CCL2

VIVIAD Phase 2b study did not meet its primary and key secondary endpoints Varoglutamstat was generally well tolerated with low discontinuation rates due to adverse events and no evidence of symptomatic ARIAs in the clinical setting VIVIAD is a comprehensive, diligently designed and high-quality study; baseline demographics in the study were highly representative of early AD patient population Company is conducting an in-depth analysis of the results, including analyses of additional pre-specified and exploratory endpoints Further update expected to be provided no later than with publication of Company’s full year 2023 financial results March 4, 2024 – Vivoryon Therapeutics N.V. (Euronext Amsterdam: VVY; NL00150002Q7) (Vivoryon), a clinical stage company focused on the discovery and development of small molecule medicines to modulate the activity and stability of pathologically altered proteins, today announced topline results from its Phase 2b European VIVIAD study of varoglutamstat (PQ912), an investigational oral glutaminyl cyclase (QPCT) inhibitor in development for the treatment of early Alzheimer’s disease (AD). The VIVIAD study did not meet its primary endpoint and did not show a statistically significant difference in change over time on cognition, as measured by a combined score (Z-score) of the Detection test, the Identification test and the ‘One Back’ test (attention and working memory domains) of the Cogstate neuropsychological test battery (NTB), called “Cogstate 3-item scale”. Additionally, the study did not meet key secondary endpoints measuring cognition (Cogstate Brief Battery, CBB, and complete Cogstate NTB), Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) and electroencephalogram (EEG) global theta power. Varoglutamstat was generally well tolerated and showed rates similar to placebo of serious and severe treatment emergent adverse events (TEAEs), low discontinuation rates due to adverse events and no evidence of symptomatic ARIAs (amyloid-related imaging abnormalities) in the clinical setting. The Company is conducting an in-depth analysis of the results, including analyses of additional pre-specified exploratory endpoints (e.g. WAIS-IV coding test, executive function and episodic memory domains, Winterlight Labs speech assessment, cerebrospinal fluid (CSF) biomarkers and additional EEG analysis) and distinct patient cohorts as defined in the statistical analysis plan, including ApoE4 status, tau level, dose level and pre-treatment. “We are profoundly disappointed by the outcome of the VIVIAD Phase 2b study of varoglutamstat in the early AD patient population given the huge unmet need for new safe and effective oral therapies,” said Frank Weber, M.D., CEO of Vivoryon. “I would like to express our gratitude to the patients, their families and caregivers, as well as the investigators for participating in the VIVIAD study, and to our incredible team at Vivoryon for their tireless efforts. While these results are not what we had hoped for, VIVIAD is a comprehensive, diligently designed and high-quality study and we are doing all we can to fully analyze the dataset as quickly as possible to gain insights into key findings that might influence varoglutamstat clinical development and help advance the science and understanding of this devastating disease.” A further update is expected to be provided no later than with the publication of the Company’s full year 2023 financial results which are expected in mid to late April 2024. Varoglutamstat (PQ912) is a differentiated oral small-molecule targeting the toxic Abeta species N3pE which is being developed as disease-modifying therapy and is designed to target AD pathology upstream of Abeta-antibody focused approaches. Varoglutamstat blocks the enzyme glutaminyl cyclase (QPCT) and its isoenzyme QPCTL. QPCT catalyzes the formation of N3pE amyloid, a particularly neurotoxic variant of Abeta peptides, which is only found in patients with AD and not present in the brains of healthy individuals. N3pE amyloid in the brain acts as a seeding element for Abeta aggregation, thus providing a starting point for plaque formation. It has been described to correlate with the cognitive ability of patients with AD. Beyond Abeta pathology, varoglutamstat has also been shown to impact synaptic impairment. Through a second mode of action, the inhibition of full CCL2 maturation via QPCTL, varoglutamstat modulates pro-inflammatory signaling and tau pathology, thereby simultaneously addressing multiple hallmarks of AD. Vivoryon has received Fast Track designation for