picovir (pleconaril) nda 21-245 treatment of acute vri in adults (common cold)

Picovir

(Pleconaril)

NDA 21-245

Treatment of acute VRI in adults

(Common Cold)

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

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

Application Issues

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

Overall Study Results

• Difficulty demonstrating treatment effects Difficulty demonstrating treatment effects – Enteroviral meningitisEnteroviral meningitis– Hand, foot, and mouth diseaseHand, foot, and mouth disease– Early VRI studiesEarly VRI studies

• Phase 3 VRI studies demonstrate Phase 3 VRI studies demonstrate – Median 0.5 day faster time to resolution in all Median 0.5 day faster time to resolution in all

randomized patientsrandomized patients– Median 1.0 day faster time to resolution in Median 1.0 day faster time to resolution in

infected patientsinfected patients

Patient Subgroups

• Discordant results in smokers Discordant results in smokers • Difficulty drawing conclusions in elderly Difficulty drawing conclusions in elderly

patientspatients• Patients with co-morbid conditions

excluded from pivotal studies

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

Identification of Infected Patients

Nasal mucus sample

TaqMan RT-PCR Assay

ELOSA (RT-PCR) Assay

Virus Culture

PCR+

PCR-

PCR-

PCR+

61% PCR+ 63% Culture+

PCR-

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

Fluorescence versus Cycle

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

TaqMan and ELOSA Gel Analysis

Gel #4

M - +22 23 24 25 26 27 28 157

147

148

149

150

151

152

153

154

155

156

M - + 158

159

160

-- + MMM-

< <

Viral Culture

• Only PCR+ samples cultured– HeLa cells expressing ICAM at 33oC

• Reported positive or negative based on presence of cytopathic effects– No serotyping conductedNo serotyping conducted

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

Time to Primary EndpointTreatment Emergent Resistance

Median

days

PBO (n=333) 8.6

Pleconaril (n=286) 6.5

Pleconaril (n=28) 4.9

Time to Primary EndpointBaseline Lack of Susceptibility

Not

Susceptible

Susceptible

PBO 4.8 days (n=45)

8.3 days (n=335)

Pleconaril 8.1 days (n=50)

6.4 days (n=314)

Food Effect

• Pleconaril exposure increased 4.0-6.5 fold Pleconaril exposure increased 4.0-6.5 fold with high fat/calorie mealwith high fat/calorie meal

• In hepatic impaired, AUC In hepatic impaired, AUC 40% (18-55%)40% (18-55%)– Partially due to lower fat and meal Partially due to lower fat and meal

• Patients instructed to take pleconaril within Patients instructed to take pleconaril within 15 minutes of full meal or snack15 minutes of full meal or snack– Adherence unknownAdherence unknown– Impact on efficacy unknownImpact on efficacy unknown

Safety

• General tolerabilityGeneral tolerability– HeadachesHeadaches– Nausea, vomiting, abdominal pain, diarrhea Nausea, vomiting, abdominal pain, diarrhea

• CYP3A4 inductionCYP3A4 induction– Menstrual disordersMenstrual disorders– Potential for unintended pregnancies Potential for unintended pregnancies – Potential interactions with other medicationsPotential interactions with other medications

• Tachycardia/palpitationsTachycardia/palpitations

Pleconaril Adult Phase 2 7-day Treatment Studies

Study Regimens Endpoint Results (median days)

843-020 Pleconaril 400 mg BID (n=335) Pleconaril 400 mg TID (n=347) PBO (n=340)

Time (days) to resolution of all VRI symptoms sustained for 48 hours

ITT Pleconaril BID 8.0 Pleconaril TID 8.0 PBO 8.0 ITT-I Pleconaril BID 8.0 Pleconaril TID 9.0 PBO 8.0

843-032 Pleconaril 400 mg TID (n=436) PBO (n=439)

