Biovie Inc. · NASDAQ:BIVI
Biovie — Investor Day (March 2023)
79 slides from Biovie's investor day presentation, Mar 23, 2023
Slide 1: BioVie Day Presentation
BioVie Day Presentation March 23, 2023
Slide 2: Forward-looking statements
Forward-looking statements This document contains forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 that involve risks, uncertainties and assumptions that could cause BioVie’s actual results and experience to differ materia
Slide 3: Agenda
Agenda • Overview • Chronic Low-grade Inflammation Science • Development programs – Alzheimer’s Disease – Parkinson’s Disease – Epigenetics & Longevity – Liver Disease • Clinical & Regulatory Strategy • Commercialization Roadmap • Social Impact • Recap ©2022 BioVie Inc. 2
Slide 4: Overview
Overview
Slide 5: Executive Summary
Executive Summary • The company is in the early stages of multiple late-stage data readouts for multiple indications addressing great unmet medical needs • Early results in Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Ascites have all been encouraging, and our KOLs/SAB have encouraged us t
Slide 6: Our journey thus far
Our journey thus far • BioVie started with a single program in refractory ascites with the backdrop that terlipressin (or any treatment) has never been approved in the US • Acquisition of the Neurmedix assets (including NE3107) expanded our horizons – The team that discovered NE3107 sought to develo
Slide 7: Our journey ahead
Our journey ahead File NDA Launch 2023 2024 2025 2026 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Mild/Moderate AD Open label Phase 3 (US) extension ?* ?* Radiance-MCI 1 Open label extension Alzheimer’s ? ? (NE3107) Radiance-MCI 2 (Global) Radiance-AD: Mild/Moderate AD Phase 3 (Global) SUNRISE-1
Slide 8: Chronic Low-grade Inflammation Science
Chronic Low-grade Inflammation Science
Slide 9: Chronic low-grade inflammation
Chronic low-grade inflammation • Inflammation is the result of the body’s natural protective processes • If insults and pro-inflammatory factors eliminated, pathology addressed • If not, low grade chronic inflammation and associated insulin resistance ensues • Inflammation and insulin resistance go
Slide 10: TNFα-mediated inflammation leads to many downstream consequences
TNFα-mediated inflammation leads to many downstream consequences • Cytokine and chemokine production (more inflammation) • Various forms of cancers • Systems dysregulation (diabetes, • Age-related cognitive impairment and dementia dyslipidemia, cardiovascular, etc.) • Parkinson’s disease • Cardiovas
Slide 11: NE3107 blocks inflammatory (but not homeostatic) ERK and NFkB
NE3107 blocks inflammatory (but not homeostatic) ERK and NFkB, which play pivotal roles in AD pathogensis Ras MEK Extracellular signals Insulin (e.g., cytokines, chemokines, Aβ, tangles, etc.) NE3107 ERK ERK NFkB Cell/Synapse growth, Inflammatory factors (e.g., p38, JNK, cytokines, etc.) repair, and
Slide 12: Activation of Inflammatory Signaling
Activation of Inflammatory Signaling Inflammatory signals (Amyloid beta, TNF, LPS, fatty acids, others) interact with toll-like receptor 4 (TLR4) and with TNF Receptor 1 (TNFR1) leading to: Translation, maturation and secretion of 01 Activation of I kappa B kinase beta (IKKβ) 06 inflammatory mediato
Slide 13: ERK plays a critical role in the NFκB scaffold complex
ERK plays a critical role in the NFκB scaffold complex Amyloid β Fatty acids LPS TNFα Cell membrane TLR-4 TNFR-1 IKKα IKKβ ABIN2 βARR1 NFκB p105 MAP3K8 MEK ERK IKKγ IKKγ IKKγ βARR2 P-RSK2 P-MSK P-NFκB p65 P-NFκB p50 Transcription of inflammatory Nucleus genes (e.g., TNF, IL-1, IL-7) ©2022 BioVie Inc
Slide 14: We believe NE3107 alters the NFκB scaffold complex
