TNF-α x TPL2

Bezisterim appears to possess broad homeostatic properties relevant to inflammation and human disorders related to aging Patients treated with bezisterim experienced 2 to 4 years age deceleration advantage compared to placebo Bezisterim modulated DNA methylation of proinflammatory genes and appeared to promote the transition of M1 proinflammatory to M2 anti-inflammatory macrophages Bezisterim was associated with 1.5 to 2.3 “fold enrichment” on gene control for hundreds of genes in pathways associated with neurodegenerative disorders and biological processes CARSON CITY, Nev., Aug. 27, 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 data from an oral presentation at the 11th Aging Research and Drug Discovery Meeting (ARDD 2024) being held August 26-30, 2024 in Copenhagen, Denmark. The presentation “Bezisterim Effects on Biological Age, Alzheimer’s Epigenetics, and Neurologic Assessments” provided an overview of clinical data to-date on bezisterim, focusing on various analyses and measurements related to longevity and its ability to affect the biological aging process broadly and chronic low-grade inflammation specifically. The presentation was given by Christopher L. Reading, BioVie’s Senior Vice President, Alzheimer’s Disease Program. “The presented clinical data provides the deepest understanding yet of how bezisterim may work at the gene level to reduce inflammation and impact disease,” said Cuong Do, BioVie’s President and CEO. “The data shows that patients treated with bezisterim experienced a two- to four-year age deceleration advantage when compared to placebo as measured by various biological clocks. The DNA methylation data also explain how bezisterim could modulate the function of specific proinflammatory genes and support the transition of M1 proinflammatory macrophages to the M2 anti-inflammatory state. Most importantly, the data shows bezisterim’s potential ability to control the expression of specific genes in pathways associated with diseases ranging from Parkinson’s and Alzheimer’s to ALS and biological processes ranging from TNF signaling to apoptosis.” As people age, a natural process called DNA methylation occurs where methyl groups are added to the surface of DNA. The over- or undermethylation of various genes have been shown to be associated with many diseases and the aging process itself. The presentation at ARDD 2024 detailed how bezisterim modulates DNA methylation and may have an impact in the following areas: The extent of DNA methylation of a person’s genome can be measured by a series of “clocks” that measure a person’s biological age, and the difference between the biological age and the number of years since birth is known as age deceleration or acceleration. In a clinical trial, patients treated with bezisterim saw an age deceleration advantage compared to those on placebo on various clocks: 3.68 years advantage on SkinBlood Clock (p=0.017), 4.77 years advantage on the Inflammation Age Clock (p=0.022), 5.0 years advantage on the Hannum Age Clock (p=0.006), 1.92 years advantage on the GrimAge Clock (p=0.068), and 3.71 years on the PhenoAge Clock (p=0.081). Bezisterim is believed to be the first drug candidate to show in a clinical trial an impact on modulating DNA methylation and age deceleration in a manner that is associated with specific diseases.DNA in blood comes predominantly from 3 cell types: monocytes/macrophages, lymphocytes, and granulocytes, and another set of clocks predicts the level of these immune cells. In the trial, the lymphocyte and granulocyte clocks are strongly and significantly correlated to observed levels of these cells for all patients. Placebo-treated patients saw a similar correlation between the monocyte clock and observed monocyte cell levels while bezisterim-treated patients did not show such correlation. Monocytes/macrophages control innate immunity and inflammation. The observed data suggest that bezisterim may support the transition of macrophages (and microglia in the CNS) from pro-inflammatory M1 state toward the M2 anti-inflammatory M2 state.Inflammatory factors, including TNFα, IL6, and