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

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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

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


Capsid binidng compound early development candidates

Capsid Binidng Compound: Early Development Candidates

1985

Disoxaril (WIN 51711)

1989

WIN 54954


Vp 63843 pleconaril

VP 63843 (Pleconaril)

1992

  • 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


Pleconaril in hydrophobic pocket

Pleconaril in Hydrophobic Pocket

ILE92


Distribution of susceptibility to pleconaril

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


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

%

Surviving

PFU

I92L

I92M

I92M

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


Ppphase

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


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


Natural history of picornavirus colds in adults

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


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/Meningoencephalitis40

    • Myocarditis62

    • Bone Marrow Transplant16

    • Neonatal Enteroviral Disease45

  • Many anecdotal accounts of dramatic improvement in patient status

  • 475 treated patients as of May 2002 of who 366 recovered


Conclusions

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


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.


There could be a place for you at purdue university

There could be a place for you at Purdue University!


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