We believe NE3107 alters the NFκB scaffold complex Amyloid β Fatty acids LPS TNFα Cell membrane TLR-4 TNFR-1 IKKα IKKβ ABIN2 βARR1 NFκB p105 MAP3K8 MEK ERK IKKγ 1. We believe NE3107 IKKγ NE3107 • binds to ERK in the NFκB βARR2 IKKγ P-RSK2 scaffold complex P-MSK X • alters the scaffold conformation P
Slide 15: Normal insulin signaling
Normal insulin signaling Insulin Cell membrane TLR-4 TNFR-1 Insulin Receptor Substrate 1 Serine-P Tyrosine-P PI3K RAF-P AKT/PKB MEK-P ERK-P Insulin Response ©2022 BioVie Inc. 14
Slide 16: Inflammation-mediated insulin resistance
Inflammation-mediated insulin resistance Amyloid β Fatty acids Insulin LPS TNFα Cell membrane TLR-4 TNFR-1 Insulin Receptor Substrate 1 Serine-P IKKα Tyrosine-P IKKβ ABIN2 1.Phosphorylates IRS1/2 on Serine βARR1 NFκB p105 2.Blocks phosphorylation on Tyrosine MAP3K8 MEK ERK IKKγ PI3K RAF-P 3.Causes i
Slide 17: NE3107 modulates inflammation at the central hub
NE3107 believed to modulates inflammation at the central hub, thereby reducing downstream inflammatory cascade Tau mRNA TRx0237, Salsalate, Ionis MAPTRx APP mRNA PU-AD, BEY2153 ABBV-8E12, BIIB092,Semorinemab, Popsiphen AAV-rh.10h COR388 Tangles Phospho-tau Tau BIIB076, Zagotenemab, Lu AF87908, ACI-3
Slide 18: Expanding beyond NE3107
Expanding beyond NE3107 • HE3291 is a sister molecule with similar activity profile as NE3107 • We are resuming discovery research to explore additional molecules and indications – We now have a much better understanding of NE3107’s presumed MOA – Enables even more precise medicinal chemistry to tar
Slide 19: Alzheimer's Disease
Alzheimer’s Disease
Slide 20: Alzheimer's Disease program overview
Alzheimer’s Disease program overview • Results from NE3107 Phase 2 exploratory biomarker trial in Mild Cognitive Impairment (MCI)/mild-AD reported at the CTAD Annual Conference in December 2022 – First data set showing impact on cognition, p-tau, and imaging biomarkers – Impact on biological aging c
Slide 21: NE3107 Phase 2 exploratory biomarker trial
NE3107 Phase 2 exploratory biomarker trial Open-Label Single-Arm 3-Month Study Inclusion criteria • 50-89 years old • Cognitive decline due to dementia • QDRS score: 1.5-12.5 • CDR score: 0.5 (MCI) or 1 (mild dementia) Active Treatment, 3 Months Exclusion criteria • Prior imaging inconsistent with A
Slide 22: Clinical outcomes assessments
Clinical outcomes assessments NE3107 Was Associated With Improvements From Baseline in Clinical Outcomes of Neuropsychological and Cognitive Assessments after 3 months of Treatment Changes from Baseline in Clinical Assessments Clinician-Rated Global Rating of Change All patients MCI/Mild All Patient
Slide 23: Biomarker improvements
Biomarker improvements Correlations between biomarkers and Changes from baseline in biomarkers clinical outcomes All MMSE ≥20 All Patients MCI/Mild AD Patients n=18 Assessment (N=23) (n=18) ADAS-Cog12 TNF-α, TNF-α r=0.46 r=0.59* −0.452 −0.563 pg/mL ADCOMS Aβ42 r=0.53* r=0.31 CSF p-tau, pg/mL −1.1 –1
Slide 24: Neuroimaging methodology
Neuroimaging methodology • Functional MRI data were submitted to blinded review and scoring by two independent clinician- readers. Inter-rater reliability was 96%; in the event of disagreement between raters, data were subjected to additional review and ultimately scored by consensus • Criteria for
Slide 25: NE3107 increased functional connectivity using BOLD imaging
NE3107 increased functional connectivity from baseline in group analysis using BOLD imaging Precuneus ROI Statistically significant regions of increased connectivity 3.1 7 Right HC ROI Left HC ROI 3.1 7 ©2022 BioVie Inc. 24
Slide 26: NE3107 associated with reduced oxidative stress in the brain
NE3107 associated with reduced oxidative stress in the brain Brain glutathione assessed by MRS of Precuneus 400 % change from baseline 300 200 100 0 Significant correlation of Glutathione with: -100 TNF-α (r=−0.44) ADAS-Cog12 (r=−0.45) 11/17 (59%) improved mean +59% change P=0.069 ©2022 BioVie Inc.
