# Presentation: 835382

## Pleconaril for Treatment of the Common ColdFDA Antiviral Drugs Advisory Committee Meeting March 19, 2002

## Agenda

**Introduction**
- Mark McKinlay, PhD
**Impact of the Common Cold**
- Frederick Hayden, MD
**Preclinical Profile and Clinical Pharmacology**
- Mark McKinlay, PhD
**Clinical Efficacy and Safety**** **
- Ellen Cooper, MD, MPH
**Benefit/Risk****  **
- Ellen Cooper, MD, MPH

## Pleconaril

- First antiviral drug with activity against picornaviruses, the predominant cause of the common cold

## Indication

- Pleconaril is indicated for the treatment of acute picornaviral upper respiratory illness (the common cold) in adults

## Impact of the Common Cold

**Frederick Hayden, MD**
**University of Virginia Health Sciences Center**

## Current Management of Viral Respiratory Illness

- Influenza virus
- 4 marketed antiviral drugs
- Vaccines
- Respiratory syncytial virus
- Prophylactic antibody products
- Aerosolized ribavirin
- Picornavirus
- No marketed antiviral drugs
- No prospect for vaccine
- Current treatments inadequate

## Human Picornaviruses

**Common Cold**
**Herpangina**
**Hand-foot-and-mouth**
**Meningitis/encephalitis Myocarditis **
**Neonatal Sepsis**
**Meningoencephalitis****                     **

**Enteroviruses**

**Rhinoviruses**

**Common Cold**
**Otitis Media**
**Sinusitis**
**Exacerbation of Asthma, ****	****COPD, and CF**
**LRT Infections in    ****	****Immunocompromised****                  ****                     **

## Incidence of Colds

- Annual incidence (colds per year)
- Children 			6 to 8
- Adults (16 to 45)  		2 to 3
- Adults (>45 years) 		1
- Rhinovirus infections
- 50% of colds on annual basis with peaks in spring and fall (up to 80%)

**Makela, et al. *****J Clin Micro.***** 1998;36:539**
**Fox, et al. *****Am J Epidemiol.***** 1975;101:122**
**Dingle, et al. *****The Press of Western Reserve University.***** 1964;1**
**Gwaltney, et al. *****N Engl J Med.***** 1966;275:1261**
**Arruda, et al. *****J Clin Micro.***** 1997;35:2864**

## 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**

## Picornavirus Colds Pathogenesis

**Nasal**
**Obstruction**

**Rhinorrhea**

**Picornavirus Colds Pathogenesis**

***Virus Infection of Nasal Epithelium***

**Cough**

**Neurogenic**
**Responses**

***Tracheobronchial ***
***Infection***

***Secondary Inflammation***
***(PMNs, kinins)***

***Mucus***
***Secretion***

***Proinflammatory***
***Cytokines***
***(IL-1, -6, -8)***

***Vasodilation***
***Serum Transudation***

***Airway***
***Hyperreactivity***

**Sore Throat**

**Cholinergic Stimulation**

**Sneezing**

## 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**

## Current Management of Colds

- Leading reason for physician visits
- ~15% 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**

## Impact of Common Colds: Summary

- Colds cause significant morbidity
- Patients seek treatment
- Current treatments target symptoms only and do not address cause of colds
- A safe and effective antiviral treatment option is needed

## Preclinical Profile and Clinical Pharmacology

**Mark McKinlay, PhD**
**ViroPharma**

## Pleconaril Mechanism of Action

**Blocks uncoating and attachment** **by binding into a hydrophobic pocket within the capsid**

## Distribution of Susceptibility to Pleconaril

- Serotypes

**10**

**1**

**0.1**

**0.01**

**0.001**

**IC****50**
******g/mL**

**IC****50**
******g/mL**

**Distribution of Susceptibility to Pleconaril**

- Serotypes

**10**

**1**

**0.1**

**0.01**

**0.001**

## Human Pharmacokinetic Profile

- 0

- 1

- 2

- 3

- 0

- 4

- 8

- 12

- 16

- 20

- 24

- Time (h)

**MIC****90**

**MIC****75**

**t****1/2****α**** = 2.8 h**

**t****1/2**** ********1****80 h**

**400 mg Single Dose (Commercial Tablet)**

- Conc. (g/mL)

