Optimizing the Use of Anthrax Vaccine Workshop on the Biology of Anthrax, Cardiff, Wales 12 March, 2014 Thomas Waytes, MD, PhD V.P. Medical Affairs

2 Q: How can a legacy vaccine be adapted to meet the evolving requirements for modern bioterror defense? Optimizing the Use of Anthrax Vaccine

Anthrax Vaccine for Pre-Exposure Use  Primes the immune system to provide protection against subsequent exposure to B. anthracis spores  Reserved for individuals at increased risk of exposure  Key desired vaccine attributes: –Provide high levels of protective antibody –Protection against all strains of B. anthracis –Convenient dosing schedule –Long-term protection following immunization –Low degree of reactogenicity –Widely available 3 Anthrax Vaccines

Anthrax Vaccine for Post-Exposure Use*  To protect unvaccinated individuals after exposure to aerosolized B. anthracis spores  Used in combination with appropriate antibiotics  Key desired vaccine attributes: –Quickly provide protective levels of antibody –Protection against all strains of B. anthracis –Minimum number of doses required for protection –Acceptable degree of reactogenicity –Long shelf life –Widely available * No anthrax vaccines are currently approved for post- exposure prophylaxis 4 Anthrax Vaccines

BioThrax ® (Anthrax Vaccine Adsorbed)  Initially licensed in the US in 1970 as a six-dose subcutaneous primary schedule (over 18 months) with annual boosters  Currently the only FDA-licensed anthrax vaccine for the active immunization of adults to prevent anthrax infection  Manufactured from sterile culture filtrate, made from a non-virulent strain of Bacillus anthracis  Primary component is protective antigen (PA), with aluminum hydroxide used as an adjuvant  More than 12 million doses have been administered to over 3 million people  Safety assessed in more than 25 scientific studies  Four year shelf life. BioThrax Vaccine BioThrax™ and any and all Emergent BioSolutions Inc. brand, product, service and feature names, logos and slogans are trademarks or registered trademarks of Emergent BioSolutions Inc. or its subsidiaries in the United States or other countries. All rights Reserved. 5

CDC Anthrax Vaccine Research Program (AVRP) Vaccination Schedule by Group GroupRouteN WeeksMonths TRT-8SCSC259 vvvvvvvv TRT-8IMIM262 vvvvvvvv TRT-7IMIM256 vsvvvvvv TRT-5IMIM258 vsvvsvsv TRT-4IMIM268 vsvvsssv Control IMIM127 ssssssss Control SCSC133 ssssssss NHPIM vvvCh v = BioThrax Vaccine, s = saline, NHP=Non-Human Primate, Ch = aerosolized B. anthracis spore challenge 6 BioThrax CDC AVRP

CDC Anthrax Vaccine Research Program (AVRP) – Early Results  Changing route of administration from subcutaneous (s.c.) to intramuscular (i.m.) resulted in a marked reduction in injection-site reactogenicity  Changing route of administration from s.c. to i.m. did not impact long-term immunogenicity  Eliminating the week-two dose of BioThrax vaccine did not alter the long-term immunogenicity Impact:  In December 2008, FDA approved BioThrax label changes to: –Change the route of administration from s.c. to i.m. –Change the dose schedule from 6-dose primary series to 5- dose primary series, by eliminating the week-two dose Ref: Marano, et al (2008), JAMA, 13: BioThrax CDC AVRP

CDC Anthrax Vaccine Immunogenicity 8 Ref: Wright, et al (2009): Safety and Efficacy of a Reduced Schedule of Anthrax Vaccine. ICAAC. BioThrax CDC AVRP

CDC Anthrax Vaccine Research Program (AVRP) – Final Results  Immune responses following the month-6 dose of the five-dose primary schedule were non-inferior to those following later doses  Immune responses following the month-42 vaccination were higher in the group that previously received only 3 doses of vaccine at 0, 1, and 6 months, than were those in the group that had received vaccine using the 5- or 6-dose schedule Impact:  In May 2012, FDA approved BioThrax label change to: –Change the dose schedule from a 5-dose to a 3-dose i.m. primary series with boosters at 12 & 18 months, then annually  In June 2013, PEI approved Market Authorization for BioThrax with a 3-dose primary series with boosters at 3-year intervals Ref: Wright, et al, (2014) Effect of reduced dose schedules and intramuscular injection of Anthrax Vaccine Adsorbed on immunological response and safety profile: A randomized trial. Vaccine ; 32: BioThrax CDC AVRP

NHP Challenges with Aerosolized B. anthracis Spores (at 30 & 52 Months) Challenge Time (mo) AVA Dilution* Number of Survivors /Total Number of Animals Challenged (%) 30 HuAVA10/10 (100.0%) 30 1:58/8 (100.0%) 30 1:106/9 (66.7%) 30 1:207/8 (87.5%) 52 HuAVA8/10 (80.0%) 52 1:59/9 (100.0%) 52 1:106/10 (60.0%) Control (all groups) Saline or no vaccination 11/45 (24.4%) 10 *All NHP immunized at 0, 1, and 6 months.; HuAVA = full human dose Adapted from: C. Quinn et al, (2012), Clin. and Vaccine Immunol.; 19: BioThrax CDC AVRP

