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A Clinical Stage Biotechnology Company
A Clinical Stage Biotechnology Company
NAS BioHoldings, Inc.
Mission:
• Develop safe and effective commercial candidates with follow on medical countermeasure utilities
Overview:
• We are a clinical stage biotech company developing candidate anti-inflammatory and anti-fibrotic compounds for both commercial and biodefense markets
Technology:
• Portfolio of small molecule neuro/anti-inflammatory compounds that reduce inflammation and normalize cell responses to oxidative stress and injury [superoxide dismutase (SOD) mimetics, NAS150, NAS114, NAS415]
• Peptide neuro/immuno-modulator [based on Substance P, NAS911]
2Confidential 2018
NAS BioHoldings, Inc.Lead Programs Persistent oxidative stress and inflammation
• Chronic neuroinflammatory disease: Progressive Supranuclear Palsy (PSP)• Chronic inflammatory state: Radiation-induced lung injury (RILI) and
Idiopathic Pulmonary Fibrosis (IPF)
Supported Countermeasure Programs
• Delayed Effect of Acute Radiation Exposure (DEARE)• Vesicants / Nerve agents (pulmonary and cognitive effects)
Clinical Status • Over 45 subjects completed Phase 1 safety studies (NAS150)• Multiple-year stability of GMP material• NAS911 safety/toxicity studies in process
Current Priorities • Phase 1B/2A in PSP patients • Phase 1B/2A in side effects of radiation exposure (RILI / pulmonary fibrosis)• Seeking development/commercialization partners
3Confidential 2018
Target Indications
Persistent Inflammatory Conditions
Initial focus: CNS Disorders and Pulmonary Fibrosis
Combined Expected Market Value of $133.5B1,2
1. https://www.grandviewresearch.com/press-release/global-central-nervous-system-cns-therapeutic-market2. https://www.ihealthcareanalyst.com/global-idiopathic-pulmonary-fibrosis-treatment-market
InflammationAt the root of most diseases
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1 . Golden, T, Patel, M. Catalytic Antioxidants and Neurodegeneration. Antioxid Redox Signal. 2009 Mar; 11(3): 555–569.2. Okin, D. (2012, September 10). Evolution of Inflammatory Diseases. Retrieved from www.sciencedirect.com/science/article/pii/S09609822120082021 3. Lee, SB et al. Kidney Int Suppl. 2010 Dec; (119): S22–S26.
Good or Bad?Good:
Body’s first line of defense to injury Protective, reflects the healing process
Bad:
Persistent / dysregulated inflammatory response linked to a number of chronic diseases1: • Neuro-degenerative diseases such as Progressive Supranuclear Palsy (PSP),
Parkinson’s Disease, ALS (Amyotrophic Lateral Sclerosis) and Alzheimer’s disease1
• Cardiovascular disease, cancer, and obesity2
• When the inflammatory response becomes aberrant or excessive in magnitude or duration, inflammation becomes detrimental
Fibrosis is a common outcome of chronic and acute inflammation3
▪ PSP is a neurodegenerative disorder impacting walking, balance, and eye movement1
▪ There are currently no treatments to slow, stop, or reverse its progression
▪ Like a number of neurodegenerative diseases, PSP has been associated with a chronic inflammatory state2
▪ PSP is estimated to affect approximately 20,000 people in the U.S. alone1
▪ The median survival from first appearance of symptoms is approximately 6-7 years3
Progressive Supranuclear Palsy (PSP)
NAS Target Indications
6Confidential 2018
1. https://www.emedicinehealth.com/progressive_supranuclear_palsy/article_em.htm#what_is_progressive_supranuclear_palsy_psp2. Fernández-Botrán, et al Parkinson Related Disor 2011 17:683. 3. Arena, JE, et al. Progressive supranuclear palsy: progression and survival. J Neurol. 2016 Feb;263(2):380-389.
Radiation-Induced Lung Injury (RILI)
NAS Target Indications
7Confidential 2018
Radiation-induced lung injury occurs as a side effectin individuals undergoing radiation therapy (RT),usually as part of lung cancer treatment
▪ Approximately 60% of cancer patients receive courses of RT during their treatment1, of which 5-10% experience some form of radiation toxicity2
▪ May occur years after the precipitating exposure, and pulmonary inflammation (pneumonitis) can become fibrotic, leading to respiratory failure and death
DEARE (Delayed Effects of Acute Radiation Exposure)
▪ Term used in the government/Homeland Security space for ‘ARS’ sequelae
▪ Pulmonary manifestations same as RILI
1. From Wirsdorfer F and Jendrossek V (2016) The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung Front. Immunol. 7:5912. “Radiation Toxicity (Radiation Sickness, Acute Radiation Syndrome) Treatment Market - Growth, Future Prospects, And Competitive Analysis, 2018-2026.” Market Research Reports.
