1 / 78

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

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

phil
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Pleconaril for Treatment of the Common ColdFDA Antiviral Drugs Advisory Committee Meeting March 19, 2002

  2. 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

  3. H3C H3C CF3 N N (CH2)3O O O N H3C Pleconaril First antiviral drug with activity against picornaviruses, the predominant cause of the common cold

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

  5. Frederick Hayden, MD University of Virginia Health Sciences Center Impact of the Common Cold

  6. 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

  7. 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

  8. 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

  9. 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

  10. Picornavirus Colds Pathogenesis Virus Infection of Nasal Epithelium Proinflammatory Cytokines (IL-1, -6, -8) Tracheobronchial Infection Neurogenic Responses Secondary Inflammation (PMNs, kinins) Cholinergic Stimulation Vasodilation Serum Transudation Mucus Secretion Airway Hyperreactivity Nasal Obstruction Sore Throat Sneezing Rhinorrhea Cough

  11. 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

  12. 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

  13. 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

  14. Preclinical Profile and Clinical Pharmacology Mark McKinlay, PhD ViroPharma

  15. RNA core Pleconaril Mechanism of Action Blocks uncoating and attachmentby binding into a hydrophobic pocket within the capsid

  16. 101 Rhinovirus Serotypes (Prototypic Strains) 53 Enterovirus Serotypes (Prototypic Strains) Distribution of Susceptibility to Pleconaril 10 10 1 1 IC50 mg/mL IC50 mg/mL 0.1 0.1 0.01 0.01 0.001 0.001 Serotypes Serotypes

  17. Human Pharmacokinetic Profile 400 mg Single Dose (Commercial Tablet) 3 2 MIC90 Conc. (g/mL) t1/2α = 2.8 h 1 t1/2180 h MIC75 0 0 4 8 12 16 20 24 Time (h)

  18. 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

  19. H3C H3C CF3 N N (CH2)3O O O N H3C H3C H3C NH2 N (CH2)3O O NH H3C Human Metabolism Pleconaril CH3 Oxidation Isoxazole Ring Opening =N-OH =N-O-Glucuronidation

  20. 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

  21. Oral Theophylline CYP 1A2 Probe Study 100.0 • Theophylline alone • Theophylline with pleconaril 10.0 Conc. (g/mL) 1.0 0.1 0 10 20 30 40 50 60 Time (h) No change in Cmax 15% increase in AUC <20% increase in t1/2

  22. IV Midazolam CYP 3A Probe Study 100.0 • Midazolam alone • Midazolam with pleconaril 10.0 Conc. (ng/mL) 1.0 0.1 0 1 2 3 4 5 6 Time (h) 28% decrease in AUC 16% decrease in t1/2

  23. Oral Contraceptive Interaction Study 1000.0 • Ethinylestradiol alone • Ethinylestradiol with pleconaril 100.0 Conc. (pg/mL) 10.0 1.0 0.1 0 5 10 15 20 25 30 35 40 45 50 Time (h) No clinically significant change in Cmax 34% decrease in ethinylestradiol AUC No effect on norethindrone pharmacokinetics

  24. 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

  25. Clinical Efficacy and Safety Ellen Cooper, MD, MPH ViroPharma

  26. Clinical Development of Pleconaril for the Common Cold Phase II Coxsackievirus A21 challenge study Two pivotal Phase III studies 2002 1999 1998 1997 1996 2001 2000 Three Phase II studies in natural colds Two Phase II pediatric studies One 6-week adult prophylaxis study

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. Demographics: ITT-I

  35. Baseline Disease Characteristics: ITT-I

  36. 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

  37. Primary Efficacy Endpoint: ITT-I

  38. Primary Efficacy EndpointStudies 043 and 044 Study 043 Study 044

  39. Consistency of Treatment Benefit: ITT-I

  40. Primary Endpoint: ITT and RT-PCR Negative ITT RT-PCR Negative

  41. Antiviral Effect: Virus Culture Study 043 Study 044 % Culture Positive N= 182 N= 185 N= 180 N= 184 N= 212 N= 195 N= 207 N= 191 p=0.835 p<0.001 p=0.016 p<0.001 Study Day Study Day

  42. 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

  43. Resolution of Individual Symptoms: ITT-I Placebo Pleconaril Study 044 Study 043 * * * * Median Days * * * * * Rhinorrhea Nasal Congestion Sore Throat Rhinorrhea Nasal Congestion Sore Throat Cough Cough Malaise Malaise Myalgia Myalgia *p<0.05

  44. Summary of Secondary Endpoints: ITT-I Percent Reduction vs. Placebo Study 043 Study 044 * 35 * 30 25 * * 20 * * * 15 10 5 0 Time to No Cold Tissue Use Nights w/Sleep Disturbance Days with Impaired Activity Days with Concomitent Symptom Med. Use Total Symptom Score *p<0.05 vs Placebo

  45. Patients with Bothersome Symptoms by Day (Post Hoc) 100 100 Study 044 Study 043 * * 75 75 % % * Placebo * * 50 * 50 * Placebo Pleconaril Pleconaril * * 25 25 * 0 0 B 1P 2A 2P 3A 3P 4A 4P 5A 5P 6A 6P B 1P 2A 2P 3A 3P 4A 4P 5A 5P 6A 6P * p<0.05 Study Day Study Day

  46. Total Symptom Severity (Post Hoc) 100 100 Study 044 Study 043 90 90 80 80 * * 70 70 * % of Baseline Placebo Placebo 60 60 * * * 50 50 * * * 40 40 * * Pleconaril Pleconaril * * * 30 * 30 * * 20 20 10 10 0 0 B 1P 2A 2P 3A 3P 4A 4P 5A 5P 6A 6P B 1P 2A 2P 3A 3P 4A 4P 5A 5P 6A 6P * p<0.05 Study Day

  47. Subgroup Analyses

  48. 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)

  49. Efficacy by Smoking Status: ITT-I (Pooled)

  50. Antiviral Effect by Smoking Status Non-Smokers Smokers % Culture Positive N= 284 N= 250 N= 279 N= 249 N= 110 N= 130 N= 108 N= 126 p=0.035 p<0.001 p=0.793 p=0.058 Study Day Study Day

More Related