Biovie Inc. · NASDAQ:BIVI
Biovie — 12th Annual Alzheimer's and Parkinson's Drug Development Summit 2024
27 slides from Biovie's conference presentation, April 2024
Slide 1: Clinical Outcomes and Biomarker Findings from a Randomized, Placebo-Controlled Trial of Bezisterim
CLINICAL OUTCOMES AND BIOMARKER FINDINGS FROM A RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF BEZISTERIM IN SUBJECTS WITH MILD TO MODERATE PROBABLE ALZHEIMER’S DISEASE Christopher L. Reading1; Jiayan Yan1; Marcia A. Testa2; Donald C. Simonson3; Hira Javaid4; Lisa Schmunk4; Daniel E. Martin-Herranz4; Rober
Slide 2: Why does DHEA show effects in mice, and not in humans?
In 2000, we asked “Why does DHEA show anti-inflammatory, insulin-sensitizing and anti- aging effects in mice, and not in humans?” DHEA MICE INFLAMMATION MEN √ ACTIVE X INACTIVE amyloid β insulin resistance cognitive decline hyperglycemia Alzheimer’s obesity NFκB dyslipidemia neuron death cytokines o
Slide 3: Differential Metabolism of Androst-5-ene-3,17-diol Between Rats, Canines, Monkeys and Humans
Differential Metabolism of Androst-5-ene-3,17-diol Between Rats, Canines, Monkeys and Humans Red = Cyp7b1 Neurosteroid: Cyp7B defines hippocampal dentate gyrus3,4 1,2 Oxidation Medicinal Chemistry 17α-ethynyl-βΑΕΤ (bezisterim) Metabolic stability 7β-hydroxyl-DHEA Oral biovailability Testosterone Est
Slide 4: Background: Bezisterim (formerly NE3107)
Background • Bezisterim (formerly NE3107) • Binds ERK5 and inhibits inflammatory,6,7 but not homeostatic ERK, NF-κB and TNF signaling8 • Decreased inflammatory mediators and insulin resistance in animal models and subjects with obese impaired glucose tolerance or type 2 diabetes9 • Improved motor ac
Slide 5: Does Bezisterim Modify Metabolic Inflammation and Longevity Relevant to Dementia?
Does Bezisterim Modify Metabolic Inflammation and “Longevity” Relevant to Processes Underlying Dementia? • The primary goal of our study was to investigate the associations between metabolic inflammation, biological aging, and dementia in a human clinical investigation • The specific aim tested whet
Slide 6: Patient Disposition and Data Source for This Presentation
Patient Disposition and Data Source for This Presentation • The trial started during the COVID-19 pandemic and enrolled a total of 439 subjects through 39 sites • We reported that upon trial completion, the Company found significant deviation from protocol and Good Clinical Practice violations at 15
Slide 7: Safety Findings: Bezisterim Treatment Was Well Tolerated
Safety Findings: Bezisterim Treatment Was Well Tolerated In the Per-Protocol (PP) population (n=57) • Treatment emergent adverse events (TEAEs) occurred in 62.5% (n=15) of patients in the bezisterim group and 72.7% (n=24) of patients in the placebo group • Bezisterim TEAEs ≥5% and > Placebo Headache
Slide 8: Bezisterim Showed Improvements Over Time in Primary and Secondary Endpoints
Bezisterim Showed Improvements Over Time in Primary and Secondary Endpoints Global Statistical Test ADAS-Cog12 CDR-SB ADCOMS Change From Baseline, LS Mean Change From Baseline, LS Mean Change From Baseline, LS Mean LS mean difference, LS mean difference, Change From Baseline, LS Mean LS mean differe
Slide 9: Treatment Modified Change From Baseline Comparable to Approved Medications
Treatment Modified Change From Baseline in Primary and Secondary Endpoints Comparable to Approved Medications • After the exclusions, the study was no longer powered for endpoints, but week 30 data suggest bezisterim vs placebo is comparable to results reported from clinical trials by approved medic
Slide 10: Could Bezisterim Treatment Modify Biological Age in 7 Months?
