Targeting Neuroinflammation: The Common Thread in Neurodegenerative - - PowerPoint PPT Presentation

Targeting Neuroinflammation: The Common Thread in Neurodegenerative Disease Progression

200 Clarendon Street, 17th Floor Boston, MA 02116 www.aztherapies.com

February, 2020

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Innovative Approach and Compelling Opportunity

Robust IP Estate with More Than 100 Patents and Applications Late Stage Lead Program – Fully Enrolled

ALZT-OP1 in Early Stage Alzheimer’s Disease; Completion Expected Q1 2021

Experienced Leadership Team Growing Pipeline with Near-term Clinical Milestones

Multiple Programs Targeting Neuroinflammation to Address Neurodegeneration

Novel Approach

Targeting Neuroinflammation by Multimodal Mechanisms as a Key Driver of Neurodegeneration

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Experienced Leadership Team

David R. Elmaleh, PhD Founder, Chairman, and CEO Karen Reeves, MD President and CMO Jay Mohr COO and CBO Head of Commercial Development Rudolph E. Tanzi, PhD Chairman, Scientific Advisory Board Brian Bartlett Chief Financial & Accounting Officer

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Program Discovery Pre-clinical Phase 1 Phase 2 Phase 3 Expected Milestones

ALZT-OP1

Early Alzheimer’s Disease

COGNITE Phase 3 trial fully enrolled, data readout in early Q1 2021

AZT-101

ALS – Phase 2a Planning Underway

IND and initiation in 1H 2020

AZT-101

Ischemic Stroke – Phase 2 Ready

Initiation 1H 2021

AZT-211 (Next-Gen)

Neurodegenerative Diseases

IND expected 2H 2020

Universal Donor CAR-Treg Program

Neurodegenerative Diseases

Pre-clinical proof-of- concept in 1H 2020

Microbiome Program

Alzheimer’s Disease

Observational study to initiate in 1H 2020

Robust Pipeline with Phase 3 Trial and Multiple Follow-on Opportunities

COGNITE Phase 3 Trial

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The Resilient Brain: Inflammation is Associated with Decreased Cognitive Function

Source: Perez-Nievas et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology, Brain 2013.

Neuroinflammation is potentially a key predictor of neurodegenerative disease and progression

Aβ Plaques Activated Microglia Neurons Activated Astrocytes Tau Tangles

Resilient No Alzheimer’s Symptomatic Alzheimer’s

Inflammation

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Anti-amyloid Aggregation: Cromolyn inhibits amyloid fibrillization and increases amyloid clearance Anti-inflammatory: Cromolyn induces a protective, phagocytic state in microglia versus neuroinflammation

ALZT-OP1: Dual Mechanisms to Reduce Neuronal Death in Alzheimer’s Disease

Source: Zhang, C et al. Cromolyn Reduces Levels of the Alzheimer’s Disease-Associated Amyloid ß-Protein by Promoting Microglial Phagocytosis. Scientific Reports, January 2018. Hori. Journal of Biological Chemistry, 2015.

Aβ oligomers form, plaques accumulate, trap in synapses; Tau tangles form Neuronal degeneration & death Alzheimer’s disease progression and dementia Microglial activation and aggravated neuroinflammation Amyloid protein precursor (APP) cleavage and Aβ (40 – 42) peptides released

% of Iba1 Positive Processes Colocalizing with Amyloid Deposits

Alzheimer’s Progression Role of ALZT-OP1 Treatment

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ALZT-OP1: Improving Memory Capabilities in Preclinical Model of AD

Source: Data on file, Mass General Hospital. Note: APP/SP1 Mice Were Treated with ALZT-OP1 for 6 Months.

