Increasing evidence supports a role for viral persistence, chronic inflammation and immune and metabolic dysregulation in driving long COVID

越来越多的证据支持病毒持续性，慢性炎症以及免疫和代谢失调在驱动长时间新型冠状病毒中的作用

Bezisterim, an anti-inflammatory and insulin-sensitizer that permeates the blood brain barrier, could represent a novel oral treatment targeting an underlying cause of long COVID symptoms

Bezisterim是一种渗透血脑屏障的抗炎和胰岛素增敏剂，可能代表了一种针对长期新型冠状病毒症状根本原因的新型口服治疗方法

CARSON CITY, Nev., April 29, 2024 (GLOBE NEWSWIRE) --  BioVie Inc. (NASDAQ: BIVI), (“BioVie” or the “Company”), a clinical-stage company developing innovative drug therapies for the treatment of neurological and neurodegenerative disorders and advanced liver disease, today announced the grant of a clinical trial award of up to $13.1 million from the U.S.

内华达州卡森市，2024年4月29日（环球通讯社）--BioVie Inc.（纳斯达克：BIVI），（“BioVie”或“公司”），一家临床阶段公司，开发用于治疗神经和神经退行性疾病以及晚期肝病的创新药物疗法，今天宣布从美国获得高达1310万美元的临床试验奖。

Department of Defense (DOD), awarded through the Peer Reviewed Medical Research Program (PRMRP) of the Congressionally Directed Medical Research Programs (CDMRP). The award can provide up to 2 years of non-dilutive funding for a Phase 2b clinical trial that will assess the Company’s anti-inflammatory and insulin sensitizer candidate, bezisterim (NE3107), for the treatment of neurological symptoms that are associated with long COVID.

国防部（DOD），通过国会指导医学研究计划（CDMRP）的同行评审医学研究计划（PRMRP）授予。该奖项可以为2b期临床试验提供长达2年的非稀释性资金，该试验将评估该公司的抗炎和胰岛素增敏剂候选人贝齐斯特林（NE3107），用于治疗与长冠状病毒相关的神经系统症状。

The Company anticipates the trial to commence by early 2025..

该公司预计该试验将于2025年初开始。。

Long COVID is a condition in which symptoms of COVID-19, the acute respiratory disease caused by the SARS-CoV-2 virus, persist for an extended period of time, generally three months or more. The Centers for Disease Control recently reported that 6.8% of adults in the United States (more than 17 million individuals) currently or previously had long COVID.1 Symptoms, which include fatigue, cognitive dysfunction and sleep disturbances, are debilitating.

长COVID是一种由SARS-CoV-2病毒引起的急性呼吸道疾病COVID-19的症状持续很长一段时间，通常持续三个月或更长时间。疾病控制中心最近报告说，目前或以前有6.8%的美国成年人（超过1700万人）患有长期新型冠状病毒。1包括疲劳，认知功能障碍和睡眠障碍在内的症状使人衰弱。

The loss in quality of life and earnings and increased medical costs has an enormous economic impact estimated to be 3.7 trillion dollars.2 To date there are no therapies proven effective for treatment..

生活质量和收入的下降以及医疗费用的增加产生了巨大的经济影响，估计为3.7万亿美元。2迄今为止，尚无有效的治疗方法。。

Chronic inflammation is one of the main hypotheses that researchers have proposed to explain the persistence of symptoms in long COVID.3   Specifically in individuals with “brain fog,” sustained systemic inflammation and persistent localized blood-brain-barrier (BBB) dysfunction are key physiological features.5 Bezisterim permeates the BBB and has been shown to modulate inflammation via the activation of NF-kB, thus representing a novel oral treatment targeting an underlying cause of long COVID symptoms..

