ZyVersa Corporate Presentation - Equisolve · Record Raising Capital and Increasing Corporate Value ZyVersa Non-Confidential 6 Stephen Glover Co-Founder, Chief Executive Officer,

Restoring Health, Transforming LivesThrough Innovation

ZyVersa Corporate PresentationQ1-2020

ZyVersa Non-Confidential 1

Corporate Overview


ZyVersa Is a Clinical Stage, Specialty Biopharma Company Focused on Renal and Inflammatory Diseases With High Unmet Needs

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Led by a team of industry veterans from top pharmaceutical companies

Experience encompasses over 15 therapeutic areas

Renal Lead: Phase 2a VAR 200, 2HPβCD Indication: Focal segmental

glomerulosclerosis (FSGS), an orphan kidney disease

Anti-inflammatory Lead: IC 100, Inflammasome inhibitor targeting ASC Component of Inflammasomes Potential early indications

- Renal: Diabetic nephropathy, lupus nephritis

- Non-renal Inflammatory Diseases: Multiple Sclerosis

~$60.0BTotal

addressablemarkets

ZyVersa Non-Confidential

With two exciting programs in attractive areas, ZyVersa is well positioned to access the public markets

Phase 2a orphan renal productcandidate leading a robust renal pipeline

Strong Board of Directors and

Advisory Boards

Highly experienced management team

with successful trackrecord

Two wholly-owned product platforms

Next generationinflammasome inhibitor platform with broad potential indications

~$75 billion total addressable

inflammatory and renal drug markets

ZyVersa’s Value Proposition

4ZyVersa Non-Confidential

Name TitleYears of Industry

ExperiencePrior Experience

Stephen C. GloverCo-Founder, CEO and President

30+

Nick A. LaBella, MS, RPH Chief Scientific Officer 30+

Pablo A. Guzman, MD, FACC Chief Medical Officer 30+

Karen A. Cashmere Chief Commercial Officer 25+

Melda Uzbil O'Connell SVP, Corporate Development 15+

Peter WolfeSVP of Finance and Administration

17+

Deep pharmaceutical experience and successful track record

>35 NDA/BLA Filings

>55 New Product Launches

>15 rare disease indications

>40 Licensing Deals & Acquisitions

$10B+ of Licensing and M&A experience

Over $250M of Private Capital Raised

Highly Experienced Leadership Team


Strong Board of Directors with Proven Track Record Raising Capital and Increasing Corporate Value


Stephen Glover

Co-Founder, Chief Executive Officer, and President

Has over 32 years of experience in biopharmaceuticals and life sciences.

Previous senior executive roles at Coherus Biosciences, Insmed, Andrx, Amgen and Roche.

Serves on the Boards of PDS Biotechnology, INCON, and Asclepius Lifesciences.

Jules A. Müsing

Chairman of the Board

Former CEO & President of Janssen ( Johnson & Johnson) companies and Ares-Serono, Inc.

Has > 40 years of executive operating experience in the pharmaceutical & biotechnology industry.

Negotiated/signed transformative licensing/M&A deals with major biopharma companies.

Previous executive roles at Johnson & Johnson, Janssen Pharmaceuticals, Ortho Biotech and Ares Serono.

Aaron Greenblatt

Chief Executive Officer, G&W Laboratories, Inc.

Previously served as Chief Commercial Officer and Executive Vice President at G&W Laboratories.

As the fourth generation CEO from the Greenblatt family, continues to focus on instilling the core values into the company culture.

Anthony Giovinazzo

Former President and CEO of Cynapsus Therapeutics

Executive Chairman of Sublimity Therapeutics.

Led Cynapsus, a Phase 3 Parkinson’s company, through a CAD $841 million all cash, all upfront M&A trade sale

Has in excess of 38 years of professional experience.

Serves on the Board of Promis Neurosciences.

Robert Finizio

Co-Founder, Chief Executive Officer, and Director of Therapeutics MD

Has over 20 years of healthcare experience.

Previous senior executive roles at CareFusion, Omnicell and Endoscopy Specialist.