Could Bezisterim Treatment Modify Biological Age in 7 Months? • Individuals appear to age at different rates • Analysis of DNA methylation “clocks” can provide evidence of changes in gene expression related to aging (biological age) • The difference between the biological age and the chronological a
Slide 11: Bezisterim Modified dAge for Aging Clocks
Bezisterim Modified dAgea for 5 Aging Clocks SkinBloodClock dAge Pheno dAge Grim dAge Hannum dAge Inflamm dAge 20 20 5 10 10 SkinBloodAge - Age Age Hannum - Age 10 0 0 InflammAge - Age PhenoAge - Age 10 0 GrimAge - Age 0 -5 -10 0 -10 -10 -10 -20 -10 -20 -20 -15 -30 -20 -30 -20 -40 -30 Placebo NE3107
Slide 12: Bezisterim Modification of Monocyte DNA Methylation May Alter SBC
Bezisterim Modification of Monocyte DNA Methylation May Alter SBC Correction for Cell Type Placebo NE3107 Placebo NE3107 Placebo NE3107 NK + CD8T + CD4T +B Cell Clock NK + CD8T + CD4T +B Cell Clock 0.15 0.20 0.6 0.9 0.9 Gran Clock % Granulocytes Gran Clock % Granulocytes 0.5 Mono Clock % monocytes M
Slide 13: Precedent For Epigenetic Memory In Long Covid Monocytes
Precedent For Epigenetic Memory In Long Covid Monocytes21 • Severe COVID-19 programs durable epigenetic changes and hyper- activation in monocytes • Circulating HSPC capture post-COVID-19 changes in hematopoiesis and stem cell programs • Post-COVID-19 HSPC convey epigenetic and transcriptional memor
Slide 14: Correlations and Principal Components
Correlations and Principal Components • Correlations • For DNA methylation data and neurological assessments from per-protocol subjects with available DNA methylation data that passed QC (n = 33), the data was normalizeda in separate correlation matrices for bezisterim and placebo • For clinical mea
Slide 15: Decreased Age Acceleration Correlated With Improvements In Neurologic Assessments
Bezisterim Decreased Age Acceleration Was Correlated With Improvements In Neurologic Assessments SkinBlood Neurologic Placebo Bezisterim Clock Assessment n = 16 n = 17 Pearson r p Pearson r p dAge GST 0.209 0.438 0.473 0.055 CDR-SB 0.110 0.686 0.413 0.099 ADAS-Cog12 0.167 0.537 0.455 0.067 MMSE −0.0
Slide 16: Bezisterim Modified Interdependence of Neurological Assessments
Bezisterim Modified Interdependence of Neurological Assessments Placebo was correlated with worsening Bezisterim yielded inverse correlations with biomarkers/measures improvement vs placebo Dementia biomarkers • ↓Fructosamine with ↑ADL ↑GFAP with ↑GST, ↓MMSE, ↑CDR-SB, (placebo: ↓Fructosamine with ↓A
Slide 17: Placebo dAge Principal Component Analysis
Placebo dAge Principal Component Analysis: Divergent PC1 vs PC2 suggestive of systems dysregulation in placebo-treated patients PCA1 included metabolic, inflammation, & dementia biomarkers • Metabolic (Glc, HOMA2, Trig, Chol, WHR, Ins, Fruc) • Inflammation (TNF, CRP, RANTES, MCP1, C1q) • Dementia Bi
Slide 18: Bezisterim Modified dAge PCA
Bezisterim Modified dAge PCA: Single PC1 suggestive of re-regulation in Bezisterim-treated patients • Only one PCA Identified Neurological assessments Metabolic (Glc, Insulin Sensitivity, Trig, Chol, BP) Microglia-related (% Mono, RANTES) DNA methylation (dAge) Excludes Inflammatory Biomarkers (CRP,
Slide 19: Treatment-Mediated PCA dAge Summary
Treatment-Mediated PCA dAge Summary • For placebo-treated subjects at study completion • PC1 identified metabolic, inflammation, and dementia biomarkers • PC2 identified chronological age and neurological assessments; age acceleration was only weakly associated with outcomes • For bezisterim-treated
Slide 20: Modified Correlations Between Clinical Measures and DNA Methylation of AD-Associated Genes
Bezisterim Modified Correlations Between Clinical Measures and DNA Methylation of AD-Associated Genes NE3107 TMEM237 cg23849778 Z' Placebo TMEM237 cg23849778 Z' NE3107 TMEM237 cg23849778 Z' Placebo TMEM237 cg23849778 Z' NE3107 TMEM237 cg23849778 Z' Placebo TMEM237 cg23849778 Z' -1.60 -1.60 -1.60 -1.
Slide 21: Divergent Correlations Were Observed With RANTES
Divergent Correlations Were Observed With RANTES • Placebo Week 30 • Increased RANTES • Significant correlates with CDR-SB (decline), TNF, Triglycerides • Trending correlations with baseline WHR, increased CRP & C1q • Bezisterim Week 30 • Increased RANTES • Significant correlates with improved MMSE,
Slide 22: Proinflammatory and Anti-inflammatory Myeloid Cell States
Proinflammatory and Anti-inflammatory Myeloid Cell States23 • Monocytes, macrophages, astrocytes and microglia can exist in a continuum between the extremes (A1 and M1: proinflammatory cytokines and chemokines, ROS, tissue destruction, to A2 and M2: anti-inflammatory cytokines, phagocytic, tissue re
Slide 23: RANTES (CCL5), Receptor = CCR5
RANTES (CCL5), Receptor = CCR5 • Proinflammatory24 • Anti-inflammatory • CCL5 is a “Janus” chemokine • CCL5 important in neurotransmission, contributing to both pro- and anti- neuron development and learning and inflammatory programs memory • Low grade inflammation can • CCL5 is decreased in AD plas
Slide 24: Summary
Summary • In this small per-protocol sample, compared to placebo, bezisterim appeared to: • Improve neurological assessments • Decrease biological age • Realign biological aging with neurological assessments • Correlations, PCA and PCR (Principal Component Regression) are consistent with the hypothe
Slide 25: Collaborators
Collaborators Donald Simonson, MD, MPH, ScD Marcia Testa, MPH, PhD Lisa Schmunk Ph.D. Hira Javaid Matt Polak Juozas Gordevicius, Ph.D. Accelerator Team at Quanterix Bobby Brooke Dani Martin-Herranz Ph.D. Medical writing and editorial Jiayan Yan support were provided by p-value Penelope Markham, Ph.D
Slide 26: References
References 1. Ahlem CN, White SK, Page TM, Frincke JM. Differential metabolism of androst-5-ene-3β,17β-diol between rats, canines, monkeys and humans. Steroids. 2011;76(7):669-674. 2. Auci DL, Ahlem CN, Kennedy MR, Page TM, Reading CL, Frincke JM. A potential role for 5-androstene-3beta,7beta,17beta
Slide 27: Abbreviations
Abbreviations • Aβ42/40, ratio of amyloid β 42 to amyloid β 40 • IGT, impaired glucose tolerance • AD, Alzheimer’s disease • IR, HOMA2 insulin resistance • ADAS-Cog12, 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale • MCP1, monocyte chemoattractant protein-1 • ADCOMS, Alzheime
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