Slide 27: Update on NM101 Phase 3 in Mild/Moderate
Update on NM101 Phase 3 in Mild/Moderate • Trial fully enrolled as of February 28, 2023 – 100 patients completed treatment at that time – Top-line data readout expected in October 2023 • Trial continues to have a good safety profile and low discontinuation rate • Blinded baseline data shows evidence
Slide 28: Radiance-MCI 1 Trial
Radiance-MCI 1 Trial • A potentially pivotal Phase 2/3, double-blind, randomized, placebo-controlled, parallel group, multicenter study of NE3107 in MCI subjects – MCI patients have a measurable loss of memory, but have not yet shown significant functional impairment – MCI is defined by Stage 2 and
Slide 29: Parkinson's Disease
Parkinson’s Disease
Slide 30: Parkinson's Disease program overview
Parkinson’s Disease program overview • Clinical development was initiated based on strong data from preclinical studies • Phase 2 NM201 trial launched with 2 main objectives – Primary: safety and drug-drug-interaction study (as requested by FDA) to demonstrate the absence of adverse interactions wit
Slide 31: NE3107 promotoric activity in rodent and marmoset models
NE3107 has similar promotoric activity to L-dopa in rodent* and marmoset* models Funded by MPTP Mouse MPTP Marmoset treated at Week 8 4 * * Placebo Mean Disease Score 3 NE3107 * L-Dopa 2 ** NE3107+L-Dopa 1 L-dopa and NE3107 combination is better than either drug alone 0 Week 8 Week 9 Week 10 Week 11
Slide 32: NE3107 decreases L-Dopa-induced dyskinesia in marmosets
NE3107 decreases L-Dopa-induced dyskinesia (LID) in marmosets* Funded by Distribution of AIMS Scores 30 NE3107 25 Score Frequency 20 15 Placebo 10 5 Amantadine 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Less Dyskinesia More Abnormal Involuntary Movement Scale (AIMS) * Funded by MJFF for Pa
Slide 33: NE3107 preserved ~2X TH+ neurons in MPTP marmosets
NE3107 preserved ~2X TH+ (dopaminergic) neurons in MPTP marmosets* Funded by Control moneys (M09100 and M11008) HE3286 (M11007) Amantadine (M10084) Note: NE3107 was originally known as HE3286 from Hollis Eden Pharmaceuticals, *Funded by MJFF for Parkinson’s Research ©2022 BioVie Inc. 32
Slide 34: Parkinson's disease clinical development program
Parkinson’s disease clinical development program • NM201 sought to satisfy FDA requirement for drug-drug interaction (DDI) study with L-Dopa and assess NE3107 promotoric and anti-LID activity • 45 patients with defined L-Dopa “off state” randomized 1:1 active:placebo, 20 mg BID for 28 days • Primary
Slide 35: Fewer motor symptoms before morning drug administration
NE3107-treatment patients experienced fewer motor symptoms before morning drug administration Day y28 Improvement in Motor Control vs. Day y1 g 0 28 change from Day 1 All Patients Patients <70 years old -5 NE3107 Placebo “On” at t=0 6 0 Day Baseline -10 Total patients 20 19 Change– from P-value* 0.0
Slide 36: Desirable pharmacokinetics – no observed DDI
Desirable pharmacokinetics – no observed DDI NE3107 Treated Plasma Levodopa 2000 Levodopa ng/mL 1500 0-8 hr 231 ngh/mL (SD 22.38) 1000 500 Mean NE3107 ng/mL in Plasma 0 0 0.5 1 2 3 4 8 100.0 Hr post Levodopa administration NE3107, ng/mL Day 1 ave Day 14 ave 10.0 01.0 0 0.5 1 2 3 4 8 Day 14 hours pos
Slide 37: Collaboration with Parkinson Study Group
Collaboration with Parkinson Study Group • The largest, pro-active, not-for-profit scientific network of Parkinson Centers in North America for over 30 years • Strict credentialing process, with over 150 Credentialed PSG Centers in North America, Hawaii, and the Caribbean • Over 350 credentialed inv
Slide 38: BioVie's Parkinson's Advisory Committee
BioVie’s Parkinson’s Advisory Committee • Anthony Lang (co-chair), MD. Author of 950+ peer-reviewed papers and 100+ book chapters in Parkinson’s Disease – Director, the Morton and Gloria Shulman Movement Disorders Clinic at Toronto Western Hospital – Jack Clark Chair for Parkinson's Disease Research
