New Cells for New Vaccines III September 29, 2007

Transcription

1 Vaccine Development in Novel Substrates: Implications for Biodefense & Pandemic Preparedness New Cells for New Vaccines III September 29, 2007 Michael Callahan M.D., DTM&H, MSPH Program Manager Defense Sciences Office

2 Threat 1 A 2006 Biodefense Risk Assessment listed 28 biological threat agents however: a unlimited number of GE threat agents exist; 3 of the 9 recent highly-virulent HDP are novel and impossible to predict (Nipah; SARS-CoV; AI) HSPD-18 published in Jan 2007 states it is impossible to maintain a 1 bug 1 drug approach to MCM development. Economic: new drug R&D costs $880M to 1.2B and takes ~ years.

3 Threat 2: Outbreak Timeline

4 Threat 2: Outbreak Timeline Nov-Jan Feb-April 15 April 16- June 16 June 17-July Predromal Escalation (R<.22) MCI operations Recovery R =0.1 to 2.8 (rare) Agent ID: April 8 Infected: fatal= 8096/774 No of labs: 19; 63 CFR= % Drug or vaccine= N/A = Agent identified

5 Market 1: Current Vaccine Timelines June-Dec Jan-May June - July Aug-Sept Oct Nov-Dec Virus Selection Production Begins FDA Tests to Confirm Production Yield determined Testing Blending Filling/ Packaging Product Release Shipping of influenza vaccine begins Vaccination Begins Immunity Develops approximately 2 weeks after vaccination Threat characterized, sequenced and CIP assessed Start search for next virus strain Approved for Public Release, Distribution

6 Market 2: Global Contract Manufacturing M-Ferm 1 Egg 1 B-Ferm 1 B-Ferm CanAm EU Asia % U.S-based Vaccine Production of Total ( 4 GMP providers) % Increase contract protein MCM manufacture by region (10 3 liters/mo) Limitation: Data represents percent of total vaccine by year. Total manufacturing capacity not presented Includes vaccine or monoclonal AB contract manufacture >100 liters Courtesy: G.E (Europe). Sinetra, Rescue Medicine International, Serum Institute India, Think Tank Beijing

7 Market 3: Export of U.S. Vaccine & mab Manufacturing ( ) Exclusion: : egg-production; some not FDA-approved EU (non GR).8 6 bac cell GR.5 6 bac cell ASIA bac cell INDIA.8 6 bac cell

8 Market 4: Manufacturer Survey Aug-Dec 2005 Interviews: 16 Executives from vaccine & mab manufacturers, 2 CMOs, the FDA and 2 VCs Challenge Question: What would prompt new R&D for rapid, resilient vaccine or mab manufacturing Key Results: 1. COGS bias, regulatory successes, profit perpetuate risk aversion 2. Investor remiss: Offshore CMOs (Marlburg Consortium) 3. Executive Direction: maintain narrow product line & committed infrastructure 4. Distrust of U.S. Government customer and FDA

9 Market 5: Performers R&D: market driven Big Pharma Licensure & Acquisition Risk Tolerance: Low IND: End-to-End Small Biotech R&D: discovery > market Collaborator & Equity (VC) Risk tolerance: Med-High IND: Early-Mid (E-2-E rare) Nature Reviews Drug Discovery (May 2004)

10 New Cells: Platform Attributes Search for innovation which builds profitability through resiliency Replace large, static, costly, single-agent trains with fast, low-cost, massively-scaleable manufacturing systems. Transition of biological threat intelligence into an effective drug (years weeks) Improve production start-up, TPP implementation, speed & simplicity. Restore each nation s health security by reducing reliance on foreign assets & strain exchange

11 MCM Innovation Targets Slow SPEED Fast transgenic plant mammalian cells COST baculovirus yeast E. coli $$$$ $ transgenic mammalian cells plant Unlikely baculovirus FDA Approval yeast E. coli Likely transgenic plant baculovirus yeast E. coli mammalian cells Platform Processing Agile Technologies Cost-effective; pink Flexible, Fast-launch Minimal Optimization Approvable Reliable Scale-up Kinetics Ease of DECON Purity & stability Structure Degradation Aggregation Glycosylation cgmp compliant Replicable; Responsive Cost effective Ease of DECON

12 Accelerated Manufacture of Pharmaceuticals Program Goals: From final product (vaccine, antibody, immune enhancer) to 3 million doses in 12 weeks or less (>10x improvement) at pennies per dose (versus $ s 100 s /dose) Distribution Statement A ()

