疫苗”在剂量控制、审批法规等方面，仍面临重重挑战，但它为全球公共卫生，提供了一个无与伦比的、充满善意的未来。 🧬 “基因漂移”：田野中的安全与伦理然而，当农田变成了“制药厂”，一个“侏罗纪公园”式的幽灵，也随之浮现——“基因漂移”（Gene Flow）。万一，一株“胰岛素玉米”的花粉，随风飘到了隔壁的“食用玉米”田里，并发生了杂交，导致不知情的消费者，吃下了含有药物成分的玉米片，怎么办？这并非杞人忧天。2002年，美国就发生过著名的“ProdiGene事件”：一家公司用于生产猪疫苗的“药物玉米”，意外地污染了附近用于食品的大豆田，导致价值数百万美元的大豆被召回销毁。这场风波，为整个PMF行业敲响了警钟。从那以后，针对PMF的监管变得空前严格。如今，绝大多数（尤其是生产强效药物的）PMF作物，都被严格限制在“物理封闭”的温室或室内“垂直农场”中进行，而非在露天大田，以杜绝任何“基因逃逸”的可能。 👨🌾 新农人：从“农民”到“生物工程师” 技术的变革，必然带来人的变革。在PMF的“农场”里，传统的“农民”正在消失，取而代之的，是一批高学历、懂技术的“生物工程师”。一个“PMF农场经理”的日常,在肯塔基州那片种植ZMapp烟草的温室里，农场经理的工作，与传统烟农截然不同。他不需要看天时、测墒情。他每天穿着白大褂，穿过数道风淋门进入“洁净区”。他的首要任务，是管理和监控“GMP（药品生产质量管理规范）”流程。他关心的，不是产量，而是每一批叶片中“目标蛋白的表达滴度”。他指挥的，不是收割机，而是一个负责“病毒载体浸润”和“无菌采收”的技术团队。他，是一个跨界于“农业”与“药学”之间的新物种，一个真正的“植物生物反应器”操作员。 📈 “绿金”赛道：万亿级的分子农业蓝图这场革命，早已溢出了制药业。它正在向人类需求的每一个高价值领域，全面渗透。美妆个护：用植物（如冰岛的ORF Genetics公司用大麦）生产昂贵的表皮生长因子（EGF）和胶原蛋白，用于高端护肤品。细胞培养（人造肉）：实验室培育“人造肉”，最昂贵的成本，是那些“喂养”细胞的“生长因子”。利用烟草、大豆等植物来“量产”这些生长因子，被视为引爆“人造肉”革命的关键。工业酶：生产用于纺织、造纸、生物燃料等领域的、更稳定、更廉价的工业酶。正在爆发的市场这不再是一个小众的科研游戏。据Verified Market Research的数据，全球植物分子农业市场，在2023年已超过13亿美元，并预计在2030年，增长至29亿美元，年复合增长率超过12%。资本，已经嗅到了“绿金”的味道。一万年来，传统农业，解决了人类的“温饱”；在过去一个世纪，农业绿色革命，解决了“产量”。而现在，我们正站在智慧农业的门槛上。我们不再满足于只从植物中，获取碳水化合物和纤维素。我们开始要求它，为我们生产“智慧”、“功能”与“价值”。从一片片“生”出抗体的烟草田，到一个“吃”下去的生菜疫苗。植物分子农业，正在用最低的成本和最快的速度，为人类文明的健康与未来，提供一个绿色的、可持续的、充满想象力的解决方案。这，是光合作用的终极胜利。 📚 参考文献世界卫生组织（WHO）关于埃博拉（Ebola）疫情及ZMapp药物的报告。 Medicago公司关于其植物源性COVID-19疫苗（Covifenz）的临床试验数据及加拿大卫生部的审批文件。《Nature Biotechnology》、《Science》等期刊上关于“瞬时表达”系统（Transient Expression Systems）和“可食用疫苗”（Edible Vaccines）的综述和研究论文。美国农业部（USDA）和食品药品监督管理局（FDA）关于“植物源性药物”（Plant-Made Pharmaceuticals, PMP）的监管框架和指导原则。关于2002年“ProdiGene事件”的调查报告和行业回顾。 Verified Market Research, MarketsandMarkets 等机构发布的《全球植物分子农业市场分析报告（2023-2030）》。 ORF Genetics（冰岛）、Moolec Science（英国）、Bright Biotech（英国）等PMF领域前沿公司的公开技术资料。查尔斯·阿恩特森（Charles Arntzen）教授关于“可食用疫苗”概念的早期研究和访谈。