慢性炎症是研究人员提出的解释长型冠状病毒症状持续存在的主要假设之一。3特别是在患有“脑雾”的个体中，持续的全身炎症和持续的局部血脑屏障（BBB）功能障碍是关键的生理特征。贝齐斯特林渗透BBB，并已被证明通过激活NF-kB来调节炎症，因此代表了一种针对长型冠状病毒症状根本原因的新型口服治疗。。

“The investigation of bezisterim in long COVID exemplifies the broad potential of therapies targeting inflammation and insulin sensitivity. This approach holds promise for a range of conditions where neuroinflammation is a key player, offering an avenue for advancements in care that are yet to be realized,” said Cuong Do, BioVie’s President & CEO.

BioVie总裁兼首席执行官库恩·多（Cuong Do）表示：“对长期新型冠状病毒中贝西斯特林的研究表明，针对炎症和胰岛素敏感性的治疗具有广泛的潜力。这种方法有望用于神经炎症是关键因素的一系列疾病，为尚未实现的护理进步提供了途径。”。

“Long COVID symptoms appear to be driven by peripheral and neuroinflammation resulting from persistence of SARS-CoV-2 RNA and spike protein. We believe the accumulating evidence behind this hypothesis supports the investigation of bezisterim to treat symptoms of long COVID and are pleased that this Department of Defense grant will enable further exploration of this molecule’s broader potential.”.

“长冠状病毒症状似乎是由SARS-CoV-2 RNA和棘突蛋白持续存在引起的外周和神经炎症引起的。我们相信这一假设背后的累积证据支持贝齐斯特林治疗长冠状病毒症状的研究，并且很高兴国防部的这项拨款将能够进一步探索这种分子的更广泛潜力。”。

Dr. Michael Peluso, who co-leads one of the first studies to examine the long-term effects of COVID and leads a Long COVID clinical trials program at the University of California, San Francisco stated “I am excited to see the trial with bezisterim receive funding given that recent advances in our understanding of the potential mechanism of action of bezisterim align with emerging evidence for the underlying pathophysiology of Long COVID”..

迈克尔·佩卢索博士（MichaelPeluso）是首批研究新型冠状病毒（COVID）长期影响的研究之一，也是旧金山加利福尼亚大学（University of California，San Francisco）长期新型冠状病毒（COVID）临床试验项目的负责人之一。他表示：“鉴于我们对贝齐斯特林潜在作用机制的理解的最新进展与长期新型冠状病毒潜在病理生理学的新证据相一致，我很高兴看到贝齐斯特林试验获得资助。”。。

The Preliminary plans for the Phase 2b, randomized (1:1), placebo-controlled, multicenter trial are to evaluate the safety and tolerability of 3 months of treatment with bezisterim, along with its ability to reduce the neurological symptoms that are associated with long COVID, in approximately 200 patients.

2b期，随机（1:1），安慰剂对照，多中心试验的初步计划是评估贝齐斯特林治疗3个月的安全性和耐受性，以及其减少与长COVID相关的神经系统症状的能力，大约200名患者。

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Terms of the Award

合同条款

This project is supported by The Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, in the amount of $499,200 for the planning phase with an option to execute the $12,6 million clinical trial after the planning phase has concluded, through the Peer Reviewed Medical Research Program under Award Number (HT9425-24-1-0300)..

该项目得到了国防部批准的负责卫生事务的助理国防部长的支持，计划阶段的资金为49.92万美元，可以在计划阶段结束后通过同行评审的医学研究计划（HT9425-24-1-0300）执行1260万美元的临床试验。。

About Long COVID

关于长COVID

Long COVID is a condition in which symptoms of COVID-19, the acute respiratory disease caused by the SARS-CoV-2 virus, persist for an extended period of time, generally three months or more. Common symptoms include lingering loss of smell and taste, hearing loss, extreme fatigue, and “brain fog,” though persistent cardiovascular and respiratory problems, muscle weakness, and neurologic issues have also been documented.