Morris Maze Memory Test

1 2 3 4 Mock-trt tg ALZT-OP1a trt tg WT control Non-treated Control (APP/PS1 Mice Without Drug Treatment) Treatment Group (APP/PS1 Mice With ALZT-OP1 Treatment) Healthy Control (Wild Type Mice Without Drug Treatment) # Times Reaching Target Location p = 0.03 Transgenic APP/PS1 mice (4- month-old) or same-age healthy controls (wild type mice) were treated weekly with I.P. injections for 6 months, trained on the Morris Maze Memory Test for 7 days, and then tested on day 8 for their ability to recall their training

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Primary Endpoint:

Mean change from baseline in Clinical Dementia Rating-Sum of Boxes (CDR- SB) at week 72, comparing combination treatment to monotherapy cromolyn and monotherapy ibuprofen

Conducted under Special Protocol Assessment (SPA) Exploratory Biomarkers Study Completion:

Anticipated Trial Completion in Q1 2021

ALZT-OP1: COGNITE Phase 3 Trial – Fully Enrolled

Randomization

Eligibility Criteria & Assessments

Week 4 Safety & Compliance Check Week 48 CDR-SB MMSE Safety Day 1 Initial Drug Dispense Week 12 CDR-SB MMSE Safety Week 24 CDR-SB MMSE Safety Week 72 CDR-SB MMSE Safety Biomarkers

n = 620

• Aged 55-79
• Confirmed early AD
• Aß-42 180-690 pg/mL
• Global CDR 0.5
• Memory Box ≥ 0.5
• WMS LMII
• CDR-SB
• MMSE

Ibuprofen Placebo Cromolyn ALZT-OP1

While there are four-arms in the trial design, ~50% of the patients are receiving cromolyn

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AZT-101 Demonstrates Significant Potential in ALS

Source: Granucci. Cromolyn sodium delays disease onset and is neuroprotective in the SOD1G93A Mouse Model of amyotrophic lateral sclerosis. Scientific Reports. 2019; Note: Study performed on 149 male and female age- and litter-matched transgenic (Tg) SOD1G93A and wild-type (Wt) SOD1G93A mice.

Key Results Provide Evidence of AZT-101 Activity in SOD1 ALS Model

Delayed disease onset and progression Reduced motor deficits in the Paw Grip Endurance (PaGE) task Spared lumbar spinal cord motor neurons & preserved neuro-muscular-junction integrity Reduced pro-inflammatory cytokine levels in the spinal cord and plasma Significant effect on motor symptoms as measured by age at paresis onset

**** p<0.0001 Onset of Paresis Neuro-muscular- Junction Denervation

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Universal Donor CAR-Treg: Immense Potential in Treating Neurodegeneration

Source: AZTherapies Data; Appel. Neurol Neuroimmunol Neuroinflamm. 2018; scFv: Single-chain Variable Fragment.

Concentration (nM)

Fronto- temporal Dementia (FTD) Alzheimer’s Disease Multiple Sclerosis (MS) ALS Progressive Supranuclear Palsy (PSP) Parkinson’s Disease

Pre-clinical Validation

Identify scFv

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Glia-binding scFv Signaling & Co-stimulation Domains CD28 CD3z Glia

CAR Technology Increases Treg Localization to CNS, Enhancing Anti-Inflammation Effects and Limiting Off- Target Suppression, Compared to Autologous Treg Infusions

Assess Efficacy

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Validate Construct

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Identified seven unique human scFv and assessed binding via ELISA All CAR constructs are stably expressed on surface of Tcells In vitro and in vivo validation of CAR-Treg constructs is ongoing ALS Progression Slowed During Autologous Treg Infusions in P1 Trial

Clinical Rationale

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2020

Upcoming Milestones

❏ Submit IND for AZT-101 in ALS ❏ Initiate and Complete Phase 2a Trial in ALS Patients ❏ Submit IND for AZT-211 ❏ Conduct Preclinical Proof-of- Concept with CAR-Treg Platform ❏ Perform Scale-up Manufacturing of ALZT-OP1 ❏ Initiate Microbiome Observational Study ❏ Continue Corporate Financings

2021

❏ Complete Phase 3 ALZT-OP1 Early AD Trial in Q1 2021 ❏ Submit NDA and Gain FDA Approval in Early AD for ALZT-OP1 ❏ Complete Commercial Preparation and Readiness for ALZT-OP1 in Early AD ❏ Initiate and Complete AZT-101 Phase 2 Stroke Trial ❏ Initiate Phase 1 Trial for AZT-211 ❏ Submit First IND for CAR-Treg ❏ Complete Microbiome Observational Study ❏ Continue Corporate Financings

2020 – 2021

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Cosine Cosine IBS Capital

Investors

Strong Institutional and Investor Support

Institutional Partners

Wooshin

Thank You

200 Clarendon Street, 17th Floor Boston, MA 02116 www.aztherapies.com