Picovir ? (Pleconaril)

1
Picovir ?(Pleconaril)

• NDA 21-245
• Treatment of acute VRI in adults
• (Common Cold)

2
Agenda

• Overview of NDA and issues
• Russ Fleischer, PA-C, MPH
• Statistical review of efficacy
• Thomas Hammerstrom, PhD
• Safety and summary
• Russ Fleischer, PA-C, MPH

3
Clinical Development Program

• VRI NDA 21-245 submitted July 31, 2001
• 2 pivotal studies
• 843-043 and 843-044 (400 mg TID x 5 days)
• 4 phase 2 studies
• 843-010
• 843-013
• 843-020
• 843-032

4
Application Issues

• Overall study results
• Patient subgroups
• Possible analysis populations
• Identification of infected patients
• Resistance
• Food effect
• Safety

5
Overall Study Results

• Difficulty demonstrating treatment effects
• Enteroviral meningitis
• Hand, foot, and mouth disease
• Early VRI studies
• Phase 3 VRI studies demonstrate
• Median 0.5 day faster time to resolution in all
  randomized patients
• Median 1.0 day faster time to resolution in
  infected patients

6
Patient Subgroups

• Discordant results in smokers
• Difficulty drawing conclusions in elderly
  patients
• Patients with co-morbid conditions excluded from
  pivotal studies

7
Possible Analysis Populations

• Infected (ITT-I)
• Identify infected patients
• Demonstrate treatment effect
• No harm in uninfected
• All randomized (ITT)
• More reflective of actual use
• Prescribed based on symptoms with no rapid
  diagnostic assay
• Prescribed to asymptomatic patients

8
Identification of Infected Patients
Nasal mucus sample
TaqMan ? RT-PCR Assay
PCR
PCR-
Virus Culture
ELOSA (RT-PCR) Assay
PCR
PCR-
61 PCR
63 Culture
PCR-
9
TaqMan RT-PCR Assay

• Qualitative
• Reported to detect 90/101 rhinovirus, 3/53
  enterovirus, and 0/2 parechovirus serotypes
• Sensitivity 93 (88-97)
• Assay run for 60 cycles
• 0.1 fluorescence level considered positive
• Quantitative
• Inadequate controls
• Lack of reproducible sampling
• Quantification of viral nucleic acid not
  validated

10
Fluorescence versus Cycle
11
ELOSA RT-PCR Assay

• Used to re-test TaqMan negative samples
• Reported to identify 101/101 rhinovirus, 53/53
  enterovirus, and 1/2 parechovirus serotypes
• Sensitivity 97 for picornavirus

12
TaqMan and ELOSA Gel Analysis
13
Viral Culture

• Only PCR samples cultured
• HeLa cells expressing ICAM at 33o?C
• Reported positive or negative based on presence
  of cytopathic effects
• No serotyping conducted

14
Resistance in Pivotal Studies

• 23.7 overall
• 13 baseline lack of susceptibility
• 10.7 loss of susceptibility (treatment-emergent)
• No data on specific serotypes
• 3/4 with baseline lack of susceptibility had
  single amino acid change at VP1 position 98
• Single amino acid substitutions led to
  100-fold decrease in susceptibility

15
Time to Primary EndpointTreatment Emergent
Resistance

• Median
• days
• PBO (n333) 8.6
• Pleconaril (n286) 6.5
• Pleconaril (n28) 4.9

16
Time to Primary EndpointBaseline Lack of
Susceptibility
17
Food Effect

• Pleconaril exposure increased 4.0-6.5 fold with
  high fat/calorie meal
• In hepatic impaired, AUC ?40 (18-55)
• Partially due to lower fat and meal
• Patients instructed to take pleconaril within 15
  minutes of full meal or snack
• Adherence unknown
• Impact on efficacy unknown

18
Safety

• General tolerability
• Headaches
• Nausea, vomiting, abdominal pain, diarrhea
• CYP3A4 induction
• Menstrual disorders
• Potential for unintended pregnancies
• Potential interactions with other medications
• Tachycardia/palpitations