疫苗

2024-08-08

·同写意

一家抗病毒明星Biotech的溃逃

本次以“突破瓶颈打造健康产业新引擎”为主题，设一场主论坛和八场主题论坛，从前沿创新突破、临床应用拓展、工艺技术优化、商业化开发等多个全新视角推动CGT技术开发与应用，成就健康产业未来。差不多十年前，著名风投公司ARCH Venture Partners联合创始人Robert Nelsen，萌生了想要创办一家药企，以应对世界上最为严重的病原体。 “这是一个疯狂的想法。”曾在渤健和Vertex从事艾滋病毒和丙肝药物开发工作的Vicki Sato，在接到Nelsen的电话时评价道。虽然传染病一直存在，但在彼时，越来越多的药企正撤出传染病领域。然而，对于以疯狂的想法发家致富的Nelsen，这没有什么值得大惊小怪的。毕竟，有时科学听起来也很疯狂：通过改造细胞来治疗癌症，找到延缓衰老的药物。凭借“用免疫系统解决病原体”的独特想法，Nelsen收获了肯定，2016年成功组建Vir Biotechnology。戏剧性的是，信誓旦旦，言犹在耳，这家Biotech却在前不久宣布停止肝炎之外的传染病项目研究，引入抗癌产品。 Vir并不孤单，曾经因抗病毒药物而声名鹊起的吉利德和Vertex，也已将不少精力转向癌症、神经学、罕见疾病和自身免疫。传染病药企发展的宿命注定如此吗？相较于行业，这更是准备重组的Vir需要回答的问题。 1 创造没有传染病的世界多年来，生物技术公司一直想要攻克传染病。但由于技术、投入产出不成比例等原因，这个领域的进展缓慢。 Nelsen获得信赖的想法是，与其试图为每种病原体想出解药，不如像研究癌症的科学家那样，利用免疫系统做这项工作。成立之初，Vir的目标是“创造一个没有传染病的世界”，并请来渤健前首席执行官George Scangos，担任Vir CEO。在一年的时间里，Vir收购了Humabs，获得5亿美元融资，并和斯坦福大学、哈佛大学等知名科研机构达成合作。 Vir开局顺利，但当时的大环境对传染病领域并不友好。 2014年，诺华几乎用整个传染病部门交换了GSK的相关癌症项目；Achaogen在2018年成功在美国推出自研的新型抗生素普拉佐米星（Zemdri），却因销售惨淡而在次年宣布破产。因而，在2019年10月IPO时，Vir股价以低于发行价18％的16.50美元开盘，并以14.02美元收盘（下跌29.9%）的表现，就并没有太让人感到意外。这种困扰并未持续多久。因为很快，COVID-19就来了。在此前，Vir就从埃博拉幸存者体内分离出了高效的中和抗体MAb114，疗效媲美再生元的REGN-EB3（三种抗体鸡尾酒），且明显优于美国另一家公司Mapp研发的ZMapp。2020年下旬，REGN-EB3、MAb114先后获得FDA批准。 COVID-19期间，在传染病领域已经有了一些积淀的Vir，从SARS康复患者体内分离出可以交叉识别COVID-19病毒的中和抗体，在此基础上开发了VIR-7831和VIR-7832两款中和抗体。 Vir抓住了风口，而MNC选择抓住了Vir。2020年4月，GSK宣布对Vir进行2.5亿美元的股权投资，共同开发上述两款产品。 2021年1月，Vir与礼来、GSK达成合作，在低风险的轻中度COVID-19患者中评估两种中和抗体疗法的组合。彼时，礼来已扩展其正在进行的BLAZE-4试验，以评估bamlanivimab与VIR-7831构成的组合疗法的效果。这次联盟，让Vir的股价飙升，一度达到141美元。 VIR-7831没有辜负期待。2021年5月，它获得FDA的紧急使用授权（EUA），通用名为sotrovimab，商品名为Xevudy，成为礼来、再生元之后第3款获得EUA的中和抗体，半年时间里取得了超10亿美元的销售额。即使面对“神兵”mRNA疫苗，中和抗体也有一战之力。数据显示，2021年COVID-19中和抗体试产规模达到110亿美元。