MCP1, are produced when molecules such as ERK, MAP3K8, and NFκB perform their roles in various interrelated pathways, and the disruption of their function would disrupt the production of the inflammatory factors. The clinical data presented shows that bezisterim has the potential to significantly modulate the methylation levels of the genes that code for ERK, MAP3K8, NFκB, TNFα, IL6, and others. The data suggest that modulating the methylation levels for the individual actors in the various pathways could lead to reduced production of the inflammatory factors themselves.The Kyoto Encyclopedia of Genes and Genomes (KEGG) provides a mapping of known genes, molecules and pathways associated with individual diseases and cellular functions. The clinical data shows that bezisterim is associated with 1.5 to 2.3 “fold enrichment” (genes modulated compared to the pathway genes) in the pathways examined (all p<0.05). This impact was found for pathways leading to Alzheimer’s Disease, Parkinson’s Disease, amyotrophic lateral sclerosis, Huntington’s disease, and the biological processes involving cellular senescence, apoptosis, and TNF signaling. About DNA Methylation and Bezisterim’s Potential Modulating Role Everything in the body is encoded for by DNA, which is comprised of a series of four bases: adenine (A), cytosine (C), guanine (G), and thymine (T). As people age, a natural process known as DNA methylation can occur whereby a methyl group is added at various places where a cytosine is adjacent to a guanine (known as a CpG group). Current technology can measure the extent of methylation at roughly 965,000 such CpG sites in our genome, and many of the specific CpG sites can be mapped to genes with known functions. When DNA methylation occurs, the function of that specific gene is impaired because the molecule responsible for decoding that gene may not be able to properly access the genetic information. Epigenetics is the study of how behavior (e.g., diet, exercise) and environment affect the way our genes work in addition to the genetic code itself, and there’s an increasing body of evidence that signs of aging are epigenetic in nature.1,2 Perhaps the most studied area of epigenetics involves DNA methylation.3 Many studies have shown that genes become over- or under-methylated as we age,4,5,6 thereby suggesting that the modulation of DNA methylation could enable the up- or down-regulation of specific genes and thus modulate the aging process. Several “biological clocks” have been created to determine the biological age of our body based upon DNA methylation levels. A person’s biological age may be different from their actual number of years since birth due to their living habits that may lead to increased or lowered levels of DNA methylation, and the difference between biological age and chronological age is known as age deceleration or acceleration. Inflammation is a natural phenomenon associated with the body protecting itself. When a stimulus arises that recruits immune cells to help, these cells may release various inflammatory factors (e.g., TNFα, cytokines, chemokines, etc.) as part of their natural function. When the original stimulus has been addressed, immune cells reduce their activity and inflammation correspondingly decreases. When living choices and conditions create a situation where the stimulus is constant, chronic low-grade inflammation can arise since immune cells are constantly at work and are constantly releasing the inflammatory factors. Chronic low-grade inflammation is believed to be the underlying biological driver of many diseases. Inflammation results from a series of intricate and interrelated pathways involving actors such as ERK, MAP3K8, NFκB, and others that work together to trigger the production of inflammatory agents such as TNFα, IL6, IL17, etc. The genes that code for these pro-inflammatory actors can also be methylated. When these proinflammatory genes are methylated in control regions, their function becomes muted and results in the downward expression of the resulting inflammatory factors. The clinical data suggest that bezisterim appears to be broadly