19
Pleconaril Adult Phase 2 7-day Treatment Studies
20
Phase 2 Limitations

• Difficulty identifying infected patients
• Outcomes impacted by
• Uncontrolled and undocumented concomitant cold
  medication use
• Inclusion of smokers
• Inclusion of patients with fever
• Inclusion of patients with allergic rhinitis
• Stringent endpoints
• Initiation of treatment late in disease

21
Studies 843-043 and 843-044Design

• Double-blind, placebo controlled
• Healthy adults gt18 years of age
• Moderate to severe rhinorrhea
• VRI symptoms lt24 hours
• Answer yes to Are your symptoms due to a
  cold?
• Excluded allergic rhinitis, fever gt100,
  underlying pulmonary, cardiac, immunocompromised,
  or serious illnesses

22
Studies 843-043 and 843-044Design

• Randomization stratified by
• Smoking status
• Pre-use of cold medications
• 400mg pleconaril or PBO TID x 5 days
• Clinic visits day 3, 6, and 18
• Patient diaries for 18.5 days
• Acetaminophen/dextromethorphan provided

23
Studies 843-043 and 843-044Design

• Ordinal severity scores for rhinorrhea, nasal
  congestion, cough, pharyngeal signs, mylagia and
  malaise
• Nasal mucus collected days 1, 3, and 6 for
  virologic testing
• Experimental TaqMan PCR assay
• Experimental ELOSA for TaqMan negative samples
• Only PCR samples cultured

24
Studies 843-043 and 843-044 Demographics (ITT)

• PBO Pleconaril
• (n1,050) (n1,046)
• Gender
• Male 31 31
• Female 69 69
• Age (mean years) 36 36
• Range 18-86 17-82
• Smokers 28 29
• Pre-treatment cold med users 30
  30
• Median hours between first symptom 19.8
  20.1
• and first dose
• Baseline severity score 9
  9
• PCR positive at baseline 61 62

Maximum score18
25
Pleconaril Efficacy Results

• Thomas Hammerstrom, PhD
• Statistical Reviewer
• Division of Antiviral Drug Products

26
Phase 2 and 3 Clinical Trials

• Pivotal Phase 3 Trials 43 and 44
• Endpoint Time to no rhinorrhea, five other
  symptoms all mild or absent, and no cold
  medication use for 48 hours
• Phase 2 Trials 10, 20 and 32
• Endpoint Time to no rhinorrhea, five other
  symptoms all mild or absent for 48 hours
• Analysis populations PCR and ITT
• ELOSA assay for trials 20 and 32
• TaqMan plus ELOSA for trial 43 and 44
• Results based on the two slightly different
  endpoints were nearly identical in studies 43 and
  44

27
PCR and Culture Status(Trial 43)

• STATUS/ARM PBO Pleconaril
• Enrolled 526 526
• PCR positive at baseline
• Positive culture 196 201
• Negative culture 104 120
• PCR negative at baseline,
• positive day 3-6 24 13
• Total PCR positive 324 334
• Never PCR positive 202 192

28
PCR and Culture Status(Trial 44)

• STATUS/ARM PBO Pleconaril
• Enrolled 524 520
• PCR positive at baseline
• Positive culture 224 206
• Negative culture 115 121
• PCR negative at baseline,
• positive day 3-6 11 16
• Total PCR positive 350 343
• Never PCR positive 174 177

29
Quartiles of Time to HealingPCR Patients
(ITT-I)

• Trial Arm N Q1 Q2 Q3 p value
• 43 PBO 300 5.0 7.5 12.5
• Pleconaril 321 4.0 7.0 11.0 0.023
• 44 PBO 339 5.0 8.5 12.5
• Pleconaril 327 4.0 7.0 11.0 0.008