varoglutamstat in early AD by the U.S. Food and Drug Administration (FDA). It is being investigated in two Phase 2 clinical studies, one in Europe (VIVIAD, NCT04498650) and one in the U.S. (VIVA-MIND, NCT03919162). Varoglutamstat has not yet been approved by any regulatory authority and the safety and efficacy have not yet been established. VIVIAD is a state-of-the-art Phase 2b study conducted in Europe and designed to evaluate the safety, tolerability, and efficacy of varoglutamstat in 259 participants with mild cognitive impairment (MCI) and mild AD (collectively referred to as “early AD”). The primary endpoint is the change over time on working memory and attention as measured by a combined score (Z-score) of the Detection test, the Identification test and the ‘One Back’ test (attention and working memory domains) of the Cogstate neuropsychological test battery (NTB), called “Cogstate 3-item scale”. Key secondary efficacy endpoints include in hierarchical order: Cogstate Brief Battery (CBB, 4-item scale), the complete Cogstate NTB (8-item scale), the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q), and electroencephalogram (EEG) global theta power. Vivoryon is a clinical stage biotechnology company focused on developing innovative small molecule-based medicines. Driven by our passion for ground-breaking science and innovation, we strive to change the lives of patients in need suffering from severe diseases. We leverage our in-depth expertise in understanding post-translational modifications to develop medicines that modulate the activity and stability of proteins which are altered in disease settings. Beyond our lead program, varoglutamstat, which is in Phase 2 clinical development to treat Alzheimer’s disease, we have established a solid pipeline of orally available small molecule inhibitors for various indications including cancer, inflammatory diseases and fibrosis. www.vivoryon.com The content above comes from the network. if any infringement, please contact us to modify.

Data from Phase 2a trial in Parkinson’s Disease suggest patients treated with NE3107 experienced significant improvements in non-motor symptoms and motor control while placebo-treated patients worsened Data from Phase 3 trial in mild to moderate Alzheimer’s Disease suggest NE3107 may have the potential to realign physiological processes in patients consistent with decreased neurocognitive decline and diseases of aging CARSON CITY, Nev., March 01, 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 two upcoming presentations at the International Conference on Alzheimer’s and Parkinson’s Diseases 2024 (AD/PD™ 2024) to be held March 5-9, 2024 in Lisbon, Portugal. Improvements in non-motor symptoms correlated with improvements in motor symptoms for Parkinson’s Disease patients The presentation Improvement of Non-Motor Symptoms with NE3107 Adjunctive to Carbidopa/Levodopa in Patients with Parkinson’s Disease: A Phase 2A, Placebo-Controlled Study will be presented at 15:10 GMT on March 9, 2024 and suggest improvements of NE3107-treated patients with non-motor symptoms. These findings complement previously reported improvement in motor symptoms in patients treated with NE3107 and demonstrate potential intrinsic, levodopa-enhancing activity of NE3107 that is consistent with data from animal models. NE3107-treated patients experienced a significant improvement of -2.4 points for the sleep/fatigue domain of the Non-Motor Symptom Scale (NMSS) in Parkinson’s Disease, whereas placebo patients experienced a worsening of +1.0 points (p=0.0159). Sleep/fatigue domain improvements correlated with motor score improvements (r=0.51; p=0.0259). More patients on NE3107 had improvements in the NMSS sleep/fatigue domain, while more patients on placebo worsened. NMSS changes for NE3107-treated patients were driven by improvements of -0.87 in fatigue/lack of energy (p= 0.0005) and improvement of -2.91 on the urge to move legs/restlessness in legs (p=0.0036). Placebo patients saw no significant change of -0.39 on fatigue (p=0.1242) and -0.71 on leg restlessness (p=0.5141). The new data on non-motor improvements complements previously presented data1 showing NE3107-treated patients saw a 3+ points advantage compared to placebo on the Part 3 (motor) score of the Motor Disease Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). In patients younger than 70 years old, the advantage was over 6 points. Furthermore, 26% of NE3107-treated patients experienced improvement in their ability to move, having Part 3 scores prior to their first morning dose of carbidopa/levodopa that