In the past 3 months, AdVax In the past 3 months, AdVax has…has…

In the past 3 months, AdVax In the past 3 months, AdVax has…has…

• Completed Phase I of research and development, identifying the most virulent strains of a keystone pathogen.

• Initiated development of a first-in-man diagnostic for Alzheimer’s and cardiovascular disease with a short-term return on investment.

• Engineered IRT mutations into bacterial targets (n= 2-4 targets with 5-10 IRT mutations per target)

• Now an active member of the Alzheimer’s Association Small Company Consortium

• Next-generation salivary diagnostics determining bioburden and preventing Alzheimer’s disease, multiple cardiovascular diseases, and neurodegenerative diseases brought to market within 6 months to one year.

• Microbiome-sparing vaccines for keystone pathogen strains directly involved in the pathogenesis of Alzheimer’s disease, multiple cardiovascular diseases, and neurodegenerative diseases.

• Reduction of disease, disease complications, and healthcare costs.

Our VisionOur VisionOur VisionOur Vision

• AdVax has sequenced and developed supragenome modeling for the most pathogenic strains of two unique pathogens of oral origin involved in the pathogenesis of Alzheimer’s and cardiovascular diseases – Treponema denticola

– Porphyromonas gingivalis

• AdVax uses our existing patented technology, developing diagnostics, monoclonal antibodies, and first-in-man vaccines for P. gingivalis & T. denticola

• AdVax brings market-leading technologies currently being used in advanced-stage development of a human rhinovirus vaccine to the emerging market of oral-systemic biology.

AdVax Science & AdVax Science & TechnologyTechnology

AdVax Science & AdVax Science & TechnologyTechnology

Meet the AdVax TeamMeet the AdVax TeamMeet the AdVax TeamMeet the AdVax TeamGarth Ehrlich, PhD, FAAAS | Systemic Microbiology & GenomicsTheoretical Modeler of Chronic Bacterial Infections: Developer of the Mucosal Biofilm Paradigm, the Distributed Genome Hypothesis, and the Rubric of Bacterial PluralityProfessor of Microbiology and Immunology & Executive Director, Center for Genomic Sciences at Drexel University, College of Medicine

Peter Lloyd Nara, MSc, DVM, PhD, FAAAS | VaccinologyDeceptive Imprinting/Immune Refocusing TechnologyChief Executive Officer, President, Chairman & co-founder of Biological Mimetics, Inc., Biological Mimetics, Inc.

Daniel L. Sindelar, DMD | Periodontics & Oral-Systemic HealthCo-founder and recent president of the American Academy for Oral Systemic Health (AAOSH)Founder and director of Oral Genomics, LLC.

Judith Miklossy, MD, PhD, DSc | Neuropathology, Neurology, PsychiatryFounder & Director of the Alzheimer’s Prevention International FoundationDirector of the International Alzheimer Research Center in Switzerland

Cardiovascular disease and neurodegenerative diseases such as

Alzheimer's have a common pathogenic etiology:

Specific strains of P. gingivalis.

• AdVax has identified the keystone pathogen strains found to be causal of the key biomarkers of inflammatory cardiovascular disease.

• These organisms have already been directly linked in clinical trials to disease.

• They are able to evade the immune system and initiate cytokine production, while also manipulating the immune system.

• These pathogens also play the key role in the neuroinflammatory pathway of Alzheimer’s and neurodegenerative disease.

Why Target Pathogens?Why Target Pathogens?

The Body’s Response to The Body’s Response to P. gingivalis P. gingivalis & & T. denticolaT. denticolaThe Body’s Response to The Body’s Response to

P. gingivalis P. gingivalis & & T. denticolaT. denticolaWhen these bacteria are in the MOUTH:•Oral/systemic vascular and organ inflammation•Chronic active/silent infection•Biofilm formation•Bleeding gums•Bone loss•Loose/lost teeth•Cavities

When these bacteria go planktonic to the HEART:•Foam cells•Ox-LDL•hs-CRP•Lp-PLA2

•MPOWhen these bacteria go planktonic to the BRAIN:•Focal and disseminated neuro-inflammation•Amyloid beta/Tau activation•Broad slow cognitive decline•Pre-AD and Alzheimer’s disease•Breakdown of BBB

Oral originOral origin

Olfactory bulb Olfactory bulb (1(1stst symptom of AD is symptom of AD is

loss of smell)loss of smell)

Entorhinal cortexEntorhinal cortex(first site of AD (first site of AD

destruction & AΒ)destruction & AΒ)

Oral pathogens found at the site of beta amyloid

deposits in 98% of Alzheimer’s brains and non-existent in all but

7% of the non-Alzheimer’s brains.

Miklossy J. Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation. 2011;8(1):90.

• “The data from the human brains and that from the in vivo mouse study suggested specific associations of P. gingivalis with AD inflammatory pathology [7].”