homeostatic for inflammatory processes and thus has specific up- and down-regulatory roles depending on which CpG and gene it affects (i.e., it does not indiscriminately reduce or increase methylation across the board). The data shows bezisterim modulates methylation for many CpGs as witnessed by the reduction of the biological age across the various clocks. With inflammatory genes, bezisterim upregulates the methylation of genes in the proinflammatory pathways, leading to reduced expression of these genes, which can reduce TNFα and other inflammatory factors. About 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. Persistently circulating viral spike proteins are believed to trigger TLR-4 driven activation of NFκB and the subsequent expression of inflammatory cytokines (IL-6, TNF, IFNγ). NE3107 has been shown to modulate the activation of NFκB and thus modulate inflammation. 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). 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. 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. patients treated with levodopa alone, and no drug-related adverse events. About 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). 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. 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. Forward-Looking Statements 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. 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. BioVie Inc. does not undertake any duty to update any statements contained herein (including any forward-looking statements), except as required by law. For Investor Relations Inquiries: Contact: Bruce Mackle Managing Director LifeSci Advisors, LLC bmackle@lifesciadvisors.com For Media InquiresMelyssa WeibleManaging Partner, Elixir Health Public Relations Ph: +1 201-723-5705mweible@elixirhealthpr.com ______________________ 1 Oberdoerffer P Nat Rev Mol Cell Biol 2007, 8:692–702.2 Campisi J J Gerontol A Biol Sci Med Sci 2009, 64A:175–178.3 Moore L Neuropsychopharmacology vol 38, pages23–38 (2013)4 Fraga MF Ann N Y Acad Sci 2007, 1100:60–74.5 Christensen BC PLoS Genet 2009, 5:e10006026 Horvath S Genome Biol 2012, 13:R97

Toll样受体(TLR)在触发先天性和适应性免疫反应中发挥着至关重要的作用。它们不仅启动先天免疫反应，而且还是先天免疫和适应性免疫之间的重要连接器。 Toll样受体(TLR)可分为十个，除了TLR10与其他不同，被认为是Toll样信号传导的免疫调节剂。特异性免疫可分为四类，涉及不同的TLR组合。BiomedicinesTH1免疫反应TH1免疫反应是对抗细胞内细菌、原生动物和真菌的宿主免疫反应，涉及的免疫细胞包括M1样巨噬细胞、产生IFN-γ的CD4+ T细胞、细胞毒性CD8+ T细胞和iNKT1等。Biomedicines涉及TH1免疫通路的自身免疫性疾病包括1型糖尿病、多发性硬化症、接触性皮炎和结核病等。关键TLR：TLR7、TLR8和TLR9这三者都位于巨噬细胞的内体区室中。TLR7、TLR8 和 TLR9对应的配体分别是单链RNA、细菌核糖体RNA和未甲基化的CpG DNA寡核苷酸。这些配体是在巨噬细胞吞噬溶酶体中细菌或原生动物的消化过程中产生的。TLR7、TLR8和TLR9主要的信号通路涉及IRF5和IRF7，它们上调IL-12和IFN-γ等下游靶标。TLR8信号转导激活IRF5，而TLR7/9信号转导激活IRF7。TLR7和TLR9首先激活MyD88复合物，包含TRAF3、TRAF6、IRAK4、IRAK1、IKKα、OPNi 和 DOCK2等等。其激活顺序为：TLR7通过激活MyD88从而首先激活IRAK1，再影响IKKα，使其触发转录因子IRF7。IRF7也可以被IRAK1磷酸化。TLR8则通过激活MyD88首先激活TAK1，再影响IKKβ。TAK1还可以激活下游分子JNK。当IKKβ易位到细胞核中时，它会触发转录因子IRF5。IRF5和IRF7的协同作用以产生IL-12，从而引发TH1反应，上调IFN-γ。TH2免疫反应TH2免疫反应是应对寄生虫的免疫反应，分为TH2a和TH2b。TH2a涉及炎性嗜酸性粒细胞、产生IL-4/5的CD4 T 细胞、具有类胰蛋白酶活性(MCt)的肥大细胞、iNKT2细胞和IgG4 B细胞。BiomedicinesTh2b则涉及嗜碱性粒细胞、产生IL-13/4的CD4 T细胞、具有类胰蛋白酶/糜酶活性的肥大细胞(MCtc)、iNKT2 细胞和产生IgE的B细胞。BiomedicinesTH2免疫与1型IgE相关的过敏性疾病密切有关，如哮喘、过敏性鼻炎和特应性皮炎等。关键TLR：TLR1、TLR2和TLR6TLR2和TLR6在嗜碱性粒细胞或肥大细胞等APC的表面上表达。TLR2可以在细胞表面与TLR6或TLR1形成异二聚体，共同识别三酰基脂蛋白，从而触发MAL接头分子，其激活MyD88非依赖性通路，产生IL-4，触发TH2免疫反应。TLR2-TLR6异二聚体则激活下游PI3K和AKT通路。TLR2激活导致TPL2(MAP3K8)被激活，继而通过IKK2介导激活NFκB通路。TPL2还激活MEK1/2和ERK1/2信号转导，从而触发TH2免疫通路。除了IL-4之外，依赖TLR6而上调的IL-25和依赖TLR1/TLR6的IL-33也是驱动TH2免疫反应的关键细胞因子。Th22免疫反应Th22免疫代表宿主针对细胞外细菌、原生动物和真菌的免疫反应。涉及中性粒细胞N1、分泌IL-22的Th细胞、iNKT17细胞和IgG2 B细胞。BiomedicinesTH22主导的免疫通路与3型免疫复合物超敏反应有关，包括阿瑟氏反应和类风湿性关节炎等疾病。关键TLR：TLR2、TLR4和TLR5与TH22免疫通路相关的主要TLR是TLR2、TLR4和TLR5，在中性粒细胞、树突状细胞和单核细胞/巨噬细胞的表面表达。TLR2同型二聚糖可识别革兰氏阳性细菌细胞壁中的肽聚糖和脂磷壁酸，同时还与真菌细胞壁中的β-葡聚糖相互作用。TLR4则负责识别革兰氏阴性菌细胞壁中的 LPS 内毒素。此外，TLR5可识别在运动细菌中发现的鞭毛蛋白。TLR4 信号转导触发MyD88、IRAK1和IRAK4组成的复合物。IRAK4激活IRAK1导致IRAK1自磷酸化及其与MyD88复合物的解离。随后，IRAK1 与泛素结合酶UBC13和UEV1A结合，促进TRAF63/TAK6复合物的泛素化。IRAK1的激活也会诱导TAK1和TRAF6激活，诱导下游NFκB易位到细胞核中，从而触发炎症基因的表达，上调IL-1、IL-6和TNF-α。此外，TAK1激活也导致转录因子AP1依赖于MAPK的激活。Thαβ免疫反应THαβ免疫是宿主针对病毒和朊病毒等传染性分子的免疫反应，涉及NK1细胞、分泌IL-10的CD4 T细胞、iNKT10细胞、CD8 T细胞和IgG1 B细胞。