Slide 39: Strong support from advisors for a more aggressive plan
Strong support from advisors for a more aggressive plan to address significant unmet medical needs “The Parkinson’s Study Group (PSG) has provided guidance to many industry partners who have successfully brought to market Parkinson's therapeutics that address the unmet needs of patients. The PSG mem
Slide 40: SUNRISE 1 and 2 in Treatment Naïve PD Patients
SUNRISE 1 and 2 in Treatment Naïve PD Patients Baseline 1º and 2º Disease Disease symptomatic progression progression endpoints endpoints endpoints • SUNRISE-1 and Sunrise-2 have the same design in levodopa naïve PD patients • 20 mg NE3107 or placebo BID, rescue medication permitted as directed by t
Slide 41: Additional endpoints
Additional endpoints Secondary endpoints Exploratory endpoints • Parkinson’s Disease Activities of Daily Living • Rate of disease progression defined by: Scale* (PADLS) • Change in MDS-UPDRS Part 3 score compared to • Time to initiation of PD therapy baseline after withholding all PD and study medic
Slide 42: Epigenetics & Longevity
Epigenetics & Longevity
Slide 43: Epigenetics & Longevity program overview
Epigenetics & Longevity program overview • Early stages of program initiated based on early findings that NE3107 may affect the biological aging process • We have identified the nucleus of academic collaborators to steer this program – Ekaterina Rogaeva, Ph.D., Professor, Department of Medicine Univ
Slide 44: Genome reacts to environment, mutations & aging: epigenetics
Genome reacts to environment, mutations & aging: epigenetics DNAm controls gene-expression • 28 million CpGs in genome • DNAm arrays: <1 million CpGs • DNAm levels at some CpGs are age-related, affecting expression of >2000 genes DNA • 25,000 genes • 6 billion base pairs no/low gene- • 4% code for p
Slide 45: DNA methylation clocks and their predictive capacity
DNA methylation clocks and their predictive capacity for aging phenotypes and health span Direction of age-related DNAm Gene expression impact M M MM M M M MM M M MM MM M M Hypomethylation Up regulation M M M M M M M M Aging M MM M M M MM M M M M M MM M M M Hypermethylation Down regulation M M M M M
Slide 46: Each DNAm clock is built according to a unique training method
Each DNAm clock is built according to a unique training method ©2022 BioVie Inc. 45
Slide 47: NE3107 decreased biological age in MCI/AD subjects
NE3107 decreased biological age in MCI/AD subjects • Dr. Steve Horvath* developed an extremely precise Biological age DNA methylation clock, the 15 DNAmSkinBloodAge 10 • The biological clock age was in close agreement 5 with the chronological age (72.3 vs 71.6; +0.98%) Years 0 at baseline -5 • After
Slide 48: Next steps
Next steps • Additional results of NE3107 modulation of DNA methylation pertaining to immunomodulatory cells, endocrine mediator expression, and their correlates will be presented at the Alzheimer's Association International Conference (AAIC) July 16-20, 2023 • Along with Drs. Rogaeva and Daskalakis
Slide 49: Liver Disease
Liver Disease
Slide 50: Refractory Ascites
Refractory Ascites • Fluid build-up in the abdomen of patients with advanced cirrhosis – Cannot be controlled with an effective dose of diuretics • No approved pharmacological treatments – unmet need • First line treatment is repeated mechanical draining by paracentesis – Surgically implanted shunts
Slide 51: Ascites Pathophysiology
Ascites Pathophysiology Decreased aldosterone metabolism Retention of salt and water Portal hypertension Vasodilation and blood pooling Low arterial pressure Ascites Activation of RAAS & SNS ©2022 BioVie Inc. 50
Slide 52: BIV201
BIV201 • Terlipressin administered as a continuous infusion – Outpatient treatment with small ambulatory infusion pump • Targets the pathophysiology of ascites – Multiple small trials and Phase 2a support efficacy in reducing ascites • Orphan and Fast Track Designations for the treatment of ascites
Slide 53: BIV201 Program Update