• In pulmonary fibrosis, ‘interstitial’ lung tissue becomesinjured and develops fibrosis.
• In most cases, pulmonary fibrosis is classified as'idiopathic' due to meeting defined diagnostic criteria, aswell as exclusion of other known causes of Interstitial LungDisease (ILD).
• IPF affects approximately 100,000 in the U.S.1 and 3million patients worldwide2
• Since 2014 two FDA-approved drugs available for IPF,Esbriet® (pirfenidone, Roche) and Ofev® (nintedanib,Boehringer), can slow the disease progression, but don’thalt the disease or enable patients to recover.
• The median survival upon diagnosis with IPF is only 3-5years3
1. https://ghr.nlm.nih.gov/condition/idiopathic-pulmonary-fibrosis#statistics2. Nalysnyk L., et al. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev. 2012;21(126):355-361.3. Cottin, Vincent, et al. “Burden of Idiopathic Pulmonary Fibrosis Progression: A 5-Year Longitudinal Follow-Up Study.” Plos One, vol. 12,no. 1, 2017, doi:10.1371/journal.pone.0166462.
Idiopathic Pulmonary Fibrosis (IPF)
NAS Target Indications
8Confidential 2018
• Acute Radiation Syndrome (ARS) is a progressive illness acquired after whole-body or extensive partial-body exposure to ionizing radiation
• Exposure can occur after unintended exposures such as nuclear detonation or accidents, or in the course of intentional cancer radiotherapy
Acute Radiation Syndrome (ARS)
NAS Target Indications
9Confidential 2018
Thus exposure to ionizing radiation results in both a model system for chronic inflammatory states and a potential indication for therapeutic development
LINK to INFLAMMATION:
Ionizing radiation generates reactive oxygen species (ROS), which cause protein, lipid and DNA damage, driving inflammation and fibrosis
ROS as Common Factor in
Multiple Diseases and Conditions
10Confidential 2018
Unified Development Strategy
Ionizing Radiation
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IPF Model Oncology
DEARE(Pulmonary Fibrosis)
Medical Countermeasure for U.S. Government
Radiation Therapy Side Effect (RILI)
Limited Therapeutic Options
ARS
Idiopathic Pulmonary Fibrosis$4.6 billion market1 by 2023
1. https://www.ihealthcareanalyst.com/global-idiopathic-pulmonary-fibrosis-treatment-market/
Confidential 2018
Market and MonetizationOpportunities
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NAS continues to strengthen the Company’s position for significant partnership, out-licensing, or sale of our
advanced programs for unmet medical needs
Our expectations are to secure a deal, or multiple deals, similar to those currently being closed between biotech
and large pharmaceutical partners
Monetization Goals
Confidential 2018
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Acquisition of mature clinical assets significantly enhances the company's value
• Global CNS therapeutic market expected to reach $128.9 billion by 20251
➢ 2017: Mitsubishi Tanabe acquires NeuroDerm and lead Phase 2 Parkinson’s Disease candidate ND0612 for $1.1 billion2
➢ 2017: Biogen acquires Phase 2 BMS-986168 (now BIIB092) for PSP and Alzheimer’s Disease from Bristol-Myers Squibb for $300M up front and up to $410M in future milestones and royalties3
➢ 2017: AstraZeneca partners with Takeda in $400M deal to co-develop Phase 1 Parkinson’s Disease candidate MEDI13414
• Global IPF treatment market expected to reach $4.6 billion by 20235
➢ 2014: Roche acquires InterMune and rights to Esbriet® for $8.3 billion6
➢ 2015: BMS acquires Promedior and Phase 2 PRM-151 for up to $1.25 billion7
➢ 2015: Adheron Therapeutics’ SDP051 completes Phase 1 and is acquired by Roche for $105M upfront plus up to $475M in milestones8
Deals – CNS Disorders and IPF
Confidential 2018
1. https://www.grandviewresearch.com/press-release/global-central-nervous-system-cns-therapeutic-market2. https://www.fiercebiotech.com/biotech/mitsubishi-tanabe-buys-up-neuroderm-1-1b-deal,
https://globenewswire.com/news-release/2017/10/18/1149045/0/en/Mitsubishi-Tanabe-Pharma-Corporation-Completes-Acquisition-of-NeuroDerm.html 3. http://investors.biogen.com/news-releases/news-release-details/biogen-licenses-phase-2-anti-tau-antibody-bristol-myers-squibb4. https://www.fiercebiotech.com/biotech/astrazeneca-takeda-ink-parkinson-s-co-development-deal 5. https://www.ihealthcareanalyst.com/global-idiopathic-pulmonary-fibrosis-treatment-market/6. https://dealbook.nytimes.com/2014/08/24/roche-to-buy-drug-maker-intermune-for-8-3-billion/7. https://news.bms.com/press-release/rd-news/bristol-myers-squibb-enters-agreement-providing-exclusive-right-acquire-promed8. https://www.prnewswire.com/news-releases/adheron-therapeutics-to-be-acquired-by-roche-300156996.html
Peer Technologies in Development
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CNS➢ Biogen’s BIIB092 recruiting for Phase 2 in PSP
