ARCTURUS THERAPEUTICS

Transcription

1 ARCTURUS THERAPEUTICS Building Next Generation of RNA Medicines S e p t e m b e r

2 A R C T U R U S T H E R A P E U T I C S FORWARD LOOKING STATEMENTS This presentation contains forward-looking statements. These statements relate to future events and involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements to be materially different from any future performances or achievements expressed or implied by the forward-looking statements. Each of these statements is based only on current information, assumptions and expectations that are inherently subject to change and involve a number of risks and uncertainties. Forwardlooking statements include, but are not limited to, statements about: expectations regarding our capitalization and resources; the adequacy of our capital to support our future operations and our ability to successfully initiate and complete clinical trials; our strategy and focus; the development and commercial potential of any of our product candidates; the timing and success of our development efforts, the success of any of our trials and our ability to achieve regulatory approval for any product candidate and the entry into or modification or termination of collaborative agreements. In some cases, you can identify forward-looking statements by terms such as may, will, should, could, would, expects, plans, anticipates, believes, estimates, projects, predicts, potential and similar expressions (including the negative thereof) intended to identify forward looking statements. Given the risks and uncertainties, you should not place undue reliance on forward-looking statements. The forward-looking statements contained or implied in this press presentation are subject to other risks and uncertainties, including those discussed under the heading "Risk Factors" in our Annual Report on Form 20-F for the fiscal year ended December 31, 2017, filed with the Securities and Exchange Commission (SEC) and in subsequent filings with the SEC. Except as otherwise required by law, we disclaim any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise. 1

3 A R C T U R U S T H E R A P E U T I C S Board of Directors Dr. Peter Farrell Chairman of the Board Andrew Sassine, MBA Director of the Board James Barlow, MA Director of the Board Dr. Magda Marquet Director of the Board Joseph E. Payne, MSc Director of the Board, Founder, President & CEO Founder and Chairman Former Portfolio Manager Former Chief Accounting Officer Chairman and Co-Founder 2

4 A R C T U R U S T H E R A P E U T I C S Corporate Overview HQ: San Diego, CA Founded: 2013 Nasdaq: ARCT Outstanding shares: 10.7 M Employees: 68 Insider Ownership: 24% Arcturus is an RNA Medicines Company Focused on Significant Opportunities in Rare, Liver, and Respiratory Diseases 3

5 A R C T U R U S T H E R A P E U T I C S Investment Highlights RNA Medicines Drug Development Company Both RNA Drug Substance and Nanoparticle-formulated Drug Products Diverse Pipeline 7 Programs: 1 Wholly-owned, 1 Co-dev (50/50), 5 Pharma Collaborations Intellectual Property LUNAR Delivery Technology, UNA Oligomer Chemistry, Drug Process Manufacturing 140 Patents & Patent Applications; Issued in US, EU, JP, China and Other Countries Strategic Partners 80% of Funding was provided by Strategic Partners prior to being public * The trademarks above are property of their respective owners 4

6 A R C T U R U S T H E R A P E U T I C S Pipeline of RNA Medicines Name RNA Modality Indication Partner Partnership Structure IND Date Route of Administration Target Organ Target Cells Prevalence Worldwide LUNAR-OTC mrna Ornithine Transcarbamylase Deficiency (OTC) Co-Dev (50/50) H IV Liver Hepatocytes 10,000 LUNAR-CF mrna Cystic Fibrosis Wholly-Owned H Nebulized Aerosol to Lung Lung Bronchial Epithelial Cells 70,000 LUNAR-HBV RNA Hepatitis B Collaboration Undisclosed IV Liver Hepatocytes 275 M LUNAR-NASH sirna NASH Collaboration Undisclosed IV Liver Stellate Cells 50 M LUNAR-GSD3 mrna Glycogen Storage Disease type III Collaboration Undisclosed IV Liver Hepatocytes 10,000 LUNAR-RARE mrna Rare Disease Collaboration Undisclosed IV Undisclosed Undisclosed Undisclosed LUNAR-RPL Replicon RNA Vaccines Collaboration Undisclosed IM Muscle Myocytes Undisclosed Four RNA Medicine Modalities mrna, gene editing RNA, sirna, replicon RNA Three Routes of Administration IV, IM, Aerosol Four Cell Types Targeted Hepatocytes, Liver Stellate Cells, Bronchial Epithelial Cells, Myocytes 5

7 A R C T U R U S T H E R A P E U T I C S LUNAR Lipid-Mediated Delivery Feature Compatibility Route of Administration Cell Type Benefit Versatile Formulated with multiple RNA modalities IV, IM, Nebulization Hepatocytes, Stellate cells, Myocytes & Lung Epithelial cells Proprietary Diverse Library of over 150 Proprietary Lipids Rational Design to Maximize Efficacy and Increase Tolerability Formulation Compositions Customized for Application and Cell Type of Interest Biodegradable Manufacturing Efficiency No Accumulation of Lipids Scalable and Reproducible Production Process Arcturus LUNAR is Enabling the Next Generation of RNA Medicines 6