• “The keystone hypothesis of Hajishengallis et al. [3] helps to explain the contribution that P. gingivalis may cause the early develop- ment of a neurodegenerative condition such as Alzheimer’s disease. In our view, P. gingivalis (highly virulent strains) access the CNS during healthy stages but only those indi- viduals with inflammatory susceptibility traits are likely to develop progressive inflammatory component representing neurodegenerative disease processes.”

Mediators of InflammationMediators of Inflammation, , 20152015

Mediators of InflammationMediators of Inflammation, , 20152015

Sim K. Singhrao, Alice Harding, Sophie Poole, Lakshmyya Kesavalu, and StJohn Crean, “Porphyromonas gingivalis Periodontal Infection and Its Putative Links with Alzheimer’s Disease,” Mediators of Inflammation, vol. 2015, Article ID 137357, 10 pages, 2015. doi:10.1155/2015/137357

P. gingivalis initiates neuroinflammatory diseases,

specifically Alzheimer's

• Pathogen-directed treatment of periodontal disease has just been found to lower patients’ Lp-PLA2 from 30% to 37%.

• Lp-PLA2 is the only test recognized by the FDA to determine who will develop atherosclerosis, have a heart attack or stroke as it is an enzyme involved with LDL cholesterol forming foam cells, which form plaque in the arteries

Cardiovascular SystemsCardiovascular Systems, 2014, 2014

Duane C. Keller. Systemic Lp-PLA-2 cardiovascular marker response to direct medication delivery periodontal treatment. Cardiovascular System. 2014;2(1):8.

CRP Levels are Higher in PD

• CRP levels were significantly elevated with severe PD (8.25 mol/l) and moderate PD (4.93 mol/l) compared to controls (1.09 mol/l).

• After adjusting for risk factors: CRP 7 fold higher in severe PD compared to controls

• P. gingivalis elevation was independently associated with high serum CRP

Journal of Clinical Microbiology Journal of Clinical Microbiology & Infectious Disease, & Infectious Disease, 20112011

Journal of Clinical Microbiology Journal of Clinical Microbiology & Infectious Disease, & Infectious Disease, 20112011

Pejcic A, Kesic LJ, Milasin J. C-reactive protein as a systemic marker of inflammation in periodontitis. Eur J Clin Microbiol Infect Dis. 2011;30(3):407-14.

• Porphyromonas gingivalis induces murine macrophage foam cell formation.

• P. gingivalis and its LPS induced foam cell formation of macrophages in the presence of LDL. Low concentration of P. gingivalis outer membrane vesicles induced foam cell formation in the presence of LDL.

• P. gingivalis may deliver virulence factors to the arterial wall to initiate or promote foam cell formation in macrophages and contribute to atheroma development.

Molecular Oral MicrobiologyMolecular Oral Microbiology, 2013, 2013

Mol Oral Microbiol. 2013 Feb;28(1):28-39. Shaik-Dasthagirisaheb YB, Huang N, Baer MT, Giblson FC 3rd.

Nowhere in this integrative causative disease model is there a better established cause and effect relationship than between

Porphoromonas gingivalis and its induction of systemic inflammatory markers—HDL, Ox-LDL, hs-CRP, Hb-

A1c, Lp-PLA2, MPO

Cardiovascular DiseaseCardiovascular DiseaseCardiovascular DiseaseCardiovascular Disease

P. gingivalis plays a key role in advancing each stage of inflammatory

cardiovascular disease

• AdVax has sequenced and developed supragenome modeling for the most pathogenic strains of two unique pathogens of oral origin involved in the pathogenesis of Alzheimer’s and cardiovascular diseases

– Treponema denticola– Porphyromonas gingivalis– Newly sequenced and identified red complex bacterial oral pathogens

• This allows for unique target identification for Immune Refocusing Technology

• AdVax partnered with Biological Mimetics Inc. to use its patented Immune Refocusing technology to develop first-in-man vaccines and monoclonal antibodies for P. gingivalis & T. denticola

• AdVax uses our existing patented technology, developing diagnostics, monoclonal antibodies, and first-in-man vaccines for P. gingivalis & T. denticola

• AdVax brings market-leading technologies currently being used in advanced-stage development of a human rhinovirus vaccine to the emerging market of oral-systemic biology.

AdVaxAdVaxAdVaxAdVax

• BMI holds background and genus species specific patents for target vaccine proteins in infectious diseases areas for humans and animal health.

• BMI has exclusive worldwide license for IRT from NIH.