BiomedicinesTHαβ 免疫与2型抗体依赖性细胞毒性超敏反应有关。涉及THαβ免疫通路的自身免疫性疾病包括Graves病、重症肌无力和系统性红斑狼疮等。关键TLR：TLR3、TLR7和TLR9TLR3、TLR7和TLR9主要在浆细胞样树突状细胞的内体区室中表达，内体区室为病毒和 TLR 之间的相互作用提供了理想的环境。TLR3可识别病毒复制过程中产生的dsRNA，而TLR7可检测该阶段也存在的ssRNA。TLR9则可识别在细菌和病毒基因组中未甲基化的CpG DNA。涉及TLR3、TLR7和TLR9的信号通路汇聚在IRF3和IRF7上，启动下游1型IFN信号通路，从而启动THαβ免疫应答。激活后，TLR3直接触发TRIF-IRF3信号通路，TLR7和TLR9激活IRAK1-IRF7信号通路。TRIF-IRF3信号通路触发涉及TRAF3、TBK1和IKKε的级联反应。另一方面，TLR7和TLR9激活MyD88通路，通过IRAK1进一步激活IKKα，在细胞核激活转录因子IRF7。IRF3和IRF7均能激活IFN-α和IFN-β的产生，从而启动THαβ免疫应答。此外，IL-27和IL-10也是驱动细胞因子之一。小结TLR不仅可以通过拮抗剂来治疗自身免疫性疾病，在其他领域也有应用。例如TLR激动剂可用于触发宿主对癌症的免疫反应，诱导癌细胞凋亡，从而作为肿瘤治疗的辅助药物。在疫苗开发中，配方里增加TLR激动剂也可以加强疫苗对致病原的效力。参考文献：1.Chu, Y.-T.; Liao, M.-T.; Tsai, K.-W.; Lu, K.-C.; Hu, W.-C. Interplay of Chemokines Receptors, Toll-like Receptors, and Host Immunological Pathways. Biomedicines 2023, 11, 2384. https://doi.org/10.3390/biomedicines110923842.Jang YH, Choi JK, et al.House Dust Mite Increases pro-Th2 Cytokines IL-25 and IL-33 via the Activation of TLR1/6 Signaling. J Invest Dermatol. 2017 Nov;137(11):2354-2361. doi: 10.1016/j.jid.2017.03.042.

BioVie Provides Updates on Other Clinical ProgramsVast majority of patients saw significant improvements in the Global Rating of Change (overall impression of patient’s daily abilities) with NE3107 treatment (p<0.0001 to p<0.05).NE3107 is associated with significant improvements in cognition as evidenced by the ADAS-Cog12 scale. 82% of 17 patients with MMSE >=20 experienced a 2.6 point decrease in ADAS-Cog12 (p=0.0046).Reductions in TNFa (considered to be an initial factor driving inflammation) after NE3107 treatment are significantly correlated with improvement in cognition.NE3107 treatment associated with trending improvements in ratio of p-tau:Ab. 60% of 10 patients with MMSE >=20 improved 0.002 in the ratio of p-tau / Ab (p=0.055).Early analyses of imaging data suggest fundamental biological improvements in blood flow and reduced oxidative stress that are consistent with the mechanism for NE3107 and are unlikely to be accounted for by placebo effect.No drug-related adverse events (AEs) were reported.Detailed results will be presented at the CTAD 2022 Annual Conference. CARSON CITY, Nev., Sept. 07, 2022 (GLOBE NEWSWIRE) -- BioVie Inc., (NASDAQ: BIVI) (“BioVie” or the “Company”) a clinical-stage company developing innovative drug therapies for the treatment of advanced liver disease and neurological and neurodegenerative disorders, today announced topline results from an investigator-Sponsored Phase 2 clinical trial of NE3107 for the treatment of Alzheimer’s Disease (AD). Updates from other trials underway are also provided. AD research has largely focused on Amyloid Beta (Ab) and phospho-tau (p-tau) for decades and has resulted in a large number of trials targeting these mechanisms.1 More recently, however, research focus has shifted towards targeting neuroinflammation, as evidenced by the 23 disease-modifying agents listed in clinicaltrials.gov in 2021 investigating inflammation or the immune system. NE3107 is the only molecule in this group that is pursuing a two-pronged approach targeting both neuroinflammation and insulin resistance. Furthermore, NE3107 is the only molecule in the group that is conducting a potentially pivotal Phase 3 trial (NCT04669028) that is currently underway in mild- to moderate-AD patients with co-primary endpoints of cognition, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12), and function, as measured by Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), whereas 17 other agents are in Phase 2. This Phase 3 trial is expected to provide topline results in mid-2023. Tumor Necrosis Factor Alpha (TNFa) is a cytokine identified as a major regulator of inflammation given that its excessive activation is associated with chronic inflammation.2 It is considered to be the central mediator of inflammation due to its role at the top of the biochemical pathway that leads to the production of other inflammatory factors such as various cytokines (e.g., IFNg, IL-1b, IL23, IL-4, IL-17), neurotoxic Aβ peptide oligomers, activation of IKK and JNK (that leads to insulin resistance), and others. A large retrospective study analyzing