BIV201 Program Update • Phase 2b - Originally targeted 30 patients randomized 2:1 • Paused enrollment based on encouraging data from the first 15 patients informing next steps – 10 randomized to BIV201; 5 randomized to standard of care – 5 completed 2 X 28-day cycles – 5 discontinued treatment durin
Slide 54: BIV201 37% advantage in ascites fluid reduction vs SOC
BIV201-treated patients experienced a 37% advantage in ascites fluid reduction compared to SOC BIV201 + SOC Mean: 34 % reduction 5/10 (50%) with >40% reduction P=0.0046 SOC only Mean: 3.1 % increase 0/5 (0%) with >40% reduction P=0.8 BIV201 vs SOC P value = 0.05 for difference ©2022 BioVie Inc.
Slide 55: Completers experienced 56% advantage in ascites fluid reduction
Patients completing BIV201 treatment experienced 56% advantage in ascites fluid reduction compared to SOC • 53% reduction in ascites volume among patient completing BIV201 treatment • 15% reduction among patients who started but did not complete treatment • 3.1% increase for SOC patients • p<0.001 ©
Slide 56: Safety
Safety • Incidence of treatment emergent adverse events similar in both groups • Overall safety consistent with patient population with advanced cirrhosis • No unexpected SAEs ©2022 BioVie Inc. 55
Slide 57: Conclusions
Conclusions • BIV201 treatment resulted in a reduction in ascites • Treatment appears to be well tolerated • Engaging FDA in discussions on next steps ©2022 BioVie Inc. 56
Slide 58: Clinical & Regulatory Strategy
Clinical & Regulatory Strategy
Slide 59: Alzheimer's Clinical Program creates maximum optionality for approval
Alzheimer’s Clinical Program creates maximum optionality for approval File NDA Launch 2023 2024 2025 2026 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Mild/Moderate AD Open label ?* ?* Phase 3 (US) extension Radiance-MCI 1 Open label extension ? ? Radiance-MCI 2 Radiance-AD: Mild/Moderate AD Phas
Slide 60: Parkinson's clinical program is straight forward
Parkinson’s clinical program is straight forward 2023 2024 2025 2026 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 SUNRISE-1 Extension study SUNRISE-2 (Global) Extension study • Both SUNRISE-1 and SUNRISE-2 are designed to serve as pivotal studies – Primary end-point of UPDRS Part 3 (motor) scores
Slide 61: Ascites program
Ascites program 2023 2024 2025 2026 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Phase 2b Phase 3 • Phase 2b paused with only one-half targeted patients enrolled due to statistically significant results demonstrating reduction of ascites fluid with BIV201 treatment • Discussions initiated with FD
Slide 62: Commercialization Roadmap
Commercialization Roadmap
Slide 63: Commercialization approach
Commercialization approach • All options are open • Partnering is an option – Initial conversation have been held Some companies interested in global collaboration Others in geographic rights – Most companies are intrigued and awaiting Phase 3 data readout • Go-alone is always an option ©2022 Bi
Slide 64: Commercial potential in US market alone
Commercial potential in US market alone Ascites Alzheimer’s Parkinson’s $1.6B $30B $3B US peak sales Annual sales for every Annual sales for every 1 million people treated 100,000 people treated • $45K/year • 15% market penetration • 10% penetration of US • 45% market penetration • $30K/year – much
Slide 65: Current finances
Current finances • $44 million cash balance as of February 28, 2023 • We have resources to fund operations through most of the year and could extend through first part of 2024 if necessary ©2022 BioVie Inc. 64
Slide 66: Social Impact
Social Impact
Slide 67: BioVie is the founding backer of Social Impact Partners
BioVie is the founding backer of Social Impact Partners Mission: To combat Alzheimer’s and other neurodegenerative conditions and enable people to lead better and healthier lives by 1) working collaboratively, 2) raising awareness, and 3) mobilizing resources that drive innovation and new solutions.