were equal to or better than Part 3 scores associated with their being in the “on” state after carbidopa/levodopa treatment at the start of the study, whereas none of the placebo patients had the similarly improved morning Part 3 scores. The difference was statistically significant (p=0.046). “These data suggest that NE3107 as adjunct therapy to levodopa may hold promise in ameliorating specific non-motor symptoms of Parkinson’s Disease, particularly in sleep/fatigue and restlessness of the legs,” stated Joseph Palumbo, BioVie’s Chief Medical Officer. “These findings extend previously reported improvement in motor symptoms with NE3107 and demonstrate potential intrinsic and levodopa-enhancing activity of NE3107 that is consistent with data from animal models and support further clinical investigation of NE3107 in late-phase trials.” Possible physiological realignment in Alzheimer’s Disease The presentation Clinical Outcomes from a Phase 3, Randomized, Placebo-Controlled Trial of NE3107 in Subjects with Mild to Moderate Probable Alzheimer’s Disease will be presented at 14:50 GMT on March 8, 2024 reconfirms topline cognitive and functional data previously presented and will provide additional biomarker data and analyses. The NM101 Trial enrolled 439 patients through 39 sites. The Company previously reported that upon trial completion, significant deviation from protocol and Good Clinical Practice violations were found at 15 sites, causing the Company to exclude all patients from these sites. After these exclusions and other exclusions per the statistical analysis plan, 57 patients in the Per-Protocol population were verified to have taken study drug from pharmacokinetics data and completed the full duration of the trial. Baseline and completion data were available for 50 subjects (NE3107, n=24 and placebo, n=26; 7 subjects randomized to placebo discontinued before day 150), and DNA methylation data were available for 33 subjects in this cohort. Due to the exclusion of data from so many sites the trial missed statistical significance but showed promising directional data on cognitive and functional measures. NE3107-treated patients saw an advantage compared to placebo of -0.95 (68% slowing of decline) on CDR-SB, -0.94 (26%) on ADAS-COG-12, -0.43 (139%) on ADAS-CGIC, -0.03 (27%) on ADCOMS, +1.02 (40%) on MMSE, and +3.08 (47%) on ADCS-ADL.2 Significant improvements for NE3107-treated patients vs. placebo were observed for biological age deceleration (-3.87 years, p=0.012), fasting glucose levels (-8.5 mg/dL, p=0.036), cholesterol (-15 mg/dL, p=0.049), HOMA2 beta cell function (+12.4%, p=0.040), HOMA2 Insulin Sensitivity (+1.95%, p=0.018), and MCP1 (-90.5 pg/mL, p=0.007). Trending improvements in HOMA2 Insulin Resistance of -0.020 (p=0.0.063) were also observed. A statistical technique called Principal Component Analysis3 identified neurological assessments and biological age deceleration as the two “principal components” that maximally explained the data across the large set of variables collected. Among NE3107-treated patients, correlations of neurological assessments and biological age deceleration with improved metabolic and glycemic control, improved neuropsychiatric indices, and levels of chemokines associated with microglial attraction to and digestion of Aβ plaques. Among placebo patients, neurological assessments and biological age deceleration were correlated with increased metabolic inflammatory measures, M1 to M2 transition, and plaque phagocytosis. “We previously reported that NE3107 appeared to decrease metabolic inflammation-driven systems dysregulation,” stated Chris Reading, BioVie’s Senior Vice President of Alzheimer’s Disease Programs. “Principal component analyses, divergent correlations, and epigenetic analysis suggest that metabolic inflammation may be a driver of biological aging and AD, and that NE3107 might have the potential to realign physiological processes consistent with decreased neurocognitive decline and diseases of aging.” “The data being presented reinforce our confidence in the potential of NE3107 to have a meaningful impact on core symptoms of both Alzheimer's disease and Parkinson's disease,” stated Cuong Do, BioVie's President and CEO. “These findings add to the growing body of evidence supporting our hypothesis that by selectively modulating inflammation and enhancing insulin sensitivity in the brain, NE3107 could offer benefits in slowing disease progression and improving the lives of patients living with these devastating conditions.” About BioVie 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 