MOVING NOVEL CONCEPTS FROM RESEARCH LABORATORY TO CLINICAL PROOF-OF-PRINCIPLE

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MOVING NOVEL CONCEPTS FROM RESEARCH LABORATORY TO
CLINICAL PROOF-OF-PRINCIPLE

• BIOPHARMACEUTICAL DEVELOPMENT PROGRAM
• BIOLOGICAL RESOURCES BRANCH
• DEVELOPMENTAL THERAPEUTICS PROGRAM
• NATIONAL CANCER INSTITUTE
• FREDERICK, MARYLAND

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Mission

• To produce clinical-grade biopharmaceuticals
  under current Good Manufacturing Practices
  (cGMPs) appropriate for Phase I/II (dose-ranging
  safety and efficacy) and proof of principle
  clinical trials of innovative biopharmaceutical
  concepts.
• To manufacture high-quality laboratory-grade
  material to support preclinical development for
  selected innovative projects.

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Key Assumptions

• Concepts are selected for novelty and innovation
  over derivatives of existing approaches.
• Many projects have been previously considered by
  Pharma and declined due to uncertain technology,
  regulatory hurdles, or small markets.
• Clinical production is focused on meeting
  requirements for initial proof-of-concept trials,
  NOT final product requirements for commercial
  development.
• Approximately 1/10 to 1/20 clinical projects may
  eventually be licensed.
• Desired size of program is based on assumptions
  1-4 (i.e., 10 to 20 projects/year to clinic).
• Intellectual Property to be retained by Project
  Originator(s).

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Where Does the Program Get Its Projects

• Peer-Reviewed Extramural Research
• Special Competitions
• Rapid Access to Intervention Development (RAID)
  Program
• Inter-Institute Program (IIP) for AIDS Projects
• National Cooperative Drug Discovery Groups
• Intramural NCI Research
• Other NIH Programs (NIAID)
• Commercial Collaborations With Government
• The NCI Selects and Prioritizes Candidate
  Projects
• BDP Provides Feasibility Analyses and Cost
  Estimates That Are Used in the Selection

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Capabilities and Resources

• Fermentation for Recombinants 20L, 80L, 100L
  and 1,000L
• Natural Products Fermentation 30, 300, 3,000
  Gallons
• Hollow Fiber Mammalian Cell Production (8
  Pathways)
• Packed Bed Mammalian Cell Production
• Process Development and Optimization
• Fermentation
• Recovery
• Refolding
• Purification
• Assays
• Etc.
• Clean Room Suite
• BL3 Suite
• QA
• QC
• Management of Required Out-Source Production and
  Testing
• CMC Documentation for IND Submission

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Major Milestones in a Typical Clinical-Grade
Production Project

• Pre-Proposal Communications With Potential
  Investigator-Applicants
• Proposal Received by NCI
• Initial Review by Staff
• Clarify Projects by Posing Generic Questions to
  Applicants
• Make Preliminary Feasibility Analysis Cost
  Estimates
• Identify Any Special Concerns

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Major Milestones (Continued)

• Peer Review by Selection Committee
• Committee May Re-Define Project Scope
• Staff Re-Examines Feasibility Cost Estimates
• Oversight Committee Review
• Staff Present Cost and Feasibility Analysis
• Determination of Scope of Project
• Re-Evaluation of Progress at Key Milestones

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Major Milestones (Continued)

• Initial Meeting of Staff With Outside
  Investigator
• Initial Project Team Meeting
• Define Deliverables
• Material Requirements
• Formulation
• Filling
• Special Concerns
• Safety
• Regulatory
• Production
• Assays
• Special Consultants
• Outline Major Milestones
• Determine Which Efforts Should Be In-House Versus
  Out-Source

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Many Projects Require Substantial Attention at
the Outset

• Expression System
• Ampicillin Selection Pressure
• Lab-scale Affinity Purification
• Protein Solubility Problems
• Low Yield
• Errors in Genetic Sequence
• Extraneous Genetic Material
• Poorly Defined Production System
• Inadequate Purification Schemes
• Analytical Approaches
• Unvalidated or Non-Existent In Vitro Potency
  Assay
• Lack of Key Reagents (e.g., Antibodies to Desired
  Product)
• Poor Biochemical Characterization
• .

