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

Targeting Neuroinflammation: The Common Thread in Neurodegenerative Disease Progression 200 Clarendon Street, 17 th Floor Boston, MA 02116 www.aztherapies.com

Innovative Approach and Compelling Opportunity Novel Approach Targeting Neuroinflammation by Multimodal Mechanisms as a Key Driver of Neurodegeneration Late Stage Lead Program – Fully Enrolled ALZT- OP1 in Early Stage Alzheimer’s Disease; Completion Expected Q1 2021 Growing Pipeline with Near-term Clinical Milestones Multiple Programs Targeting Neuroinflammation to Address Neurodegeneration Experienced Leadership Team Robust IP Estate with More Than 100 Patents and Applications 2

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 Brian Bartlett Chief Financial & Accounting Officer Philip Ashton-Rickardt, PhD Senior Vice President, Immunology Rudolph E. Tanzi, PhD Chairman, Scientific Advisory Board 3

Robust Pipeline with Phase 3 Trial and Multiple Follow-on Opportunities Program Discovery Pre-clinical Phase 1 Phase 2 Phase 3 Expected Milestones COGNITE Phase 3 Trial COGNITE Phase 3 trial fully ALZT-OP1 enrolled, data readout in early Early Alzheimer’s Disease Q1 2021 AZT-101 Initiation in 1H 2020 (IND Approved) ALS – Phase 2a Ready AZT-101 Initiation 1H 2021 Ischemic Stroke – Phase 2 Ready AZT-211 (Next-Gen) IND expected 2H 2020 Neurodegenerative Diseases Universal Donor Pre-clinical proof-of-concept in CAR-Treg Program 1H 2020 Neurodegenerative Diseases Microbiome Program Observational study to initiate in 1H 2020 Alzheimer’s Disease 4

The Resilient Brain: Inflammation is Associated with Decreased Cognitive Function Inflammation Symptomatic Alzheimer’s Resilient No Alzheimer’s A β Plaques Tau Tangles Activated Astrocytes Activated Microglia Neurons Neuroinflammation is potentially a key predictor of neurodegenerative disease and progression 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 5 resilient to Alzheimer’s pathology. Neurobiol Dis. 2019.

ALZT-OP1: A Multimodal Combination Approach to Treat Complex Progression of AD Cromolyn ✓ A novel, inhalable cromolyn with a low dose formulated oral ibuprofen ✓ Re-engineered physical delivery to cross the blood brain barrier ✓ Well characterized safety Oral Tablet 17.1 mg capsule for daily inhalation via dry powder inhaler profile ✓ Ongoing COGNITE Phase 3 Targets neuroinflammation and Ibuprofen neurotoxic peptides clinical trial fully enrolled with Shifts microglia into trial completion in Q1 2021 10 mg tablet for oral neuroprotective, phagocytic state ✓ 505(b)2 pathway administration Inhibits pro-inflammatory cytokine conducted under FDA Targets neuroinflammation as a production; oligomerization of A β Special Protocol COX1/COX2 non-specific NSAID peptides; and mast cell Assessment (SPA) May boost cromolyn efficacy by degranulation promoting microglial ✓ Speed-to-market strategy recruitment to A β plaques 6

Cromolyn: Dual Mechanisms to Reduce Neuronal Death in Alzheimer’s Disease Amyloid protein precursor A β oligomers form, plaques Microglial activation and Neuronal degeneration Alzheimer’ s disease (APP) cleavage and A β accumulate, trap in aggravated & death progression and dementia (40 – 42) peptides released synapses; Tau tangles form neuroinflammation Alzheimer’s Progression Role of ALZT-OP1 Treatment Anti-amyloid Aggregation: Cromolyn inhibits amyloid Colocalizing with Amyloid Deposits fibrillization and increases amyloid clearance % of Iba1 Positive Processes Anti-inflammatory: Cromolyn induces a protective, phagocytic state in microglia versus neuroinflammation Source: Zhang, C et al. Cromoly n Reduces Levels of the Alzheimer’s Disease -Associated Amyloid ß-Protein by Promoting Microglial Phagocytosis. Scientific Reports , January 2018. Hori. Journal of 7 Biological Chemistry, 2015.

Pro-inflammatory Microglia Damage Neurons and Synapses Multi-modal approach aligns with current views on neuroinflammation as a leading cause of neurodegenerative disease and progressive brain damage Neurotoxic Microglia (M1) Attack Neurons Microglia in Brain During AD Progression “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 8 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.

ALZT-OP1: Improving Memory Capabilities in Preclinical Model of AD Morris Maze Memory Test 4 # Times Reaching Target Location Transgenic APP/PS1 mice (4- p = 0.03 3 month-old) or same-age healthy controls (wild type mice) were treated weekly with I.P. injections for 6 months, trained on the 2 Morris Maze Memory Test for 7 days, and then tested on day 8 for their ability to recall their training 1 0 Non-treated Control Treatment Group Healthy Control Mock-trt tg ALZT-OP1a trt tg WT control (APP/PS1 Mice (APP/PS1 Mice With (Wild Type Mice Without Drug ALZT-OP1 Without Drug Treatment) Treatment) Treatment) 9 Source: Data on file, Mass General Hospital.