30
Quartiles of Time to HealingAll Randomized
Patients (ITT)

• Trial Arm N Q1 Q2 Q3 p value
• 43 PBO 526 4.0 7.5 12.5
• Pleconaril 526 4.0 7.0 11.5 0.13
• 44 PBO 524 4.5 8.0 13.0
• Pleconaril 520 4.0 7.0 11.5 0.014

31
Quartiles of Time to HealingPCR Patients

• Trial Arm N Q1 Q2 Q3 p value
• 20 PBO 128 5.0 8.0 13.0
• Pleconaril 147 5.0 9.0 13.0 0.70
• 32 PBO 205 8.5 12.5 gt20
• Pleconaril 173 8.5 12.0 17.5 0.51

32
Quartiles of Time to HealingAll Randomized

• Trial Arm N Q1 Q2 Q3 p value
• 20 PBO 334 5.0 8.0 15.0
• Pleconaril 340 4.0 8.0 12.0 0.011
• 32 PBO 432 8.0 12.0 19.5
• Pleconaril 427 8.0 12.0 19.5 0.82

33
Loss to Follow-UpPCR Patients

• Trial 43 44
• Arm PBO Pleconaril PBO Pleconaril
• Enrolled 300 321 339 327
• Day 0 5 11 8 6
• Days 1-5 11 8 5 4
• Days 6-15 2 2 1 3
• Days gt16 46 46 57 46

34
Impact of Pre-Treatment Cold Medication Use (PCR
Non-Users)

• Trial Arm N Q1 Q2 Q3
• 43 PBO 215 4.5 7.5 11.5
• Pleconaril 220 3.5 6.5 10.5
• 44 PBO 219 5.0 8.5 12.5
• Pleconaril 214 3.5 6.5 10.5

35
Impact of Pre-Treatment Cold Medication Use (PCR
Users)

• Trial Arm N Q1 Q2 Q3
• 43 PBO 85 6.5 9.0 14.5
• Pleconaril 101 4.0 7.5 13.5
• 44 PBO 120 5.0 8.5 13.0
• Pleconaril 113 4.5 8.5 12.0

36
Impact of Smoking(PCR Non-Smokers)

• Trial Arm N Q1 Q2 Q3
• 43 PBO 224 5.0 7.5 12.0
• Pleconaril 219 3.5 6.5 10.5
• 44 PBO 249 5.0 8.5 12.5
• Pleconaril 240 3.5 6.5 10.5
• 32 PBO 206 6.0 10.5 15.5
• Pleconaril 173 5.5 8.0 13.5

37
Impact of Smoking(PCR Smokers)

• Trial Arm N Q1 Q2 Q3
• 43 PBO 76 5.5 8.0 13.5
• Pleconaril 102 5.5 9.0 14.0
• 44 PBO 90 5.0 8.5 12.5
• Pleconaril 87 5.5 9.0 15.0
• 32 PBO 75 7.5 10.5 16.0
• Pleconaril 67 7.5 11.0 19.5

38
Gender Analysis-PCRTrials 43 and 44

• Gender Arm N Q1 Q2 Q3
• Female PBO 427 5.5 8.5 13.5
• Pleconaril 439 4.0 7.0 11.5
• Male PBO 212 4.0 7.0 11.0
• Pleconaril 209 3.0 6.0 11.0

39
Smokers by Gender-PCRTrials 43 and 044

• Gender Arm N Q1 Q2 Q3
• Female PBO 109 5.5 9.0 13.0
• Pleconaril 122 6.0 9.0 14.5
• Male PBO 57 3.5 6.5 12.0
• Pleconaril 67 4.5 8.5 14.5

40
Time to Resolution of Individual Symptoms-Trial
43 (PCR)

• Symptom Arm N Q1 Q2 Q3 P
• Rhinorrhea PBO 300 4.0 7.0 11.0
• Pleconaril 321 3.0 6.0 10.5 .040
• Congestion PBO 284 4.0 6.5 10.0
• Pleconaril 310 3.5 5.5 8.5 .021
• Cough PBO 224 3.5 6.0 10.5
• Pleconaril 251 3.0 6.0 11.0 .51
• Malaise PBO 258 2.5 4.5 8.0
• Pleconaril 280 2.5 4.0 6.5 .039