and Alzheimer’s Disease • Prolonged dosing: In PSP study, drug will be
administered via IV every 4 weeks for 48 weeks (NCT03068468)
➢ Abbvie Pharmaceuticals and Voyager Therapeutics • Abbvie’s ABBV-951 Phase 2 for PSP and Alzheimer’s • Voyager’s VY-AADC01 Phase 2 for Parkinson’s disease• 2018-Initiated collaboration for the development of
gene therapies for neurodegenerative disorders
IPF➢ KD025 from Kadmon Corporation, LLC
• Currently in Phase 2 trial for IPF
➢ GP-101 (Aerodone™) from Avalyn Pharma (Previously Genoa Pharma)
• Currently in Phase 1 trial for treating IPF with the inhaled version of Pirfenidone
➢ GlaxoSmithKline has two candidates in Phase 1 for IPF, GSK3008348 and GSK2126458
Confidential 2018
NAS1 and NAS4 Series Technology
and Mechanism
NAS1 and NAS4 Series Technology
Metalloporphyrin Superoxide Dismutase Mimetics(SODmimetics)
NAS150 (formerly known as AEOL-10150)NAS114 (formerly known as AEOL-11114)
NAS415 (formerly known as AEOL-20415 )
SOD Mimetic Program
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Newly in-licensed small molecule anti-oxidants provide strong clinical and preclinical candidates for multiple indications.
NAS150, NAS114, NAS415 • Catalytically augment Superoxide Dismutase and Catalase• Increased effectiveness compared to scavenger anti-oxidants• Reduce oxidative stress • Result in decreased production of chemicals associated with inflammation
and fibrotic responses
Confidential 2018
Category Anti-oxidant Relative Activity1
Non-enzymatic (Scavengers)
ascorbate (Vitamin C)α-tocopherol (vitamin E)β-carotene (pro-vitamin A)NAC (N-acetylcysteine)
1
Enzymatic superoxide dismutase catalase
1000-10,000
SOD-mimetics NAS150 (example) 1000-10,000
1. “Endogenous Antioxidants Are the Potent First Line of Defense against Reactive Oxygen Species.” https://biofoundations.org/endogenous-antioxidants-are-the-potent-first-line-of-defense-against-reactive-oxygen-species/ Accessed 16May2018 BioFoundations, 10 Oct. 2016.
Lead Compound: NAS150
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➢ Demonstrated efficacy in multiple animal models of pulmonary fibrosis (radiation and chemicals - chemotherapeutics, toxic industrial chemicals and chemical warfare agents)
➢ Reverses multiple biomarkers of inflammation, oxidative stress, and immune response that ultimately drive DNA oxidation, fibrosis, and airway obstruction
➢ 3 Phase 1 studies in 48 subjects under ALS and Lung ARS INDs support safety for repeated administrations at relevant dose levels
➢ FDA granted Fast Track designation for lung-ARS in June 2017
➢ Pursuing Orphan Drug Designation in PSP for NAS150
NAS150 has shown success in multiple clinical and biodefense animal models
Confidential 2018
Evidence for Role of Neuro-inflammation
and Oxidative Stress in PSP
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• Oxidative stress in PSP-affected areas of the brain (relative to age-matched controls)
➢ Deterioration in glucose metabolism1,2,3
➢ Elevated oxidative lipid damage1,2,3
➢ Abnormal lipid and protein peroxidation4
• Neuro-inflammation in PSP-affected areas of the brain (relative to age-matched controls)
➢ Activated immune cells5,6,7
➢ Elevated pro-inflammatory cytokines8
1. Albers, et al. Frontal Lobe Dysfunction in Progressive Supranuclear Palsy: Evidence for Oxidative Stress and Mitochondrial Impairment. 2000 J Neurochem 74:8782. Yu, Lixia, et al. "Dietary lycopene supplementation improves cognitive performances in tau transgenic mice expressing P301L mutation via inhibiting oxidative stress and tau hyperphosphorylation." Journal of Alzheimer's Disease 57.2 (2017): 475-482.3. Garrido, et al. "Update on the Diagnosis and Management of Progressive Supranuclear Palsy." Current Geriatrics Reports 5.2 (2016): 85-94.4. Lee, et al. Brain regional iron contents in progressive supranuclear palsy. Parkinsonism Relat Disord. 2017 Dec;45:28-32.5. Marras, et al. Anti-inflammatory drug use and progressive supranuclear palsy. Parkinsonism Relat Disord. 2018 Mar;48:89-92.6. Tong, et al. Brain monoamine oxidases in human parkinsonian disorders. Brain. 2017 Sep 1;140(9):2460-2474.7. Gerhard, Alexander. "TSPO imaging in parkinsonian disorders." Clinical and translational imaging 4.3 (2016): 183-190.8. Fernández-Botrán, et al. Cytokine expression and microglial activation in progressive supranuclear palsy. Parkinson Related Disor 2011 17:683
Confidential 2018
NAS150 Reduces
Oxidative Stress and Fibrosis
21Confidential 2018
Oxidative Stress
• NAS150 was as effective as Esbriet® (pirfenidone)
in normalizing markers of lung DNA oxidation (8OH-2dG) and ROS
generation (NADPH oxidase, NOX4) which were increased in the bleomycin
model of pulmonary fibrosis.
