Moving Novel Concepts From Research Laboratory To Clinical Proof-of-Principle

1. 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

2. 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.

3. 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 1/10-1/20 clinical projects may eventually be licensed. • Desired size of program is based on assumptions #1-4, i.e., 10-20+ projects/year to clinic. • Intellectual Property to be retained by Project Originator(s).

4. 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

5. 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

6. 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

7. 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

8. 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

9. Many Projects Require SubstantialAttention 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 Analytical Approaches Unvalidated or Non-Existent In Vitro Potency Assay Lack of Key Reagents, e.g., Antibodies to Desired Product Poor Biochemical Characterization

10. Many Projects Require Substantial Attention At The Outset (Continued) Regulatory and Safety Inappropriate Cell Banks Difficult or Unidentified Toxicology Systems Failed Vendor Qualification Other Intellectual Property Concerns Delays in Material Transfer Agreements Contracting Delays

11. 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

12. 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)

13. Summary Of Major cGMP Project Milestones During Past 12 Months Ch-EB6 MoAb (Affinity Purification Reagent) 6 gms Ch14.18 MoAb (Clinical) 1,473 Vials PCLUS 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

14. 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

15. Selected Examples Of Projects Leading To Commercial Development IL-2 DPT (DABL-IL2) R&D 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) R&D supported under National Cooperative Drug Discovery Group Mechanism. Manufacture of first clinical lot. Further development underway by company.

16. 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 LymphomaManufacture 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.

17. 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

18. 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.

19. Our next speaker is: Dr. Rao Vishnuvajjala Pharmaceutical Resources Branch Developmental Therapeutics Program