Eric Richman

Former President & CEO of PharmAthene; Chairman of LabConnect

More than 25 years of experience as a life science executive.

As a founding member of MedImmune, was responsible for commercialization of rare disease and oncology products.

Former Venture Partner at Brace Pharma Capital; serves on the Boards of ADMA Biologics and NovelStem International.

Andrew (DW) Kim

Founder and CEO, Riverstone Investment Co., Ltd.

Chairman of INCON and NDFOS.

Has in excess of 15 years of professional experience.

Former Co-founder & CIO at Liberty Investment Co., Ltd..


Renowned Anti-inflammatory Scientific Advisory Board, Recognized As Pioneers/Leaders in Inflammasome Inhibitor Space

W. Dalton Dietrich, III, PhD

Kinetic Concepts Distinguished Chair in Neurosurgery & Scientific Director, The Miami Project to Cure Paralysis, UM

Senior Associate Dean, Discovery Science & Co-director, Institute for Neural Engineering, UM

Professor, Neurological Surgery, Neurology, Biomedical Engineering & and Cell Biology, UM

Helen Bramlet, PhD

Professor, Department of Neurological Surgery, UM

The Miami Project to Cure Paralysis, UM

Robert W. Keane, PhD

Professor Physiology & Biophysics, Neurological Surgery & Microbiology, and Immunology, UM


Alan Herman, PhD

Chairman Emeritus, former Chief Scientific Officer, Coherus Biosciences

Formerly: Genentech, Amgen, Merck, Coherus Biosciences

Juan Pablo de Rivero Vaccari, PhD

Research Assistant Professor, Department of Neurological Surgery, UM


Distinguished Faculty Member of The Center for Cognitive Neuroscience and Aging, UM

Miguel S. Barbosa, PhD

Former Global Head and Vice President of Immunology Research and External Innovation at Janssen Research & Development, Pharmaceutical Companies of Johnson & Johnson

William F. Bennett, PhD

Principal, Bioscope Associates

Formerly: Genentech, Sensus Corporation, Cor Therapeutics

Doug H. Farrar

CEO, Flatirons Biotech, Inc

Former Cofounder and Chief Technical Officer, Coherus Biosciences

Daniel G. Baker, MD

Former Vice President, Immunology Research and Development, Janssen Pharmaceutical Companies of Johnson & Johnson

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https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwiTy6eggenhAhVJq1kKHWsHBFoQjRx6BAgBEAU&url=https://www.linkedin.com/in/dougfarrar64&psig=AOvVaw13Y_iHlW67cQvHYZyNSu2w&ust=1556204923195548

Top Tiered Renal Scientific Advisory Board, Known for Leadership in Glomerular Research and Advocacy

Alessia Fornoni MD, PhD

Professor of Medicine and Chief, Katz Family Division of Nephrology and Hypertension, University of Miami Miller School of Medicine

Jonathan J. Hogan, MD

Assistant Professor of Medicine and Clinical Director of the Glomerular Disease Center, Perelman School of Medicine, University of Pennsylvania

Pablo A. Guzman, MD, FACC

Chairman, Scientific Advisory Board

Chief Medical Officer, ZyVersa Therapeutics

Marlene Haffner, MD, MPH

Principal & Founder, Orphan Solutions & Haffner Associates

Former Director of Orphan Products Development, FDA

Sharon G. Adler, MD

Professor of Medicine, David Geffen School of Medicine, UCLA

Chief, Division of Nephrology and Hypertension, Harbor-UCLA Medical Center

Program Director, Nephrology Fellowship Training Program, Harbor-UCLA Medical Center

Debbie S. Gipson, MD, MS

Professor, Department of Pediatrics, University of Michigan

Director, Kidney Research Network Coordinating Center


Gerald B. Appel, MD

Director Glomerular Kidney Center and Professor of Medicine, Columbia University Medical Center of The New York-Presbyterian Hospital

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Two Wholly-Owned Product Platforms, Each With “Pipeline Within a Product” Potential


Attractive Novel Inflammasome Inhibitor (IC 100, a Monoclonal Antibody)Targeting Inflammatory Diseases ($60B Market)

