Targeted Human Immunoglobulin to WHO Priority Pathogens Using Transchromosomic (Tc) Bovine

Transcription

1 Targeted Human Immunoglobulin to WHO Priority Pathogens Using Transchromosomic (Tc) Bovine Lead Institution: SAB Biotherapeutics, Inc. (USA) Participating Institutions: LFB (France), Novavax, Inc. (USA), United States Naval Medical Research Center, CSIRO Health and Biosecurity Australian Animal Health Laboratory 22 July

2 Targeted Human Immunoglobulin Proposal SAB Biotherapeutics (SAB) has successfully developed a unique transchromosomic (Tc) bovine platform that can rapidly produce potent, fully human, immunoglobulins against a variety of disease targets, including viruses, bacteria, and toxins, in significant quantities (up to 600g/month/animal of highly purified immunoglobulin). Utilizing the Tc bovine platform, we propose to expand our preparedness capability and rapidly develop target specific human polyclonal antibodies. We would manufacture, test, and release product and conduct preclinical studies, file a U.S. Investigational New Drug (IND) Application, and conduct a Phase I clinical trial. 2

3 Targeted Human Immunoglobulin Proposal We would also manufacture approximately 10,000 doses that would be available for a Phase II clinical trial or for an Emergency Use Authorization. There would be hyperimmunized plasma remaining to produce another 50,000 doses. The project could be scaled up as necessary. Although the cost may vary greatly depending on the target, the estimated cost of the project is $39,540,000 USD for the first targeted product, which includes development of dedicated manufacturing facilities that could be utilized in subsequent target products without cost duplication. 3

4 Overview of Tc Bovine Immunoglobulin Production Process * Antibody Reagent Targeted antibodies ready for use either purified or spiked in human plasma *Matsushita H, Sano A, Wu H, Wang Z, Jiao J-a, Kasinathan P, et al. (2015) Species-Specific Chromosome Engineering Greatly Improves Fully Human Polyclonal Antibody Production Profile in Cattle. PLoS ONE 10(6): e doi: /journal.pone

5 LFB Company Profile LFB is a biopharmaceutical group that develops, manufactures and markets medicinal products for the treatment of serious and often rare diseases namely Immunology, Intensive Care and Hemostasis. LFB is a majority state-owned public limited company, vested by French law with a public health mission. Number one in France and 6 th in the world for plasma-derived medicinal products, the LFB group is also one of the leading European companies for the development and production of proteins and innovative treatments derived from biotechnologies. LFB is a global company with distribution and research/production collaborations in over 40 countries including; Brazil, Saudi Arabia, and other countries in the hot zone for emergent epidemics 5

6 Fully Human Polyclonal Antibody Product Timeline This is a usual product timeline. This rapid timeline allows SAB to respond quickly to new and emerging diseases. Within 14 weeks (3.5 months) after the first vaccination (V1), the first batch of product will be released. Tc Bovine vaccination Tc Bovine Plasma Collection Manufacture 2 wks QC Testing 3 wks QA Review 2-3 wks

7 Antibody Production Facilities Tc Bovines produce targeted human antibody Plasma donors: typical collection Pilot manufacturing facilities Benefits of the Tc Bovine Platform Fully human antibody Targets many diseases Large quantities Rapid Development cgmp Compliance Patent protection

8 Large Scale Purification Purification will be carried out in modular cleanroom pods, which can be rapidly assembled and validated. 8

9 Current Projects SAB is currently working on a number of infectious disease targets: WHO Priority Pathogens MERS CoV (SAB-301) Phase 1 Clinical Trial Ongoing Ebola (SAB-139) WHO Serious Pathogens requiring attention Zika (SAB-155 NEW) Other Diseases with epidemic potential Dengue (SAB-123) Influenza (SAB-100) Other Disease Candidates with Relevant Data VEE (SAB-131) Hanta (SAB-126) Mycoplasma (SAB-136) Phase 1 Clinical Trial Ongoing 9