Time (days) to resolution of all VRI symptoms sustained for 24 hours

ITT Pleconaril 9.0 PBO 9.0 ITT-I Pleconaril 9.0 PBO 9.5

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

Studies 843-043 and 843-044Design

• Double-blind, placebo controlled • Healthy adults >18 years of age• Moderate to severe rhinorrhea• VRI symptoms <24 hours • Answer “yes” to “Are your symptoms due

to a cold?”• Excluded allergic rhinitis, fever >100,

underlying pulmonary, cardiac, immunocompromised, or serious illnesses


• 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


• 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

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

PBO Pleconaril

(n=1,050) (n=1,046)

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 score=18

Pleconaril Efficacy Results

Thomas Hammerstrom, PhD

Statistical Reviewer

Division of Antiviral Drug Products

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

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

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

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

Quartiles of Time to HealingAll Randomized Patients (ITT)


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

Quartiles of Time to HealingPCR+ Patients


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 >20

Pleconaril 173 8.5 12.0 17.5 0.51

Quartiles of Time to HealingAll Randomized


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

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 >16 46 46 57 46

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

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


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

Impact of Smoking(PCR+ Non-Smokers)


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

Impact of Smoking(PCR+ Smokers)


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

Gender Analysis-PCR+Trials 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

Smokers by Gender-PCR+Trials 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

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



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



Rhinorrhea PBO 338 4.5 7.5 12.0

Pleconaril 327 3.0 6.010.5 .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



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

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

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


• 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


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

Safety Review

• VRI safety database (n=4,468)– 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

General Adverse Events >2%in Pivotal Studies

PBO Pleconaril

(n=1,050) (n=1,046)

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 <1% 2%

Menstrual Disorders

• Early menses/intermenstrual bleeding, Early menses/intermenstrual bleeding, menorrhagia, menstrual disorder NOSmenorrhagia, menstrual disorder NOS

• Observed in 5-7 day treatment studiesObserved in 5-7 day treatment studies• Significant increased frequency in 6-week Significant increased frequency in 6-week

prophylaxis studyprophylaxis study– Women re-consented– Barrier method recommended– Menstrual disorders targeted AEs

Menstrual Disorders

PBO Pleconaril

OC users 0/223(0%)

7/229(3.1%)

Non-OC users 1/792(0.1%)

1/787(0.1%)

PBO Pleconaril QD Pleconaril BID

OC users 22/81(27%)

57/98(58%)

47/58(81%)

Non-OC users 22/132(16%)

17/128(13%)

24/144(16%)

Treatment Studies

Prophylaxis Study

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 >1000 hours

• Maximum and duration of induction unknown• Potential to effect

– immunosuppressants, antiarrhythmics, calcium channel blockers, protease inhibitors, Viagra

Potential Risk of Unintended Pregnancies

• 20% OC users (n=690)• 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

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

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

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

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


• Identification of infected patients possible Identification of infected patients possible • Quantitative performance not establishedQuantitative performance not established• No serotyping of positive culturesNo serotyping of positive cultures• ResistanceResistance

– Delayed resolution in patients with baseline lack Delayed resolution in patients with baseline lack of susceptibilityof susceptibility

– Shorter duration of illness in patients with loss of Shorter duration of illness in patients with loss of susceptibility susceptibility

– Single amino acid substitutions can lead to Single amino acid substitutions can lead to significant resistancesignificant resistance


• 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


• SafetySafety– CYP3A4 inductionCYP3A4 induction

• Menstrual disordersMenstrual disorders• Potential for OC failure and unintended pregnanciesPotential for OC failure and unintended pregnancies• Potential to impact efficacy of other medications Potential to impact efficacy of other medications

– Tachycardia/palpitationsTachycardia/palpitations– General tolerabilityGeneral tolerability

• HeadachesHeadaches• Nausea, vomiting, abdominal pain, diarrheaNausea, vomiting, abdominal pain, diarrhea

PleconarilReview Team

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

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

picovir (pleconaril) nda 21-245 treatment of acute vri in adults (common cold)

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