Introduction to ACAM2000 Smallpox Vaccine

1. Introduction to ACAM2000 Smallpox Vaccine David Wonnacott, PhD Senior Vice President of Quality and Regulatory

2. Acambis Overview • Acambis develops novel vaccines to prevent and treat infectious diseases • Acambis locations: • Cambridge, UK (Head Office) – Canton, MA (manufacturing) • Cambridge, MA (R&D) – Rockville, MD (lyophilization, fill/finish) • 200+ employees

3. “Answering The Call” • Critical demand for new and improved smallpox vaccine • Commercial manufacturing ceased after elimination of disease (1970’s) • Strategic National Stockpile required new source of vaccine • ACAM2000 is unique • Needed to establish safety and efficacy in absence of disease • Highly targeted use managed by government agencies

4. Manufacturing Original Bioreactor Calf skin vaccines, begun in 1805 Today’s Bioreactor ACAM2000, 2001 - ongoing

5. Differences from Currently Licensed Smallpox Vaccine

6. Parallel Clinical Development and Manufacturing Timeline for Smallpox Vaccine (ACAM2000) 192.5 million doses delivered to SNS* Terrorist and anthrax attacks CDC contract awarded to Acambis Fast Track Designation 9/11 and 10/01 11/01 12/02 12/04 12/06 8/02 10/02 2/05 8/06 IND filed Clinical trial program (Phase I - III) BLA filed * SNS – Strategic National Stockpile

7. Acambis Presentations

8. History of Smallpox Disease, Vaccination, and Eradication John Neff, MD Seattle Children’s Hospital and Regional Medical Center

9. Topics to be Covered • History of Smallpox • Control, eradication, and potential for bioterrorism use • Smallpox Vaccination • Development, protection, adverse events • Description of Smallpox • Clinical types and expected mortality • Conclusions

10. History of Smallpox

11. Overview of Smallpox • First appeared possibly 1100 BC • Origin was probably from closely related animal pox viruses of the orthopox virus group • Smallpox became worldwide and endemic throughout Europe and caused pandemics with high mortalities in the Americas • Responsible for estimated 300 million deaths in 20th century

12. Control of Smallpox • Variolation developed in Far East and introduced to Europe • 1796: First vaccinia-based vaccination by Edward Jenner • 1967: Enhanced WHO eradication program • 1972: Vaccination ended in US • 1977: Last natural case of smallpox (Somalia) • 1978: Last death/case of smallpox, lab acquired – air vent system, Janet Parker in Birmingham, England • 1980: WHO declared smallpox eradicated • 1984: Official repositories of variola designated as CDC in Atlanta, GA and Vector in Novosibirsk, Russia

13. Smallpox – Current Concerns • Soviet government bioweapons program • Aimed to produce smallpox in large quantities and adapt it for use in bombs and ICBMs • Industrial capacity capable of producing many tons of smallpox virus annually • Stocks in official repositories may not be secure • With break-up of Soviet Union, security at Vector was poor • Risk that rogue states did not destroy stocks • Could be used for bioterrorism purposes

14. Smallpox Vaccination

15. History of Vaccinia as Smallpox Vaccine • Vaccinia obtained from animals, presumably cows or horses • Member of Orthopox family • Related to both cowpox and variola • Initially propagated from person to person • The coordinated use of two standardized vaccinia strains, Lister and NYCBH, were responsible for eradicating smallpox worldwide by 1980

16. Evidence of Protection • Cutaneous Reaction (dermal take) • “Major reaction” correlates with • Protection against smallpox • Development or presence of neutralizing antibodies and T cells • Neutralizing Antibodies • Neutralizing antibodies correlate with protection against smallpox in humans • Mice and monkeys with neutralizing antibodies and T cell depletion are protected • Passive immunization provides some protection • T cells may also play an important role

17. Protection from Vaccination • Complete protection for three to five years • Partial protection for up to 25 years • Perhaps long-term protection against death Fenner F et al. Smallpox and its Eradication, pp53