the electronic medical records of 56 million unique patients demonstrated the linkage between TNFa and AD by showing that patients with rheumatoid arthritis and psoriasis taking TNF blocking agents had significantly lower AD risk.3 Preclinical studies showed NE3107 is a modulator of TNFa production through its ability to modulate the activation of the Extracellular Regulated Kinase (ERK) and Nuclear Factor kappa B (NFkB).4 By down regulating the activation of ERK and NFkB, NE3107 has been shown to reduce the production of TNFa.5 The Company’s newly generated data supporting a new patent application show that NE3107 inhibits inflammatory ERK activation and blocks the phosphorylation of TNF receptor 1 (TNFR1) in an IKK-MAP3K8-MEK dependent pathway to decrease forward-feeding TNF inflammatory cascades, thereby lowering the expression of other downstream inflammatory factors. Since the NE3107 Phase 3 trial underway is focused on cognition and function and is not focused on collecting neuroinflammatory biomarkers, the Company supported a Phase 2 investigator-initiated trial (NCT05227820) to explore the link between NE3107’s role in neuroinflammation and insulin resistance to the biomarkers historically used by the AD research community. It also was designed to provide, if possible, a glimpse into what can be expected regarding cognition and function when the Phase 3 trial reads out next year. This was done by using a modified ADAS-Cog12 scale for cognition and the Global Rating of Change (GRoC), which is an instrument that can be administered more easily in general clinical practices than the ADCS-CGIC. The Phase 2 trial— A Phase II Open-Label Study for the Use of Anti-Inflammatory, Insulin-Sensitizing NE3107 for Treatment of Cognitive Decline Due to Degenerative Dementias (NCT05227820) — is an exploratory biomarker study conducted by Dr. Sheldon Jordan6, who served as principal investigator for the trial. The trial was intended to explore NE3107’s potential role in real-world clinical practice as an exploratory precursor informing the design of subsequent placebo-controlled blinded studies. Results from Phase 2 Exploratory Biomarker Trial The trial enrolled a total of 23 patients – 17 patients with Mini-Mental State Examination (MMSE) scores greater than or equal to 20 (i.e., mild cognitive impairment [MCI] to mild AD) and 6 patients with MMSE <20 (i.e., moderate AD) – in an open-label, single arm study. The trial measured changes in cognition through verbal and visual test procedures, changes in biomarkers of Alzheimer’s disease and inflammation that can be measured in cerebral spinal fluid (CSF) and serum samples, and with functional magnetic resonance imaging techniques in patients before and after treatment with 20 mg of NE3107 twice daily for 3 months. Initial results showed that the measurements for most patients improved with NE3107 treatment, although MCI/mild AD patients showed greater change. The Global Rating of Change is a frequently used outcome measure that tracks improvements in a patient’s conditions, abilities and overall sense of well-being as perceived by the clinician, the caretakers and the patients. A large proportion of MCI/mild AD patients in the trial showed improvements as evidenced by an increase of the GRoC scale after treatment with NE3107 compared to baseline as scored by the clinician (94% of 17 patients improved, p=0.0001), the study partner (65% of 17 patients improved, p=0.078), and the patient (88% of 17 patients improved, p=0.0039). A similar pattern of improvements was observed within the total pool of patients.Several tools were used to assess changes in cognition, including a modified ADAS-Cog12, the Quick Dementia Rating Scale (QDRS), Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). 82% of 17 MCI/mild AD patients improved with a mean ADAS-Cog12 change of -2.6 points (p=0.046) equating to a mean percentage change of -25.1% (p=0.0026). 