13 Novel Cells: Large Scale (Case: DARPA s AMP Program) DARPA-Hard Challenge: From final product (vaccine, antibody, immune enhancer) to millions of doses in 12 weeks or less (>10x improvement) at pennies per gram (versus $100 s / gram) Current Research Adaptation of industrial enzyme manufacturing in fungal systems Bacterial fermentation for production of high affinity antibody fragments Plant and mushroom based platforms Antibody Marine platforms coelenterate-mollusk Recombinant, Engineered Proteins Commodity Based Material $ $0.005/gm Consumer Products $ $1/gm Personal Care Products $ $10/gm Pharmaceutical Products $ $10,000.00/gm Focus: Redirect Explosive Biological Production Processes Distribution Statement A ()

14 Novel Cells: Redirected Industrial Enzyme Systems Aspergillus Fungal Fermenter Train Engineered Aspergillus a fast growing fungus with flexible gene cassettes Extensive, well-characterized genetic toolbox Achieves high protein concentrations in 3-4 days Proteins produced with minimal fragments Recombinant, Engineered Proteins Commodity Based Material $ $0.005/gm Consumer Products $ $1/gm Personal Care Products $ $10/gm Pharmaceutical Products $ $10,000.00/gm Small proteins expressed at > 30 g/l Amylase, an industrial detergent (50 60 kd) Large Proteins >100 kd produced at 6 g/l ß-Galactosidase, for cellulose degradation (116 kd; correctly folded; intact N- & C- terminals) One company produced a single chain human-like mab within 72 hrs of gene insertion

15 Novel Cells: Key Challenges Post-translational events: Glycosylation Folding Amidation Sequence integration & clone selection Difficulties with scale-up from pilot to large scale

16 Novel Cells: Product Design Attributes and Goals of product must be defined in advance of any investment. These requirements include master cell line Commonly overlooked Pre-Pre IND considerations: 1. All Routine Master File requirements 2. History of handling since characterization (mosaic risk) 3. Quality & purity of protein; presence of residual material: nucleic acid, membrane, protein fragments 4. Presence of platform-specific contaminants: odd amino-acids, folding aberrancies (efficacious but different) 5. Characteristics which will impact DSP, formulation, F&F, storage, reconstitution Approved for Public Release

17 National Security Vaccines Access to proprietary, foreign or HDP not required * Platform: Flexible, Portable, Minimum Infrastructure Pre-existing infrastructure and footprints Massive manufacturing capability Meets any dose requirement ( µg/dose) Minimal fragmentation, contamination; high solubility U.S. controlled (for U.S. Government Agencies) No dependence on foreign companies * AMP systems using subunit vaccines require only cdna

18 Modern Vaccine R&D Pre-development Phase: Prior to beginning development, end goals of vaccine must be defined, which will determine full development program. Key Development issues for Target Product Profile (TPP) are: 1. Clinical indication (with risk/benefit profile) 2. Market and market size 3. Estimated dosage, therapeutic duration and shelf life stability* 4. Delivery system/formulation (e.g., IV, SQ, oral, inhaled) and staffing equipment needs* 5. End user setting (e.g., hospital, clinic, pharmacy, medical monitoring) * Factors impacting manufacturing strategy Compiled from Audit of 3 large scale Vaccine MNC and interviews with FDA

19 Future Vaccines Formulations Temperature stable: thermo & cryo-stable Purity: formulation devoid of cryptic protease or contaminants Dose-sparing: key epitope(s), adjuvants reduce total protein requirement Route: Mass-administration using aerosol, mucosal and I.D. routes Efficacy: validation using human immune proxies and predictive biomarkers Easy to manufacture: use of fast, flexible, replicatable platforms Summary: manufacturers or emergency-use vaccines are expanding TPPs considerations to include the administration environment

20 Future Vaccines Delivery Systems Easy Delivery: simple, safe Pre-filled: required for mass-scale vaccination; reduce dilution errors and contamination. Needle-free delivery: reduce needlesticks; decrease pain Single dose/disposable: reduce contamination Self-contained/ tamper-proof: sterile non-reuseable Compatibility: delivery system should not require reformulation Safe for all cohorts: Children, adults and seniors Summary: emergency vaccines require safe, stable, potent, prefilled, single-dose, delivery that is easy, fast, efficient and safe which can be given by skilled care givers, without risk of contamination.

21 Summary Demand for new vaccines outstrips current capability; a wide array of novel expression systems are under development Market forces & commercial attributes of protein expression influence receptiveness to novel systems New cells provide both solutions & new problems for long-term safety & efficacy, storage & administration Enabling systems will improve acceptance of novel cell technologies within the next 3-5 years