Biovie Inc. · NASDAQ:BIVI
Biovie — ARDD Copenhagen 2024
22 slides from Biovie's conference presentation, 2024
Slide 1: Bezisterim Effects on Biological Age, Alzheimer's Epigenetics, and Neurologic Assessments
Bezisterim Effects on Biological Age, Alzheimer’s Epigenetics, and Neurologic Assessments Christopher Reading, PhD BioVie Inc. ARDD Copenhagen, 2024
Slide 2: Exogenous DHEA: why effects in mice but not humans
Exogenous DHEA In 2000, we asked “Why does DHEA show • anti-inflammatory MICE INFLAMMATION MEN • insulin-sensitizing • neuroprotective √ ACTIVE X INACTIVE • anti-aging effects in mice, and not in humans?” • amyloid b • insulin resistance • cognitive decline • hyperglycemia • Alzheimer’s • obesity •
Slide 3: Bezisterim Developed by Understanding Differential Metabolism of Androst-5-ene-3,17-diol
Bezisterim Developed by Understanding the Differential Metabolism of Androst-5-ene-3,17-diol Between Rats, Canines, Monkeys and Humans1 Red = Cyp7b1 Neurosteroid: Cyp7B defines hippocampal dentate gyrus3,4 1 Oxidation Medicinal Chemistry 17α-ethynyl-βΑΕΤ (bezisterim) 7β-hydroxyl-DHEA Metabolic stabi
Slide 4: Bezisterim: In vitro, in vivo and clinical findings align with expected pharmacology
Bezisterim In vitro, in vivo and clinical findings align with expected pharmacology • Binds extracellular-signal regulated kinase5, (ERK), and inhibits inflammatory6,7, but not homeostatic8 ERK, NFκB and TNF signaling. It is more potent than βAET for inhibition of NFκB transcription • These activiti
Slide 5: Positive Signals of Bezisterim Clinical Activity in Dementia
Positive Signals of Bezisterim Clinical Activity in Dementia Open label 14-week study in MCI and Mild AD • Improved neurological, neuroimaging, and dementia and inflammation biomarkers in an open-label 14-week study in MCI and mild AD14 • Observed 3.4-year decrease from baseline in biological age (H
Slide 6: Bezisterim Subjects Showed a Lower Biological Age Than Placebo at 30 Weeks
Bezisterim Subjects Showed a Lower Biological Age Than Placebo Subjects at 30 Weeks Difference between biologic and chronological age (dAge) as calculated by different epigenetic aging clocks18-22 (SkinBlood Clock difference consistent with previous study15) A consistent trend was observed when usin
Slide 7: Appeared to Modify Monocyte Methylome
Bezisterim Appeared to Modify Week 30 Monocyte Methylome Consistent with hypothesis of a transition from pro- to anti-inflammatory 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 % G
Slide 8: Analysis of Promoter Methylation
Analysis of Promoter Methylation • Increased promoter methylation has been associated with decreased gene expression, however gene expression was not measured in this study • Monocytes represent less than 10% of leukocytes; if significant promoter methylation differences were predominantly represent
Slide 9: Increases in Promoter Methylation of Genes Associated with Disease Progression
Bezisterim Increases in Promoter Methylation of Genes Associated with Disease Progression, Inflammation and Metabolic Regulation • Compared to placebo, bezisterim subjects had significantly (FDR p<0.05) increased methylation in promoter CpGs of 4934 genes • The top 50 genes (FDR p< 0.005) genes iden
Slide 10: Alzheimer's Disease Pathway Enrichment Suggests Positive Impact by Bezisterim
Alzheimer’s Disease Pathway Enrichment Suggests Positive Impact by Bezisterim • Genes with promoter methylation significantly increased (p<0.05) in bezisterim compared to placebo AD subjects were examined for enhancement of the KEGG Alzheimer’s disease pathway • There was a 1.6-fold enrichment (127
Slide 11: Key Genes in the AD Pathway for Promoter Methylation
Key Genes in the AD Pathway for Promoter Methylation Increased in Bezisterim Compared to Placebo Subjects Activity may reduce gene expression • ADAM10 • α-Secretase, decreases Aβ • APP • Decreases Aβ • Bid • Apoptosis death domain agonist • ATF6 • ER stress response decreased in Alzheimer’s disease
