Download Pleconaril

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
• 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 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
Rhinoviruses
Enteroviruses
Common Cold
Otitis Media
Sinusitis
Exacerbation of Asthma,
COPD, and CF
LRT Infections in
Immunocompromised
Common Cold
Herpangina
Hand-foot-and-mouth
Meningitis/encephalitis
Myocarditis
Neonatal Sepsis
Meningoencephalitis
Capsid Binidng Compound:
Early Development Candidates
H3C
N
1985
O
O
N
Disoxaril (WIN 51711)
H3C
1989
O
Cl
N
O
O
Cl
WIN 54954
N
O
VP 63843 (Pleconaril)
H3C
1992
H3C
N
O
O
H3C
N
CF3
N O
• Not metabolized by CYP450 enzymes
• Microsome T1/2 = >200 min
Protection by Pleconaril of
Adult Mice Infected With CVB3
100
mg/Kg/Day
75
%
Surviving
200
20
2
0
50
25
0
0
2
4
6
8
10 12 14 16 18
Days Post-Infection
Pevear et al Antimicrob Agents Chemother, 1999.
Structural Studies of Anti-rhinovirus Agents
1985 - 2002
Purdue University
Eddy Arnold
Sungsoo Kim
John Badger
S.Krishnaswamy
Michael Chapman
Ming Luo
Andrea Hadfield
Jodi Muckelbauer
Kyung Kim
Marcos Olivera
ViroPharma(Stirling Winthrop)
Guy Diana
Frank Dutko
Jim Groarke
Mark McKinlay
Dan Pevear
Alan Simpson
Tom Smith
Gerd Vriend
Rui Zhao
Ying Zhang
University of Wisconsin
Beverly Heinz
Wai-Ming Lee
Roland Rueckert
Debbie Shepard
Wensheng Wang
Pleconaril in Hydrophobic Pocket
ILE92
Distribution of Susceptibility
to Pleconaril
101 Rhinovirus Serotypes
(Prototypic Strains)
EC50
mg/mL
53 Enterovirus Serotypes
(Prototypic Strains)
10
10
1
1
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
Thermal Instability of Coxsackie B3
Viruses with Reduced Drug Susceptibility
Wild type
100
10
%
Surviving
PFU
1
I92L
I92M
I92M
0.1
0
15
Time at 46oC (min)
30
First Phase 3
Human Clinical Trials
with Pleconaril
Coxsackie Respiratory Infection
Mucus Production
Pleconaril
Placebo
Mean Mucus
Weights
12
10
8
6
4
2
0
1
2
3
4
5
Study Day
P = 0.016
6
7
8
Adult VRI Study
PCR+ Patients
Primary Endpoint
Tissue Use
Total Symptom Score
% Nights with Sleep
Disturbed
Symptom Relief
Medication
Placebo
Pleconaril
N= 205
N = 173
9.4 days
7.7 days
98
75
59
48
Reduction
18%
P = 0.07
23%
P = 0.03
19%
P = 0.023
18.1
13.7
24%
P = 0.029
2
1
50%
P = 0.209
Second Phase 3
Human Clinical Trials
with Pleconaril
h
a Phase 3 design
s
e
• 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
•
•
•
•
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 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
Antiviral Effect:
Percentage Change in Relative Virus Levels
12
Placebo
(N=262)
Placebo
(N=301)
Pleconaril
(N=276)
Pleconaril
(N=290)
9
% of
Baseline
RT-PCR
Level
6
3
p = 0.011
p < 0.001
p < 0.001
p = 0.121
0
Day 3
Day 6
Study 043
Day 3
Day 6
Study 044
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 Patients (2001)
–
–
–
–
–
Chronic Meningoencephalitis
Encephalitis/Meningoencephalitis
Myocarditis
Bone Marrow Transplant
Neonatal Enteroviral Disease
51
40
62
16
45
• Many anecdotal accounts of dramatic improvement in
patient status
• 475 treated patients as of May 2002 of who 366 recovered
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
th
March 19 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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