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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