P2a VAR 200 Targeting Orphan Kidney Disease, FSGS ($2B Market)

Novel Inflammasome Inhibitor Targeting ASC

Significant Proof of Concept: Pre-clinical support for multiple indications (MS, Acute Lung Injury, Spinal Cord Injury, Traumatic Brain Injury, Stroke)

Opportunity for Indication Expansion: Targeting ASC offers potential indication expansion across multiple therapeutic areas, including renal diseases, such as diabetic nephropathy and lupus nephritis, atherosclerosis, neurological conditions, such as Alzheimer’s disease, and certain cancers

Excellent Preclinical Safety Profile: Rodent and NHP

Excellent Tissue Penetration: Broad, prolonged tissue distribution demonstrated

Strong IP Protection: 13 patents related to therapeutics and biomarker diagnostics.

Differentiated MOA: Attenuates initiation and perpetuation of the innate inflammatory response by targeting ASC, a component of multiple types of inflammasomes, with potential to treat a broad range of inflammatory diseases. Competitive pipeline products target the sensor molecule, blocking inflammasome formation and initiation of the innate inflammatory response. Associated with only one type of inflammasome each, with potential to target fewer inflammatory conditions.

2-Hydroxypropyl-Beta-Cyclodextrin

FDA clearance for Phase 2a: Study may proceed letter received February 21st, 2020

Differentiated MOA: Targets underlying pathology (disease-modifying) by eliminating excess intracellular lipids that result in kidney damage and dysfunction. Competitive pipeline targets hypertension and inflammation.

Significant Proof of Concept: Pre-clinical data in 3 different animal models of kidney disease (FSGS, Alport syndrome, diabetic kidney disease). Robust safety profile.

De-risked Opportunity: FDA concurrence to move directly to phase 2a, bypassing phase 1, based on strong pre-clinical program and human POC in NPC.

Strong IP Protection: 7 years orphan drug exclusivity in US, 10 years in EU; exclusive worldwide license to IP related to 2HPβCD for treatment of kidney diseases.

Opportunity for Indication Expansion: As a cholesterol efflux mediator, offers potential indication expansion across multiple kidney diseases, including Alport syndrome, diabetic kidney disease, and other forms of chronic kidney diseases comprising the $13B renal market.

Multiple Life Cycle Opportunities Via Drug Delivery Mechanisms

Pipeline Targeting Inflammatory and Renal Diseases

ZyVersa’s two proprietary platforms target unmet medical needs with unique MOAs;offer multiple opportunities for expansion beyond initial targeted indications

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Key Milestones: ASC Inhibitor

Q1-2021: Pre-IND Meeting

Q2-2021: IND Filing

Q3-2021: Phase 1 Trial

Key Milestones: VAR 200

Jan-2020: Filed IND

Q2-2020: Ph2a Begins

Q1-2021: Interim Analysis


VAR 200: Renal Program2-Hydroxypropyl-Beta-Cyclodextrin (2HPβCD)


Glomerular Diseases Are the 3rd leading Cause of Chronic Kidney Disease, Which Affects 15% of the Adult Population


National Kidney Foundation; NIH National Institute of Diabetes and Digestive and Kidney Diseases; Nephcure; Cohen EP: Nephrotic Syndrome. e-medicine, updated December 21,2015

Primary Causes of Glomerular Disease

Focal Segmental Glomerulosclerosis (FSGS)

Minimal-Change Nephropathy

Membranous Nephropathy

Hereditary Nephropathies (i.e. Alport Syndrome)

Secondary Causes of Glomerular Disease

Diabetes Mellitus

Lupus Erythematosus

Amyloidosis and Paraproteinemias

Viral Infections (i.e. Hepatitis B & C, HIV)

Glomerular Disease

Injury to the kidneys’ filtration system, glomerular podocytes, causes protein to leak into the urine (proteinuria), and as it progresses nephrotic syndrome is common

Nephrotic syndrome

- Proteinuria (> 3.5g/day)

- Hypoalbuminemia (<3.5g/dL)