Slide 12: Inflammatory Gene Expression Decreased by Compounded Sequential Kinase Methylation
Inflammatory Gene Expression Decreased by Compounded Sequential Kinase Increased Promoter Methylation with Bezisterim vs Placebo Cytokines, TGFβ +4% TGFβ +4% Inflammation Signal BMP +11% HRAS +13% Cytokines Amyloid β KRAS +10% MAP4K1 +14% MAP4K2 +4% MAP4K2 +4% MAP4K3 +12% MAP4K MAP3K1 +10% MAP3K5 +1
Slide 13: KEGG Pathways Enrichment
Bezisterim KEGG Pathways Enrichment Pathway Fold Enrichment FDR Adjusted P Genes/pathway Genes Alzheimer’s disease 1.6 6.2e -6 110/384 Amyotrophic lateral sclerosis 1.7 1.8e -7 112/364 Neurodegeneration 1.6 1.7e -6 134/476 multiple diseases Parkinson’s disease 1.7 7.0e -6 82/266 Huntington’s disease
Slide 14: 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 Change From Baseline, LS Mean −4 −1 −0.1 −0.25 −2 0 0.00 0.0 Improvement Improvement
Slide 15: Directional Improvements for Metabolic and Inflammatory Biomarkers
Directional Improvements From Baseline for Metabolic and Inflammatory Biomarkers with Bezisterim There were non-significant directional improvements in fasting insulin, HOMA2 insulin resistance, triglycerides, fructosamine, adiponectin, leptin, systolic and diastolic blood pressure, and weight (data
Slide 16: Biomarker Correlations With Neurological Assessments
Placebo Bezisterim Measure GST Biomarker GFAP Pearson R 0.671 P<0.1 1.7e -4 Pearson R 0.253 P<0.1 Biomarker Correlations With 0.023 Neurological Assessments Global Statistical Test pTau 0.444 0.174 Systolic BP 0.431 0.028 0.313 Cholesterol −0.060 0.495 0.014 NfL 0.169 0.480 0.018 • Changes from base
Slide 17: Biomarker Correlations With Neurological Assessments
Placebo Bezisterim Measure GST Biomarker GFAP Pearson R 0.671 P<0.1 1.7e -4 Pearson R 0.253 P<0.1 Biomarker Correlations With pTau Systolic BP 0.444 0.431 0.023 0.028 0.174 0.313 Neurological Assessments Cholesterol −0.060 0.495 0.014 NfL 0.169 0.480 0.018 • Changes from baseline in biomarkers in be
Slide 18: Biomarker Correlations With Neurological Assessments
Placebo Bezisterim Measure GST Biomarker GFAP Pearson R 0.671 P<0.1 1.7e -4 Pearson R 0.253 P<0.1 Biomarker Correlations With pTau Systolic BP 0.444 0.431 0.023 0.028 0.174 0.313 Neurological Assessments Cholesterol −0.060 0.495 0.014 NfL 0.169 0.480 0.018 • The chemokine RANTES can alter astrocyte
Slide 19: Biomarker Correlations With Neurological Assessments
Placebo Bezisterim Measure GST Biomarker GFAP Pearson R 0.671 P<0.1 1.7e-4 Pearson R 0.253 P<0.1 Biomarker Correlations With pTau Systolic BP 0.444 0.431 0.023 0.028 0.174 0.313 Neurological Assessments Cholesterol −0.060 0.495 0.014 NfL 0.169 0.480 0.018 • SkinBloodClock (SBC) dAge at completion co
Slide 20: Increased Methylation of Gene Promoters may be Associated with Clinical Improvements
Bezisterim Increased Methylation of Gene Promoters may be Associated with Clinical Improvements • We identified 18 significant (FDR p<0.05) bezisterim subject clinical measure changes from baseline correlations with individual CpGs of genes that may be beneficial for AD subjects • There were 6 signi
Slide 21: Summary
Bezisterim Summary • Analog of the neurosteroid βAET and may recapitulate, in humans, the beneficial effects on diseases of aging seen with DHEA in rodents • Decreases inflammatory signal transduction and restores insulin sensitivity • Well-tolerated safety profile to date • Decreases biological age
Slide 22: Collaborators
Collaborators Jiayan Yan Donald Simonson, MD, MPH, ScD Clarence Ahlem Penelope Markham Jeffrey Zhang Harvey Yuan Lixia Wang Stephen O’Quinn Joseph Palumbo Marcia Testa, MPH, PhD Lisa Schmunk Juozas Gordevicius Hira Javaid Bobby Brooke Dani Martin-Herranz ©2024 BioVie Inc. I Corporate presentation 22