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

2

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

3

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 Philip Ashton-Rickardt, PhD Senior Vice President, Immunology

4

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 Ready

Initiation in 1H 2020 (IND Approved)

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

5

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; Isabel Barroeta-Espar et al. Distinct cytokine profiles in human brains resilient to Alzheimer’s pathology. Neurobiol Dis. 2019.

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

6

ALZT-OP1: A Multimodal Combination Approach to Treat Complex Progression of AD

✓ A novel, inhalable cromolyn with a low dose formulated

• ral ibuprofen

✓ Re-engineered physical delivery to cross the blood brain barrier ✓ Well characterized safety profile ✓ Ongoing COGNITE Phase 3 clinical trial fully enrolled with trial completion in Q1 2021 ✓ 505(b)2 pathway conducted under FDA Special Protocol Assessment (SPA) ✓ Speed-to-market strategy

17.1 mg capsule for daily inhalation via dry powder inhaler Targets neuroinflammation and neurotoxic peptides Shifts microglia into neuroprotective, phagocytic state Inhibits pro-inflammatory cytokine production; oligomerization of Aβ peptides; and mast cell degranulation

Cromolyn

10 mg tablet for oral administration Targets neuroinflammation as a COX1/COX2 non-specific NSAID May boost cromolyn efficacy by promoting microglial recruitment to Aβ plaques

Ibuprofen

Oral Tablet

7

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

Cromolyn: 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

8

Pro-inflammatory Microglia Damage Neurons and Synapses

Source: “Alzheimer’s in a Dish; Park et al., Nature Neurosci. (2018); Hoozemans et al (2011) CNS & Neurol Disorders–Drug Targets, 10: 57-67; Heneka et al (2005) Brain 128, 1442-1453.

Neurotoxic Microglia (M1) Attack Neurons

“Beyond the amyloid approach, an alternate line of thought based on the role of mast cells and microglia is neuroinflammation and the potential targeting of these cells for the treatment of AD represents a paradigm shift in therapeutic strategies.” - GlobalData Dec 2018

Microglia in Brain During AD Progression

Multi-modal approach aligns with current views on neuroinflammation as a leading cause of neurodegenerative disease and progressive brain damage

9

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

Source: Data on file, Mass General Hospital.

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

10

Cromolyn Anti-inflammatory Effect Validated in Multiple Recent Publications

2019 2018 2017 2016 2015 Independent AZTherapies

2015 2019 2019 2018 2019 2016 2019 2016 2016 2017

11

ALZT-OP1: Phase 1 Studies Confirmed Crossed the Blood-Brain-Barrier

• AZT-002 Phase 1a study1:

– Cromolyn (17.1 mg) and ibuprofen (10 mg) pharmacokinetics in healthy volunteers – cromolyn and ibuprofen reached desired concentrations in plasma and CSF, the latter indicating blood brain barrier crossing

• AZT-004 Phase 1b study2:

– Cromolyn (17.1 mg) and ibuprofen (10 mg) pharmacokinetics in healthy volunteers and AD patients – cromolyn and ibuprofen reached desired concentrations in plasma and CSF, the latter indicating blood brain barrier crossing

1 Brazier, et al: Pharmacokinetics of Cromolyn and Ibuprofen in Healthy Volunteers; Clin Drug Investig (2017). 2 Data on file, AZTherapies, Inc.

Study Patients Cmax Tmax Cromolyn AZT-002 (4 Hour CSF) Healthy Adults 0.24 ng/mL 3.7 hours AZT-004 (8 Hour CSF) Healthy Adults 0.4 ng/mL 3.6 hours AD Patients 1.4 ng/mL 3.8 hours Ibuprofen AZT-002 (4 Hour CSF) Healthy Adults 3.9 ng/mL 2.6 hours AZT-004 (8 Hour CSF) Healthy Adults 4.1 ng/mL 3.0 hours AD Patients 6.0 ng/mL 4.0 hours ALZT-OP1 Pharmacokinetics (CSF)

12

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

13

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

14

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

`

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

`

Validate Construct

`

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

`

15

IP Portfolio: Select Examples

1 Listed pending applications are in the public domain, with additional pending applications that have yet to be disclosed.