长COVID是一种由SARS-CoV-2病毒引起的急性呼吸道疾病COVID-19的症状持续很长一段时间，通常持续三个月或更长时间。常见症状包括持续的嗅觉和味觉丧失，听力下降，极度疲劳和“脑雾”，尽管也有持续的心血管和呼吸系统问题，肌肉无力和神经系统问题的记录。

The Centers for Disease Control recently reported that 6.8% of adults in the United States (more than 17 million individuals) currently or previously have long COVID.1 The loss in quality of life and earnings and increased medical costs has an enormous economic impact estimated to be $3.7 trillion.2 To date there are no non-pharmacological or pharmacological therapies proven effective for treatment of long COVID..

美国疾病控制中心最近报告称，目前或之前，美国有6.8%的成年人（超过1700万人）患有长期新型冠状病毒。1生活质量和收入的下降以及医疗费用的增加产生了巨大的经济影响，估计为3.7万亿美元。2迄今为止，还没有非药物或药物疗法被证明对治疗长期新型冠状病毒有效。。

Chronic inflammation is one of the main hypotheses that researchers have proposed to explain the persistence of symptoms in long COVID.3 The expression of proteins associated with inflammation (LGALS9, CCL21, CCL22, TNF, CXCL10 and CD48) and immune regulation (IL1RN and CD22) have been shown to be elevated in individuals with long COVID versus full-recovered individuals.4 Specifically in individuals with “brain fog,” sustained systemic inflammation and persistent localized blood-brain-barrier (BBB) dysfunction are key physiological features.5 Thus, drugs modulating inflammation, and that work to regulate the BBB integrity, could represent potential therapeutic mechanisms for treating neurological symptoms of long COVID..

慢性炎症是研究人员提出的解释长冠状病毒症状持续存在的主要假设之一。3与炎症相关的蛋白质（LGALS9，CCL21，CCL22，TNF，CXCL10和CD48）和免疫调节（IL1RN和CD22）的表达已被证明在长冠状病毒患者与完全恢复的个体中升高[4]。特别是在“脑雾”患者中，持续的全身炎症和持续的局部血脑屏障（BBB）功能障碍是关键的生理特征。因此，调节炎症和调节BBB完整性的药物可能代表治疗长冠状病毒神经症状的潜在治疗机制。。

About Bezisterim

关于Bezisterim

Bezisterim (NE3107) is an orally bioavailable, BBB-permeable, insulin-sensitizer that is also anti-inflammatory. In addition, it is not immunosuppressive and has a low risk of drug-to-drug interaction. Bezisterim has the potential to reduce symptoms of long COVID, including fatigue and cognitive dysfunction.

Bezisterim（NE3107）是一种口服生物可利用，BBB可渗透的胰岛素增敏剂，也具有抗炎作用。此外，它不具有免疫抑制作用，药物间相互作用的风险较低。Bezisterim有可能减轻长期新型冠状病毒的症状，包括疲劳和认知功能障碍。

Persistently circulating viral spike proteins are believed to trigger TLR-4 driven activation of NFkB and the subsequent expression of inflammatory cytokines (IL-6, TNF, IFNg). NE3107 has been shown to modulate the activation of NFkB and thus modulate inflammation..

据信持续循环的病毒刺突蛋白会触发TLR-4驱动的NFkB激活和随后的炎性细胞因子（IL-6，TNF，IFNg）的表达。NE3107已被证明可以调节NFkB的激活，从而调节炎症。。

Bezisterim is being investigated for Alzheimer’s disease (AD) and Parkinson’s disease (PD). BioVie has conducted and reported efficacy data on its Phase 3 randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate bezisterim in patients who have mild-to-moderate AD (NCT04669028).

Bezisterim正在接受阿尔茨海默病（AD）和帕金森病（PD）的调查。BioVie在其3期随机，双盲，安慰剂对照，平行组，多中心研究中进行并报告了疗效数据，以评估轻度至中度AD患者的bezisterim（NCT04669028）。

Results of a Phase 2 investigator-initiated trial (NCT05227820) showing bezisterim-treated patients experienced improved cognition and biomarker levels were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) annual conference in December 2022. An estimated six million Americans suffer from AD.