• BMI and AdVax will co-own new identified Red Complex oral pathogens– Initial immune refocused P. gingivalis and

T. denticola patents being drafted

AdVax Intellectual Property in AdVax Intellectual Property in Partnership with BMIPartnership with BMI

AdVax Intellectual Property in AdVax Intellectual Property in Partnership with BMIPartnership with BMI

Oral Genomics Diagnostics & Therapeutics Vaccines

Description First-of-kind salivary diagnostics performed by physicians to determine

microbial burden & subsequent risk for

inflammatory disease

Paradigm-changing diagnostics, medical

devices, and monoclonal antibody-based

therapeutics

Next-generation prophylactic,

microbiome-sparing vaccines

Timeline 6 months – 1 year 2 years 3 - 6 years

Cost $200,000 $2 Million $5 - 10 Million

Revenue $25 - $50 million per yearEarly detection &

prevention of disease

$100 million/year& a solution for prevention

& early detection of Alzheimer’s disease

$1 - 2 billion/year& a cure for one cause of Alzheimer’s disease

AdVax SolutionsAdVax SolutionsAdVax SolutionsAdVax Solutions

Diagnostics TimelineDiagnostics TimelineDiagnostics TimelineDiagnostics Timeline

6 month time frame

Test 1: Salivary DiagnosticsFirst-of-kind salivary diagnostics performed by physicians to determine microbial burden & subsequent risk for CVD, Alzheimer’s, RA, Diabetes, Glaucoma, etc.

Test 2: Buccal Inflammatory TestingDetermines inflammatory risk for Alzheimer’s disease.

Research & Developmen

t

Research & Developmen

t

COMPLETED Market-ready

diagnostics

General Overview of Vaccine General Overview of Vaccine TimelineTimeline

General Overview of Vaccine General Overview of Vaccine TimelineTimeline

Seed and Bridge Funding

Series A

Year 1 Year 2 Year 3

Supragenome, Cataloguing, & IP

Targeted & Developed Vaccine

for PG

Pre-Clinical & IND-enabling studies

Phase 1

Value Inflection Point Value Inflection Point& Exit Point

Value Inflection Point& Exit Point

Ehrlich DGH Studies – Sequencing & Molecular Cataloguing

Vaccine, Nanobody, & Monoclonal Antibody Development Timeline

Quarter 1 Quarter 2 Quarter 3 Quarter 4

4 months 6 months 2 mos.

6 months 3 months

acquisition of a broad array of clinical strains of each

species (N = 10) of periodontal pathogen associated with AD

Sequence a minimum of 20 strains of each

periodontal pathogen (N = 200)

perform comparative genomics on each species including supragenome modeling,

identify core genes, identify core gene subset under immune selection for each

species

prepare recombinant proteins for at least 4 candidate core genes for each species and

collect human sera from AD and periodontal patients.

Determine which of the candidate core proteins react with human

serum from patients with periodontal disease creating an

active target list

Map IDNPE’s on bacterial targets (n=1-2 bacterial sp.)

Engineer IRT mutations into bacterial targets (n= 2-4

targets with5-10 IRT mutations per target)

Express IRT bacterial proteins in commercially licensable

systems/

Immunogenicity studies in 2 lab animal species

COMPLETED

Nara IRT vaccine and mAb development

Product Launch TimelineProduct Launch TimelineProduct Launch TimelineProduct Launch Timeline

Salivary Diagnostics & Inflammatory Testing

Animal-ready, first-in-man vaccines and monoclonal antibody-based therapeutics for Alzheimer’s & CVD-causing pathogens. Full body scan for early detection of Alzheimer’s disease.

First-in-man vaccines and monoclonal antibody-based therapeutics for Alzheimer’s & CVD-causing pathogens

6 YEARS2 YEARS< 1 YEAR

Value Inflection PointSalivary Diagnostic

Revenues

Value Inflection Point& Exit Point*

Value Inflection Point& Exit Point*

*Capitalizing on existing relationships with Big Pharma

Immune RefocusingImmune Refocusing& Deceptive Imprinting & Deceptive Imprinting

Immune RefocusingImmune Refocusing& Deceptive Imprinting & Deceptive Imprinting

AdVax Science & Technology

Vaccination as we understood it for 250 years:

Licensed vaccines today basically work by inducing protective immune responses against the naturally occurring

immunodominant critical structural functional domains needed by the pathogen to infect & transmit.

That is okay as long as the pathogen has a lower/limited mutability and little antigenic variation!

The problem comes when natural immunity from a pathogen is

misdirected to a binding non-neutralizing, strain- or serotype restricted, disease-enhancing B & T cell responses and the pathogen has the capability for

high/fast rates of mutability and antigenic variation

The Unmet Need The Unmet Need The Unmet Need The Unmet Need

– Infectious diseases from the common cold to malaria account for 18.5% morbidity and 23% mortality worldwide and remain one of the most economically costly medical conditions of the developed and developing nations.

– ~ 984 identified human pathogens known

• There are currently vaccines for only 17, with 6 in development.