18. Historic Understanding of Adverse Events: Data from US Routine Vaccination Programs in 1960s

19. Clinical Description of Smallpox

20. Smallpox

21. Progression of Smallpox Source: CDC

22. Clinical Features of Smallpox • Discrete • Confluent • Flat • Hemorrhagic

23. Areas of normal skin between pustules even on face Smallpox – Discrete Source: CDC

24. Confluent rash on face and forearms Smallpox – Confluent Source: CDC

25. Pustules confluent or semiconfluent – appear flat Smallpox – Flat Source: CDC

26. Widespread hemorrhage into skin, early and late forms, 98% case fatality Smallpox – Hemorrhagic Source: CDC

27. Smallpox Mortality Mortality from infection with variola major in unvaccinated individuals can be up to 50%

28. Conclusions

29. Conclusions • Smallpox is a devastating disease with a very high mortality rate in the non-immune • Vaccination historically associated with significant adverse events • Populations are immunologically vulnerable following eradication and end of vaccination programs • In the United States, few people have been vaccinated in 34 years Continued

30. Conclusions (Continued) • As long as variola virus exists anywhere, there will be the need to have a smallpox vaccine available in the event of a bioterrorism threat or laboratory accident • It is in our best interest to have a modern smallpox vaccine available

31. ACAM2000 Smallpox Vaccine Development Program Thomas P. Monath, MD Former Acambis Chief Scientific Officer

32. Vaccine Development Goals Met • Purified clone derived from Dryvax®(NYCBH vaccinia strain) • Well characterized seed lot free of adventitious agents • GMP manufacturing in cell culture (Vero) using modern standards • Meets all release specifications including potency ≥ 108 PFU/mL • Clinical safety similar to or better than Dryvax® • Demonstrated clinical efficacy (some differences from Dryvax®)

33. Indication/Use • Vaccination with ACAM2000 is indicated for protection of persons determined to be at high risk for smallpox infection • Not for routine vaccination of general population • Stored and controlled by Strategic National Stockpile (SNS)

34. Topics to be Covered • Introduction • Nonclinical data • Clinical data • Safety • Efficacy • Conclusions

35. Nonclinical Summary • Toxicology studies in mice and cynomolgus macaques inoculated IC show ACAM2000 less neurovirulent than Dryvax® • ACAM2000 and Dryvax® have similar immunogenicity in mice and monkeys • Both vaccines protect mice and cynomolgus macaques against lethal homologous and heterologous poxvirus challenge

36. ACAM2000 Is Less Neurovirulent than Dryvax®3-4 Day-old Mice Inoculated IC, n=32/Group

37. ACAM2000 and Dryvax® Elicit Similar Immune Responses and Protect Cynomolgus Monkeys against Lethal Monkeypox Challenge (3.8 x 107 PFU IV)

38. Topics to be Covered • Introduction • Nonclinical data • Clinical data • Safety • Efficacy • Conclusions

39. ACAM2000 Clinical Studies

40. Subjects Evaluated for Safety * Phase III study enrollment curtailed due to myocarditis AEs. Planned enrollment 2040 ACAM2000 and 680 Dryvax®

41. Phase III Subject DispositionSafety Population

42. Phase III DemographicsSafety Population

43. Common Adverse Events • Expected AEs known to be associated with smallpox vaccinations • Inoculation site reactions, lymphadenitis, feverishness, chills, fatigue, malaise, myalgia • The incidence of these AEs was higher for Dryvax® than ACAM2000

44. Solicited Adverse Events Occurring in ≥10% of Subjects by Treatment Group, Phase III

45. Serious Adverse Events – All Studies

46. Myocarditis • Prospective case ascertainment Phase I (H-400-002) and Phase III • ECGs at screening, Day 10 and 21 (Phase III) or screening and Day 15 (Phase I) • Troponin I and/or CK-MB at screening and Day 10 (Phase III) or Day 15 (Phase I) • Provoked cardiac AEs (clinic visits, diaries) • Myocarditis seen only in vaccinia-naïve subjects • Previous under-reporting based on passive surveillance and symptomatic cases only

47. Myocarditis – Phase I (H-400-002) and Phase III (Vaccinia-naïve Subjects, Standardized Case Ascertainment)

48. Topics to be Covered • Introduction • Nonclinical data • Clinical data • Safety • Efficacy • Conclusions

49. Vaccine Efficacy • Efficacy cannot be demonstrated in disease setting due to eradication of smallpox • Cutaneous Response is a generally accepted surrogate of protection (WHO, ACIP) • Neutralizing Antibodies are a correlate of protection • May be more accurate reflection of vaccine effectiveness in previously vaccinated subjects with modified ‘takes’ • Historical data suggest relatively low titers are protective • Mack et al., 1972 (protective titer >1:32) • Sarkar et al., 1975 (protective titer >1:20)

50. Phase III Trials Efficacy Analyses