- Edema

Nephrotic syndrome leads to end-stage renal disease, requiring dialysis and kidney transplant

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Excess Cholesterol in Podocytes Contributes to the Pathology of Glomerular Diseases

The kidneys’ filtration system, the nephron, includes a network of small capillaries known as the glomerulus

Podocytes, which have long projections called foot processes, wrap around the capillaries; the space between them is known as a slit diaphragm (a lipid raft-like structure) serving as a selective barrier to prevent loss of protein in the urine (proteinuria)

Maintenance of podocyte intracellular cholesterol at appropriate levels is critical to support the structural integrity and function of the podocytes and slit diaphragm; excess levels can compromise structural integrity

ZyVersa Confidential

Image from: http://schoolbag.info/biology/humans/22.html

Fornoni A, Merscher S, Kopp JB. Lipid biology of the podocyte—new perspectives offer new opportunities. Nature reviews Nephrology. 2014;10(7):379-388. doi:10.1038/nrneph.2014.87.at

FSGS, Alport Syndrome, and Other Glomerular Diseases Are Associated With Excess Podocyte Cholesterol Resulting From Decreased Cholesterol Efflux

FSGS Patient’s Podocyte Histology (Neptune)

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Pedigo CE et al. Local TNF causes NFATc1-dependent cholesterol mediated podocyte injury. J Clin Invest 2016; Sep 1;126(9):3336-3350. doi: 10.1172/JCI85939; D’Agati VD, Kaskel FJ, Falk RJ. Focal Segmental Glomerulosclerosis. N Engl J Med 2011; 365:2398-2411

Podocyte Lipid Accumulation

Distorted Podocyte Structure

Damaged Podocyte Foot-

Process

Podocyte Detachment

Protein Leakage Into Urine (Nephrotic Syndrome)

Impaired Glomerular

Filtration BarrierPodocyte Loss

Normal: Intact podocytes foot process

Abnormal: Flattened podocytes

Excess Podocyte Cholesterol Causes Structural Damage to the Kidney’s Filtration Barrier, Resulting in Proteinuria and Nephrotic Syndrome

Image Adapted From D’Agati et al: N Engl J Med 2011; 365:2398-2411

Healthy KidneyChronic Kidney Disease

Current FSGS Treatment Addresses Hypertension (Vasodilation) and Inflammation Associated With Sclerosis (Steroids/CIs); Lipid Pathology Not Addressed

Intracellular podocyte lipid accumulation from reduced cholesterol efflux causes podocyte injury and flattened foot processes leading to proteinuria

• No current treatments address podocyte lipid accumulation

Arteriole vasoconstriction increases arteriole pressure leading to reduced blood flow and decreased glomerular filtration rate (GFR)

• Treated with ACE inhibitors and ARBs to dilate the arterioles

Glomerular inflammation results in distorted, more porous endothelial cells and contracted mesangial cells leading to proteinuria and decreased GFR

• Treated with steroids and calcineurin inhibitors (CIs) to reduce or eliminate the inflammation

No FSGS-specific Drugs Available


Image Adapted From Radica et al: Clin J Am Soc Nephrol 12: 2032–2045, 2017

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VAR 2002-Hydroxypropyl-Beta-Cyclodextrin (2HPβCD)


ZyVersa’s Lead Candidate, 2-Hydroxypropyl-Beta-Cyclodextrin (2HPβCD) Promotes Cholesterol Removal from Podocytes, Slowing Progression of Podocyte Injury and Renal Disease


Comprised of 7 Sugar Molecules Bound Together in a 3-D Ring

2HPβCD has a hydrophobic core that entraps and passively removes intracellular cholesterol from the kidney

2HPβCD is believed to promote active cholesterol removal through upregulation of cholesterol efflux transporters ABCA1 and ABCG1

Cholesterol removal restores renal structure and function

Image of βCD Adapted From Lopez et al: LoS Comput Biol 7(3): e1002020. doi:10.1371/journal.pcbi.1002020