## Human Pharmacokinetic Profile

- Dose proportional (50-1000 mg)
- Food significantly increases bioavailability
- Large volume of distribution despite >99% plasma protein binding
- <1% dose excreted in urine as pleconaril
- No clinically significant changes in PK profile
- Renal impairment, elderly, gender

## Human Metabolism

**CH****3**** Oxidation**
**Isoxazole Ring Opening**

**=N-OH**
**=N-O-Glucuronidation**

**Pleconaril**

## Effects of Pleconaril on CYP 450

- Inhibition
*In vitro*
- No inhibition of CYP 2A6, 2C8, 2D6, 2E1, 3A4
- Weak inhibition of CYP 1A2, 2C9, 2C19
- Phase I
- No effect on S- or R-warfarin (2C9 probe)
- Small effects on theophylline (1A2 probe) AUC and t1/2
- Induction of CYP 3A
- Phase I
- Increased CYP 3A activity with midazolam and ethinylestradiol

## Oral Theophylline CYP 1A2 Probe Study

- No change in Cmax
- 15% increase in AUC
- <20% increase in t1/2

- Theophylline alone
- Theophylline with pleconaril

- 0.1

- 1.0

- 10.0

- 100.0

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- Time (h)

- Conc. (g/mL)

## IV Midazolam CYP 3A Probe Study

**Midazolam alone**
**Midazolam with pleconaril**

- 28% decrease in AUC
- 16% decrease in t1/2

**0.1**

**1.0**

**10.0**

**100.0**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

- Time (h)

- Conc. (ng/mL)

## Oral Contraceptive Interaction Study

**Ethinylestradiol alone**
**Ethinylestradiol with pleconaril**

- No clinically significant change in Cmax
- 34% decrease in ethinylestradiol AUC
- No effect on norethindrone pharmacokinetics

**0.1**

**1.0**

**10.0**

**100.0**

**1000.0**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**45**

**50**

- Time (h)

- Conc. (pg/mL)

## Preclinical Safety

- Low acute toxicity potential
- No significant findings in 1- and 6-month studies
- No genotoxicity
- No teratogenicity
- No effects on male or female fertility
- No effects on growth, viability, development, or reproductive performance of offspring following maternal exposure *in utero *through weaning

## Clinical Efficacy and Safety

**Ellen Cooper, MD, MPH**
**ViroPharma**

##  Clinical Development of Pleconaril for the Common Cold

**1996**

**1997**

**1998**

**1999**

**2000**

**2001**

**2002**

**Phase II**
** ****Coxsackievirus A21 challenge study **

**Three Phase II studies **
**in natural colds**** **

**Two pivotal **
**Phase III studies**

**Two Phase II**
**pediatric studies**
**One 6-week adult prophylaxis study**

## Insights Gained from Phase II Studies

- Clinical presentation of picornavirus colds
- Patient self-diagnosis of a cold
- Significant rhinorrhea
- Systemic symptoms not prominent
- Absence of fever
- Factors masking treatment effect
- Smokers
- Allergic rhinitis
- Use of concomitant cold symptom relief medication
- Endpoint development
- Alleviation of all symptoms captures the earlier phase of illness

## Pivotal Phase III Clinical Trials 

- 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

## Study Design

- Central randomization 1:1 to pleconaril 400 mg TID x 5 days or placebo
- Stratification on smoking status and prior use of cold symptom relief medication
- Concomitant use of cold symptom relief medication was discouraged
- Acetaminophen and dextromethorphan provided

## 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**

## Study Analysis Populations

- Intent-to-treat-infected (ITT-I)
- Pre-specified primary efficacy population
- All RT-PCR+ patients
- 65% of ITT
- Intent-to-treat (ITT)
- All randomized patients
- Safety database
- All RT-PCR negative patients
- Not picornavirus-infected
- No expectation of efficacy

## Demographics: ITT-I

|  | Study 043 |  | Study 044 |  |
| --- | --- | --- | --- | --- |
|  | Placebo
N=326 | Pleconaril
N=337 | Placebo
N=356 | Pleconaril
N=344 |
| Median Age (yrs) | 35  | 33  | 35  | 33  |
| Female | 65% | 68% | 71% | 67% |
| Race (White) | 83% | 80% | 90% | 90% |
| Smoker | 27% | 32% | 27% | 28% |