Lung Fibrosis
• NAS150 was as effective as Esbriet® (pirfenidone)
in normalizing fibrosis-associated BALF TGF-β1 levels and lung collagen
(hydroxyproline) in the bleomycin model of pulmonary fibrosis
NAS1 and 4 Series Recent Development Milestones
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NAS9 Series Technology
and Mechanism
Technology: NAS911
1Arg
2Pro
3Lys
4Pro
5Gln
7Phe
6Gln - NH2
9Gly
10Leu
11Met
8Phe
• Mediates immune response, fibrosis and repair
• Two amino acid modification of endogenousSubstance P
[gly9 –> sar9 and met11 –> met(O2)11]
Substance P Analog
24Confidential 2018
• Impacts multiple pathways to treat fibrosis ➢ Vasodilatory via NK1-receptor1
➢ Stem cell stimulation and mobilization2
➢ Local anti-inflammatory response3
➢ Facilitates normalized wound healing without fibrosis4
• “Gold standard” bleomycin model of pulmonary fibrosis5
➢ Prevented weight loss and lung mass increase (data on file)
• Ionizing radiation model ➢ Decreased inflammatory cell infiltration (data on file, Mil.Med. in press)➢ Appears to be beneficial in both the early-phases (inflammatory) and late-
phases (pulmonary fibrosis)
• Granted “orphan status” by the FDA for IPF therapy (confirming suitability of radiation as acceptable IPF model by FDA)
NAS911
Lead Program: Pulmonary Fibrosis
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1. Mechiche, H, et al. "Neurokinins induce relaxation of human pulmonary vessels through stimulation of endothelial NK1 receptors." Journal of cardiovascular pharmacology 41.3 (2003): 343-355; Drapeu G et al., Neuropeptides (1987) 43-54; Newby DE et al., Br J Clin Pharmacol (1997) 493-4992. Rameshwar P et al., Blood (1993) 391-398; Hong HS et al., Nat Med (2009) 425-4353. Cottrell GS et al., JBC (2006) 27773-27783; Roosterman et al., PNAS (2007) 11838-11845; Leal EC et al., Am J Pathol (2015) 1638-16484. Leal EC et al., Am J Pathol (2015) 1638-1648; Park JH et al., Wound Rep Regen (2016) 337-348; Suvas J Immunol (2017) 1543-15525. Jenkins RG et al., Am J Respir Cell Mol Biol (2017) 667-679 Confidential 2018
DevelopmentPrograms
Lead Programs Development Overview 2018-2020
• Progress NAS150 into Phase 1B/2A clinical trial for Progressive Supranuclear Palsy (PSP)
• Formulation study currently underway to progress NAS150 into Phase 2 clinical trials for Idiopathic Pulmonary Fibrosis (IPF) and provide improved route of administration
• Submit IND for Phase 1B/2A study of NAS150 in RILI (side effect of radiotherapy for cancer treatment)
• Planned formulation project for NAS911 complexation and conjugation to provide additional IP opportunity, as well as improved stability and effectiveness
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28Confidential 2018
Post- Funding Pipeline
Focused Programs
Trailing Programs
Grant Supported Programs
Candidate Indication(s) Pre-clinical Phase 1 Phase 2 Phase 3NAS150 Radiation-Induced Lung Injury (RILI)
NAS150 Idiopathic Pulmonary Fibrosis (IPF)
NAS150 Amyotrophic Lateral Sclerosis (ALS)
NAS150 Progressive Supranuclear Palsy (PSP)
NAS911 Idiopathic Pulmonary Fibrosis (IPF)
NAS911 Hematopoietic-Acute Radiation Syndrome (H-ARS)
NAS114 Progressive Supranuclear Palsy (PSP)
NAS114 Parkinson's Disease
NAS114 Epilepsy
NAS911 Influenza
NAS911+SPR4 Hematopoietic-Acute Radiation Syndrome (H-ARS)
NAS911+SPR4 Gastrointestinal-Acute Radiation Syndrome (GI-ARS)
NAS911+SPR4 Radiation-Induced Mucositis
NAS911+SPR4 Radiation-Induced Dermatitis
NAS911 Gastrointestinal-Acute Radiation Syndrome (GI-ARS)
NAS911 Radiation-Induced Mucositis
NAS911 Radiation-Induced Dermatitis
NAS415 Cystic Fibrosis
NAS415 Infectious Disease
Development Stage
IND-related
activities leading to clinical trials
IP-related
preclinical advances
Potential Broader Applications
• Diseases with Neuro-inflammation