2022年12月，阿尔茨海默病临床试验（CTAD）年会上介绍了一项由研究者发起的第二阶段试验（NCT05227820）的结果，该试验显示贝齐斯特林治疗的患者认知能力和生物标志物水平有所改善。估计有600万美国人患有AD。

A Phase 2 study of bezisterim in PD (NCT05083260) has been completed, and data presented at the AD/PD™ 2023 International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders in Gothenburg, Sweden in March 2023 showed significant improvements in “morning on” symptoms and clinically meaningful improvement in motor control in patients treated with a combination of bezisterim and levodopa vs.

帕金森病患者贝齐斯特林的第二阶段研究（NCT05083260）已经完成，2023年3月在瑞典哥德堡举行的AD/PD™2023阿尔茨海默氏病和帕金森氏病及相关神经系统疾病国际会议上提供的数据显示，贝齐斯特林和左旋多巴联合治疗的患者的“早晨”症状显着改善，运动控制有临床意义。

patients treated with levodopa alone, and no drug-related adverse events..

单独使用左旋多巴治疗的患者，无药物相关不良事件。。

About BioVie Inc.

关于BioVie Inc。

BioVie Inc. (NASDAQ: BIVI) is a clinical-stage company developing innovative drug therapies for the treatment of neurological and neurodegenerative disorders and advanced liver disease. In neurodegenerative disease, the Company’s drug candidate bezisterim inhibits inflammatory activation of ERK and NFkB (e.g., TNF signaling) that leads to neuroinflammation and insulin resistance, but not their homeostatic functions (e.g., insulin signaling and neuron growth and survival).

BioVie Inc.（纳斯达克股票代码：BIVI）是一家临床阶段公司，开发用于治疗神经和神经退行性疾病以及晚期肝病的创新药物疗法。在神经退行性疾病中，该公司的候选药物bezisterim抑制导致神经炎症和胰岛素抵抗的ERK和NFkB的炎症激活（例如TNF信号传导），但不抑制其稳态功能（例如胰岛素信号传导和神经元生长和存活）。

Both are drivers of AD and PD. In liver disease, the Company’s Orphan drug candidate BIV201 (continuous infusion terlipressin), with U.S. Food and Drug Administration (“FDA”) Fast Track status, is being evaluated and discussed with guidance received from the FDA regarding the design of Phase 3 clinical testing of BIV201 for the treatment of ascites due to chronic liver cirrhosis.

两者都是AD和PD的驱动因素。在肝病方面，该公司的孤儿候选药物BIV201（持续输注特利加压素）具有美国食品和药物管理局（“FDA”）的快速通道状态，正在接受FDA关于设计BIV201治疗慢性肝硬化腹水的3期临床试验的指导进行评估和讨论。

The active agent is approved in the U.S. and in about 40 countries for related complications of advanced liver cirrhosis. For more information, visit www.bioviepharma.com..

该活性药物在美国和大约40个国家被批准用于治疗晚期肝硬化的相关并发症。有关更多信息，请访问www.bioviepharma.com。。

Forward-Looking Statements

前瞻性声明

This press release contains forward-looking statements, which may be identified by words such as 'expect,' 'look forward to,' 'anticipate' 'intend,' 'plan,' 'believe,' 'seek,' 'estimate,' 'will,' 'project' or words of similar meaning. In this press release, forward-looking statements include, but are not limited to, the potential impact of bezisterim on cognition and function among study participants and topline data from the bezisterim trial.

本新闻稿包含前瞻性陈述，可以用“期望”、“期待”、“预期”、“打算”、“计划”、“相信”、“寻求”、“估计”、“意志”、“项目”或类似含义的词语来识别。在本新闻稿中，前瞻性声明包括但不限于bezisterim对研究参与者认知和功能的潜在影响以及bezisterim试验的主要数据。

Although BioVie Inc. believes such forward-looking statements are based on reasonable assumptions, it can give no assurance that its expectations will be attained. Actual results may vary materially from those expressed or implied by the statements herein due to the Company's ability to successfully raise sufficient capital on reasonable terms or at all, available cash on hand and contractual and statutory limitations that could impair our ability to pay future dividends, our ability to complete our pre-clinical or clinical studies and to obtain approval for our product candidates, our ability to successfully defend potential future litigation, changes in local or national economic conditions as well as various additional risks, many of which are now unknown and generally out of the Company's control, and which are detailed from time to time in reports filed by the Company with the SEC, including quarterly reports on Form 10-Q, reports on Form 8-K and annual reports on Form 10-K.

