MOVING NOVEL CONCEPTS FROM RESEARCH LABORATORY TO

CLINICAL PROOF-OF-PRINCIPLE

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

MissionMission

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.

Key AssumptionsKey Assumptions

1. Concepts are selected for novelty and innovation over derivatives of existing approaches.

2. Many projects have been previously considered by Pharma and declined due to uncertain technology, regulatory hurdles, or small markets.

3. Clinical production is focused on meeting requirements for initial proof-of-concept trials, NOT final product requirements for commercial development.

4. Approximately 1/10 to 1/20 clinical projects may eventually be licensed.

5. Desired size of program is based on assumptions #1-4 (i.e., 10 to 20+ projects/year to clinic).

6. Intellectual Property to be retained by Project Originator(s).

Where Does the Program Get Its Projects

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

Capabilities and ResourcesCapabilities 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

Major Milestones in a Typical Clinical-Grade Production Project

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

Major Milestones (Continued)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

Major Milestones (Continued)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

Many Projects Require Substantial Attention at the Outset

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

.

Many Projects Require Substantial Attention at the Outset (Continued)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

Typical Results of One Review Cycle of Project Candidates

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

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

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)

Summary of Major cGMP Project Milestones During Past 12 MonthsSummary 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

Summary of Major cGMP Project Milestones During Past 12 Months

(Continued)

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

Summary of Major cGMP Project Milestones During Past 12 Months

(Continued)

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

Selected Examples of Projects Leading to Commercial Development

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.

Selected Examples of Projects Leading to Commercial Development (Continued)

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.

Selected Examples of Projects Leading to Commercial Development (Continued)

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.

The Idea is Not Enough: Characteristics of Projects With Eventual Commercial Development

(With Some Exceptions)

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

SummarySummary

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.

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

BIOPHARMACEUTICAL DEVELOPMENT PROGRAMDr. Gautam Mitra, Director

Development LaboratoryJianwei Zhu, HeadBob TestermanAndy BurnetteJuliet LuoVinay VyasYueqing XieJoan TuckerLoren WardNacole LeeXiaojin Wu

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Purification LaboratorySteven Giardina, HeadAparna KolhekarMary KoleckEarl NelsonScott JendrekTim OuelletteDavid Nellis

Fermentation Jianwei Zhu, SupervisorPhil Rothchild, SupervisorDenise EkstromGary SpencerJohn RoachRay Rose

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Cell CultureBeverly Keseling, Head

Clinical ManufacturingEd Wang, HeadKen HuyserSamir Shaban

BL-3/GMP UnitJinhua Lu

Molecular Biology LaboratoryBarry Kobrin, HeadMoria Artlip

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Quality AssuranceDoug Gaum, HeadDon DuvallKen SechlerSheryl RuppelLori LawsonSandy Gibson

Quality ControlDennis Michiel, HeadBill UtermahlenCheryl MowenTerry SumpterLinda DamuthTrevor Broadt

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Bioanalytical Development LaboratoryGopalan Soman, HeadAbraham KallarakalWanda HartmannXiaoyi YangEying ChenHengguang JiangNirmala Saptharishi

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

BIOLOGICAL RESOURCES BRANCHDr. Karen MuszynskiDr. Morris KelseyDr. Toby HechtDr. Craig ReynoldsDr. Rosemarie AurigemmaDr. Jason Yovandich

Our next speaker is:

Dr. Shanker GuptaPharmaceutical Resources BranchDevelopmental Therapeutics Program