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11 Middle East Respiratory Coronavirus (MERS-CoV) 11

12 MERS-CoV Using the Tc bovine platform, SAB and the collaboration developed SAB-301, an anti-middle East respiratory syndrome coronavirus (MERS) antibody product. Two experimental vaccines were evaluated as potential antigens. SAB-300 was produced using a clade A gamma-irradiated whole killed virion vaccine (Jordan strain) SAB-301 was produced using a clade B spike protein nanoparticle vaccine (Al Hasa strain) It was determined that SAB-301 was a better candidate due to the ease, cost, safety, and production capability of spike protein versus whole killed virus (for example, biosafety level-3 laboratory and manufacturing facilities). SAB-301 is currently being evaluated for safety and pharmacokinetics in a Phase I clinical trial conducted at the United States National Institutes of Health (NIH). 12

13 MERS-CoV In Vivo Mouse Viral Clearance Study The efficacy of SAB-301 (prophylaxis and treatment) was examined in transduced adenovirus (Ad5-hDPP4) BALB/c mice which were infected with EMC/2012 strain of MERS-CoV. Prophylaxis (A) Mice were treated by intraperitoneal (IP) injection with a single 100 or 500μg ( 5 or 25 mg/kg) dose of control higg or SAB-301. Twelve hours later, mice were infected intranasally with MERS-CoV (1x10 5 pfu). No additional antibody injections were given over the 5-day course of the infection. Virus titers in the lungs were measured at 1, 3 and 5 days post infection. 13

14 MERS-CoV In Vivo Mouse Viral Clearance Study Cont d Treatment (B) Mice were infected intranasally with MERS-CoV (1x10 5 pfu). Either 24 or 48 hours post inoculation, mice were treated with 500µg of SAB-301. Virus titers in the lungs were measured 5 days after infection. SAB-301 was able to rapidly reduce MERS-CoV lung titers in Ad5-hDPP4- transduced mice with a single prophylactic or therapeutic injection. 14

15 MERS-CoV SAB-301 has also been evaluated by a tissue cross reactivity study and rabbit toxicology studies. The tissue cross reactivity study showed that SAB-301 does not have any non-specific binding to rabbit or human tissues. For the rabbit toxicology studies, rabbits receiving the highest dose possible based on volume limitations (370 mg/kg) of SAB-301 showed no significant clinical or pathological adverse effects. Three previous cgmp lots of purified, potent, fully human immunoglobulins against MERS-CoV (SAB-301) have been produced and were used in pre-clinical studies, viral and TSE clearance validation studies, and the Phase I human clinical trial. Funding for manufacture of further material for use in a Phase II human clinical trial is currently being provided by the Biomedical Advanced Research and Development Authority (BARDA, a US federal agency). 15

16 Ebola (EBOV) 16

17 Ebola The Tc Bovine system was used to rapidly produce an anti-ebov higg, which was then evaluated in a mouse challenge model using mouse adapted Ebola virus (maebov). The vaccine used for Tc bovine vaccination consisted of recombinant glycoprotein (GP) developed by Novavax from the 2014 Makona EBOV strain. Hyperimmunization resulted in Tc bovine sera with high titers of human IgG against EBOV GP, as illustrated by virus neutralization assays, surface plasmon resonance (SPR), and GP specific ELISA. One day after lethal challenge of BALB/c mice with a maebov, 100mg/kg of purified anti-ebov IgG (SAB-139) was administered via the intraperitoneal route and produced 90% protection. 17

18 NHP Challenge Study using SAB-139 (V6-V8) Antibody treatments at 150 mg/kg for first three treatments, 125 mg/kg for fourth treatment Group 1 (n=2): Irrelevant Control antibody: Day +1, +4, +7, + 10 Group 2 (n=6): SAB-139 (V6-V8) - early intervention: Day +1, +4, +7, + 10 Group 3 (n=6): SAB-139 (V6-V8) - late intervention: Day +3, +6, +9, + 12 Challenge dose is 1,000 pfu EBOV Makona strain Post-challenge (day): Negative Ab control and SAB 139 anti-ebola Ab (early intervention) Blood draw Antibody treatment SAB 139 anti-ebola Ab (late intervention) All animals were observed daily for clinical disease Blood draw for qpcr, blood chemistry, and CBC analysis By NIH/NIAID