在2022年，由于sotrovimab的贡献，Vir的营收超过16亿美元，在COVID-19期间的营收增长率一度达到1334%。Sotrovimab在40多个国家获得上市批准、临时授权或紧急使用授权，Vir市值水涨船高，一度接近200亿美元。 2 Biotech，起落落落随着COVID-19消退，相关红利也逐渐消失。据GSK年报，在2022年，sotrovimab销售额为23亿英镑，增长100%。到了2023年，销量下滑幅度直逼去年涨幅，达到98%，仅有4400万英镑。而在此前，由于病毒不断变异，sotrovimab的效力已经逐渐减弱。2021年3月，Vir宣布sotrovimab一项针对住院患者的III期临床ACTIV-3停止入组，原因是独立数据和安全监察委员会经分析认为对获益可能较小。 2022年4月，卫生保健提供者情况说明书中包含的数据显示，sotrovimab的授权剂量不太可能对BA.2亚型有效，sotrovimab在美国任何州或地区授权均被撤销。时来天地皆同力，运去英雄不自由。随后，REGEN-COV（再生元）、Evusheld（阿斯利康）等COVID-19中和抗体也相继撤出美国市场。2023年2月，GSK宣布不再与Vir就COVID-19相关项目进行继续合作。 COVID-19像是Vir发展的一个分界线，一边是泛着金光的光明未来，一边是迷雾笼罩的原始丛林。在剔除COVID-19项目后，当时Vir管线中走在前面的只有两个处在临床II期的肝炎项目，分别是单抗VIR-3434（Tobevibart）和siRNA药物VIR-2218（Elebsiran），均引进自Alynlam。 Tobevibart旨在抑制乙肝病毒和丁肝病毒进入肝细胞，中和乙肝病毒和丁肝病毒病毒体，并降低血液中的病毒体和亚病毒颗粒水平；Elebsiran可降解乙肝病毒RNA转录本并限制乙肝表面抗原的产生，可能对乙肝病毒和丁肝病毒具有直接的抗病毒活性。数据显示，2022年约有130万⼈死于病毒性肝炎，与结核病并列成为当年传染病中第二大死亡原因，仅次于COVID-19。但需要指出的是，乙肝市场并不是一个容易吃上的“饼”。就目前来说，乙肝病毒形成的cccDNA（共价闭合环状DNA）难以被清除，导致乙肝很难被彻底治愈，即使现在追求的功能性治愈也存在诸多问题，停药后容易复阳，中途放弃探索的药企也不在少数。比如，同样获得快速通道资格的在研乙肝新药ABI-H0731、ABI-H2158（Assembly Biosciences）均已折戟沙场。本身的技术难度之外，如何追赶并超越“前辈”，甚至抢占已上市产品的市场份额，也是颇不容易。 GSK、吉利德等巨头都有处在中后期的肝炎在研药物。GSK用于慢性乙肝治疗的Bepirovirsen在今年2月获得FDA“快速通道”资格；3月，吉利德Vemlidy扩充适应症，获得FDA批准治疗六岁及以上乙肝患者。尴尬的是，Vir能否在肝炎领域杀出一片天尚有待观察，该公司关注的另一重点领域流感也出了岔子。 2023年7月，Vir用于预防症状性甲型流感的VIR-2482在II期研究中未达到主要或次要疗效终点，股价大跌近45%。到年底，Vir宣布进行重组，裁员12%，并关闭位于密苏里州圣路易斯和俄勒冈州波特兰的研发设施。 3 选择更具性价比的路 8月1日，Vir宣布了一项战略性改革，透露将不再继续COVID-19和流感方面的工作，叫停基于T细胞的病毒载体平台，并把病毒学业务限制在其乙型和丁型肝炎项目中，专注于“近期的高价值机会”。具体来看，管线中的下一代COVID单克隆抗体VIR-7229、针对流感A和B的神经氨酸酶靶向单克隆抗体VIR-2981、临床前治疗性癌症疫苗VIR-1949，以及进入I期试验的HIV疫苗VIR-1388，都将不复存在。同时，Vir还披露了一项与赛诺菲达成的许可协议，获得后者三个临床阶段的条件激活CD3双抗，以及可切割蛋白酶掩蔽平台的独家使用权。 3款产品分别为： • SAR446309，一种双掩蔽HER2xCD3分子，目前正在I期开发中，用于治疗转移性、治疗抵抗性HER2阳性肿瘤，如乳腺癌和结直肠癌。 • SAR446329，一种双掩蔽PSMAxCD3候选物，处于I期临床试验阶段，针对患有转移性、去势抵抗性前列腺癌的患者。 • SAR446368，针对EGFR的双重掩蔽CD3 TCE，其IND已获得批准。预计1期临床试验将在2025年第一季度或更早启动，用于各种EGFR阳性癌症。不难看出，Vir新的重点锚定了癌症。 Vir的选择也许对标了赛诺菲、礼来、辉瑞等起初也是“传染病”起家的巨头，在某款产品中获得巨额利润后转向更大的疾病领域。需要指出的是，这些巨头已经拥有了巨大的资本积累。与Vir基本退出传染病领域形成对比的是，今年6月，吉利德预防HIV的III期试验取得积极结果，一年两针，100%有效。欢呼声掩盖了失意者的落寞，但现实困境确实横亘在前。囿于传染病的患者群体、地区、患病率、付费能力等现实因素，产品市场并不稳定，在大多数拥有支付能力的国家，癌症、自身免疫性疾病、神经退化才是“主要矛盾”。此外，药企公共沟通的不足可能也进一步加深传染病药物研发的困境。根据Endpoints数据，从2010年到2020年，风险资本向癌症投入的现金是传染病的5倍多。回望Vir的来时路，很遗憾一个为传染病而生的公司还是走向了更“稳妥”的选择。丁肝成了“最后的倔强”。6月初，Vir更新了在研项目的利好进展。 II期试验SOLSTICE的初步数据显示，tobevibart单药或与elebsiran联用治疗丁型肝炎病毒感染中耐受性良好，受试者在第12周和第24周实现了高病毒学应答率，且病毒学应答持久至48周，患者丙氨酸转氨酶（ALT）水平正常化的比率高。完整的24周治疗数据有望在2024年第四季度报告。FDA已授予tobevibart和elebsiran组合药物快速通道资格，用于治疗慢性丁型肝炎病毒感染。接受tobevibart与elebsiran联合疗法的HDV患者快速达到病毒学抑制和ALT水平正常化，图源：药明康德 2024年第二季度，Vir的收入为310万美元，低于去年同期的380万美元。截至2024年6月30日，Vir拥有14.3亿美元的现金、现金等价物和投资。在战略重组的工作中，Vir将裁员25%，在其运营中取消大约140个职位。年底时，员工人数将降至约435人，比去年的峰值减少了约200人。而作为与赛诺菲协议的一部分，Vir将从后者引进一些“具有丰富的T细胞接合剂科学和开发专业知识的关键员工”。这些调整预计将节省5000万美元，直至2025年底，Vir计划将这些资金重新投资于从赛诺菲获得的候选药物。未来，这家Biotech计划利用PRO-XTEN技术在多个领域进行创新开发，加强在癌症治疗领域的产品线，也将拓展至抗感染领域。不可否认，传染病仍是一个巨大的潜在市场。GlobalData预计，传染病市场将以每年5.7%的速度增长，2029年达到年销售额1500亿美元。问题是，这条赛道上，对于“脱胎换骨”的Vir能跑到什么位置，或许就不是那么乐观了。参考文献： 1、Vir Lays Off 25% of Staff, Abandons Most Virus Work and Pivots to Cancer in Sanofi Deal；biospace 2、Can investing in infectious disease pay off? Vir Biotechnology’s tightrope walk shows it’s a struggle；statnews 3、Vir Biotechnology官网 4、100%肝炎患者病毒持久抑制近1年！创新疗法亮眼结果公布；药明康德 5、After Big Pharma abandoned infectious diseases, 5 biotech contrarians decided to go all in. Then Covid-19 changed everything；endpoints 同写意媒体矩阵，欢迎关注↓↓↓