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 conducted and reported efficacy data from its randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate NE3107 in patients who have mild to moderate Alzheimer's disease (NCT04669028). Results of a Phase 2 investigator-initiated trial (NCT05227820) showing NE3107-treated patients experienced improved cognition and biomarker levels were presented at the Clinical Trial in Alzheimer’s Disease (CTAD) annual conference in December 2022. An estimated six million Americans suffer from Alzheimer’s. A Phase 2 study of NE3107 in Parkinson’s disease (NCT05083260) has completed, and data presented at the International Conference on Alzheimer's and Parkinson's Disease and Related Neurological Disorders conference 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 NE3107 and levodopa vs. patients treated with levodopa alone, and no drug-related adverse events. 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 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. In this press release, forward-looking statements include, but are not limited to, the potential impact of NE3107 on cognition and function among study participants and topline data from the NE3107 trial. 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 MackleManaging DirectorLifeSci Advisors, LLCbmackle@lifesciadvisors.com For Media InquiresMelyssa WeibleManaging Partner, Elixir Health Public Relations Ph: +1 201-723-5705mweible@elixirhealthpr.com _________________________1 A Randomized, Phase 2a, Double-Blind, Placebo-Controlled Clinical Trial With NE3107 Adjunctive to Carbidopa/Levodopa in Patients With Parkinson’s Disease. Presented at the 2023 International Congress of Parkinson’s Disease and Movement Disorders, August 27-31, 2023 in Copenhagen, Denmark2 ADAS-Cog12 = 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (lower is improvement); ADCOMS = Alzheimer’s Disease Composite Score (lower is improvement); ADCS-ADL = Alzheimer’s Disease Cooperative Study-Activities of Daily Living (higher is improvement); ADCS-CGIC = Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (lower is improvement); CDR-SB = Clinical Dementia Rating, Sum of Boxes (lower is improvement), MMSE = Mini Mental State Examination (higher is improvement).3 Principal component analysis is a statistical method for identifying/combining separate variables to a few “principal components” that maximally explain the variance of all the underlying variables. In the process, the method provides an approximation of the original data represented by the many individual variables using only a few major components.

The absence of a single immune cell receptor has been linked to both fewer defenses against mycobacterial infections, such as TB, and damaging buildup of sticky residue in the lungs. The macrophage is one of the body's most important inhabitants. Meaning "big eater" in Greek, this immune cell consumes and digests problematic elements from microbes and cancer cells to dust and debris. Macrophages are especially important in the lungs, where they both fight bacterial infection and clear the lungs of excess surfactant, a protein- and lipid-rich layer that's essential to healthy function but can create a sticky buildup if not controlled. In a recent study, investigators from Rockefeller University and other institutions have discovered a never-before-documented genetic disorder that causes the improper functioning of these cells. The researchers made their discovery by drawing an unexpected connection between a select group of sick children. Throughout their lives, these nine children had battled severe diseases such as pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent bacterial and viral infections that left them gasping for breath from often cyst-plagued lungs. But as genomic data revealed, the children shared another characteristic: the absence of a chemical receptor that is supposed to call alveolar macrophages into action. It's the first time that this missing receptor, called CCR2, has been linked to disease. The researchers, including Rockefeller's Jean-Laurent Casanova and Institut Imagine's Anna-Lena Neehus, recently published their results in Cell. The study also found that the children are missing half of their alveolar macrophages, which are located in the air sacs of the lungs. "It was surprising to find that CCR2 is so essential for alveolar macrophages to properly function," says Casanova. "When it comes to lung defense and cleanup, people without it are operating at a double loss." Chemical communication