• Only one licensed monoclonal antibody for infectious disease (Synagis-RSV)

• Increasing rate of drug/antibiotic resistance with viral, bacterial, and parasitic pathogens.

• 87 new human pathogens have emerged since 1980.

• Most of these pathogens are resistant to current vaccine and monoclonal antibody technologies due to their ability to use molecular decoys, mutate and exist in numerous strains

• Vaccines are the only known medical product that can be given to prevent infection.

• Unmet and completely open multi-Billion dollar markets exist for multiple pathogens.

Class II PathogensClass II PathogensClass II PathogensClass II Pathogens

How do Class II pathogens accomplish this feat?

““Deceptive Imprinting”Deceptive Imprinting”““Deceptive Imprinting”Deceptive Imprinting”

AdVax, in partnership with BMI, has the market-leading

technology to overcome deceptive imprinting

Bacterial Pilius Adhesion Bacterial Pilius Adhesion ProteinsProteins

Bacterial Pilius Adhesion Bacterial Pilius Adhesion ProteinsProteins

Type IV Pili ribbon and space filling structure(mapped decoys)

Immune Evading Decoys (red box)

An integrated platform for simultaneous discovery and

development of vaccines and monoclonal antibodies from the

same antigen

Rational Antigen DesignRational Antigen Design Rational Antigen DesignRational Antigen Design

Immune Refocusing Technology

ImmunodominantType Specific

Non-ProtectiveAntibodies

Broadly ReactiveProtective and

TherapeuticAntibodies

ImmunodominantHypervariable

Decoy Epitopes

Antibodies-Preventative, Therapeutic & Diagnostic

Immune Dampen

andImmune Refocus

- Oligosaccharide

Immune Refocusing TechnologyRecombinant Virus/Protein Approach

Elicit and Identify

Novel Immune Responses

To Targeted Regions

Vaccine CandidatesRecombinant therapeutic proteins

Delivery vectors

FundingFundingFundingFunding

expression, GMP production, preclin safety IND submission/ approval Ph1A/B safety, dose setting, POC

Cardiovascular PG Vaccine

Pharma Partner for Ph2/3 Registration, Market

Launch[up front payment, milestones,

royalties]

reward investorsfund

pipeline developme

nt

PG therapeutic mAb

Trep vaccine

Trep therapeutic mAb

Investment & Business Investment & Business StrategyStrategy

Investment & Business Investment & Business StrategyStrategy

expression, GMP production, preclinical safety IND submission/ approval Ph1A/B safety, dose setting, POC

PG Cardiovascular Vaccine

• Vaccine efficacy proven using laboratory scale, non-GMP material.

• Plans for GMP material for safety and clinical study:o Contract with CRO + QC capabilities) – Discussions suggest

favorable contract terms are possible.

Overall risk: low/manageable

Development Plan OutlineDevelopment Plan OutlineDevelopment Plan OutlineDevelopment Plan Outline

• GMP, quality control/compliance, regulatory strategy outsource in part to RegSource Consulting (high efficiency, strong track record)

• Pre-clinical vaccine efficacy/safety low risk.• Dose-ranging straightforward, no PK risk (not required).• Clinical study lead, Cleveland Clinic -strong clinical trials

design experience leading to current DX and TX of PG’s role in cardiovascular disease.

Overall risk: low to moderate clinical trials design already established

Development Plan OutlineDevelopment Plan OutlineDevelopment Plan OutlineDevelopment Plan Outline

expression, GMP production, preclinical safety IND submission/ approval Ph1A/B safety, dose setting, POC

PG Cardiovascular Vaccine

Overall risk: low to moderate clinical trials design already established with FDA

40-80 healthy volunteers

2 injection, 3 test doses

challenge in 20 volunteers, monitor disease and virus

shedding

Safety up to 6 months, antibody titers/lab testing for

bacterial killing

Development Plan OutlineDevelopment Plan OutlineDevelopment Plan OutlineDevelopment Plan Outline

expression, GMP production, preclinical safety IND submission/ approval Ph1A/B safety, dose setting, POC

PG Cardiovascular Vaccine

Timeline to LicensureTimeline to LicensureTimeline to LicensureTimeline to Licensure

• Seed Bridge Funding: $500,000 • Series A Funding: $2-5M• Possibility for establishing NFP

Institute in donors nameTHE RETURN:Multiple Exits: Phase 1, Phase 2a/2b.Value inflection points: Discovery, IND

filing, Phase 1, Phase 2

Capital NeedsCapital NeedsCapital NeedsCapital Needs

Multiple seed and Series A funding opportunities are being sought for the

company's financing of both the development of novel point of care diagnostics worth $100s of millions per year and monoclonal antibodies and vaccines worth more than $1-2

billion per year.

Investment OpportunitiesInvestment OpportunitiesInvestment OpportunitiesInvestment Opportunities

PG Cardiovascular Vaccine Pre-clinical Program