Slide 68: SIP's Goals
SIP’s Goals 1. Mobilize 1 million new healthcare workers to support individuals and families. 2. Increase public/private funding of Alzheimer's medical research 3x in 5 years and expand Medicaid/Insurance Coverage for services needed. 3. Invest and grow in 10 companies annually who advance innovativ
Slide 69: Meet our global consortium and youth board schools
Meet our global consortium and youth board schools ©2022 BioVie Inc. 68
Slide 70: Recap
Recap
Slide 71: Executive Summary
Executive Summary • The company is in the early stages of multiple late-stage data readouts for multiple indications addressing great unmet medical needs • Early results in Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Ascites have all been encouraging, and our KOLs/SAB have encouraged us t
Slide 72: Expected Catalysts & anticipated timelines
Expected Catalysts & anticipated timelines File NDA Launch 2023 2024 2025 2026 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Mild/Moderate AD Open label Phase 3 (US) extension ?* ?* Radiance-MCI 1 Open label extension Alzheimer’s ? ? (NE3107) Radiance-MCI 2 (Global) Radiance-AD: Mild/Moderate AD P
Slide 73: Appendix
Appendix 72
Slide 74: Inflammation drives systems dysregulation
Inflammation drives systems dysregulation • Patients with increasing metabolic disease show greater variability for individual hematology, metabolic and chemistry values • Indicates increasing dysregulation DL: dyslipidemic placebo group, IGT: impaired glucose tolerant placebo group, Naïve: treatmen
Slide 75: NE3107 decreased systems dysregulation in a Phase 2 study
NE3107 decreased systems dysregulation in a Phase 2 study • Heteroscedasticity* investigated by analyzing data distributions for normality (Shapiro-Wilks 𝑊𝑊 test) – Deviations from normal distribution represents dysregulation • Placebo patients had significantly abnormal data distributions after…
Slide 76: NE3107's inhibition of inflammatory signaling
NE3107’s inhibition of inflammatory signaling NE3107 binds to ERK in the NFκB scaffold complex, and alters the scaffold conformation, inhibiting Persistent Downstream Phosphorylation of inflammatory actions including IKKβ, MAP3K8, activation (chronic TNF production, MEK, ERK low-grade secretion infl
Slide 77: Homeostatic insulin signaling
Homeostatic insulin signaling Hyperglycemia increases insulin, which binds to the insulin 01 receptor (IR) on cells in muscle, liver, adipose tissue, brain, pancreas, etc. Insulin binding to IR triggers IR phosphorylation of insulin receptor substrate 1 & 2 (IRS1/2) on tyrosine, activating 02 Phosph
Slide 78: Inflammatory inhibition of Insulin signaling
Inflammatory inhibition of Insulin signaling IKKβ is a serine Inflammatory kinase, and As in macrophage mediators (e.g., phosphorylates serine lineage cells, the NFkB resting scaffold Amyloid β, alpha- on IR, blocking PI3K synuclein, TNF, fatty and ERK homeostatic is present in these acids) activate
Slide 79: NE3107 restoration of Insulin sensitivity
NE3107 restoration of Insulin sensitivity NE3107 Restores Inhibits activation Inhibits serine Restores insulin-stimulated phosphorylation of insulin-stimulated of IKKβ homeostatic IRS1/2 PI3K signaling ERK signaling ©2022 BioVie Inc. 78