41
Time to Resolution of Individual Symptoms-Trial
43 (PCR)

• Symptom Arm N Q1 Q2 Q3 P
• Myalgia PBO 160 2.5 3.5 6.0
• Pleconaril 164 1.5 2.5 4.5 .0001
• Sore throat PBO 258 2.0 3.0 6.0
• Pleconaril 274 1.5 2.5 4.5 .0001
• Cold Med Use PBO 109 2.0 3.0 5.0
• Pleconaril 102 2.0 3.0 4.5 .24

42
Time to Resolution of Individual Symptoms-Trial
44 (PCR)

• Symptom Arm N Q1 Q2 Q3 P
• Rhinorrhea PBO 338 4.5 7.5 12.0
• Pleconaril 327 3.0 6.0 10.5 .0023
• Congestion PBO 317 4.0 6.5 10.0
• Pleconaril 313 3.5 6.0 10.0 .20
• Cough PBO 232 3.5 7.0 12.5
• Pleconaril 240 3.5 6.0 11.0 .37
• Malaise PBO 292 3.0 4.0 6.5
• Pleconaril 274 2.5 4.0 7.5 .51

43
Time to Resolution of Individual Symptoms-Trial
44 (PCR)

• Symptom Arm N Q1 Q2 Q3 P
• Myalgia PBO 169 2.0 3.5 6.0
• Pleconaril 157 2.0 3.0 6.0 .10
• Sore throat PBO 292 1.5 3.0 5.0
• Pleconaril 274 1.5 3.0 5.0 .77
• Cold Med Use PBO 138 2.0 3.5 5.5
• Pleconaril 109 2.0 3.0 5.0 .63

44
Secondary EndpointsPCR Patients

• Trial Endpoint Pleconaril PBO Difference P
• 43 Days impaired 3.48 3.85 -.38
  .19
• 44 Days impaired 3.52 3.70 -.17
  .50
• 43 Nights impaired 2.73 3.45 -.72
  .005
• 44 Nights impaired 2.96 3.28 -.31
  .20
• 43 Complications .08 .06 .02
  .38
• 44 Complications .06 .04 .01
  .48

45
Efficacy Conclusions-1

• Pleconaril is statistically significantly
  superior to placebo in the PCR population
• If the assay has low false negative rate, then
  the PCR population includes most infected
  subjects and statistical significance confirms
  the pleconaril effect

46
Efficacy Conclusions-2

• Pleconaril showed no statistically significant
  benefit in the PCR populations of trials 20 and
  32, with a slightly different endpoint and
  slightly different recruitment criteria
• Pleconaril will be used in the whole population,
  in which the estimated benefit is approximately
  0.5 day

47
Efficacy Conclusions-3

• Pleconaril has no effect in smokers. This
  absence of benefit has been confirmed in three
  separate studies 43, 44, and 32

48
Safety Review

• VRI safety database (n4,468)
• 2,488 treated with pleconaril
• 1,986 treated with placebo
• No deaths or significant laboratory abnormalities
• Adverse events generally similar
• DCs due to adverse events similar
• Headache, GI most common for both groups

49
General Adverse Events gt2in Pivotal Studies

• PBO Pleconaril
• (n1,050) (n1,046)
• Headache 21 23
• Diarrhea 7 7
• Nausea 4 6
• Vomiting 2 2
• Abdominal pain 4 2
• Sinusitis 2 3
• Bronchitis 3 3
• Increased cough 3 3
• Dizziness 1 2
• Rhinitis 3 2
• Menstrual disorders lt1 2