component (Parkinson’s Disease,
Epilepsy, Alzheimer’s Disease, ALS)
• Post-Bone Marrow Transplant
Pulmonary Infections
• Influenza
• GI symptoms of ARS
• Reperfusion syndrome
• Cardiovascular disease / remodeling
/ fibrosis
• Veterinary medicine - Canine
Pulmonary Fibrosis and Canine
Influenza 29Confidential 2018
Diseases with Unmet Medical Need
Confidential 2018 30
Indications U.S. Market SizeGlobal Market Value
(USD)
Idiopathic Pulmonary Fibrosis (IPF) 100,0006 $4.6B by 20231
Progressive Supranuclear Palsy (PSP) 20,0008 (Movement disorders)$1B by 202614
Radiation Therapy Side Effects: Lung Injury, Oral Mucositis, and Dermatitis
1,220,44215,16,17 Undetermined
Parkinson’s Disease 651,4007 $5.69B by 20222
Epilepsy 3.4M9 $5.47B by 20243
Amyotrophic Lateral Sclerosis (ALS) 30,00010 $306M by 202511
Cystic Fibrosis 30,0004 $13.9B by 202512
InfluenzaDuring season: 20% of
general population13 $10.2B by 20225
1. https://www.ihealthcareanalyst.com/global-idiopathic-pulmonary-fibrosis-treatment-market/2. www.prnewswire.com/news-releases/parkinsons-disease-treatment-market-61-cagr-to-2022-led-by-carbidopalevodopa-segment-6536315933. https://www.grandviewresearch.com/press-release/global-epilepsy-drugs-market4. https://www.grandviewresearch.com/press-release/global-cystic-fibrosis-cf-therapeutics-market5. http://industry-experts.com/verticals/healthcare-and-pharma/global-influenza-market-vaccines-and-therapeutics6. https://ghr.nlm.nih.gov/condition/idiopathic-pulmonary-fibrosis#statistics7. Tysnes, et al. Epidemiology of Parkinson's disease. J Neural Transm (Vienna). 2017 Aug;124(8):901-905. 8. https://www.emedicinehealth.com/progressive_supranuclear_palsy/article_em.htm#what_is_progressive_supranuclear_palsy_psp9. https://www.cdc.gov/epilepsy/about/fast-facts.htm
10. http://www.alsa.org/news/media/quick-facts.html11. https://www.credenceresearch.com/press/global-amyotrophic-lateral-sclerosis-als-treatment-market12. https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/13. https://www.cdcfoundation.org/businesspulse/flu-prevention-infographic/14. https://www.factmr.com/report/329/movement-disorder-market15. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html, 16. https://www.cancer.net/cancer-types/head-and-neck-cancer/statistics, 17. https://www.cancer.gov/about-cancer/understanding/statistics
Intellectual Property
➢ NAS911
o Two issued U.S. and foreign patents; three pending patents
o Research plan includes developing patentable composition of matter
➢ NAS150; NAS114; NAS415
o Broad IP portfolio with 56 patents granted worldwide, additional IP pending
➢ IP strategy
o Advance: Submit applications based on existing research efforts of
collaborators focusing on key therapeutic areas: adjuvant therapies with
existing drugs
o Harvest: Secure currently maturing research occurring at NAS collaborator
labs
o Mining: Review key research material, identify and determine effort to
secure latent property
31Confidential 2018
Professional Support
• Legal Counsel
➢ Corporate – Manatt, Phelps & Phillips, LLP, California
➢ FDA– Hyman, Phelps & McNamara P.C., Washington, DC
➢ Intellectual Property – Young Basile, Michigan
• Auditors – Liggett & Webb PA, New York
• Private & Public Market Advisory – Maxim Group, New York
• Grant Writing/Council – Eva Garland Consulting, LLC, North Carolina
32Confidential 2018
Confidential 2018 33
Management & Board of Directors
Board of DirectorsExecutive Officers
Michael K. Wilhelm – President, Chief Executive Officer, Chairman Mr. Wilhelm has extensive experience leading early-stage companies. Prior to New Amsterdam Sciences, he co-founded ImmuneRegen BioSciences, Inc., of which NAS acquired certain R&D and IP. Mr. Wilhelm also serves as Managing Director of Foresight Capital Corporation.