61% of all 23 patients improved with a mean change of -1.04 (p=ns).A similar pattern of improvement was observed using the QDRS. 71% of 17 MCI/mild AD patients improved with a mean change of –1.35 (p=.0051). Improvements in ADAS-Cog12 were correlated with improvements in the Global Rating of Change as reported by the clinician (R=0.52, p<0.05) and the caretaker (R=0.46, p<.05).62% of 13 MCI/mild AD patients had decreased plasma TNF with a mean change of -0.55 pg/mL (p=0.22). Importantly, improvements in TNFa statistically correlated to improvements in ADAS-Cog12 (R=0.70, p=0.0077).The ratio of p-tau to Ab42 has been shown by the Mayo Clinic and others to be an effective predictor of PET Ab status.7 63% of 16 patients improved with a mean change in the ratio of -0.0033 (p=0.069).While quantitative scoring of imaging data is currently underway, review of imaging scans and data by the study’s Principal Investigator (who is an imaging expert) indicates that NE3107 treatment in patients with MMSE >=20 is associated with certain changes in the brain. Among patients with MMSE >=20: 24% had increased blood flow in the brain while 6% declined. Blood flow is a marker for metabolism and brain activity.41% to 47% had reduced the hyperactivation associated with cognitive impairment that results when the hippocampus (part of the brain that plays a major role in learning and memory) is stressed while 6% declined. This is a marker for network connectivity in the brain41% had increased levels of glutathione (considered the master antioxidant and regulator of oxidative stress8) in the brain while 35% declined. No treatment related AEs were reported. The Company will present the final data and statistical analyses, which may deviate from the initial result presented here, at the Clinical Trial in Alzheimer’s Disease (CTAD) annual conference, to be held in San Francisco, CA November 29-December 2, 2022. Platform presentations and posters will provide detailed findings on changes on biomarker, neuropsychological assessments, and advanced MRI imaging. Research papers are being prepared to present the findings and will be submitted to peer-reviewed journals for publication. “Through our work, we are seeking to deepen our understanding of brain degeneration and ultimately identify promising treatments that have the potential to counteract the degenerative process. Results from this trial provide encouraging signals that NE3107 may offer significant potential to reduce neuroinflammation and potentially improve metabolic parameters such as glutathione in the brain, and warrant further study in this patient population,” said Dr. Jordan. “I was surprised to see imaging data changes and how so many patients had increased GRoC score, indicating they can perform more activities of daily living." “We are delighted to support the work of Dr. Jordan and his team and are very pleased to have this initial data-driven validation of NE3107’s potential role for the treatment of people suffering from cognitive impairment and dementia,” stated Dr. Joseph Palumbo, BioVie’s Chief Medical Officer. “Despite this being an open label study, the insights provided are instructional and directionally very interesting. While it is not possible to isolate the placebo effect in an open label study as a placebo-controlled double blinded trial can, results on TPO arterial spin label imaging, hippocampal blood oxygen level-dependent imaging, brain NMR spectroscopy measuring glutathione, and peripheral TNF reduction from this study provide helpful information to plan our next steps.” “This study provides us with an early opportunity to assess the effects of NE3107’s mechanism of action in the brain, and these topline results represent the first detailed data linking NE3107’s role in neuroinflammation and insulin resistance with the traditional biomarkers of interest to the AD research community,” added Cuong V. Do, President and CEO of BioVie. “I was excited about correlation of TNFa reduction with improvements in cognition and how treated patients saw an improvement in the ratio of p-tau:Ab. We supported Dr. Jordan’s Investigator-Sponsored trial as an exploratory biomarker study to guide our efforts to design future placebo-controlled trials to examine the potential impact of NE3107 on traditional AD biomarkers and measures of