50
Menstrual Disorders

• Early menses/intermenstrual bleeding,
  menorrhagia, menstrual disorder NOS
• Observed in 5-7 day treatment studies
• Significant increased frequency in 6-week
  prophylaxis study
• Women re-consented
• Barrier method recommended
• Menstrual disorders targeted AEs

51
Menstrual Disorders
Treatment Studies
Prophylaxis Study
52
CYP3A4 Induction

• IV midazolam AUC ?28 (24-33)
• Ethinyl estradiol AUC ?35 (29-40)
• No significant change in norethindrone PK
• Single dose T1/2 180 hours
• Multiple dose T1/2 gt1000 hours
• Maximum and duration of induction unknown
• Potential to effect
• immunosuppressants, antiarrhythmics, calcium
  channel blockers, protease inhibitors, Viagra?

53
Potential Risk of Unintended Pregnancies

• 20 OC users (n690)
• 13 pregnancies
• 8 pleconaril
• 2 in 156 OC users (400 BID in 6-week study)
• 1 ongoing (EDC June 10, 2002)
• 1 abortion
• 5 placebo
• 1 in OC user
• Outcome unknown

54
Potential Risk of Unintended Pregnancy

• CYP3A4 induction of ethinyl estradiol likely to
  impact at least entire cycle
• 10.4 million women between 15-44 used of a pill
  form of contraception
• Expected OC failure 1/100 women/year of use
  (range 0-2.5)
• 2/156 in 6 weeks appears higher than expected
• Pleconaril not teratogenic, mutagenic, or
  genotoxic in animal studies

AGI, 1998
55
Tachycardia/Palpitations

• Theophylline CYP1A2 probe study
• 15 healthy theophylline-naïve volunteers
• Theophylline 450 mg day 1, pleconaril 400 mg TID
  days 4-10, 450 mg theophylline dose on day 8
• 3/15 tachycardia/palpitations during
  pleconaril/theophylline administration
• ? abdominal pain, nausea, dizziness, syncope
• Theophylline AUC ?15 (4-28)
• No significant PK changes in 3 with palpitations

56
Tachycardia/Palpitations

• Adult VRI studies
• 7 pleconaril with palpitations/tachycardia (0.3)
• 3 reported onset within one hour of ingestion
• 4 discontinued
• 1 serious (ER visit)
• No pleconaril re-challenge
• 2 placebo (0.1)
• 1 on day 5 within 1 hour
• 1 on day 2 within 30 minutes

57
Summary of Application Issues

• Overall study results
• Efficacy in phase 2 not demonstrated
• Efficacy in phase 3
• 0.5 day benefit in all randomized
• 1.0 day benefit in PCR
• Efficacy in smokers not demonstrated
• No data in patients with co-morbid conditions

58
Summary of Application Issues

• Identification of infected patients possible
• Quantitative performance not established
• No serotyping of positive cultures
• Resistance
• Delayed resolution in patients with baseline lack
  of susceptibility
• Shorter duration of illness in patients with loss
  of susceptibility
• Single amino acid substitutions can lead to
  significant resistance

59
Summary of Application Issues

• Analysis populations
• Expected uses
• Prescribed to symptomatic with no diagnostic
  assay
• Prescribed to asymptomatic for use at first
  symptom
• Food requirement
• Administration with a full meal
• Requires initiation within 24 hours of symptom
  onset

60
Summary of Application Issues

• Safety
• CYP3A4 induction
• Menstrual disorders
• Potential for OC failure and unintended
  pregnancies
• Potential to impact efficacy of other medications
  
• Tachycardia/palpitations
• General tolerability
• Headaches
• Nausea, vomiting, abdominal pain, diarrhea

61
PleconarilReview Team

• Nara Battula
• Anita Bigger
• Jim Farrelly
• Leslie Furlong
• Zi Qiang Gu
• Tom Hammerstrom
• Katherine Laessig
• Steve Miller
• Julian ORear

• Kellie Reynolds
• Destry Sillivan
• Greg Soon
• Kathleen Whitaker
• Jenny Zheng