The Emerging Role of Nucleic Acid Therapeutics: Resuscitating Cardiovascular Drug Development with Disruptive Therapies

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The Emerging Role of Nucleic Acid Therapeutics: Resuscitating Cardiovascular Drug Development with Disruptive Therapies

Moderator Panelist Panelist Panelist

Michael C. Rice, MS, MBA James Hamilton, MD, MBA William Marshall, PhD Barry S. Ticho, MD, PhD, FACC Principal, Head of Advanced Therapeutics Vice President President, CEO, Co-Founder, & Chief Medical Officer Cello Health BioConsulting, Previously Head of Clinical Development Director Stoke Therapeutics Defined Health Arrowhead Pharmaceuticals miRagen

6 Nucleic Acids Therapeutics Provide a Conventional Drug-Like Advancement Towards Enabling Genotypic Modulation of Disease Pathophysiology Increasing Complexity of Therapeutic Interventions

Phenotypic Genotypic

1980s 1990s 2000s

Peptides and Protein Gene Correction & Cell Therapy & Antibodies Nucleic Acids Therapeutics Augmentation Regenerative Med

Drug delivery, formulation and enabling platforms: technology (non-viral and viral) improvements in biodistribution, PK and PD, and devices

• Plasma/tissue derived • Plasma Polyclonal Igs • Immune Modulators • Viral vectors • Autologous/allo-geneic cell proteins ‒ • Monoclonal antibodies • Antisense Oligonucleotides Retro/ therapy ‒ • Recombinant Proteins Lentiviral • Other cells: • mAB fragments • Exon skipping ‒ AdV, AAV ‒ – Clotting factors e.g. ES, iPS • Scaffolds • RNAi (siRNA, saRNA, shRNA) • Non-viral – Cytokines • Mitochondrial transfer ‒ Plasmids/ – Hormones • Darpins • mRNA • Devices ‒ Fragments – Growth factors • Intrabodies • miRNA ‒ Encapsulation • ‒ • Peptides Gene editing with Scaffolds • Diabodies • lncRNA Meganucleases ‒ Implants • Enzyme Replacement • Bispecific mABs • Aptamers ‒ Zinc Fingers ‒ Micro-organs ‒ TALENS ‒ Aphaeresis • Protein Degraders • Bispecific T-Cell Engagers • Ribozymes ‒ CRISPR/Cas9 • Base Editing

Spinraza [Biogen] Waylivra [Akcea/Ionis] SMA FCS Oligonucleotide Therapeutics: product of nearly 40 years of research and development. 2016 US Approval 2019 EU Approval $750K (Y1), $350K (Y2+) $400K/year

Kynamro (Ionis/Akcea) Exondys 51 [Sarepta] Tegsedi [Akcea/Ionis] HoFH DMD hATTR Discovery of ASO 2013 US Approval 2016 US Approval 2018 US Approval

ASO 1972 $375K/year $892K/year $450K/year

1980 2000 2005 2010 2015 2020

microRNA RNAi Onpattro [Akcea/Ionis] Fire/Mello win Nobel Prize GalNAc Targeting Discovered Discovered hATTR 2006 2014 RNAi 1993 1998 2018 US Approval $450K/year

Givlari [Akcea/Ionis] . Steady incremental improvements have addressed multiple technological hurdles. hATTR 2019 US Approval  Duration of action, potency, toxicity (local and systemic), specific tissue delivery $575K (Y1), $442K (Y2+) . Approvals limited to rare populations and not yet translated to broad clinical cohorts Inclisiran Efficacy/ Safety LDL-C Reduction 2019 . Inclisiran and earlier stage antisense and RNAi drugs targeted for CVD (e) $4.500?

© Cello Health BioConsulting 2019 8 Progress in Oligonucleotide Based Drugs Enabled by DNA/RNA Chemical Modifications, Delivery Technology, Target/Indications Selection and Engineering to Fine Tune Therapeutic Index

 These consist of base modifications, sugar modifications, internucleoside linkage modifications, and conjugates of small and large molecules to essentially every position of a dinucleotide.  Key formulations and conjugate strategies used in later stage clinical trials to enhance delivery.

https://doi.org/10.1016/j.cmet.2018.03.004

Lead NAT Therapeutic Number of Programs in Company Candidate Therapeutic Area* Modality Development Status 1. Ionis Pharmaceuticals Marketed Cardiovascular, Metabolic ASO 46 2. WaVe Life Sciences Phase 2/3 Neuromuscular ASO 23 3. Alnylam Pharmaceuticals Marketed Metabolic siRNA 21 4. ProQR Therapeutics Phase 3 Sensory ASO 17 5. Sarepta Therapeutics Marketed Neuromuscular ASO 16 6. Dicerna Pharmaceuticals Phase 3 Metabolic siRNA 14 7. Biogen Marketed Neuromuscular ASO 11 7. Quark Pharmaceuticals Phase 3 Sensory siRNA 11 8. OliPass Phase 1 Neurology ASO 8 9. Ribomic Preclinical Autoimmune/inflammatory Aptamer 7 9. Silence Therapeutics Phase 1 Hematology siRNA 7 10. Arrowhead Pharmaceuticals Phase 3 Hepatology siRNA 6 10. AstraZeneca Phase 2 Cardiovascular mRNA 6 10. Idera Pharmaceuticals Preclinical Cardiovascular, Autoimmune/Inflammatory ASO 6 10. Sylentis Phase 3 Sensory siRNA 6