cognition and function. We are very grateful for the work of Dr. Jordan and his team on this important study and look forward to the team’s presentation at CTAD later this year.” Commenting on the mixed results observed in AD research over the decades, Mr. Do added, “AD drug development at BioVie is based on the evidence that AD pathology is multifactorial in nature. While Ab and p-tau are important factors, decades of research on dozens of agents have not conclusively correlated improvements on these individual factors to improvements in cognition. We believe additional factors such as inflammation, insulin resistance, metabolic dyshomeostasis, apoptosis, oxidative stress, and glucose utilization also play critical roles in AD etiology. Data shows that NE3107’s ability to reduce TNFa (the major regulator of inflammation) is highly correlated to improvements in cognition. We are pleased that the Principal Investigator observed these changes in 23 patients in only 3 months. We hypothesize that the modulation of TNFa levels and its inflammatory activation via TNFR1 lead to a multitude of changes among the many factors downstream from this master regulator, which collectively lead to improvements in neuronal health and cognition.” Update on other clinal trials In addition to the Phase 2 exploratory biomarker trial, the Company has three other trials underway. The potentially pivotal Phase 3 trial for NE3107 in AD (NCT04669028) has enrolled one-half of the targeted 316 patients. In blinded data, no drug-related adverse events have been seen in daily medical reviews. The study pre-specified the potential to increase enrollment up to 400 patients as deemed appropriate through a review by the data safety monitoring board (DSMB) in a manner that is blinded to the Company. This DSMB review will take place later this year and will determine if a sample size adjustment is needed for the purpose of enhancing the probability of achieving statistical significance. If no sample size adjustments are needed, the Company expects full enrollment of the study by the end of the year, enabling topline data readout by mid-2023. The study may be delayed if additional patients need to be enrolled in the event of a DSMB recommendation.The Phase 2 trial (NCT05083260) is enrolling 40 patients to examine NE3107 in Parkinson’s disease (PD) with two design objectives. The primary objective is a drug-drug interaction study as requested by the FDA to demonstrate the absence of adverse interactions of NE3107 with levodopa in humans (no indications of adverse DDI were observed in prior animal studies). The secondary objective is to explore an efficacy signal and determine if preclinical indications of promotoric activity and apparent enhancement of levodopa activity in MPTP rodents and marmosets can be observed in humans. In preclinical studies, NE3107 had promotoric activity equal to levodopa and the combination of NE3107 with levodopa was superior to either agent alone, providing the most “on time” without dyskinesia. The Company expects the trial to be fully enrolled in the next couple of months and data readout by the end of 2022. Similar to the AD Phase 3, no drug-related adverse events have been seen in daily medical reviews. We are detecting an efficacy signal among patients who have completed 28 days of treatment, but more data is needed to quantify the full therapeutic impact.The Phase 2b trial for BIV201 in refractory ascites (NCT04112199) is enrolling 30 patients with co-primary endpoints measuring the incidence of ascites-related complications over 180 days and change in ascites fluid removed over 90 days. The trial is taking much longer than expected. Patient recruitment has been hampered by Covid-19, which appears to have disproportionately affected this population of very sick patients. The pace of patient screening, however, appears to be picking up in recent weeks. At this pace, the Company anticipates data readout by mid-2023. The updated corporate overview and additional information can be found at https://bioviepharma.com/investors/. About BioVie BioVie Inc. (NASDAQ: BIVI) is a clinical-stage