IPO并购

2020-10-15

·BioSpace

Regeneron’s Inmazeb Becomes First Ebola Treatment Approved by FDA

Inmazeb is the world’s first treatment for Ebola. Regeneron announced that the U.S. Food and Drug Administration approved Inmazeb, a three-antibody cocktail to treat Ebola infections in adults and children. Inmazeb is the world’s first treatment for Ebola. Although Regeneron Pharmaceuticals has been in the news lately for its antibody cocktail against COVID-19 that was used to treat President Trump, it’s not the only arrow in the company’s quiver. Today it announced that the U.S. Food and Drug Administration (FDA) approved Inmazeb, a three-antibody cocktail to treat Ebola infections in adults and children. It has also been approved for newborns of mothers who have tested positive for Ebola. Inmazeb is made up of three monoclonal antibodies: atoltivimab, maftivimab and odesivimab-ebgn. The cocktail was engineered using the company’s VelocImmune platform and associated VelociSuite technologies. The antibodies have similar structure, but bind to different, non-overlapping antigens on Zaire ebolavirus glycoprotein. They neutralize the virus by blocking its ability to invade patients’ bodies and by recruiting other immune cells to target infected cells. Ebola is rare and deadly and typically causes outbreaks in sub-Saharan Africa, although there were 11 people treated in the U.S. during the 2014 to 2016 epidemic. There is currently an ongoing outbreak in the Democratic Republic of the Congo (DRC). The disease spreads through contact with blood, body fluids and tissues of animals, and through contact with infected people, as well as through sexual contact with someone sick with the disease, as well as after recovery from the disease. The early signs of the disease include fever, aches and pains, severe headache, and abdominal pain, weakness, diarrhea and vomiting, then moves onto hemorrhaging, bleeding or bruising. The average case fatality rate of Ebola virus disease (EVD) is about 50%. In 2019, the FDA approved an Ebola vaccine, Merck’s Ervebo. “We are incredibly proud that the FDA has approved Inmazeb, which is also known as REGN-EB3,” said George D. Yancopoulos, president and chief scientific officer of Regeneron. “This is the first time the FDA has approved a treatment specifically for Ebola, which has caused a number of deadly outbreaks. Decades of investment in our VelociSuite rapid response technologies, the dedication of world-class scientists, and the courageous contributions of healthcare providers and patients, together with remarkable cooperation between leading international health organizations and govenrments, have led to this important moment.” As part of a deal announced in July, Regeneron will produce a specific number of Inmazeb doses over six years to the Biomedical Advanced Research and Development Authority (BARDA). In response to the 2018 outbreak in the DRC, Regeneron worked with the World Health Organization (WHO), FDA and other global health organizations to provide Inmazeb under a compassionate use protocol and include it in the four-arm PALM (Pamoja TuLinde Maisha) Trial. With BARDA, Regeneron plans to continue to offer the therapy for free in response to outbreaks in the DRC through the MNEURI protocol for compassionate use. “Since 2015, BARDA has partnered with Regeneron to develop a life-saving treatment for Ebola Zaire,” said Gary Disbrow, acting director of BARDA. “The Food and Drug Administration’s approval of Inmazeb shows the power of public private partnerships to bring forward these critical treatments and improve global public health. BARDA is continuing our collaboration with Regeneron on other life-threatening diseases such as MERS and COVID-19, and we look forward to continued success.” The therapy’s safety and efficacy were demonstrated in the 681-patient PALM Trial, which was initiated in 2018 in the DRC. The trial was jointly sponsored by the WHO, the National Institutes of Health (NIH) and the Institut National de Recherche Biomedical (INRB) in the DRC. The trial was halted early after a pre-specified interim analysis showed Inmazeb was superior to Gilead’s remdesivir, currently the only approved therapy for COVID-19, and Mapp Biopharmaceutical’s ZMAPP.