Alzheimer’s Disease (ALZT-OP1, AZT-101)

TBD

Method of Use: Cromolyn + Ibuprofen for Treating AD; Exp: 2030 Formulation: Cromolyn +/- Ibuprofen Formulations; Exp: 2034 Composition of Matter: AZT-211 Exp: 2030 Method of Use: Cromolyn +/- Ibuprofen (IP, IV, SubQ) for Treating AD; Exp: 2030 Method of Use: Cromolyn + Cholinesterase Inhibitor/Select Aβ Antibody for Treating AD; Exp: 2033 Composition of Matter: CAR-Tregs for Treating Neurodegenerative Disease; Exp: ~2039 Method of Use: Cromolyn for Treating ALS; Exp: ~2037

Granted Pending1

Key examples demonstrate the robust portfolio with IP protection well beyond 2030; additional patent applications not yet in the public domain further extending our exclusivity timeline

Non-Exhaustive IP Examples

Additional Programs (NCE, ALS, CAR-Treg)

Formulation: Cromolyn Formulations; Exp: 2034

16

ALZT-OP1 WW Revenue Forecast

Note: Based on a detailed forecast of the US. A scale up factor was used to estimate ROW revenues. Source: Health Advances model.

U.S. + ROW Revenue Forecast 2030 WW Revenue $4.5 B

$0.9 $1.3 $1.8 $2.0 $2.3 $2.4 $2.5 $2.7 $0.6 $0.9 $1.2 $1.4 $1.5 $1.6 $1.7 $1.8 $0.0 $0.5 $1.5 $2.2 $3.0 $3.4 $3.8 $4.0 $4.3 $4.5 $0.0 $0.5 $1.0 $1.5 $2.0 $2.5 $3.0 $3.5 $4.0 $4.5 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 Revenues (USD B)

Rest-of-World Revenue U.S. Revenue

Based on the strength of the product profile shared with physicians and payers, ALZT-OP1 can expect to generate WW peak revenues of ~$4.5B

17

2020

Upcoming Milestones

✓ Submit IND for AZT-101 in ALS

(IND Approved) ❏ Initiate and Complete Phase 2a Trial in ALS Patients ❏ Conduct Preclinical Proof-of- Concept with CAR-Treg Platform ❏ Submit IND for AZT-211 ❏ Perform Scale-up Manufacturing

• f 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

18

Cosine Cosine IBS Capital

Investors

Strong Institutional and Investor Support

Institutional Partners

Wooshin

19

Board of Directors and Advisory Boards

Board of Directors Business Advisory Board Scientific Advisory Board

David R. Elmaleh, PhD, Chair CEO, AZTherapies, Inc. George D. Behrakis Investor/Former Biopharma Executive Peter Conti, MD, PhD

• Prof. of Radiology, USC

Keith Greenfield The Dover Group Gillian Sandler Cosine Capital, LLC David Taft IBS Capital, LLC Ronald Tompkins, MD, ScD

• Prof. of Surgery, Harvard

Rudolph E. Tanzi, PhD, Chair

• Prof. of Neurology, Harvard

Adam Boxer, MD, PhD

• Prof. of Neurology, UCSF

Martin R. Farlow, MD

• Prof. of Neurology, Indiana University

Seth P. Finkelstein, MD

• Assoc. Prof./Neurologist, Mass General

Bradley T. Hyman, MD

• Prof. of Neurology, MGH Inst of Neurodegenerative Disease Center

Keith A. Johnson, MD

• Prof. of Radiology/Neurology, Harvard

Scott E. Kasner, MD Chief Vascular Neurology, UPenn Vijay K. Kuchroo, DVM, PhD

• Prof. of Neurology, Harvard

Megan Levings, PhD Prof., Department of Surgery, University of British Columbia Ziv Neeman, PhD Director of Diagnostic Imaging Institute, Technion Medical School Eran Segal, PhD

• Prof. of Computer Science, Weizmann Institute of Science

Sangram S. Sisodia, PhD

• Prof. of Neurobiology, University of Chicago

Shahin Tabatabaei, MD Assoc Prof. Urology, Mass General Steven L. Wagner, PhD Assoc Prof. of Neurosciences, UCSD Michael Porter, Chair Prof., Harvard Business School Isabelle Bajeux-Besnainou

• Prof. of Finance, McGill

William S. Belichick New England Patriots Noah Gottdiener Chair/CEO, Duff and Phelps David H.P. King Co-founder and Managing Partner Peak Capital Holdings Thierry Porté Managing Director, JC Flowers

Thank You

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