company developing innovative therapies to overcome unmet medical needs in chronic debilitating conditions. In neurodegenerative disease, the Company’s drug candidate NE3107 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). Both are drivers of Alzheimer’s and Parkinson’s diseases. The Company is conducting a potentially pivotal Phase 3 randomized, double blind, placebo controlled, parallel group, multicenter study to evaluate NE3107 in patients who have mild to moderate Alzheimer's disease (NCT04669028) and is targeting primary completion in mid-2023. An estimated six million Americans suffer from Alzheimer’s. A Phase 2 study of NE3107 in Parkinson’s disease (NCT05083260) is enrolling patients and expects to have topline data readout by the end of 2022. In liver disease, the Company’s Orphan drug candidate BIV201 (continuous infusion terlipressin), with FDA Fast Track status, is being evaluated in a US Phase 2b study for the treatment of refractory ascites due to liver cirrhosis with top-line results anticipated in mid-2023. BIV201 is administered as a patent-pending liquid formulation. The active agent is approved in about 40 countries for related complications of advanced liver cirrhosis but is not available in the US or Japan. For more information, visit http://www.bioviepharma.com/. Forward-Looking Statements 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. 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, 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. BioVie Inc. does not undertake any duty to update any statements contained herein (including any forward-looking statements), except as required by law. Abbreviations Used AbAmyloid betaADAlzheimer’s diseaseADAS Cog 12Alzheimer's Disease Assessment Scale-Cognitive subscale 12ADCS-CGICAlzheimer's Disease Cooperative Study-Clinical Global Impression of Change ScaleAKIAcute kidney injuryCSFCerebral spinal fluidCTADClinical Trials on Alzheimer’s Disease (a medical conference)DSMBData and Safety Monitoring BoardERKExtracellular signal regulated kinase 1 and 2GRoCGlobal Rating of ChangeHRSHepatic renal syndromeIKKIkappaB kinase, an inflammatory signaling protein that activates NFkBINFgInterferon gammaIL-1bInterleukin one betaIL- 4, 17, 23Interleukin 4, 17, 23JNKc-Jun N-terminal kinases, an inflammatory signaling protein kinaseMAP3K8Mitogen-activated protein kinase kinase kinase 8, an inflammatory signaling protein involved in pathological inflammationMCIMild cognitive impairmentMEKMitogen and ERK kinase, an ERK activating protein kinaseMMSEMini Mental State ExaminationMoCAMontreal Cognitive AssessmentNE310717a-ethynyl-androst-5-ene-3b,7b,17b-triolNFkBNuclear factor kappa-light-chain-enhancer of activated B cellsp38One of several mitogen-activated protein kinases involved in inflammatory signalingPDParkinson’s diseasepgpicogramp-tauHyperphosphorylated tau proteinQDRSQuick Dementia Rating ScaleTNFaTumor necrosis factor alphaTNFR1Tumor necrosis factor receptor R1 For Investor Relations Inquiries:Contact:Bruce MackleManaging DirectorLifeSci Advisors, LLCbmackle@lifesciadvisors.com 1 Cummings et al. 2022 DOI: 10.1002/trc2.122952 Jang et al. Int J Mol Sci. 2021 Mar; 22(5): 2719.3 Zhou et al. 2020 PLoS ONE 15(3): e0229819.4 Lu 2010 Am J Physiol Endocrinol Metab 298 E1036; Wang 2010 J Pharmacol Exp Ther 333 705 Offner 2009 J Pharmacol Exp Ther 329 11006 Dr. Jordan is Adjunct Clinical Associate Professor of Neurology at UCLA. Dr. Jordan is board certified by the American Board of Psychiatry & Neurology, American Board of Clinical Neurophysiology, American Board of Addiction Medicine, and American Board of Interventional Pain Medicine. He was elected as Fellow of the American Academy of Neurology and holds additional certifications from the American Society of Neuroimaging in Magnetic Resonance Imaging, Computed Tomography and Ultrasonography. Dr. Jordan is the senior author of a recent paper on quantitative MRI imaging in dementia (Kuhn et al., 2021 Quant Imaging Med Surg 11)7 Campbell et al. Alzheimers Dement (Amst). 2021; 13(1): e12190.8 Teskey et al. Advances in Clinical Chemistry Volume 87, 2018, Pages 141-159