**Demographics: ITT-I**

## Baseline Disease Characteristics: ITT-I

|  | Study 043 |  | Study 044 |  |
| --- | --- | --- | --- | --- |
|  | Placebo
N=326 | Pleconaril
N=337 | Placebo
N=356 | Pleconaril
N=344 |
| Median Time from Symptom Onset (hrs) | 20  | 20  | 20  | 20  |
| Prior Cold Medication Use | 30% | 32% | 33% | 35% |
| Median Total Symptom Score | 9 | 9 | 9 | 9 |

**Baseline Disease Characteristics: ITT-I**

## Primary Efficacy Endpoint

- Time from initiation of study drug to
- Absence of rhinorrhea
- Five other cold symptoms absent or mild
- Sustained for four consecutive reporting periods (~48 hrs)
- Without use of concomitant cold symptom relief medications
- Endpoint occurs at the beginning of the 48-hour interval

## Primary Efficacy Endpoint: ITT-I

|  | Study 043 |  |  | Study 044 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Days | Placebo | Pleconaril | p-value | Placebo | Pleconaril | p-value |
|  | N=326 | N=337 |  | N=356 | N=344 |  |
| 25th Percentile | 4.1 | 3.3 |  | 4.3 | 3.3 |  |
| Median | 7.2 | 6.6 | 0.037 | 7.7 | 6.2 | 0.001 |
| 75th Percentile | 11.7 | 10.8 |  | 12.3 | 10.4 |  |

**Primary Efficacy Endpoint: ITT-I**

## Primary Efficacy EndpointStudies 043 and 044

**Study 043**

**Study 044**

## Consistency of Treatment Benefit: ITT-I

**Consistency of Treatment Benefit: ITT-I**

|  | Study 043 |  |  | Study 044 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Median Days | Placebo
N=326 | Pleconaril
N=337 | p-value
 | Placebo
N=356 | Pleconaril
N=344 | p-value
 |
| Symptom Alleviation Sustained for 24 hrs | 6.8  | 5.8 | 0.008 | 6.3  | 5.7 | 0.002 |
| Symptom Alleviation Sustained for 48 hrs | 7.2  | 6.6 | 0.037 | 7.7  | 6.2 | 0.001 |
| Symptom Alleviation Sustained for 72 hrs | 7.9  | 6.9 | 0.011 | 8.1  | 7.0 | 0.007 |

## Primary Endpoint: ITT and RT-PCR Negative

|  | Study 043 |  |  | Study 044 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Placebo | Pleconaril | p-value | Placebo | Pleconaril | p-value |
|  | N=200 | N=189 |  | N=168 | N=176 |  |
| Median Days | 5.9 | 6.1 | 0.639 | 5.9 | 6.0 | 0.776 |

|  | Study 043 |  |  | Study 044 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Placebo | Pleconaril | p-value | Placebo | Pleconaril | p-value |
|  | N=526 | N=526 |  | N=524 | N=520 |  |
| Median Days | 6.9 | 6.4 | 0.201 | 7.1 | 6.2 | 0.015 |

**Primary Endpoint: ITT and RT-PCR Negative**

**RT-PCR Negative**

**ITT**

## Antiviral Effect: Virus Culture

**Antiviral Effect: Virus Culture**

**Study Day**

**p=0.835**

**p<0.001**

**% Culture Positive**

**Study 043**

**Study 044**

**Study Day**

**p=0.016**

**p<0.001**

**N=**
**182**

**N=**
**185**

**N=**
**180**

**N=**
**184**

**N=**
**212**

**N=**
**195**

**N=**
**207**

**N=**
**191**

## Secondary Clinical Endpoints

- Time to resolution of individual cold symptoms
- Time to patient-assessed “no cold”
- Daily tissue counts
- Nights of sleep disturbance
- Days of impaired activity
- Days of cold symptom medication
- Sum of total symptom severity scores