Adis Insight, Clarivate Analytics Cortellis, *Note: Therapeutic area of lead candidate. 0 20 40 60

NAT by Phase* (n=458) NAT by Therapeutic Area (n=465**) 400 3 Neurology 4 350 6 3 1 Sensory Neuromuscular 9 300 10 Autoimmune/Inflammatory 21 91 Cardiovascular 250 25 Metabolic Hepatology 200 25 Dermatology Respiratory 150 27 57 Unspecified 100 Hematology 29 Renal 50 55 Musculoskeletal 47 Rheumatology 0 52 Endocrine Multisystem Other

^Note: Oncology and infectious disease indications have been excluded. *Note: Phase 1/2 agents are grouped with Phase 2, Phase 2/3 agents are grouped with Phase 3; **Note: Agents with multiple lead indications in different therapeutic areas were counted in each therapeutic area.

© Cello Health BioConsulting 2019 11 CVD NAT Pipeline Biased Towards mRNA Knockdown (ASO/siRNA) – Competing with mAbs For Validated Targets Expressed in Liver and Creating New Markets for Novel Targets

Cardiovascular NAT by Lead Indication Cardiovascular NAT by Modality (n=45) (n=53*) 2 1 4 Antisense oligonucleotide Lipid metabolism 1 siRNA 1 1 5 20 2 Hypertension Aptamer 2 Unspecified CVD Undisclosed/Unspecified/Other 2 miRNA 19 Cardiac failure 13 2 mRNA Vascular disease 3 Ischemia Cardiovascular NAT by Target (n=45) Myocardial infarction 15 6 Stroke 10 13 Clotting/Thrombosis 5 2 2 2 5 4 3 6 8 Atherosclerosis 0 Hereditary angioedema Restenosis

*Note: Assets with multiple lead indications were double-counted;

© Cello Health BioConsulting 2019 12 Pivotal Year for NAT Drugs as Numerous Products Grow the Rare Disease Market Beyond Rare Neuromuscular Disorders and Proteinopathies Setting Stage for Broader CVD Indications

Top 20 Nucleic Acid Therapeutic Products by WW Sales (2019 – 2024E) MRT5005 (Translate Bio) 10,000 ARO-ANG3 (Arrowhead) 9,000 MRG-106 (miRagen) Lumasiran (Alnylam) 8,000 DCR-PHXC (Dicerna) Waylivra (Akcea) 7,000 ARO-AAT (Arrowhead) NS-065 (Nippon Shinyaku) 6,000 Casimersen (Sarepta) 5,000 Vyondys 53 (Sarepta) ARO-APOC3 (Arrowhead) 4,000 Fitusiran (Sanofi) Givlaari (Alnylam) 3,000 RG6042 (Roche) Exondys 51 (Sarepta) 2,000 Vutrisiran (Alnylam) 1,000 Tegsedi (Akcea) Onpattro (Alnylam) 0 Inclisiran (Novartis) 2019 2020 2021 2022 2023 2024 Spinraza (Biogen) Antisense/RNAi in development for CV indications EvaluatePharma

2013-2020 Nucleic Acid Therapy Total Deal Value and Number of Deals by Year (n=137, $M) $18,000.00 35 Asset Purchase/Investment M&A Partnership Number of Deals $16,000.00 30 $14,000.00 25 $12,000.00 $10,000.00 20 $8,000.00 15 $6,000.00

10 Number of Deals $4,000.00 Total Deal Value ($M) Deal Value Total $2,000.00 5 $- 0 2013 2014 2015 2016 2017 2018 2019 2020 (YTD)

Partnership

M&A

Asset Purchase / Investment

*Note: Number of deals includes deals with disclosed and undisclosed values

Company Deal Type Upfront Cash Notes TMC took an exclusive Medco (Licensor) Development and global license to commercialization $25M Alnylam’s RNAi 2013 Alnylam license candidates that block PCSK9. Amgen received Development and Amgen (Licensor) exclusive license commercialization $35M option to RNAi ARC- Arrowhead license 2016 LPA program. Agreement between Akcea and Novartis to Collaborative Novartis (Licensor) develop and research and product $75M commercialize AKCEA- 2017 Ionis/Akcea license option APO(a)-LRx and AKCEA-APOCIII-LRx. Novartis took option to license ASO TQJ230 Novartis (Licensor) Option to license $150M and test in a P3 2019 exercised Ionis/Akcea cardiovascular outcomes trial. Ionis and Pfizer entered into a Development and Pfizer (Licensor) worldwide exclusive 2019 commercialization $250M licensing agreement Ionis/Akcea license for antisense therapy AKCEA-ANGPTL3-LRx.