The FDA “Animal Rule” Criteria  There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product  The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well- characterized animal model for predicting the response in humans  The animal study endpoint is clearly related to the desired benefit in humans, which is generally the enhancement of survival or prevention of major morbidity  The kinetics, pharmacodynamics, and other relevant data in animals and humans, allows selection of an effective dose in humans 11 PEP Strategy

Time Point (Days) GMT TNA NF 50 Pre-Exposure (GUP) Studies Choose TNA Titer Associated with High Degree of Protection Confirmation of Clinical Results and Calculation of Predictive Vaccine Efficacy Relationship Between TNA Titer and Protection Clinical Trial Data Relationship Between TNA Titer and Protection PEP Strategy PEP Strategy Strategy to Derive an Immune Correlate of Protection

Immune Correlate of Protection Derived from Pre-exposure (GUP) Models* 13 Purpose: Establish relationship between pre-challenge TNA titer and survival in animals to derive correlate of protection  Dosage: Undiluted to 1:256  Schedule: Days 0 and 28  Anthrax challenge: Day 70 –Simulates timing of human exposure to residual spores after antibiotics –200 LD 50 = 20 million spores in the rabbit; very robust challenge  Immunological endpoint: TNA titers  Sample sizes: –24 rabbits/group (12 controls) –8 monkeys/group (8 controls) Ref: Ionin et al, (2013), Clin. Vaccine Immunol. 20: *PEP studies supported by BARDA contract HHSO C (G.U.P = General Use Prophylaxis) PEP Strategy

Rabbit GUP Model: Stratifies the Immune Response Prior to Challenge 14 Ref: Ionin et al, (2013), Clin. Vaccine Immunol. 20: Anthrax Challenge (200 LD 50 ) PEP Strategy

Pivotal Clinical Study: Immunogenicity Endpoints 15  Design: –200 subjects each to receive BioThrax vaccine by the s.c. route at days 0, 14, and 28 –Repeated measurement of immune responses (TNA)  Proposed Primary Immunogenicity Endpoint: –The proportion of subjects achieving a TNA response of at least 0.56 at Day 63 (five weeks following the third vaccination on Day 28)  Proposed Secondary Endpoints with Defined Success Criteria: –Proportion above threshold achieving a TNA of at least 0.56 at Day 70 –Average proportion achieving a TNA of at least 0.56 between Day 63 to Day 100 (inclusive)  Proposed Success Criterion: –Lower bound of the 2-sided 95% CI of the proportion of subjects who meet or exceed a TNA titer of 0.56 must be ≥ 40% on Day 63 Ref: Ionin et al, (2013), Clin. Vaccine Immunol. 20: PEP Strategy

16 BioThrax vaccine was administered as 3 s.c. PEP doses on Days 0, 14, and 28 The study met the prospectively defined success criteria for the primary and first two secondary immunogenicity endpoints for which success criteria were prospectively defined BioThrax is not currently approved for post-exposure prophylaxis *PEP studies supported by BARDA contract HHSO C PEP Strategy Study Conclusion

Increased and Accelerated Immune Response when BioThrax Vaccine is Given with CPG 7909 Adjuvant 17 Ref: Rynkiewicz, et al, (2011), Vaccine, 29: BioThrax Vaccine Plus CPG 7909

NuThrax TM (Anthrax Vaccine Adsorbed with CPG 7909): Development Strategy*  A dose-ranging study of candidate NuThrax formulations demonstrated that, compared to BioThrax vaccine, each formulation elicited a higher and accelerated immune response after 2 doses given 2 weeks apart  Additional studies of doses and dosing regimens are currently underway to further assess NuThrax immunogenicity and reactogenicity Ref: Hopkins, et al, (2013), Vaccine, 31: * AV7909 studies supported by NIAID contracts HHSN C and HHSN C. 18 BioThrax Vaccine Plus CPG 7909

BioThrax Vaccine – Using it Smarter  Reduced reactogenicity using intramuscular route  Reduced doses in primary series (0, 1, 6-months)  Three-year booster schedule (Germany)  Expanded availability (new production facility)  Four-year shelf life  Potential for 3-dose PEP indication  Potential for new anthrax vaccine with accelerated protective response using CpG adjuvant 19 Optimizing the Use of Anthrax Vaccine

20 THANK YOU VERY MUCH FOR YOUR ATTENTION Optimizing the Use of Anthrax Vaccine “BioThrax™ and NuThrax TM and any and all Emergent BioSolutions Inc. brand, product, service and feature names, logos and slogans are trademarks or registered trademarks of Emergent BioSolutions Inc. or its subsidiaries in the United States or other countries. All rights Reserved..”