## Resolution of Individual Symptoms: ITT-I

**Resolution of Individual Symptoms: ITT-I**

- Study 044

*******  ****p<0.05**

- Study 043

**Median**
**Days**

**Placebo**

**Pleconaril**

- *

- *

- *

- *

- *

**Rhinorrhea**

**Nasal ****Congestion**

**Sore Throat**

**Cough**

**Malaise**

**Myalgia**

**Rhinorrhea**

**Nasal ****Congestion**

**Sore Throat**

**Cough**

**Malaise**

**Myalgia**

- *

- *

- *

- *

## Summary of Secondary Endpoints: ITT-I

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**Time to No Cold**

**Tissue Use**

**Nights w/Sleep**
** ****Disturbance**

**Days with **
**Impaired Activity**

**Days with **
**Concomitent**
** ****Symptom **
**Med. Use**

**Total Symptom**
** ****Score**

**Study 043**

**Study 044**

**Percent **
**Reduction **
**vs.**
**Placebo**

*******p<0.05 vs Placebo**

- *

- *

- *

- *

- *

- *

- *

## Patients with Bothersome Symptoms by Day (Post Hoc)

- *

- *

- *

- *

******* p<0.05**

- *

**%**

- *

- *

- *

- *

- *

**Study 043**

**Study 044**

**Placebo**

**Pleconaril**

**0**

**25**

**50**

**75**

**100**

**B**

**1P**

**2A**

**2P**

**3A**

**3P**

**4A**

**4P**

**5A**

**5P**

**6A**

**6P**

**Study Day**

**0**

**25**

**50**

**75**

**100**

**B**

**1P**

**2A**

**2P**

**3A**

**3P**

**4A**

**4P**

**5A**

**5P**

**6A**

**6P**

**Study**** Day**

**Placebo**

**Pleconaril**

**%**

## Total Symptom Severity (Post Hoc)

**% of **
**Baseline**

******* p<0.05**

**Study Day**

**Study 044**

*****

*****

*****

*****

*****

*****

*****

**Study 043**

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**B**

**1P**

**2A**

**2P**

**3A**

**3P**

**4A**

**4P**

**5A**

**5P**

**6A**

**6P**

**Placebo**

**Pleconaril**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**B**

**1P**

**2A**

**2P**

**3A**

**3P**

**4A**

**4P**

**5A**

**5P**

**6A**

**6P**

**Placebo**

**Pleconaril**

## Subgroup Analyses

## Prospectively defined strata
Smoking status
Prior use of cold symptom relief medication
Significant interaction between treatment and smoking status (p<0.05) 
No interaction between treatment and prior use of cold symptom relief medication (p>0.10)
No interaction between treatment and demographic subsets (age, gender, race)

- Smoking status
- Prior use of cold symptom relief medication
- Significant interaction between treatment and smoking status (p<0.05)
- No interaction between treatment and prior use of cold symptom relief medication (p>0.10)
- No interaction between treatment and demographic subsets (age, gender, race)

**Subgroup Analyses**

## Efficacy by Smoking Status: ITT-I (Pooled)

|  | Non-Smokers |  |  | Smokers |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Days | Placebo | Pleconaril | p-value | Placebo | Pleconaril | p-value |
|  | N=498 | N=477 |  | N=184 | N=204 |  |
| 25th Percentile | 4.3 | 3.2 |  | 4.3 | 4.1 |  |
| Median | 7.3 | 6.0 | <0.001 | 7.4 | 8.3 | 0.692 |
| 75th Percentile | 12.0 | 9.8 |  | 12.3 | 13.0 |  |

**Efficacy by Smoking Status: ITT-I (Pooled)**

## Antiviral Effect by Smoking Status

**Antiviral Effect by Smoking Status**

**Study Day**

**p=0.035**

**p<0.001**

**% Culture Positive**

**Non-Smokers**

**Smokers**

**Study Day**

**p=0.793**

**p=0.058**

**N=**
**284**

**N=**
**250**

**N=**
**279**

**N=**
**249**

**N=**
**110**

**N=**
**130**

**N=**
**108**

**N=**
**126**

## Total Symptom Severity by Smoking Status (Post Hoc)

**% of **
**Baseline**

**Study Day**

**Smokers**

**Non-Smokers**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**B**

**1P**

**2A**

**2P**

**3A**

**3P**

**4A**

**4P**

**5A**

**5P**

**6A**

**6P**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**B**

**1P**

**2A**

**2P**

**3A**

**3P**

**4A**

**4P**

**5A**

**5P**

**6A**

**6P**

**Placebo**

**Placebo**

**Pleconaril**

**Pleconaril**

******* p<0.05**

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

## Clinical Virology

## Distribution of Baseline Susceptibility

## Primary Endpoint: Baseline Susceptibility

|  | Study 043 |  |  | Study 044 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Placebo | Pleconaril | p-value | Placebo | Pleconaril | p-value |
|  | N=154 | N=147 |  | N=181 | N=167 |  |
| Median Days | 8.1 | 6.3 | 0.003 | 8.6 | 6.5 | 0.002 |