8 A R C T U R U S T H E R A P E U T I C S LUNAR Mechanism of Delivery LUNAR Associates with Cell Membrane Lipid Particle in Endosome Enters Cell Via Endocytosis Increased Acidity as Endosome Ages ph-mediated Disruption RNA in Cytosol Rapid Biodegradation of Vehicle RNA Processing and Translation 7

9 A R C T U R U S T H E R A P E U T I C S Arcturus mrna Manufacturing DNA Template Production IVT and Capping Reaction Purification Process Buffer Exchange & Concentration Features Optimized IVT Method Improved Capping Reaction Proprietary Purification Process Efficient Scalable to > 1Kg Adaptable Benefits Reduced Cost; Higher Purity Reduced Cost of Goods Higher Purity in a Shorter Time Entire Process Less Than One Week Access Large Patient Populations Can Utilize a Variety of Modifications Arcturus Internal mrna Production: Up to 30 g in Less Than One Week 8

10 L U N A R A N D m R N A P L A T F O R M S A R E D R I V I N G D E V E L O P M E N T P I P E L I N E OTC Deficiency Market Opportunity Ornithine Transcarbamylase (OTC) Deficiency: The most common urea cycle disorder The urea cycle converts neurotoxic ammonia to water-soluble urea that can be excreted in urine Deficiency in OTC causes elevated blood ammonia, which can lead to neurological damage, coma, and death 10,000 worldwide prevalence Unmet Medical Need Present standard of care involves a strict diet (low protein, high fluid intake) plus ammonia scavengers (sodium phenylbutyrate) Present standard of care does not effectively prevent spikes of ammonia. OTC Deficiency patients are typically referred for liver transplant. LUNAR-OTC Aims to Restore Enzyme Function Expression of OTC enzyme in liver has potential to restore normal urea cycle activity to detoxify ammonia, preventing neurological damage and removing need for liver transplantation 9

11 A R C T U R U S T H E R A P E U T I C S LUNAR-OTC Disease Normalization Following Single and Repeat Dosing in OTC Mouse Model Urinary Orotic Acid Single Dose Survival of OTC-deficient Mice on High Protein Diet Weekly LUNAR-OTC Treatment Preclinical POC studies have shown that LUNAR -delivered human OTC mrna reduces Urinary Orotic Acid levels in a well-established mouse model of OTC deficiency LUNAR-OTC is Targeted for IND Submission in H

12 L U N A R A N D m R N A P L A T F O R M S A R E D R I V I N G D E V E L O P M E N T P I P E L I N E Cystic Fibrosis Market Opportunity Cystic Fibrosis: The most common rare disease in the United States Caused by genetic mutations in the CFTR gene, resulting in aberrant flux of ions in and out of cells, causing thick mucus buildup in lung airways Chronic airway obstruction leads to infection and inflammation, which causes permanent tissue scarring and respiratory failure 70,000 worldwide prevalence Unmet Medical Need No CFTR functional corrector is approved for treatment of all patients Present standard of care does not effectively prevent long-term effects of mucus accumulation. CF patients with late-stage loss of respiratory function require lung transplant LUNAR-CF Aims to Restore CFTR Function An mrna replacement therapy has the potential to deliver a new copy of CFTR into the lungs of CF-patients, independent of any genotype A functional CFTR protein can restore chloride channel efflux in the airways, reducing mucus accumulation, tissue scarring and minimizing the progressive respiratory dysfunction observed in CF-patients 11

13 P R O O F O F C O N C E P T I N C F M O D E L S O F D I S E A S E LUNAR-CF In Vitro Protein and Functional Profile of Arcturus CFTR mrnas Validated Protein Expression: Western-Blot detection of mature CFTR protein Functional Assay: Transepithelial Conductance in an epithelial cell model (FRT) Natural Human CFTR mrna Human CFTR mrna (Arcturus) CFTR optimized-mrnas transfected in CFBE cells Arcturus codon optimized mrnas (Comps 2, 7, 8, 9) express higher levels of protein than the natural sequence (Comp1) Arcturus codon optimized mrnas are several folds more active than the natural sequence LUNAR-CF is Targeted for IND Submission in H

