Preclinical and Biodistribution Assessments Supporting Development of Gene Therapy Products

Janet M. Benson, PhD, DABT Lovelace Respiratory Research Institute, Albuquerque, NM 7004-1

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Three subsidiaries

About LRRI

Founded in 1947 in the State of New Mexico

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LRRI – Commercial and non-government contracts

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LBERI – Government Grants and Contracts LSR – For Profit Entity conducting clinical trails throughout USA.

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80 PhDs, MDs, and DVMs $67 million revenue (projected for 2008) $50 million endowment 450,000 square feet of facilities 7004-2

Inhalation Toxicology Laboratory (325,000 sq. ft.) LRRI Headquarters and Research Facility (125,000 sq. ft.)

Principal Research Activities

Inflammation (triggers, mediators, cell damage and repair) Lung cancer (responsible genes, early detection) Asthma and immunology (determinants of allergic asthma, immunosuppression) Infectious disease (defenses, impairment of resistance to viruses and bacteria) Emphysema (mechanisms, animal models, tobacco and environmental causes) Preclinical studies of new drugs (efficacy, safety, FDA compliance) Development of Countermeasures against Biological/Chemical/Nuclear Threats Safety and Biodistribution of Gene Therapeutics 7004-4

FY 2008 Forecasted Revenue $67MM

LSR 10% State 1% Pharmaceutical 7% Trade Associations, Other Commercial Sources, etc., Sponsored Construction 6% NIH Sponsored Construction 5% NIH 42% Trade Associations, Other Commercial Sources, etc., 16% Endowment Contributions 3% = NIH Sponsored Construction EPA 1% = Trade Associations, etc., Sponsored Construction DOD 7% DOE Cooperative Agreement 2% DOE Other 0% 7004-5

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Role of the Pharmacology/Toxicology Testing Core Assess the biodistribution and/or safety of gene therapy products in studies conducted using Good Laboratory Practice Guidelines.

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The objective of the Pharmacology/Biodistribution Studies is to assess:

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Vector tropism Gene expression efficiency and kinetics Vector Clearance

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The objectives of the Toxicology Studies are to

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identify any potential adverse effects Identify a no adverse effect level. 7004-6

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Pharmacology Toxicology Testing Core Key Personnel PI: Janet Benson, PhD, DABT

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30 years experience in basic and applied toxicology at LRRI

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25+ years experience directing studies under FDA or EPA regulatory guidelines Co PI: Thomas March, DVM, PhD, DACVP

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11 years at LRRI as a toxicologic pathologist Experienced in study design and animal model development Experienced in histological assessment in a variety of species and under regulatory guidelines.

Virologist: Adriana Kajon, PhD

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8 years at LRRI Molecular epidemiology of adenovirus respiratory infections Animal modeling of adenovirus pathogenesis 7004-7

Scope of Research (Benson) – Animal Model Development, Efficacy and Safety Evaluations

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Safety and Biodistribution of Gene Therapy Products (NHLBI).

Toxicity/Toxicokinetics/Pathophysiology of ingested and inhaled ricin (NIAID).

Animal Model Development and Efficacy Assessment of Botulinum Toxin Therapeutics (NIAID) Development and Assessment of Countermeasures against sulfur mustard induced toxicity to the lung, skin and eye (NINDS).

Immunotoxicity/Developmental Toxicity of Inhaled Brevetoxin (Florida Red Tide; NIEHS).

Commercial Clients.

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LRRI Scientific Staff Supporting the Core

Board-certified toxicologists Board-certified laboratory animal veterinarians Virologists Immunologists Board-certified veterinary pathologists Certified quality assurance specialists Certified health and safety specialists Supporting Consultants 7004-9

Indoor Kennels (Canine or Swine)

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Large Animal Necropsy

Clinical Chemistry

Hematology

Histopathology

Flow Cytometry

Basic Overview of the RSA Sumbission and Review Process

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Investigator Registers with the program, receive password and further instructions.

Investigator selects RSA type(s) and begins RSA completion process – contact Core if desired.

Submit preliminary RSA.

Core staff and Investigator work to complete and submit final version of RSA.