Hal N. Siegel, Ph.D. – Chief Scientific OfficerDr. Siegel brings extensive scientific and regulatory affairs expertise, and his previous positions included Chief Scientific Officer and Vice President at ImmuneRegen BioSciences, Vice President of Regulatory and Scientific Affairs at Zila, Inc., and consultant to multiple life science and IT companies.
Rick J. Leimbach - Chief Financial OfficerMr. Leimbach has extensive experience in both the public and private sectors. He currently serves as Principal and CFO Advisor at Carrollton Partners. He now advises public and private companies with their financial reporting, corporate governance needs and helps to position them to raise capital and achieve the next level of success.
Matthew E. Silpe, Director
Mr. Silpe is an experienced business executive and entrepreneur. He is currently the Chief Operating Officer of June Jacobs Labs (JJL), an industry leader in the development and manufacturing of personal care products, and Principal of Millennium Capital Group, a company he founded.
Theodore E. Staahl, M.D., Director
Dr. Staahl is the founder of the Cosmetic, Plastic and Reconstructive Surgery Center; and is a former-President of the California Academy of Cosmetic Surgeons.
Gerard E. Toepfer, Director
Mr. Toepfer is the owner and President of Imageworx, a partner of Labelworx, and a partner of Greenmarket Purveying Company. He specializes in cosmetic, medical, and pharmaceutical packaging, and has experience in sales management, business development, and growth management in a manufacturing setting.
Michael K. Wilhelm, Chairman
Confidential 2018 34
Scientific Advisory Board
Bert Maidment, Ph.D.
Former Associate Director of the Radiation and NuclearCountermeasures Program at the National Institutes of Health, NationalInstitute of Allergy and Infectious Diseases, Division of Allergy,Immunology and Transplantation
Ron Manning, Ph.D.
Former Branch Chief, Chemical, Radiological and Nuclear MedicalCountermeasures; Division of Chemical, Biological, Radiological andNuclear (CBRN) Medical Countermeasures; Biomedical Advanced Researchand Development Authority (BARDA) and Director of SNBL USA Ltd
Manisha Patel, Ph.D.
Professor, Department of Pharmaceutical Sciences, Skaggs School ofPharmacy and Pharmaceutical Sciences, University of Colorado
Albert Polito, M.D.
Chief of the Division of Pulmonary Medicine of Mercy Medical Center;Directed the Pulmonary Outpatient Clinics and the Pulmonary FellowshipProgram at Johns Hopkins Hospital
Pranela Rameshwar, Ph.D.
Professor at the Rutgers New Jersey Medical School, Department ofMedicine, Division of Hematology-Oncology
Ted Ross, Ph.D.
Director, Center for Vaccines and Immunology and Professor, GRAEminent Scholar of Infectious Disease, University of Georgia College ofVeterinary Medicine
Subhrajit Saha, Ph.D.
Assistant Professor in Department of Radiation Oncology at KansasUniversity Medical Center. Member of KU Cancer Center, with asecondary appointment in the Department of Cancer Biology
Theodore Staahl, M.D.
Founder and surgeon, the Cosmetic, Plastic and Reconstructive SurgeryCenter; Past President of the California Academy of Cosmetic Surgeons
Juan Carlos Alvarez, MAIS, RCP, AE-C, CCE, CTI
Senior Clinical Coordinator, Genentech/Roche Pharmaceuticals. IdiopathicPulmonary Fibrosis Clinical Educator for patients and medical professionals
Teresa Barnes
Former Vice President of Patient Outreach and Program Support at theCoalition for Pulmonary Fibrosis; created Fibrosis Across Organs effort(convened by the American Thoracic Society, ATS), former chairperson, ATSPublic Advisory Roundtable
Rick Cantwell
Subject Matter Expert on counterterrorist procedures and methodologies.President of Odell International. Chairman of the North CarolinaHomeland Security Task Force. Co-chairs the Charlotte-MecklenburgHomeland Security Working Group
John Dann, M.D., D.D.S.
Board Certified maxillofacial and craniofacial surgeon; graduate of HarvardUniversity Dental School and the Washington University Medical School
Brian Day, Ph.D.
Professor and Vice Chair of Research, National Jewish Health, Denver, COand inventor of metalloporphyrin anti-oxidants; former Chief ScientificOfficer at Aeolus Pharmaceuticals, Inc.
Jacob Finkelstein, Ph.D.
Professor in the Departments of Pediatrics, Neonatology andEnvironmental Medicine at the University of Rochester Medical Center
Jeffrey Friedman M.D.
Diplomate of the American Board of Cosmetic Surgery; American Board ofOtolaryngology Head and Neck Surgery
Susan Leeman, Ph.D.