BCIQ; Medco/Alnylam (2013); Amgen/Arrowhead (2016); Novartis/Akcea-Ionis (2017); Novartis/Akcea-Ionis (2019); Pfizer/Akcea-Ionis (2019)

© Cello Health BioConsulting 2019 15 Pivotal Data for NVS/Alnylam’s GalNAc Liver Targeted PCSK9 siRNA, Inclisiran, for Treatment of Hypercholesterolemia and Potentially 2° Cardioprevention Demonstrates Broad Utility

Inclisiran is a long-acting, synthetic siRNA directed against PCSK9, Pivotal data demonstrate that twice annual dosing of inclisiran provides which is conjugated to triantennary N-acetylgalactosamine similar efficacy as biweekly/monthly mABs Repatha and Praluent. ~50% carbohydrates (GalNAc) that bind to asialoglycoprotein receptors reduction in LDL-C on top of maximal tolerated statins. AEs similar to expressed on hepatocytes, leading to the uptake of inclisiran. mABs.

N Engl J Med. 2020 Mar 18, PMID: 32187462

© Cello Health BioConsulting 2019 16 $9.7B Buyout Signals Shift in the siRNA Field as Pivotal Data in Large Cohorts of Patients Involving Patient Outcomes Derisks the Technology for Other Broad Indications

 Novartis has a challenge in front of itself to leverage Inclisiran’s 11/24/2019 differentiating qualities and lessons learned from less than stellar launches of the mABs to justify their $9.7B investment.  Twice annual “vaccine-like” dosing schedule may be enough differentiation for payers to strongly consider making inclisiran a preferred therapy in the hypercholesterolemia space.  Recent analysis suggests Novartis will push for a physician- WW PCSK9 Market Value US$ (mln) administered ‘buy and bill’ model, which they argue will 3500 improve compliance and thus real-world outcomes, compared 3000 Repatha (AMGN) Inclisiran (NVS) to self-administered mAbs. Praluent (SNY) Repatha (Astellas) 2500  Novartis is expected to launch inclisiran at a price below the 2000 ICER recommended price for PCSK9 antibodies and provide a unique contractual guarantee between manufacturer, 1500 physicians and payers to ensure compliance and offset costs 1000 on CV events. However, with ongoing outcomes trial not set to 500 readout until 2024, we may have to wait for full MACE data before truly knowing how disruptive this new therapy and 0 healthcare delivery model will be.

Evaluare Pharma, News Releases

MARCH 2020

APRIL 2020

News Releases

19 Panel Discussion

The Emerging Role of Nucleic Acid Therapeutics: Resuscitating Cardiovascular Drug Development with Disruptive Therapies

Moderator Panelist Panelist Panelist

 Antisense oligonucleotides can modulate gene expression  siRNA binds with Argonaute (Ago) to form an RNA-induced through two different mechanisms based on post-hybridization silencing complex (RISC). The RISC binds the complementary events sequence of the target mRNA and degrades it. The components of complex can be recycled, leading to extended efficacy

Enzymatic RNA degradation through cleavage by RNase H Occupancy that sterically blocks translation

e.g. fomivirsen

e.g. mipomersen

Adv Exp Med Biol. 2019;1157:133-177, Front Plant Sci. 2017 Feb 14;8:200. e.g. patisiran

 mRNA therapies harness the natural translation abilities of the cell  Antisense therapies can also upregulate protein production via to make the corresponding protein Exon Skipping and splice modifiers

Moderna Website, J Neuromuscul Dis. 2016; 3(2): 157–167.

 AstraZeneca and Moderna are developing intracoronary VEGF-A mRNA for Myocardial Infarction and Heart failure  VEGF-A is a potent angiogenic factor that promotes growth of blood vessels  Preclinical data suggests that expression of VEGF-A in ischemic heart tissue could increase blood flow and partially restore cardiac function

https://investors.modernatx.com/static-files/c65fc37f-5528-478d-823d-10458749058b

 microRNAs are short (approximately 20-25 nucleotides long), single- stranded RNA molecules that regulate gene expression and play a vital role in influencing the pathways responsible for many disease processes, including cardiovascular disease and fibrosis.  microRNAs function by preventing the translation of messenger RNAs into proteins and/or by triggering degradation of these messenger RNAs.  Studies have shown that microRNA gene regulation is often not a decisive on and off switch but a subtle function that fine-tunes cellular phenotypes that becomes more pronounced during stress or disease conditions.  microRNAs can be modulated with chemically synthesized oligonucleotides by either decreasing the activity (anti-miRs or inhibitors) or increasing the levels (pro-miRs or mimics) of expressed microRNAs.  These modulators can then directly affect the protein expression of the specific microRNA’s targets. Typically, in laboratory settings, microRNA mimics are introduced as double stranded oligonucleotides and inhibitors are introduced as single strand oligonucleotides.

Miragen Website; http://www.miragen.com/microrna-platform/

https://www.nature.com/articles/s41467-018-04252-2.pdf; Verve Therapeutics Website

26 Panel Discussion

The Emerging Role of Nucleic Acid Therapeutics: Resuscitating Cardiovascular Drug Development with Disruptive Therapies

Moderator Panelist Panelist Panelist