19 % S u r v iv a l NHP Challenge Study 2 Survival N H P S u r v iv a l Irre le v a n t A b C o n tro l E a rly In te rv e n tio n L a te In te rv e n tio n D a y s P o s t-c h a lle n g e SAB-139 (V6-V8) provided 100% protections in NHPs against EBOV in both early and late interventions

20 Vision The Tc Bovine system has been proven to produce high neutralizing polyclonal antibodies using any number of target antigens. Our vision would be to maintain a herd of Tc Bovine specifically for emerging infectious diseases. When needed, we could rapidly develop and produce target specific human polyclonal antibodies. 20

21 Deliverables, Costs, and Timelines The proposal consists of tasks divided into two main categories: Emergency Response Readiness Emergency Response Readiness would include annual costs associated with the preparedness required to quickly respond to emerging infectious diseases, as well as a one-time cost of a dedicated purification facility. Development, Manufacturing, and Testing Consists of antigen discovery and production, immunizing Tc Bovine against the target antigen, collecting plasma, cgmp manufacturing, and testing. 21

22 Deliverables, Costs, and Timelines Emergency Response Readiness One aspect of Emergency Response Readiness would be to maintain a herd of Tc Bovine that would be available for emerging infectious diseases. Tc Bovine used as production animals must be over six months of age prior to vaccination. Due to the age required prior to vaccination, and the gestation time prior to birth, there is long lead time before Tc bovine are available for use. By maintaining a readily available herd, this lead time is eliminated. Emergency Response Readiness would also include pathogen surveillance, identification, and acquisition, in order to rapidly respond and produce antigen. The annual costs for herd maintenance and pathogen surveillance/acquisition would be approximately $2,300,000. A purification suite and equipment dedicated to emerging infectious diseases would be assembled and validated. This purification suite would be readily available to rapidly produce products for priority pathogens. The one-time cost would be approximately $15,000,000. The annual lease for the facility housing the purification suite would be approximately $525,

23 Deliverables, Costs, and Timelines Development, Manufacturing, and Testing The first steps in Development, Manufacturing, and Testing include antigen discovery and production, immunizing Tc Bovine against the target antigen, and collecting initial plasma. Immunizations and plasma collection would continue in order to have frozen hyperimmunized plasma available for production. This proposal is estimated using 10 Tc Bovine, however, this can be scaled up as necessary depending on scope/scale of the infectious disease outbreak. Antigen discovery and production would cost approximately $1,500,000. Immunizations and plasma collections would cost approximately $800,000 for a 22 month period. An initial lot would be manufactured (designated Preclinical Lot ) that would be used for preclinical/ind enabling studies. This includes in vitro ($40,000) and in vivo ($500,000) studies, tissue cross-reactivity studies ($200,000), and toxicology studies ($500,000). The Preclinical lot would cost approximately $2,000,000. During the IND enabling studies, an initial clinical lot will be produced at a cost of $2,500,000. This includes manufacturing, testing, and QA release. This initial clinical lot would be intended for use in a Phase I clinical study. 23

24 Deliverables, Costs, and Timelines Development, Manufacturing, and Testing An IND would be filed in the United States to allow export and collaboration to conduct a Phase I clinical trial either in the U.S. or abroad, including LMICs. The costs associated with the IND preparation and filling would be approximately $350,000. Although the cost of the Phase I clinical trial could vary greatly depending on where it is conducted, the approximate cost would be $4,000,000. An additional lot (after initial scale up) would be manufactured to be used in either a Phase II study, or to be available for use pending an Emergency Use Authorization or approval based on animal rule from the U.S. FDA. The additional lot at scale would cost approximately $8,000,