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2 HPβCD Has a Novel Target Product Profile; Expected to Be the First, and Only Renal Product Addressing Lipid Pathology

Feature VAR 200

API 2-Hydroxypropyl-Beta Cyclodextrin

Mechanism of Action Extraction of intracellular renal lipids for metabolism and excretion

Indications Focal Segmental Glomerulosclerosis (FSGS) – Lead Candidate

Alport Syndrome

DKD

Key Claims At launch: to induce and maintain partial or complete remission of proteinuria in patients with nephrotic syndrome from primary FSGS or Alport Syndrome

Label extension: to reduce the rate of progression of nephropathy in patients with nephrotic syndrome from primary FSGS or Alport Syndrome

Expected Dose 3g* or 6g administered 2 times weekly

Route of Administration Intravenous initially

Subcutaneous expansion

How Supplied Single Use Vial (IV Administration)

Single Use Cartridge/Device (Subcutaneous Administration)

Storage Conditions Room Temperature


*Effective dose in FSGS animal model was 40 mg/kg; this translates into a 2,800 mg (2.8g) dose in the typical 70 kg adult; a 3g dose is expected to be feasible for subcutaneous delivery

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2HPβCDScientific Support


Strong Pre-clinical Support for 2HPβCD, With POC in 3 Different Animal Models of Kidney Disease

FSGS Model(40 mg/kg daily)

Compared to controls, 2HPβCD:

Protected against kidney cell damage

Reduced urinary protein (proteinuria) beginning at 8 weeks, with significant difference at 10 weeks

The effect of 2HPβCD on proteinuria was reproducible in two studies with a total

of three 2HPβCD treatment arms

Alport Syndrome Model(4,000 mg/kg 3 times weekly)


Significantly reduced cholesterol levels in kidney cells

Significantly reduced kidney cell fibrosis and protected against damage

Significantly reduced urinary and serum proteins starting at 3 weeks

Normalized serum lipid profile

Diabetic Kidney Disease Model(4,000 mg/kg 3 times weekly)


Significantly reduced cholesterol levels in kidney cells

Protected against kidney cell damage

Reduced urinary protein starting 8 weeks

Significantly reduced body weight and improved metabolic control (reduced blood sugar and serum insulin)

Enables clinical development to progress directly to Phase 2a in FSGS patients


2-Hydroxypropyl-Beta-Cyclodextrin Has Potential to Delay Progression of Renal Disease, Improve Quality of Life, and Reduce Heath Economic Burden

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Provide a first-in-class Disease Modifying Treatment with potential to:

Induce remission of proteinuria (reduce urinary protein)

Delay progression to end stage renal disease (time to dialysis or transplant)

Improve quality of life

Reduce health economic burden associated with kidney disease


IC 100 Inflammasome Inhibitor ProgrammAb Targeting ASC


Immune-related Inflammatory Disorders Affect 5 – 7% of Population in Western Societies, With an Increasing Prevalence1


1. El-Gabalawy, H., Guenther, Lyn C., and Bernstein, Charles, N. (2010). Epidemiology of Immune-Mediated Inflammatory Diseases: Incidence, Prevalence, Natural History, and Comorbidities. The Journal of Rheumatology Supplement. May 2010, 85 2-10; 2. Shaw PJ, McDermott MF, Kanneganti TD. Inflammasomes and autoimmunity. Trends Mol Med. 2010;17(2):57-64.; 3. Arakelyan A, Nersisyan L, Poghosyan D, et al. Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles. PLoS One. 2017;12(11); 4. Kuek A, Hazleman BL, Ostör AJ. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J. 2007;83(978):251-60.