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Many Projects Require Substantial Attention at
the Outset (Continued)

• Regulatory and Safety
• Raw Material Qualification
• Inappropriate Cell Banks
• Difficult or Unidentified Toxicology Systems
• Failed Vendor Qualification
• Other
• Intellectual Property Concerns
• Delays in Material Transfer Agreements
• Contracting Delays

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Typical Results of One Review Cycle of Project
Candidates

• 20 Projects Submitted for Review
• 6 Selected
• 2 Clinical Development for Phase I Trials
• 2 Further Preclinical Development. May be
  re-reviewed for clinical production.
• 2 Production to Support Preclinical Development
  Only

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Examples of BDP Projects in Various Stages During
12-Month Interval

• Monoclonal Antibodies (19)
• Other Mammalian Cell Products (3)
• Recombinant Proteins (14)
• Natural Products (1)
• DNA Vaccines (3)
• Genetically-modified Organisms for Vaccines (4)
  or Gene Therapy (2)
• Oligonucleotides (3)
• Synthetic Peptides (Many)
• Other (1)

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Summary of Major cGMP Project Milestones During
Past 12 Months

• Ch-EB6 MoAb (Affinity Purification Reagent)
  6 gms
• Ch14.18 (Anti-GD2 MoAb for Neuroblastoma
  Phase III Multi-Center Trial) (2 Lots)
  1,473 Vials
• PCLLUS 3-18MN Peptide Vaccine (HIV) 145
  Vials
• PCLUS 6.1-18MN Peptide Vaccine (HIV)
  145 Vials
• LMB-2 (Anti-TAC PE38) Immunotoxin (2 Lots)
  3,155 Vials
• 1D12 MoAb (Affinity Purification Reagent)
  15 gms
• He-Fi 1 MoAb (Clinical) (2 Lots) 1,070
  Vials
• Geldanamycin (Antitumor Antibiotic) (4 Lots)
  700 gms

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Summary of Major cGMP Project Milestones During
Past 12 Months (Continued)

• HPV-16 E7 (12-20) Peptide Vaccine (HPV) 711
  Vials
• HPV-16 E7 (86-93) Peptide Vaccine (HPV) 740
  Vials
• HPV-16 E6 Peptide Vaccine (HPV) 180 Vials
• HPV-18 E6 Peptide Vaccine (HPV) 954 Vials
• MuB3 MoAb (Clinical) 49 gms
• HSV-863 MoAb (Clinical) 32 gms
• Patient-Specific Id Vaccines (Lymphoma) 18
  Vaccines
• Patient-Specific Peptide Vaccines 6
  Vaccines

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Summary of Major cGMP Project Milestones During
Past 12 Months (Continued)

• Allogeneic Pancreatic Cell Vaccine 11
  Patients
• c-myb Antisense Oligodeoxynucleotide 6,000 Vials
• Bradykinin Antagonist (Preclinical Studies)
  29 Grams
• EGFR VIII Peptide 500 Vials
• Ch 11-1F4 (Anti-Amyloidosis Antibody)
  GMP Chimeric Clone
• Anti-her2/ScFv (Preclinical) 500
  mg
• rPA (Anthrax Vaccine for Clinical Phase I Trials
  400 mg
• SEB (Staph Enterotoxin B Vaccine 2 Lots)
  1,647 Vials
• 7G7 (B6 Anti-IL-2R MoAb Clinical Bulk)
  7 gms

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Selected Examples of Projects Leading to
Commercial Development

• IL-2 DPT (DABL-IL2) RD supported through
  National Cooperative Drug Discovery Group
  mechanism. Licensed for cutaneous T-cell
  lymphoma.
• Anti-EGFR Antibody Manufacture of preclinical
  material and chimerization of antibody.
  Currently in licensing trials in head and neck
  cancer, other malignancies.
• Anti-GD2-IL2 Fusion Protein (Melanoma) RD
  supported under National Cooperative Drug
  Discovery Group Mechanism. Manufacture of first
  clinical lot. Further development underway by
  company.

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Selected Examples of Projects Leading to
Commercial Development (Continued)

• Patient-Specific Id Vaccines for Myeloma
  Lymphoma Manufacture of 30 vaccines/year.
  Entering controlled trials in lymphoma. CRADAs
  signed for development for lymphoma and myeloma
  indications.
• Anti-CD22/PE38 Immunotoxin for Lymphoma
  Manufacture of clinical material for initial
  trials. Being developed by company.
• Anti-CD25/PE38 Immunotoxin for Lymphoma
  Manufacture of clinical material for initial
  trials. Licensed by company.
• IL7 Cytokine Manufacture of preclinical and
  clinical material for initial clinical studies.
  CRADA signed with company.