14 L U N A R A N D m R N A P L A T F O R M S A R E D R I V I N G D E V E L O P M E N T P I P E L I N E GSD Type III Market Opportunity Glycogen Storage Disease type III Caused by genetic mutations in the glycogen debranching enzyme (AGL), which leads to a toxic glycogen-byproduct (limit dextrin) accumulation in liver and muscle Symptoms include hepatomegaly, hypoglycemia, hyperlipidemia, some progressive liver cirrhosis, and muscle disease later in life 10,000 worldwide prevalence Glycogen Storage Disease type III Present standard of care involves a hard-to-manage diet (high protein, including frequent night-time feeding) Despite dietary management, progressive liver dysfunction may occur. These GSDIII patients are typically referred for liver transplant LUNAR-GSDIII Aims to Restore Enzyme Function Expression of AGL in liver has potential to restore breakdown of glycogen to normal levels, removing need for diet restrictions and liver transplantation 13

15 G Glycogen l y c o g e n c Content o n t e n t % % w w/w / w P R O O F O F C O N C E P T I N D I S E A S E M O D E L LUNAR-GSD3 Functional Activity of LUNAR-GSD3 Observed in Mouse Model RNA Glycogen Levels in GSD Type III KO Mice L i v e r G l y c o g e n PAS Staining in GSD Type III KO Mice L i v e r G l y c o g e n WT control W t c o n t r o l KO Vehicle V e h c o n t r o l LUNAR-GSD ( 1 0 mw g t / ck og n) t r o l Vehicle LUNAR-GSD3 V e h c o n t r o l ( 1 0 m g / k g ) 5 N o n - F a s t i n g 0 0 Non-Fasting N o n - F a s t i n g F a s t i n g Fasting F a s t i n g Hypertrophic hepatocytes with pale staining cytoplasm (GSD III phenotype) Improved phenotype after treatment 14

16 R e la tiv e E x p re s s io n I V D E L I V E R Y T O L I V E R LUNAR Targeting Liver LUNAR-mRNA delivery to Liver LUNAR-siRNA delivery to Liver Cell Subtypes T a rg e t K n o c k d o w n in L iv e r C e ll T y p e s 1.5 P B S L U N A R L U N A R 2 Liver 0.5 LUNAR-GFP 0.0 H e p a to c y te s S te lla te C e lls C e ll T y p e LUNAR-Luc LUNAR-siRNA LUNAR-1 delivers to Hepatocytes LUNAR-2 delivers to Hepatocytes and Stellate cells Functional Delivery of LUNAR -RNA Formulations in Liver Cell Subsets 15

17 N E B U L I Z A T I O N A N D D E L I V E R Y T O L U N G LUNAR Targeting Lung Nebulization LUNAR delivery into lung epithelial airways LUNAR-GFP mrna Control PBS LUNAR-Luc mrna Functional Delivery of LUNAR -mrna into Lung Epithelial Cells 16

18 Serum Titer % TNF IFN + Cells % T N F + I F N + c e l l s I M D E L I V E R Y A N D V A C C I N E P R O O F O F C O N C E P T W I T H H A m R N A LUNAR Targeting Muscle (Vaccines) Intramuscular (IM) administration HA Inhibition Titer and T-Cell responses Drug Product LUNAR Manufacturing Hemagglutination Inhibition Titer (Day 35) CD8+ T-Cell Responses (Day 35) LUNAR-Luc mrna PBS LUNAR 1 LUNAR 2 PBS LUNAR 1 LUNAR 2 P B S L U N A R 1 L U N A R 2 LUNAR -mrna Platform Promotes Antigen-Specific Responses for Vaccine Applications 17

19 H B s A g n o r m. to h A lb (r e la tiv e to c o n tr o l) I N T E R N A L R N A D E V E L O P M E N T P L A T F O R M S UNA Oligomer Efficacy in LUNAR-HBV (sirna) LUNAR-HBV (sirna) effectively knocks-down HBV Gene Products in AAV-HBV Mouse Model Inhibition of HBsAg Secretion in HBV-infected Primary Human Hepatocytes In h ib itio n o f H B s A g S e c re tio n in H B V -In fe c te d 1 H u m a n H e p a to c y te s U N A 1 U N A 2 U N A T re a tm e n t D a y Triple UNA Oligomer Combo Demonstrates Excellent Efficacy to Treat All HBV Genotypes 18

20 I N T E R N A L R N A D E V E L O P M E N T P L A T F O R M S Drug Substance: mrna Design Arcturus proprietary mrna optimization platform Sustained hepo activity in NHPs upon repeat dosing Optimized conditions mrna sequence Chemistry Process optimization Improved protein expression and duration Improved functional activity Weekly Dosing in Non-Human Primates Proprietary mrna Optimization Platform Demonstrates Sustained Activity Upon Repeat Dosing in NHPs 19

21 P R O P R I E T A R Y R E P R O D U C I B L E & S C A L A B L E P R O D U C T I O N P R O C E S S Drug Product: LUNAR Formulation & Production LUNAR Reproducibility LUNAR Scalability Particle Size % Encapsulated RNA Particle Size % Encapsulated RNA LUNAR Has Been Successfully Scaled From Milligram to Multigram Batch Sizes 20

22 Enabling a New Era of Nucleic Acid Medicines