IID Overview2.3,4

Characterized by excessive or chronic activation of the immune system, resulting from aberrant changes in innate and adaptiveimmunity; cytokine dysregulation is pivotal to the pathophysiology

Chronic inflammation triggers and contributes to complex diseases, such as certain cancers, atherosclerosis, stroke, ischemicheart disease, and even psychiatric disorders (major depressive disorder, schizophrenia and post-traumatic stress disorder)

Autoimmune/Autoinflammatory Diseases Result from development of immune reactivity towards native antigens

Classified as inflammation against self

Can cause multi-organ involvement, but the primary end-organ target typically drives the clinical presentation and disease definition

IID Comprises > 80 conditions, including type 1 diabetes, Crohn’s disease, rheumatoid arthritis, and multiple sclerosis

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Anti-inflammatory Drug Market Is Large and Growing


1. Credence Research, Inc. Anti-inflammatory Therapeutics Market - Growth, Future Prospects and Competitive Analysis, 2018-2026; 2. Absolute Reports. Global Anti-Inflammatory Therapeutics Market Research 2018, size, Revenue, Growth Factors, key drivers, opportunities with global forecast 2023

Anti-inflammatory growth drivers: Rising prevalence of inflammatory diseases and strong drug pipeline

Unmet need for novel anti-inflammatory drugs, with improved, more predictable efficacy, and fewer side effects $64

$131

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$40

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$80

$100

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Anti-inflammatory Market ($Billions)1

2017 2026P

CAGR = 8.5%

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Inflammasomes Are the Central Signaling Hubs of the Innate Inflammatory Response


Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21(7):677-87

Multiple inflammasomes are involved in innate immunity

Inflammasomes are molecular complexes comprised of:

- Sensor molecules including NLRP1, NLRP2, NLRP3, NLRC4, AIM2, and Pyrin (NLRP3 best known)

- Adaptor protein ASC

- Pro-caspase 1

Each of the sensor molecules respond to different pathogens or danger signals

ASC, which recruits pro-caspase 1 into the inflammasome, is involved with multiple sensor molecules and their associated inflammasomes

Caspase-1 activates the cytokine IL-1β to trigger an immune response

Inflammasomes are named by their associated sensor molecule

• NLRs (NOD-like receptor protein): Sense pathogens or endogenous sterile dangerous signals to activate the inflammasome

• AIM2 (Absent in melanoma 2): Senses bacterial and viral DNA to activate the inflammasome

• Pyrin: Senses bacterial toxins that modify RhoA GTPase to activate the inflammasome

• ASC (Apoptosis associated speck-like protein containing a caspase activating recruitment domain): Mediates the interaction between the NLR sensor and pro-caspase 1 in the inflammasome complex

• Caspase 1: Activates the cytokine IL-1β to trigger inflammation

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Common Inflammasomes

Multiple Inflammasomes Are Linked to Each of Numerous Inflammatory Disorders

Shaw PJ, McDermott MF, Kanneganti TD. Inflammasomes and autoimmunity. Trends Mol Med. 2010;17(2):57-64.

Inflammasomes and Disease

Dysregulated inflammasome activation is involved in a myriad of diseases and conditions:

Autoimmune Diseases: Multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis and colitis

Metabolic Diseases: Diabetes, atherosclerosis, non-alcoholic fatty liver disease and gout

Neurodegenerative Diseases: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis

Secondary Injury: Spinal cord injury, traumatic brain injury and stroke

Cancer: Lung cancer and melanoma

Activation of multiple inflammasomes, not just one inflammasome type, is pathogenic in each of numerous inflammatory diseases

Disease/Condition Inflammasomes Implicated References

Multiple Sclerosis AIM2, NLRP1, NLRP2, NLRP3, NLRC4 Huang et al., 2004; Soulika et al., 2009; Maver et al.,

2017; Freeman et la., 2017; Noroozi et al, 2017; Soares

JL et al, 2019

Lupus Nephritis AIM2, NLRP3 Choubey and Panchanathan, Clin.Immun.176:42-48,

2017; Cytokine, 2019; Fu et al, Arthr. And Rheum.,

2019

Diabetic Nephropathy AIM2, NLRP3 Anders and Muruvue, 2011; Hutton et al., 2013

CNS Injury AIM2, NLRP1, NLRP2, NLRP3 de Rivero Vaccari et al., 2008, 2009, 2012; Abulafia,

2009; Liu et al., 2013; Bartolotti et al., . 2018

Alzheimer’s Disease AIM2, NLRP1, NLRP3 Ahmed et al., 2017; Venegas et al., 2017; White et al.,

