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Preclinical Testing of Nucleic Acid-based Therapeutics

Preclinical Testing of Nucleic Acid-based Therapeutics. Dr. Michael Templin Technical Director. 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

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Preclinical Testing of Nucleic Acid-based Therapeutics

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  1. Preclinical Testing of Nucleic Acid-based Therapeutics Dr. Michael Templin Technical Director

  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 • 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

  4. Nucleic Acid-based Therapeutics: Key Endpoints • 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 • 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 - differentiate background (class) effects from effects specific to a development candidate • 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

  5. Nucleic Acid-based Therapeutics: Key Endpoints (cont.) • 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 • 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 • 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.)

  6. Thank you. Criteria for Sexual Maturity www.snbl.com

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