Natural History of Picornavirus Colds in Adults

1. Natural History of Picornavirus Colds in Adults • 69% self-diagnosed cold within 8 hours • Sore throat most common first symptom • Rhinorrhea most bothersome symptom • Fever uncommon • Sleep disturbed 4 days • 7-to 11-day duration of symptoms • 25% have symptoms for 2 weeks Arruda, et al. J Clin Micro. 1997;35:2864 Monto, et al. J Infect Dis. 1987;156:43 Gwaltney, et al. JAMA. 1967;202:294

3. Current Management of Colds • Leading reason for physician visits • ~17% of colds result in an office visit • Antibiotics • 30-50% of visits result in antibiotic prescription • No reduction in symptoms or complications • No treatment for the underlying viral cause McIsaac, et al.J Fam Prac. 1998;47:366 Gonzales, et al.JAMA. 1997;278:901 Gonzales, et al.Ann Intern Med. 2001;134:479 Rosenstein, et al.Pediatrics. 1998;101:181

4. Current Management of Colds • 75% of patients with colds self medicate • Symptom relief treatments • Cough preparations (84%), combination cold products (83%), analgesics (83%), decongestants (57%), antihistamines (56%) • Benefits are variable and transient • Do not shorten illness duration • Side effects and precautions McIssac, et al. J Fam Prac. 1998:47:366 SVI Consumer Segmentation,October 2001

6. Human Picornaviruses Enteroviruses Rhinoviruses Common Cold Herpangina Hand-foot-and-mouth Meningitis/encephalitis Myocarditis Neonatal Sepsis Meningoencephalitis Common Cold Otitis Media Sinusitis Exacerbation of Asthma, COPD, and CF LRT Infections in Immunocompromised

7. Capsid Binidng Compound: Early Development Candidates 1985 Disoxaril (WIN 51711) 1989 WIN 54954

8. VP 63843 (Pleconaril) 1992 • Not metabolized by CYP450 enzymes • Microsome T1/2 = >200 min

10. Protection by Pleconaril ofAdult Mice Infected With CVB3 Pevear et al Antimicrob Agents Chemother, 1999.

11. Structural Studies of Anti-rhinovirus Agents1985 - 2002 Purdue University Eddy Arnold Sungsoo Kim Alan Simpson John Badger S.Krishnaswamy Tom Smith Michael Chapman Ming Luo Gerd Vriend Andrea Hadfield Jodi Muckelbauer Rui Zhao Kyung Kim Marcos Olivera Ying Zhang ViroPharma(Stirling Winthrop) University of Wisconsin Guy Diana Beverly Heinz Frank Dutko Wai-Ming Lee Jim Groarke Roland Rueckert Mark McKinlay Debbie Shepard Dan Pevear Wensheng Wang

18. Pleconaril in Hydrophobic Pocket ILE92

21. 101 Rhinovirus Serotypes (Prototypic Strains) 53 Enterovirus Serotypes (Prototypic Strains) Distribution of Susceptibility to Pleconaril 10 10 1 1 EC50 mg/mL 0.1 0.1 0.01 0.01 0.001 0.001 Serotypes Serotypes

26. Ile 98 to Met Constriction of Drug-Binding Pocket in HRV16

27. Thermal Instability of Coxsackie B3 Viruses with Reduced Drug Susceptibility Wild type % Surviving PFU I92L I92M I92M Time at 46oC (min)

28. First Phase 3Human Clinical Trialswith Pleconaril

29. Coxsackie Respiratory InfectionMucus Production P = 0.016

30. Adult VRI StudyPCR+ Patients

31. Second Phase 3Human Clinical Trialswith Pleconaril

32. Phase 3 design PPPhase • Two randomized, placebo-controlled trials of identical design • 2096 patients randomized • Protocol 043: 1052 patients • Protocol 044: 1044 patients • 197 centers across the US and Canada • Enrollment from August – November 2000

33. Entry Criteria • Otherwise healthy subjects ≥18 years old • Answer ‘Yes’ to “Do you have a cold today?” • Moderate or severe rhinorrhea • At least one other respiratory symptom • nasal congestion, cough, sore throat • Symptom duration ≤24 hrs • Exclusions • active allergic rhinitis or asthma • fever ≥100ºF

34. Patient Self-Assessments (Days 1-18) • Rhinorrhea, nasal congestion, cough, sore throat, malaise, myalgia: absent, mild, moderate, or severe, twice daily • Presence or absence of cold twice daily • Tissue counts once daily • Sleep disturbance once daily • Impairment of normal activity level once daily • Concomitant use of cold symptom relief medications

35. Virological Assessments Nasal mucus sample Baseline, Day 3, and Day 6 Baseline RT-PCR + Baseline RT-PCR – Virus culture Virus culture + Virus culture – Culture Day 3 and Day 6 samples Susceptibility testing on culture positive samples

36. Placebo (N=262) Pleconaril (N=276) Placebo (N=301) Pleconaril (N=290) Antiviral Effect: Percentage Change in Relative Virus Levels 12 9 6 3 0 % of Baseline RT-PCR Level p< 0.001 p= 0.011 p< 0.001 p= 0.121 Day 3 Day 6 Day 3 Day 6 Study 044 Study 043

37. Safety Conclusions: 5 Day Treatment • Most common adverse events were headache and GI symptoms • No clinically significant effects on laboratory safety parameters • Increased menstrual disorders in OC users; 3.5% with pleconaril treatment dose • No evidence of increased incidence of pregnancy in women taking pleconaril • Safety profile supports empiric treatment of colds

38. Compassionate Use Program • Compassionate Use Patients (2001) • Chronic Meningoencephalitis 51 • Encephalitis/Meningoencephalitis 40 • Myocarditis 62 • Bone Marrow Transplant 16 • Neonatal Enteroviral Disease 45 • Many anecdotal accounts of dramatic improvement in patient status • 475 treated patients as of May 2002 of who 366 recovered

39. Conclusions • Pleconaril is the first antiviral drug to treat the predominant cause of the common cold • Pleconaril reduces the duration and severity of picornavirus colds • Safety profile supports empiric treatment

40. FDA committee decision March 19th 2002 Potential of producing virulent viral strains too great relative to benefits gained Problem of women on birth control drugs: warning messages are thought to be ineffective Benefits of an anti-common cold drug too small relative to possible risks of side effects. Concern over inappropriate use with the possibility of generating virulent strains Committee voted 15 to 0 against licensing of drug.

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