尽管BioVie Inc.认为此类前瞻性陈述是基于合理的假设，但它无法保证其预期会实现。实际结果可能与本文声明中明示或暗示的结果有很大差异，这是由于公司有能力以合理的条件或根本不可能成功筹集足够的资本，现有现金以及可能损害我们支付未来股息的能力的合同和法定限制，我们完成临床前或临床研究以及获得候选产品批准的能力，我们成功防御未来潜在诉讼的能力，当地或国家经济状况的变化以及各种额外风险，其中许多风险目前尚不清楚，通常不在公司的控制范围内，这些风险在公司向美国证券交易委员会提交的报告中不时详细说明，包括表10-Q的季度报告，表8-K的报告和表10的年度报告-K。

BioVie Inc. does not undertake any duty to update any statements contained herein (including any forward-looking statements), except as required by law..

除法律要求外，BioVie Inc.不承担更新本文所载任何声明（包括任何前瞻性声明）的任何义务。。

References

参考文献

1Ford ND, Agedew A, Dalton AF, Singleton J, Perrine CG, Saydah S. Notes from the Field: Long COVID Prevalence Among Adults — United States, 2022. MMWR Morb Mortal Wkly Rep 2024;73:135–136. DOI: http://dx.doi.org/10.15585/mmwr.mm7306a4.

1Ford ND，Agedew A，Dalton AF，Singleton J，Perrine CG，Saydah S.现场笔记：成年人中的长期新型冠状病毒流行-美国，2022年。MMWR Morb Mortal Wkly Rep 2024；73:135-136。内政部：http://dx.doi.org/10.15585/mmwr.mm7306a4.

2Cutler, David M. 2022 The economic costs of Long COVID: An update. long_covid_update_7-22.pdf (harvard.edu)

2Cutler，David M.2022长冠状病毒的经济成本：更新。long\u covid\u update\u 7-22.pdf（哈佛大学教育部）

3Evans RA, Leavy OC, Richardson M, et al. Clinical characteristics with inflammation profiling of Long-COVID and association with one-year recovery following hospitalisation in the UK: a prospective observational study. The Lancet Respiratory Medicine. 2022;10(8):761-775.

3Evans RA，Leavy OC，Richardson M等人。英国长期新型冠状病毒肺炎的临床特征及其与住院后一年恢复的关系：一项前瞻性观察性研究。柳叶刀呼吸医学。2022年；10（8）：761-775。

4Yin K, Peluso MJ, Luo X, et al. Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Nature Immunology. 2024;25:218-225.

4Yin K，Peluso MJ，Luo X等。长COVID表现为T细胞失调，炎症和对SARS-CoV-2的不协调的适应性免疫反应。自然免疫学。2024年；25:218-225。

5Greene C, Connoly R, Brennan D, et al. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nature Neuroscience. 2024;27:421-432.

5Greene C，Connoly R，Brennan D等人。长期新型冠状病毒相关认知障碍患者的血脑屏障破坏和持续全身炎症。自然神经科学。2024年；27:421-432。

For Investor Relations Inquiries:

投资者关系查询：

Bruce Mackle

Bruce Mackle

Managing Director, LifeSci Advisors, LLC

LifeSci Advisors，LLC董事总经理

bmackle@lifesciadvisors.com

bmackle@lifesciadvisors.com

For Media Relations Inquiries:

对于媒体关系查询：

Melyssa Weible

Melyssa Weible

Managing Partner, Elixir Health Public Relations

Elixir Health公共关系管理合伙人

mweible@elixirhealthpr.com

mweible@elixirhealthpr.com