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Selected Examples of Projects Leading to
Commercial Development (Continued)

• Anti-Amyloid Antibody for Amyloidosis.
  Chimerization of Murine Antibody. Manufacture of
  preclinical material for evaluation. Clinical
  production and Cooperative Group Trials to be
  reviewed by DDG. Project recently licensed by
  outside Pharmaceutical Company.
• Anti-her2 Single Chain Antibody Targeted
  Liposomes Delivering Chemotherapeutic Agents.
  Process development and manufacture of initial
  clinical material underway. Project recently
  licensed and further development in collaboration
  with outside Pharmaceutical Company.
• Pancreatic Cancer Cellular Vaccines. Manufacture
  of material for Phase I clinical Trial. Recently
  licensed by outside Pharmaceutical Company that
  will help defer costs of material for follow-on
  Phase II clinical trial.

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The Idea is Not Enough Characteristics of
Projects With Eventual Commercial
Development(With Some Exceptions)

• What The Investigator Has Already Done
• Defined Candidate Molecule
• Comparisons With Similar Products
• Characteristics of Molecule Consistent With
  Pharmaceutical Requirements
• Production Adequate
• Product Characterization Adequate
• Laboratory Standard
• In vitro Potency Assay
• Stability Studies
• Reproducible Model Systems
• Early Animal Work Includes Some Toxicology
• Scale-up Requirements Practical for Initial
  Clinical Trials
• General Previous Experience of Investigator

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Summary

• A flexible and adaptive approach to
  facilitation of clinical proof-of-concept
  evaluation of promising new biopharmaceutical
  concepts appears to be a cost-effective approach
  to increasing the number of innovative clinical
  development candidates.

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ACKNOWLEDGEMENTS

• BIOPHARMACEUTICAL DEVELOPMENT PROGRAM
• Dr. Gautam Mitra, Director
• Development Laboratory
• Jianwei Zhu, Head
• Bob Testerman
• Andy Burnette
• Juliet Luo
• Vinay Vyas
• Yueqing Xie
• Joan Tucker
• Loren Ward
• Nacole Lee
• Xiaojin Wu

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ACKNOWLEDGEMENTS

• Purification Laboratory
• Steven Giardina, Head
• Aparna Kolhekar
• Mary Koleck
• Earl Nelson
• Scott Jendrek
• Tim Ouellette
• David Nellis
• Fermentation
• Jianwei Zhu, Supervisor
• Phil Rothchild, Supervisor
• Denise Ekstrom
• Gary Spencer
• John Roach
• Ray Rose

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ACKNOWLEDGEMENTS

• Cell Culture
• Beverly Keseling, Head
• Clinical Manufacturing
• Ed Wang, Head
• Ken Huyser
• Samir Shaban
• BL-3/GMP Unit
• Jinhua Lu
• Molecular Biology Laboratory
• Barry Kobrin, Head
• Moria Artlip

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ACKNOWLEDGEMENTS

• Quality Assurance
• Doug Gaum, Head
• Don Duvall
• Ken Sechler
• Sheryl Ruppel
• Lori Lawson
• Sandy Gibson
• Quality Control
• Dennis Michiel, Head
• Bill Utermahlen
• Cheryl Mowen
• Terry Sumpter
• Linda Damuth
• Trevor Broadt

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ACKNOWLEDGEMENTS

• Bioanalytical Development Laboratory
• Gopalan Soman, Head
• Abraham Kallarakal
• Wanda Hartmann
• Xiaoyi Yang
• Eying Chen
• Hengguang Jiang
• Nirmala Saptharishi

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ACKNOWLEDGEMENTS

• BIOLOGICAL RESOURCES BRANCH
• Dr. Karen Muszynski
• Dr. Morris Kelsey
• Dr. Toby Hecht
• Dr. Craig Reynolds
• Dr. Rosemarie Aurigemma
• Dr. Jason Yovandich

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Our next speaker is Dr. Shanker
Gupta Pharmaceutical Resources Branch Developmenta
l Therapeutics Program