More formally known as C-C motif chemokine receptor 2, CCR2 sits on the surface of alveolar macrophages, a kind of monocyte (or white blood cell). It responds to the presence of a chemical ligand, or binding molecule, known as CCL-2, which is also expressed by monocytes. The receptor and ligand work together to summon macrophages to the site of an infection, and to maintain the appropriate level of surfactant; too little can lead to collapsed lung tissue, and too much can result in narrowed airways. It was among these immune cells that first author Neehus, of Casanova's lab at the Institut Imagine in Paris, was seeking evidence of genetic deficiencies that might alter their behavior. While combing through the genomic data on 15,000 patients in a database, she found two Algerian sisters, then aged 13 and 10, who'd been diagnosed with severe PAP, a syndrome in which surfactant builds up and the gas exchange that takes place in alveoli is hindered. About 90% of PAP cases are caused by antibodies that cripple a protein that stimulates the growth of infection-fighting white blood cells. The girls, however, didn't have the PAP autoantibodies. Instead, they had no CCR2 -- a newly identified genetic mutation. Perhaps its lack was connected to their pulmonary conditions, Neehus thought. "It looked interesting and promising," she recalls. She soon found seven other children in the cohort who had the same CCR2 mutation and serious lung conditions: two more pairs of siblings, and one trio of siblings. They were from the United States and Iran. Diminished capacity To explore the impact the variant might have on the children, the researchers analyzed the children's clinical histories, lung tissue samples, and genetic data. Several key findings emerged. "First we discovered that these patients have only half the normal counts of pulmonary alveolar macrophages, which explains the different types of lesions they have across the pulmonary tissues," says Casanova. With only half a crew, the reduced cleanup unit couldn't keep up with its workload, leading to tissue injury. The macrophages were otherwise normal, as were the children's other immune cells. Without CCR2 signaling, monocytes have no idea where they're needed. In the study, a live-imaging analysis of the monocytes from the lungs of a 10-year-old girl with CCR2 deficiency showed the cells milling about aimlessly, unsure where to go. (See gif at top.) In contrast, live imaging of monocytes from a healthy control patient shows them migrating in the same direction, summoned by the teamwork of CCR2 and CCL-2. A troubled inheritance This directionlessness also makes those with a CCR2 deficiency more susceptible to mycobacterial infections, because the macrophages can't find their way to the tissue clusters where mycobacteria take up residence, and thus digest the invaders. This had dire effects for three of the children in the study, who developed bacterial infections after being vaccinated with a live-attenuated substrain of Mycobacterium bovis, an agent of tuberculosis. Their immune systems failed to assemble a legion of macrophages at the vaccination site in the shoulder, causing tissue destruction or hard nodes that had to be surgically removed, or lymph node infections. (All of the children were effectively treated with antibiotics.) The children inherited the deficiency from their parents -- and yet their parents were healthy. "Each of the parents carries one disease copy of the gene, and both parents gave the affected copy to their children," says Neehus. "The parents aren't affected because they each only have one copy, whereas the kids have two." Several children were the result of consanguineous marriages, in which the parents are related. The offspring of such pairings have a higher risk of inheriting the mutation that causes CCR2 to disappear. The diagnostic test The absence of CCR2 leads to another effect: an excess of the chemokine CCL-2. Lacking its receptor, CCL-2 builds up in the blood and plasma. This outcome may provide a diagnostic test for screening patients with unexplained lung or mycobacterial disease; the detection of high CCL-2 levels could provide some clarity about the condition's genetic underpinnings. In future research, Casanova and his team will mine their database of genomes for patients with gene mutations in CCL-2 rather than in its receptor, CCR2, to understand how such errors may influence the development of disease. Neehus says, "With more follow-up studies, we could potentially cure the patients by using gene therapy to correct the mutation."