Professor in the Department of Pharmacology and ExperimentalTherapeutics at the Boston University School of Medicine
Contact Information
Michael Wilhelm, [email protected]
Hal Siegel, Ph.D., [email protected]
www.NewAmsterdamSciences.com
35Confidential 2018
Additional Scientific and Clinical
Development Details
36Confidential 2018
ROS is a Primary Driver of Fibrosis
37
ROS links Fibrosisand Inflammation
➢ Chronic oxidative stress elevates ROS which activate TGF-β1 to enhance pro-fibrotic signaling pathways and pro-fibrotic genes such as NOX4, αSMA and COL I.
➢ NOX4 generates additional ROS and activates NF-ĸB and JNK kinases
➢ Fibroblast proliferation, ECM production and EMT drive fibrosis
➢ ROS responsible for oxidizing DNA, inducing genetic damage following radiation exposure
From Morry J et al., Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes and nanoparticles Redox Biol 11:240-253 (2017)
Confidential 2018
NAS150 Protects Lung Tissue
from RILI
38Confidential 2018
NAS150 decreases the severity of damage and increases the percentage of lung tissue with no damage from radiation therapy at 20 weeks post-RT
NAS150 Enhanced Survival Post-Irradiation Model/IPF
39Confidential 2018
Once daily treatment for 60 days doubles 180-day survival and increases mean and median survival times – MacVittie T et al., Rad Res (2017) 187:298-318
NAS150 Reduces
Oxidative Stress and Fibrosis
40Confidential 2018
Oxidative Stress
• Lung DNA oxidation (8OH-2dG) increased 1.8-fold after bleomycin
➢ NAS150 decreased 8OH-2dG by 100%
➢ Esbriet decreased 8OH-2dG by 100%
• Lung NADPH oxidase (NOX4) increased 1.3-fold after bleomycin
➢ NAS150 decreased NOX4 levels by 90%
➢ Esbriet decreased NOX4 levels by 100%
Lung Fibrosis
• Lung collagen (hydroxyproline) increased two-fold after bleomycin
➢ NAS150 decreased hydroxyproline levels by 70%
➢ Esbriet® (pirfenidone) decreased hydroxyproline levels by 90%
• TGF-β1 levels in BALF increased two-fold after bleomycin
➢ NAS150 decreased TGF-β1 levels by 100%
➢ Esbriet decreased TGF-β1 levels by 90%
NAS150 Status
41
• Multiple clinical opportunities➢ Preclinical data supports anti-fibrotic capabilities following 1) radiation
(IPF and oncology model), 2) bleomycin (IPF model), 3) CWAs (chemical warfare agents), and 4) CNS neuroinflammation ➢ Neuroinflammation applications include PSP, Parkinson’s Disease,
Epilepsy and CWA-cognition as well as, theoretically, Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s Disease and stroke
➢ Multiple completed Phase 1 studies demonstrate safety and no SAEs
• Chemistry Manufacturing and Controls support clinical expansion and eventual commercialization➢ NAS150 subject to new patent pending (through 2034) for
metalloporphyrin GMP manufacturability and enhanced commercial value
➢ Improved formulation dose escalation study with pharmacokinetics completed
• Next-gen NAS114 and NAS415 (with oral bioavailability) benefit from over $30MM BARDA investment in NAS150 regarding manufacturing and development plus have enhanced oral bioavailability and CNS access supporting Parkinson’s Disease and other CNS applications
Confidential 2018
Neuro-inflammation and Oxidative Stress in PSP
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• Multiple studies show change in biomarkers for oxidative stress in PSP affected areas of the brain compared to age matched control group
➢ Significant increase in well-established marker for oxidative lipid damage1,2,3
➢ Decrease in ratio of biomarkers that indicate the marked deterioration of glucose metabolism in cortex of PSP patients1,2,3
➢ Abnormal lipid and protein peroxidation in PSP affected individuals4
• Biomarkers for neuro-inflammation found in affected areas of the brain compared to age matched control groups
➢ Activated CNS immune cells found in affected regions of patients with PSP5,6,7
➢ Pro-inflammatory cytokines elevated, while anti-inflammatory cytokines comparable to control group in affected areas of PSP brain8
1. Albers, et al. Frontal Lobe Dysfunction in Progressive Supranuclear Palsy: Evidence for Oxidative Stress and Mitochondrial Impairment. 2000 J Neurochem 74:8782. Yu, Lixia, et al. "Dietary lycopene supplementation improves cognitive performances in tau transgenic mice expressing P301L mutation via inhibiting oxidative stress and tau hyperphosphorylation." Journal of Alzheimer's Disease 57.2 (2017): 475-482.3. Garrido, et al. "Update on the Diagnosis and Management of Progressive Supranuclear Palsy." Current Geriatrics Reports 5.2 (2016): 85-94.4. Lee, et al. Brain regional iron contents in progressive supranuclear palsy. Parkinsonism Relat Disord. 2017 Dec;45:28-32.5. Marras, et al. Anti-inflammatory drug use and progressive supranuclear palsy. Parkinsonism Relat Disord. 2018 Mar;48:89-92.6. Tong, et al. Brain monoamine oxidases in human parkinsonian disorders. Brain. 2017 Sep 1;140(9):2460-2474.7. Gerhard, Alexander. "TSPO imaging in parkinsonian disorders." Clinical and translational imaging 4.3 (2016): 183-190.8. Fernández-Botrán, et al. Cytokine expression and microglial activation in progressive supranuclear palsy. Parkinson Related Disor 2011 17:683