25 Deliverables, Costs, and Timelines Deliverables 1. A dedicated large scale facility, equipment, and a dedicated Tc bovine herd ready to respond to emerging infectious diseases. 2. An initial lot for use in preclinical/ind enabling studies 3. An initial clinical lot for use in a Phase I Clinical Trial 4. A filed U.S. Investigational New Drug Application 5. A completed Phase I Clinical Trial 6. A clinical lot available for either a Phase II study, or to be available for use pending an Emergency Use Authorization from the U.S. FDA. 7. An additional liters of hyperimmunized plasma available for manufacturing. 25

26 Deliverables, Costs, and Timelines Cost Year 1 Year 2 Total Emergency Response Readiness One-Time Cost $15,000, $15,000,000 Annual Cost $2,825,000 $2,825,000 $5,650,000 Development, Manufacturing, and Testing Per Target Cost $6,890,000 $12,000,000 $18,890,000 Total Cost $24,715,000 $14,825,000 $39,540,000 26

27 Month Task Cost Pathogen Surveillance, Identification, and Acquisition $500,000/year 2 Herd Cost $1,300,000/year 3 Herd Maintenance $500,000/year 4 Dedicated Purification Suite $10,000,000 5 Purification Suite Validation and Overhead $5,000,000 6 Dedicated Facility Lease $525,000/year Month Task Cost Antigen Discovery and Production $1,000,000 2 Immunizations V1-V22 $300,000 3 Plasma Collection $500,000 4 Preclinical Lot Manufacturing $1,500,000 5 In Vitro Testing $40,000 6 In Vivo Animal Studies $500,000 7 Initial Clinical Lot Manufacturing, Testing, and $2,000,000 Release 9 Tissue Cross-Reactivity Study $200, Toxicology Study Data $500, Toxicology Study Final Report N/A 12 IND Filling $350, Phase I Clinical Trial $4,000, Emergency Response Readiness Timeline with Cost Development, Manufacturing, and Testing Timeline with Cost Additional Large Scale Manufacturing, Testing, and Release $8,000,000 27

28 Collaborations Michael Kurilla Peter Jahrling Lisa Hensley Gene Olinger Reed Johnson John Beigel David Spiro Erik Stemmy Matthew Frieman Christopher Coleman Thomas Luke Kanakatte Raviprakash Gabriel DeFang Jay Hooper Connie Schmaljohn Callie Bounds John Dye Greg Glenn Gale Smith Larry Ellingsworth Sven Andreasson Lou Fries Jin-an Jiao Jerry Pommer Hua Wu Jake Miles Becky Jones Elizabeth Noonan Stanley Pearlman Jincun Zhao Rudragoda Channappanavar

29 CSIRO Australian Animal Health Laboratory John Lowenthal Total BSL3 space: 2900 m 2 / 30,00 sq ft Animal rooms 1000 m 2 Total BSL4 space: 550 m 2 / 6,000 sq ft Animal rooms 150 m 2 Infectious Diseases Research 45 staff Diagnostic Response Program 80 staff Animal staff / Vets 25 staff Core expertise: development and testing of therapeutics and vaccines correlates of immunity virology, pathogenesis, diagnostics Ferret model for Ebola replicates human disease a new model for Ebola to assess efficacy of therapeutics and vaccines less reliance on NHPs & facilitates regulatory approval MERS-CoV alpacas as a surrogate for camels pigs as a model for human disease assess efficacy of therapeutics and vaccines accelerate FDA approval

30 Contact Information Eddie J. Sullivan, Ph.D. Tel: +1 (605) Sami Chtourou, Ph.D. Tel: / James F. Cummings, M.D. JCummings@novavax.com, Tel: +1 (240) Maya Williams, Ph.D. Maya.williams1.mil@mail.mil, Tel: +1 (301) Dr. John Lowenthal john.lowenthal@csiro.au, Tel:

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