2017; Wu et al., 2017LeBlanc, 2018; Lang et al., 2018

Parkinson’s Disease NLRP1, NLRP3 Lenart et al., 2016; Mao et al., 2017; Sarkar et al.,

2017; vonHerrmann et al., 2019

Rheumatoid Arthritis AIM2, NLRP1, NLRP3, NLRP6 Goh et al, 2017; Grandemange et al., 2017; Li et al.,

2019; Addobbatti et al., 2018; Lin and Luo, 2016; Sode

et al., 2015; Wang et al., 2014

Inflammatory Bowel Disease AIM2, NLRP1, NLRP3, NLRP6, NLRC4 Vanhove et al., 2015; Ratsimandresy et al., 2017;

Lazaridis et al., 2017; Kanneganti et al., 2017; Normand

et al., 2011; Levy et al., 2015; Seregin et al., 2017; Tye

et al., 2018; Williams et al., 2018; Opipari and Franchi,

2015


Inflammasomes Activate the Innate Immune Response


Inflammasomes and the Innate Inflammatory Response

In response to pathogens or other immune triggers, an intracellular sensor molecule (i.e. NLRP3) recruits ASC, which recruits pro-caspase-1 to form the NLRP3 inflammasome

The NLRP3 inflammasome is the organizing center that recruits additional ASC and pro-caspase-1 to form a large filamentous signaling platform, known as an ASC Speck

ASC Specks provide a scaffold for optimal pro-caspase-1 recruitment, and trigger conversion of pro-caspase 1 to active caspase 1, which converts pro-IL-1β to active IL-1β, which triggers the inflammation process

ASC Specks are released outside the cell to create a signaling platform that induces a massive extracellular inflammatory response

Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21(7):677-87; Franklin BS, Bossaller L, De Nardo D, et al. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat Immunol. 2014;15(8):727-37; Shaw PJ, McDermott MF, Kanneganti TD. Inflammasomes and autoimmunity. Trends Mol Med. 2010;17(2):57-64.

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Inflammasome Formation

ASC Speck

Inflammasome Activation of Cytokines Impact the Adaptive Immune Response


Inflammasomes and the Adaptive Inflammatory Response

Through activation of cytokines, inflammasomes have a role in adaptive immunity by amplifying T and B cell responses

IL-1β can act on lymphocytes in several ways including upregulating IL-2 receptor expression, prolonging survival of T cells, enhancing antibody production by B cells, and increasing B cell proliferation

IL-1β and IL-18 play a critical role in driving the differentiation and amplification of Th17 and Th1 cells, respectively

Shaw PJ, McDermott MF, Kanneganti TD. Inflammasomes and autoimmunity. Trends Mol Med. 2010;17(2):57-64.

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Image Adapted From Shaw et al: Trends Mol Med. 2010;17(2):57-64

IC 100 Attenuates Intracellular Initiation of the Inflammatory Response & Extracellular Perpetuation of Inflammation Without Broad Suppression of the Immune System

Mechanism of Action

IC 100 inhibits ASC, blocking inflammasome formation and initiation of the inflammatory response

IC 100 inhibits the ASC component of ASC Specks, disrupting their structure and function, thereby preventing perpetuation of the massive inflammatory response

By targeting ASC and the ASC Speck, a unique inflammatory signaling platform, IC 100 can inhibit different types of inflammasomes at multiple points of activation. We believe ASC inhibitors will have greater efficacy than targeting individual inflammasome or cytokine targets.