**Primary Endpoint: Baseline Susceptibility**

**Baseline**
**IC****50**** >3.8****μ****g/ml**

|  | Study 043 |  |  | Study 044 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Placebo | Pleconaril | p-value | Placebo | Pleconaril | p-value |
|  | N=19 | N=26 |  | N=26 | N=24 |  |
| Median Days | 4.0 | 7.3 | 0.185 | 5.6 | 8.9 | 0.391 |

**Baseline**
**IC****50**** ******** ****3.8****μ****g/ml**

## Post-Baseline Viruses with Reduced Susceptibility

|  | Placebo | Pleconaril |
| --- | --- | --- |
|  | N=294 | N=263 |
| 10-fold reduction from baseline in susceptibility | 2 (0.7%) | 28 (10.7%) |

**Post-Baseline Viruses with**** Reduced Susceptibility**

- Incidence

## Clinical Outcome

| Endpoint | Placebo†
N=333 | Pleconaril†
N=286 | Pleconaril Reduced Susceptibility
N=28 |
| --- | --- | --- | --- |
| Primary (Illness duration in median days) | 8.6 | 6.5 | 4.9 |
| Time to No Cold 
(median days) | 7.7 | 6.8 | 4.2 |
|  |  |  |  |

**†**** **All patients infected with a susceptible isolate minus the 28 from whom an isolate with reduced susceptibility was isolated

**Post-Baseline Viruses with**** Reduced Susceptibility**

## Post-Baseline Viruses with Reduced Susceptibility

- Virus less stable *in vitro*
- Specific amino acid substitution in drug binding pocket at position 98, 122, or 180
- Similar profile to lab-derived viruses selected for reduced susceptibility
- Reduced virulence in murine model

*In Vitro* Characterization

## Overall Efficacy Conclusions	

- Pleconaril reduces the median duration of picornavirus colds by one day
- Pleconaril reduces the severity and duration of multiple cold symptoms
- The antiviral and clinical benefits of pleconaril are evident by second day

## Clinical Safety

##  Exposure to Pleconaril

- Total (5 to 7 days)
**3896**

- Adults
**3218**

- Children
**678**

- Phase 1
**350 **

- Phase 2/3
**2868**

- Meningitis
**396**

- Cold
**2472**

- Cold Tablet
**1480**

- Prophylaxis
- (6 weeks)
**712**

## Adverse Events (≥5%)

- Adult Phase 2/3 Cold Studies (Tablet)

|  | Placebo
N=1484 | Pleconaril 
400 mg TID
N=1480 |
| --- | --- | --- |
| SAE | 6 (0.4%) | 7 (0.5%) |
| ≥1 AE | 799 (54%) | 809 (55%) |
| Headache | 323 (22%) | 348 (24%) |
| Diarrhea | 97 (7%) | 114 (8%) |
| Nausea | 57 (4%) | 89 (6%) |

## Severe Adverse Events (≥0.5%)

|  | Placebo
N=1484 | Pleconaril 
400 mg TID
N=1480 |
| --- | --- | --- |
| ≥1 Severe AE | 74 (5.0%) | 60 (4.1%) |
| Headache | 22 (1.5%) | 24 (1.6%) |
| Diarrhea | 3 (0.2%) | 9 (0.6%) |
| Nausea | 8 (0.5%) | 3 (0.2%) |

- Adult Phase 2/3 Cold Studies (Tablet)

## Discontinuations Due to Adverse Events (≥0.3%)

|  | Placebo
N=1484 | Pleconaril 
400 mg TID
N=1480 |
| --- | --- | --- |
| Discontinuation due to AE | 40 (2.7%) | 51 (3.4%) |
| Headache | 6 (0.4%) | 7 (0.5%) |
| Diarrhea | 3 (0.2%) | 9 (0.6%) |
| Nausea | 5 (0.3%) | 6 (0.4%) |
| Vomiting | 4 (0.3%) | 6 (0.4%) |
| Bronchitis | 5 (0.3%) | 4 (0.3%) |
| Sinusitis | 2 (0.1%) | 4 (0.3%) |

- Adult Phase 2/3 Cold Studies (Tablet)

## Clinical Laboratory Safety

- No clinically significant changes in
- Hematology values
- Renal or liver function values
- Laboratory safety values