Cromolyn Anti-inflammatory Effect Validated in Multiple Recent Publications Independent AZTherapies 2019 2019 2019 2017 2019 2018 2016 2019 2017 2016 2016 2018 2015 2016 2015 10

ALZT-OP1: Phase 1 Studies Confirmed Crossed the Blood-Brain-Barrier • AZT-002 Phase 1a study 1 : ALZT-OP1 Pharmacokinetics (CSF) Study Patients Cmax Tmax – Cromolyn (17.1 mg) and ibuprofen (10 mg) pharmacokinetics in healthy AZT-002 Healthy Adults 0.24 ng/mL 3.7 hours volunteers – cromolyn and ibuprofen (4 Hour CSF) Cromolyn reached desired concentrations in plasma Healthy Adults 0.4 ng/mL 3.6 hours and CSF, the latter indicating blood brain AZT-004 barrier crossing (8 Hour CSF) • AZT-004 Phase 1b study 2 : AD Patients 1.4 ng/mL 3.8 hours – Cromolyn (17.1 mg) and ibuprofen (10 AZT-002 Healthy Adults 3.9 ng/mL 2.6 hours mg) pharmacokinetics in healthy (4 Hour CSF) volunteers and AD patients – cromolyn Ibuprofen and ibuprofen reached desired Healthy Adults 4.1 ng/mL 3.0 hours AZT-004 concentrations in plasma and CSF, the (8 Hour CSF) latter indicating blood brain barrier AD Patients 6.0 ng/mL 4.0 hours crossing 1 Brazier, et al: Pharmacokinetics of Cromolyn and Ibuprofen in Healthy Volunteers; Clin Drug Investig (2017). 11 2 Data on file, AZTherapies, Inc.

ALZT-OP1: COGNITE Phase 3 Trial – Fully Enrolled Eligibility Criteria & Assessments Primary Endpoint: ALZT-OP1 n = 620 Mean change from baseline in Clinical • Aged 55-79 Dementia Rating-Sum of Boxes (CDR- SB) at week 72, comparing • Confirmed early AD Cromolyn combination treatment to monotherapy • Aß-42 180-690 pg/mL cromolyn and monotherapy ibuprofen • Global CDR 0.5 • Memory Box ≥ 0.5 Ibuprofen Conducted under Special Protocol • WMS LMII Assessment (SPA) • CDR-SB • MMSE Placebo Exploratory Biomarkers Study Completion: Day 1 Week 4 Week 12 Week 24 Week 48 Week 72 Anticipated Trial Completion Initial Drug Safety & CDR-SB CDR-SB CDR-SB CDR-SB MMSE MMSE MMSE Dispense Compliance MMSE in Q1 2021 Safety Safety Safety Check Safety Biomarkers While there are four-arms in the trial design, ~50% of the patients are receiving cromolyn 12 Randomization

AZT-101 Demonstrates Significant Potential in ALS Neuro-muscular- Key Results Provide Evidence of Junction Denervation AZT-101 Activity in SOD1 ALS Model Reduced pro-inflammatory cytokine levels in the spinal cord and plasma Spared lumbar spinal cord motor neurons & preserved neuro-muscular-junction integrity Onset of Paresis Delayed disease onset and progression Significant effect on motor symptoms as **** p<0.0001 measured by age at paresis onset Reduced motor deficits in the Paw Grip Endurance (PaGE) task Source: Granucci. Cromolyn sodium delays disease onset and is neuroprotective in the SOD1 G93A Mouse Model of amyotrophic lateral sclerosis. Scientific Reports. 2019; 13 Note: Study performed on 149 male and female age- and litter-matched transgenic (Tg) SOD1 G93A and wild-type (Wt) SOD1 G93A mice.

Universal Donor CAR-Treg: Immense Potential in Treating Neurodegeneration Glia-binding scFv CAR Technology Increases Treg Localization to CNS, Signaling & Enhancing Anti-Inflammation Effects and Limiting Off- Co-stimulation Target Suppression, Compared to Autologous Treg Infusions CD3 z CD28 Domains Glia ` Clinical Rationale ` Identify scFv ` Validate Construct ` Assess Efficacy Alzheimer’s ALS Disease Fronto- Multiple Pre-clinical temporal Sclerosis Validation Dementia (MS) (FTD) Progressive Parkinson’s Supranuclear Disease Palsy (PSP) Concentration (nM) ALS Progression Slowed Identified seven unique All CAR constructs are In vitro and in vivo During Autologous Treg human scFv and assessed stably expressed on validation of CAR-Treg Infusions in P1 Trial binding via ELISA surface of Tcells constructs is ongoing 14 Source: AZTherapies Data; Appel. Neurol Neuroimmunol Neuroinflamm. 2018; scFv: Single-chain Variable Fragment.