IC 100 Blocks Inflammasome Formation

IC 100 Disrupts ASC Speck Structure & Function


IC 100 Scientific Support


Preclinical Data Demonstrate IC 100 Has Potential As a Treatment for Spinal Cord Injury, Traumatic Brain Injury, and Stroke

Spinal Cord Injury (SCI)Anti-ASC tool antibody was

administered at 50 mcg in a rat model of contusive cervical spinal cord injury 20 min after injury

- Improved histopathological and behavioral outcomes were demonstrated, consistent with decreased inflammasome activation


Traumatic Brain Injury (TBI)

Anti-ASC tool antibody was administered ICV at 15 mcg in a rat model of traumatic brain injury immediately after injury

- Improved histopathological outcomes were demonstrated with anti-ASC tool antibody compared to IgG control

- Results were consistent with decreased inflammasome activation

Stroke

Anti-NLRP1 tool antibody was administered into the right lateral ventricle at 5 mcg in a stroke mouse model immediately after stroke

- Decreased inflammasome activation was demonstrated with anti-NLRP1 tool antibody compared to control

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Preclinical Data Demonstrate IC 100 Has Potential As a Treatment for Acute Lung Injury, and Multiple Sclerosis


Multiple Sclerosis (MS)

IC 100 was administered IP to EAE-induced mice at 10, 30, or 45 mg/kg on day 8 before appearance of clinical symptoms, followed by treatment every 4 days for 32 days

- IC 100 at 30 mg/kg resulted in a lower number of activated myeloid cells in the spinal cord and spleen, a lower number of microglial cells in the spinal cord, and improved clinical outcomes consistent with these changes, when compared to PBS controls

Acute Lung Injury (ALI)

Acute lung injury was induced by delivering extracellular vesicles (EV) from mice with traumatic brain injury into naïve mice, followed by IV administration of IC 100 at 5 mg/kg 1 hour after EV delivery; animals were sacrificed 24 later

- IC 100 inhibited inflammasome activation and improved histopathological outcomes in lung tissue compared to PBS, anti-hTNF controls

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ASC As Biomarker


ASC Has Potential as a Serum Biomarker With High Sensitivity and Specificity


Keane RW, Dietrich DW, de Rivero Vaccari JP. Inflammasome Proteins as Biomarkers of Multiple Sclerosis. Frontiers in Neurology. Multiple Sclerosis and Neuroimmunology. 2018 Mar 19;9:135.

Disease/Condition ASC (pg/ml)

Multiple Sclerosis > 352.4

Depression > 273.7

Stroke > 404.8

TBI > 275

Mild Cognitive

Impairment (MCI)> 264.9

Healthy < 195.3

BIOMARKERCut-off point

(pg/ml)Sensitivity Specificity AUC 95% CI p-value

Caspase-1 >1.302 89% 56% 0.848 0.703-0.9929 0.0034

ASC >352.4 84% 90% 0.9448 0.9032-0.9864 <0.0001

Two-tailed t-test. Caspase-1: N = 9 control and 19 MS; ASC: N = 115 control and 32 MS

ASC Levels Are Elevated in Various Inflammatory Diseases

ASC Has Higher Specificity Than Caspase-1 as a Biomarker for MS

ASC Is a Good Predictive Biomarker of Inflammasome-mediated PathologyASC Levels Correlate with Disease Outcomes in TBI and Disease Severity in MS


Traumatic Brain Injury Multiple Sclerosis

In brain injured patients, levels of ASC proteins within the first 5 days after injury were predictive of

outcomes 5 months after trauma

In patients with MS segmented into those with mild or moderate disease severity, serum

ASC levels were higher in patients with moderate versus mild disease

IC 100 Value Proposition


Key Attributes of IC 100 Versus NLRP3 Small Molecules

Key AttributesIC 100

ASC Inhibitor

NLRP3 Inhibitor

(SM)

• Inhibits Multiple Inflammasomes Pathogenic in Inflammatory Diseases

• Attenuates, Not Suppress the Immune Response

• Attenuates Perpetuation of the Immune Response

• Attenuates T-cells & B-cells in Adaptive Immune Response

• Exhibits Target Engagement Specificity, With No Off-target Effects

• Effective for Both Acute and Chronic Inflammation

• Low Immunogenicity

• Safe & Well Tolerated

• Potential For Companion Biomarker

• Dosing Frequency: Every 3-6 months Daily



Documents

ZyVersa Corporate Presentation - Equisolve · Record Raising Capital and Increasing Corporate Value ZyVersa Non-Confidential 6 Stephen Glover Co-Founder, Chief Executive Officer,