Pharm/Tox Core completes Feasibility Assessment (ongoing process from start) Application submitted for Scientific Review Board review Application submitted for Steering Committee Review Recommendations on funding submitted to the Gene Therapy Group..

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RSA Process - Beginnings

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Investigator should ideally begin the process by having discussions with the FDA regarding appropriate experimental design.

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LRRI staff can be part of these discussions Guidance provided by FDA should be shared with LRRI and GTRP/NHLBI staff early on, so required resources can be identified.

Source of GLP or GMP-grade vector product should be identified.

Investigator will register with Program Draft RSA form will be submitted and Core will assist in developing to final stage.

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Pharm/Tox RSA Section I Investigator Information

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Investigator Name, and Contact Information (Alternate contact)

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Biographical Sketch Are you a NHLBI investigator?

Funding Sources 7004-18

Pharm/Tox RSA Section II Study Information

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Study Title Study Abstract Rationale for Conducting Study Identify Disease Category (Heart, Lung, or Blood) Targeted Disease Target organ, tissues or cells Gene /Vector Name Route of Administration 7004-19

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Pharm/Tox RSA Section II Continued Study Design

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Tox, Biodistribution study, or both?

Animal Species, numbers, sex Normal animals or disease model? If disease model, how established?

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Vector Doses (rational for establishing, sites delivery method).

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Has delivery device been approved for clinical use?

Euthanasia Schedule 7004-20

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Pharm/Tox RSA Section II Continued Study Endpoints

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Assays indicating toxicity/efficacy (tissue, timing?) Assays for gene product or vector. Antibodies developed to protein product/vector?

Physiological endpoints – (pulmonary function, electrocardiograms, echocardiograms?)

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Clinical pathology (hematology, serum chemistry, coagualtion profiles).

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Histopathology (need for microdissection, immunohistochemistry?) 7004-21

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Pharm/Tox RSA Section II Concluded Description of the Clinical Study Any other RSA ’s submitted relating to this RSA or clinical study.

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RSA Section III Regulatory Information

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Have you discussed the study design with FDA in a pre-IND setting?

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If “Yes”, list date(s) and provide discussion summary.

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Information ideally shared with Core and NHLBI early to enable assessment of resources required and feasibility assessments.

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If “No”, then this needs to be done.

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Reason(s) for Pharmacology/Toxicology testing

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Initial testing required by FDA?

Is this study to provide follow-up testing required by FDA? List reasons.

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RSA Section IV Study-Specific Support

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Current and Pending funding for this study

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NIH NHLBI Other (institution or company) None 7004-24

RSA Section V Vector Information

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Has the material been made?

Vector/Gene Name Vector Source ( a GTRP core – specified, or other source) Lot numbers Amounts to be provided, Grade (GMP, Partial GMP, or non GMP) Product details (titer, vehicle, storage conditions, stability, special handling procedures, known toxicities.

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Method used to make vector.

Vector Construct 7004-25

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RSA Section V Vector Information Continued Vector Construct

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Transgene, promoter, serotypes, transgene species specificity, packaging cell line.

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Sequence data Vector map Strategy in constructing the vector.

Expected level of transgene expression Criteria for therapeutic gene expression Tissue specificity of transgene expression?

Will primers for specific transcript or probe to detect gene expression be provided to the Core – if so, upload requested detail.

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Pharmacology/Toxicology Testing Requested Testing Assays

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Hematology

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Serum Chemistry Biodistribution Histopathology Testing organs for viral genomes Transgene expression and antibodies Biomarkers of Gene Function Other.

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Timelines (constraints) 7004-27

Feasibility Assessment

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Feasibility assessed based on:

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Core capacity and capabilities Timeline Vector Availability Vector stability or other characteristics Special animal requirements Other resource requirements Cost analysis 7004-28

Summary

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Preclinical Assessment of Gene Therapy products is complex – more complex than for traditional compounds

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Early interaction with the FDA and communication of these discussions with the Core and NHLBI will facilitate RSA development, assembly of required resources, and feasibility assessment. 7004-29

PI Contact Information

Janet Benson LRRI 505-348-9457 [email protected]

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