上市批准临床研究疫苗

100 项与 Porgaviximab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10974	-	-	-

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
埃博拉病毒性疾病	临床3期	美国	National Institute of Allergy & Infectious Diseases	2018-11-21
埃博拉病毒性疾病	临床3期	刚果共和国	National Institute of Allergy & Infectious Diseases	2018-11-21

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03719586 (CTgov)	临床2/3期	埃博拉病毒性疾病	681	Remdesivir (Arm A: Remdesivir Plus Optimized Standard of Care (oSOC))	範糧築餘醖糧製遞觸觸 = 蓋糧窪獵憲壓齋範願構壓鏇構膚膚糧選艱繭範 (鏇選艱淵廠遞鹽壓窪齋, 窪鏇構膚襯獵構鹹鏇鑰 ~ 醖衊膚網醖獵淵顧簾鬱) 更多	-	2021-09-08
				MAb114 (Arm B: MAb114 Plus Optimized Standard of Care (oSOC))	範糧築餘醖糧製遞觸觸 = 鏇壓網夢淵壓構壓膚鬱壓鏇構膚膚糧選艱繭範 (鏇選艱淵廠遞鹽壓窪齋, 鹹鹽廠齋鬱範衊觸鏇齋 ~ 構鬱選鏇蓋遞淵壓鹽鬱) 更多
NCT02363322 (PREVAIL II, CTgov)	临床1/2期	埃博拉病毒性疾病	72	A/Current Standard of Care Alone (A/Current Standard of Care Alone)	醖廠鬱鹹淵襯觸壓鏇衊 = 鹽簾顧觸窪壓願壓選遞窪窪築繭選積艱鏇遞網 (壓繭夢鹹艱齋襯淵壓範, 獵壓範襯餘鑰窪糧糧鹹 ~ 餘範餘願願廠餘鹹蓋願) 更多	-	2019-05-14
				A/Current Standard of Care Alone+B/Current Standard of Care Plus ZMapp (B/Current Standard of Care Plus ZMapp)	醖廠鬱鹹淵襯觸壓鏇衊 = 鬱廠觸鬱壓壓積鬱鏇艱窪窪築繭選積艱鏇遞網 (壓繭夢鹹艱齋襯淵壓範, 選顧衊艱糧廠鏇積鹹醖 ~ 鏇願衊獵齋願鹽遞選網) 更多
NCT02363322 (Pubmed \| Br Dent J \| N Engl J Med) 人工标引	临床1/2期	埃博拉病毒性疾病	71	Standard of Care+ZMapp	淵製廠選憲鑰製鏇鏇餘(廠築鹹壓範憲顧廠築衊) = 鹽積膚願築膚廠範餘繭獵網構齋餘遞艱構觸遞 (襯壓廠廠願構遞夢繭廠 )	积极	2016-10-13
				Standard of Care Alone	淵製廠選憲鑰製鏇鏇餘(廠築鹹壓範憲顧廠築衊) = 壓淵顧齋夢鹹醖艱艱壓獵網構齋餘遞艱構觸遞 (襯壓廠廠願構遞夢繭廠 )