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Summary SOD Mimetics
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Potential Bio-Defense Applications as Medical Countermeasures✓ ARS (survival); completed non-human primate study✓ DEARE (pulmonary and GI)✓ Sulfur mustard gas (pulmonary and dermal)✓ Chlorine gas (pulmonary)✓ Neurotoxins (cognition)
Clinical indicationsNAS150
• Idiopathic Pulmonary Fibrosis• Thoracic radiation (oncology)• CNS (e.g., Progressive Supranuclear Palsy [PSP])
NAS114• Parkinson’s Disease (or epilepsy or PSP next-gen)
NAS415 (thiocyano-metalloporphyrin – with anti-infective properties)• Cystic Fibrosis
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Government Funding based on TRL
• Technology Readiness Level (TRL) scales are used by the Department of Defense to gauge the maturity of a technology, specifically a Medical Countermeasure (MCM) in development for a specific biodefense indication – Each TRL is strictly defined by development and clinical maturity
(Pre-clinical, Phase 1, etc.)
• Organizations like NIH, DoD, and BARDA typically seek to fund candidates at TRL 6 or higher
• NAS150 has moved into TRL 7 and received a $4M NIH grant for furthering research as a Sulfur Mustard exposure treatment
• NAS has recently been awarded a $250,ooo discovery grant by the U.S. Army to further research NAS911’s efficacy as an influenza therapeutic
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Technology Readiness Level (TRL)
45Confidential 2018
New Amsterdam Sciences Biodefense Pipeline
Candidate
Biodefense (Animal Rule)
Indication TRL1 TRL2 TRL3 TRL4 TRL5 TRL6 TRL7 TRL8 TRL9
NAS150 Acute Radiation
Syndrome (ARS)- Lung
NAS150 Sulfur Mustard Gas
Exposure
NAS150 Nerve Gas
Exposure
NAS911 Acute Radiation Syndrome
(H-ARS) - Hematopoietic
NAS911
Delayed Effects Acute
Radiation Exposure
(DEARE) - Lung
Technology Readiness Level
Influenza
• As an immunomodulator, NAS911 has demonstrated immune activity in multiple animal models, both as an adjuvant and as a standalone agent
• In a rat model of seasonal influenza infection1, NAS911 treatment, when compared to Tamiflu-treatment, exhibited:➢ lower morbidity (lung histopathology and body weight change) and➢ lower mortality
• In a ferret model of highly pathogenic (potentially pandemic) avian H5N1 influenza infection2, NAS911 treated animals demonstrated: ➢ faster recovery (pyrexia and overall scoring) and ➢ lower mortality (100% survival in NAS911-treated animals at control animal
LD50 at 5 days post-infection)
• In the ferret model using pandemic (A/Turkey/Turkey/1/2005) avian virus3, treated animals exhibited less pyrexia, weight loss, lower total sickness scores and less mortality than controls
NAS911
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1. Data on file from studies performed at Virion Systems
2. Data on file from studies performed by Dr. Ted Ross, University of Pittsburgh
3. Data on file from study performed at Health Protection Agency UK, study reference 3654 Confidential 2018
• We believe that NAS911, through NK1-R binding, restores the immune system post-irradiation by stimulating differentiation of hematopoietic stem cells1
➢ NAS911 has repeatedly been found to increase precursors to platelets, and red and white blood cells, the latter of which ultimately becomes functional cells of the immune system2
• NAS is well positioned to earn a BARDA grant to continue development as a medical countermeasure to chemical, biological, radiological and nuclear (CBRN) threats like DEARE
• NAS911 potentially could be administered with/after Neupogen® or Leukine® to provide longer term protection in survivors of ARS who are at increased risk of pulmonary fibrosis (DEARE) and/or infection3
DEARE
NAS911
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1. Hong, et al. "A new paradigm for stem cell therapy: substance-P as a stem cell-stimulating agent." Archives of pharmacal research 34.12 (2011): 2003-2006; Hemogenix data on file; Rameshwar data on file2. https://www.phe.gov/about/barda/Documents/barda-strategic-plan.pdf available from https://www.phe.gov/about/barda/Pages/2011barda-stratplan.aspx last accessed 9Mar20183. Li C et al., Cell Biosci (2015) 5:65
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