SNBL-USA Preclinical Testing of Nucleic Acid-based Therapeutics

1. SNBL-USA • Preclinical Testing of Nucleic Acid-based Therapeutics • Today’s precision path to tomorrow’s medical innovations

2. Scope of Studies and Experience with Nucleic Acid-based Therapeutics • 10+ years of Company experience; and a core group of Study Directors, scientists, and pathologists for this drug class • 95+ studies performed at SNBL USA since 2001 (finalized or currently in progress) • Diverse study types and duration • Acute, definitive, and chronic toxicology studies in rodent and NHPs • Safety pharmacology studies in NHPs • DART studies in mice and rabbits • Multiple routes of administration • IV (bolus and infusion), SC, and IM • Localized administration • Direct administration to CNS • Multiple constructs and formulations • Single-stranded and double-stranded (ASO, siRNA, microRNA) • Saline-based, complex (lipid, polymer, conjugates) and dynamic systems (bacterial and viral vector) for delivery

3. General and focused procedures and endpoints • Test article handling • Routes of Administration (IV, SC, etc.) • Cageside observations • Injection site observations • Body weight and food consumption • ECG and ophthalmology • Hematology and serum chemistry • Coagulation parameters • Urinalysis • Toxicokinetics/biodistribution • Necropsy/organ weights/tissue collection • Histopathology • Study reporting • Complement • Cytokines/Chemokines • IgG/IgM analysis • Anti-drug antibodies • PCR • Anti-KLH antibodies • Platelet assays • Flow Cytometry SNBL has extensive experience with all phases of GLP compliant Toxicology studies for Nucleic Acid-based Therapeutics

4. Nucleic Acid-based Therapeutics: Key endpoints • Histopathology - differentiate background (class) effects from effects specific to a development candidate SNBL Approach: Core group of in-house pathologists; monitor for drift in terminology within and across studies • Activation of complement – can be a rate-limiting step for reporting and concerns about GLP compliance • SNBL Approach: Assays have been established in-house • Cytokines/Chemokines - changes (increase/decrease) observed in rodents and NHP; monitoring needed for certain candidates • SNBL Approach: Multiplex assays have been established at SNBL for evaluation in mouse and NHP • Flow cytometry – when appropriate, flow cytometry provides essential data for pharmacology or immunomodulation • SNBL Approach: GLP compliant assays for T, B, and NK cells, and specific subsets for each cell type (CD3+, CD4+ T cells; CD19, CD20+ B cells; etc.)

5. Nucleic Acid-based Therapeutics: Additional endpoints • Platelet Interactions - Severe thrombocytopenia has been an infrequent observation in toxicology studies • SNBL Approach: Investigate mechanism of action via functional assays and surface markers; identifying susceptible animals for monitoring • Toxicokinetics/Biodistribution - Essential endpoint; commonly a rate-limiting step for reporting time lines • SNBL Approach: Priority area for SNBL Analytical Services; Best option is to work with Sponsors; internal focus on ELISA or multiplex-based assays • Anti-Drug Antibodies - relatively new endpoint for consideration; recommendations have not been well established SNBL Approach: Work closely with Sponsor to identify assay objectives and criteria; capitalize on ADA assays for other drug classes • PCR analysis– mRNA “knock down”, repression/de-repression assays SNBL Approach: Procedures established and validated for GLP compliance; Work with Sponsor for target(s)-specific assays

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