Natural history of picornavirus colds in adults
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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.

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Natural history of picornavirus colds in adults
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

Current management of colds
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

Current management of colds1
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

Human picornaviruses
Human Picornaviruses



Common Cold



Meningitis/encephalitis Myocarditis

Neonatal Sepsis


Common Cold

Otitis Media


Exacerbation of Asthma, COPD, and CF

LRT Infections in Immunocompromised

Capsid binidng compound early development candidates
Capsid Binidng Compound: Early Development Candidates


Disoxaril (WIN 51711)


WIN 54954

Vp 63843 pleconaril
VP 63843 (Pleconaril)


  • Not metabolized by CYP450 enzymes

  • Microsome T1/2 = >200 min

Protection by pleconaril of adult mice infected with cvb3
Protection by Pleconaril ofAdult Mice Infected With CVB3

Pevear et al Antimicrob Agents Chemother, 1999.

Structural studies of anti rhinovirus agents 1985 2002

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

Distribution of susceptibility to pleconaril

101 Rhinovirus Serotypes

(Prototypic Strains)

53 Enterovirus Serotypes

(Prototypic Strains)

Distribution of Susceptibility to Pleconaril















Ile 98 to met constriction of drug binding pocket in hrv16
Ile 98 to Met Constriction of Drug-Binding Pocket in HRV16

Thermal instability of coxsackie b3 viruses with reduced drug susceptibility
Thermal Instability of Coxsackie B3 Viruses with Reduced Drug Susceptibility

Wild type







Time at 46oC (min)

First phase 3 human clinical trials with pleconaril
First Phase 3Human Clinical Trialswith Pleconaril

Coxsackie respiratory infection mucus production
Coxsackie Respiratory InfectionMucus Production

P = 0.016

Adult vri study pcr patients
Adult VRI StudyPCR+ Patients

Second phase 3 human clinical trials with pleconaril
Second Phase 3Human Clinical Trialswith Pleconaril


Phase 3 design


  • 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

Entry criteria
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

Patient self assessments days 1 18
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

Virological assessments
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

Placebo (N=262)

Pleconaril (N=276)

Placebo (N=301)

Pleconaril (N=290)

Antiviral Effect:

Percentage Change in Relative Virus Levels






% of




p< 0.001

p= 0.011

p< 0.001

p= 0.121

Day 3 Day 6

Day 3 Day 6

Study 044

Study 043

Safety conclusions 5 day treatment
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

Compassionate use program
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


  • 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

Fda committee decision march 19 th 2002

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.