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;35:2864Monto, et al. J Infect Dis. 1987;156:43Gwaltney, et al. JAMA. 1967;202:294

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;47:366Gonzales, et al. JAMA. 1997;278:901Gonzales, et al. Ann Intern Med. 2001;134:479Rosenstein, et al. Pediatrics. 1998;101:181

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. 1998:47:366SVI Consumer Segmentation, October 2001

Human Picornaviruses

Common ColdHerpanginaHand-foot-and-mouthMeningitis/encephalitis Myocarditis Neonatal SepsisMeningoencephalitis

EnterovirusesRhinoviruses

Common ColdCommon ColdOtitis MediaSinusitisExacerbation of Asthma,

COPD, and CFLRT Infections in Immunocompromised

N

O

ONO

CH3

NO

CH3

N

O

O

Cl

Cl

Capsid Binidng Compound: Early Development Candidates

Capsid Binidng Compound: Early Development Candidates

Disoxaril (WIN 51711)Disoxaril (WIN 51711)

WIN 54954WIN 54954

1985

1989

VP 63843 (Pleconaril)VP 63843 (Pleconaril)

• Microsome TMicrosome T1/21/2 = >200 min = >200 min

NO

CH3

N

N O

O

CH3

CH3

CF3

• Not metabolized by CYP450 enzymesNot metabolized by CYP450 enzymes

1992

Protection by Pleconaril ofAdult Mice Infected With CVB3

0 2 4 6 8 10 12 14 16 180

25

50

75

100

200 20 2

% Surviving

mg/Kg/Day

0

Days Post-Infection

Pevear et al Antimicrob Agents Chemother, 1999.

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

ILE92

101 Rhinovirus Serotypes (Prototypic Strains)

53 Enterovirus Serotypes(Prototypic Strains)

Serotypes

10

1

0.1

0.01

0.001

EC50

g/mL

Distribution of Susceptibility to Pleconaril

Serotypes

10

1

0.1

0.01

0.001

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

Thermal Instability of Coxsackie B3 Viruses with Reduced Drug Susceptibility

0 15 300.1

1

10

100 Wild type

I92L

I92MI92M

%Surviving

PFU

Time at 46oC (min)

First Phase 3Human Clinical Trials

with Pleconaril

Coxsackie Respiratory InfectionMucus Production

0

2

4

6

8

10

12

Mea

n M

ucu

s W

eig

hts

1 2 3 4 5 6 7 8

Study Day

Pleconaril Placebo

P = 0.016

Adult VRI StudyPCR+ Patients

PlaceboN= 205

PleconarilN = 173

Reduction

Primary Endpoint 9.4 days 7.7 days18%

P = 0.07

Tissue Use 98 7523%

P = 0.03

Total Symptom Score59 48 19%

P = 0.023

% Nights with Sleep Disturbed

18.1 13.7 24% P = 0.029

Symptom Relief Medication

2 1 50%P = 0.209

Second Phase 3Human Clinical Trials

with Pleconaril

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

Phase 3 design

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)

• 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 AssessmentsNasal 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

Antiviral Effect: Percentage Change in Relative Virus Levels

% ofBaselineRT-PCRLevel

1212

99

66

33

00 Day 3 Day 6

Placebo (N=262)

Pleconaril (N=276)

p = 0.011

p = 0.121

Day 3 Day 6

Placebo (N=301)

Pleconaril (N=290)

p < 0.001

p < 0.001

Study 044Study 043

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 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

Compassionate Use Program

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 19th 2002

1. Potential of producing virulent viral strains too great relative to benefits gained

2. Problem of women on birth control drugs: warning messages are thought to be ineffective

3. Benefits of an anti-common cold drug too small relative to possible risks of side effects.

4. Concern over inappropriate use with the possibility of generating virulent strains

5. Committee voted 15 to 0 against licensing of drug.

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