## Six-Week Prophylaxis Study

- N=1069 healthy adults
- Treatment arms
- Pleconaril 400 mg BID or 400 mg QD
- Placebo
- Total dose administered over 5 times larger than the 5-day treatment regimen
- Evaluations were performed at baseline and at Weeks 2, 4, 6, 8, and 12

## Menstrual Disorders: Six-Week Study

|  |  | Pleconaril |  |
| --- | --- | --- | --- |
|  | Placebo | 400 mg QD | 400 mg BID |
| All Women | 51/245 (21%) | 79/245
(32%) | 66/232
(28%) |
| OC Users | 20/81
(25%) | 52/98 
(53%) | 40/58 
(69%) |

## Menstrual Disorders: Summary

- No event was severe in pleconaril groups
- <1% in each group discontinued treatment
- 3.5% of women taking OCs and pleconaril in 5-7 day cold treatment studies reported a menstrual disorder
- Mechanism: Likely the result of increased CYP 3A4 activity

## Pregnancy: Six Week Study

| Age | BC Method | Estimated Conception | Outcome |
| --- | --- | --- | --- |
| Placebo (N=245 women) |  |  |  |
| 26 | Condom | Wk 9 | Spont. abortion |
| Pleconaril 400 mg QD (N=245 women) |  |  |  |
| 34 | Condom | – 1.7 wk | Spont. abortion |
| Pleconaril 400 mg BID (N=232 women) |  |  |  |
| 28 | Abstinence | Wk 1.7 | Ongoing |
| 29 | OC | Wk 1.4 | Elect. abortion |
| 34 | Condom | Wk 3.6 | Ongoing |
| 31 | OC | Wk 6 | Ongoing |
| 30 | Abstinence | Wk 3.3 | Elect. abortion |

## Pregnancy: 5-7 Day Treatment Studies

| Age | BC Method | Estimated Conception |  | Outcome |
| --- | --- | --- | --- | --- |
| Placebo (N=1505 women) |  |  |  |  |
| 35 | Diaphragm | – 0.4 wk | Spont. abortion |  |
| 20 | Condom | – 1 wk | Normal |  |
| 32 | OC | - | Lost to f/u |  |
| 29 | Condom | – 1 wk | Normal |  |
| Pleconaril (N=1900 women) |  |  |  |  |
| 25 | Condom | - |  | Normal |
| 28 | Condom | – 4 wk |  | Normal |

## 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

## Planned Clinical Studies

## Drug Interaction Studies

- Theophylline interaction
- PK/PD in chronic theophylline users
- CYP 3A induction
- PK interaction of pleconaril 400 mg TID x 5 days and oral midazolam to assess duration of induction
- Two cycle OC PK/PD interaction study of pleconaril 400 mg BID x 3 weeks to assess maximum PK induction and PD effects (ongoing)

## Treatment Studies

- Adults
- Safety and efficacy in patients with respiratory            co-morbidities
- Post-marketing investigation of the impact of pleconaril on antibiotic use
- Pediatrics
- Safety and efficacy in the treatment of colds
- Reduction in lower respiratory morbidity in children with asthma
- Virus transmission and drug susceptibility
- Family transmission study, virus challenge model, and monitoring study being considered

## Benefit-Risk Summary

**Ellen Cooper, MD, MPH**
**ViroPharma**

## Benefits of Pleconaril

- First antiviral treatment for the common cold
- Reduces the duration and severity of  picornavirus colds
- More rapid reduction in symptom severity beginning on the second day of treatment
- Impacts multiple cold symptoms
- Antiviral activity parallels clinical benefit
- Safe and well tolerated for 5-day treatment

## Risks:  Drug Interactions

- Theophylline
- Slight increase in steady-state plasma concentrations
- Oral contraceptives
- Increased incidence of menstrual irregularities
- CYP 3A substrates
- Decreased plasma concentrations of drugs with narrow concentration response relationships

## Guidance for Physicians

- Empiric treatment
- Self-diagnosed cold with rhinorrhea and no fever
- Start pleconaril within a day of onset of cold symptoms
- Information for patients
- Take pleconaril with food (meal or snack)
- Most common side effects: headache, nausea, diarrhea
- Women on OCs: use an additional method of birth control
- Drug interactions: refer to labeling
- Limited data in elderly and patients with
- 	co-morbidities

## Benefit-Risk 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
- Treatment benefits outweigh potential risks
- Pleconaril represents an important new option for the treatment of the common cold