A New Once-Daily A New Once-Daily Formulation of IsotretinoinFormulation of Isotretinoin

Accutane NFAccutane NF

John McLane, PhDJohn McLane, PhDRoche Medical Science and Safety Roche Medical Science and Safety

David Young, PharmD, PhDDavid Young, PharmD, PhDGloboMax LLCGloboMax LLC

Rationale for New Formulation of IsotretinoinRationale for New Formulation of Isotretinoin

New Formulation Development ProgramNew Formulation Development Program

Dose/Exposure Response RelationshipDose/Exposure Response Relationship

Risk Management of Two FormulationsRisk Management of Two Formulations

Benefit of New FormulationBenefit of New Formulation

Accutane Dose Efficacy StudiesAccutane Dose Efficacy Studies

Publication N DoseEfficacy

Rank (mg/kg)

Conditions

Farrell 1980 14 1.0 0.5 0.1 FedJones 1981 22 1.0 = 0.5 > 0.1 FedPlewig 1981 127 1.0 > 0.5 > 0.2 FedStrauss 1984 150 1.0 0.5 0.1 FedPeck 1979 14 2.0 = 1.0 Fasted

Variability in Accutane Exposure Variability in Accutane Exposure

Dosing without food results in a significant reduction in exposure Dosing without food results in a significant reduction in exposure

Physician SurveyPhysician Survey

– 68% of patients instructed to take Accutane with food68% of patients instructed to take Accutane with food

– 21% of patients instructed to take Accutane once a day (approximately 1 21% of patients instructed to take Accutane once a day (approximately 1 mg/kg) mg/kg)

– Prescribers report that 33% of patients do not take Accutane Prescribers report that 33% of patients do not take Accutane consistently with foodconsistently with food

– Prescribers report that 22% of patients do not consistently take the Prescribers report that 22% of patients do not consistently take the second dose in a BID regimensecond dose in a BID regimen

Overall Effect: Overall Effect: significantsignificant patient variability in exposurepatient variability in exposure

Accutane Dosing IssuesAccutane Dosing Issues Inconsistency in dosing recommendationsInconsistency in dosing recommendations

– once a day or twice a dayonce a day or twice a day– with or without food with or without food

Individual tolerabilityIndividual tolerabilityPrescriber survey shows that the principal reasons for Prescriber survey shows that the principal reasons for patients withdrawing from therapy are:patients withdrawing from therapy are:– mucocutaneous effects (19%)mucocutaneous effects (19%)– triglyceride elevations (17%)triglyceride elevations (17%)

ComplianceCompliance– Noncompliance would result in under/over dosing Noncompliance would result in under/over dosing

which may affect efficacy and safetywhich may affect efficacy and safety

The New Formulation (NF) of Isotretinoin The New Formulation (NF) of Isotretinoin is as Safe and Efficacious as Accutaneis as Safe and Efficacious as Accutane

Simplifying dosing recommendationsSimplifying dosing recommendations– The NF can be given with or without foodThe NF can be given with or without food– The NF can be given QD The NF can be given QD

Individual tolerabilityIndividual tolerability– The NF has fewer and less intense mucocutaneous eventsThe NF has fewer and less intense mucocutaneous events– The NF has fewer patients with elevated triglycerides The NF has fewer patients with elevated triglycerides

Compliance with dosing regimen Compliance with dosing regimen – More predictable exposure from NF decreases the impact of More predictable exposure from NF decreases the impact of

individual noncomplianceindividual noncompliance

Rationale for New Formulation of IsotretinoinRationale for New Formulation of Isotretinoin

New Formulation Development ProgramNew Formulation Development Program

Dose/Exposure Response RelationshipDose/Exposure Response Relationship

Risk Management of Two FormulationsRisk Management of Two Formulations

Benefit of New FormulationBenefit of New Formulation

Clinical Development Program for NFClinical Development Program for NFPivotal Clinical ProgramPivotal Clinical Program

– efficacy and safety trialefficacy and safety trial

Pharmacokinetic ProgramPharmacokinetic Program– food effect on bioavailabilityfood effect on bioavailability– bioequivalence bioequivalence – dose proportionalitydose proportionality

Hormonal Contraceptive Interaction ProgramHormonal Contraceptive Interaction Program– in vitro studiesin vitro studies– clinical evaluationsclinical evaluations

Clinical Study ObjectiveClinical Study Objective

Compare the efficacy and safety:Compare the efficacy and safety:

New FormulationNew Formulation vs. vs. AccutaneAccutane

Once per dayOnce per day Twice per dayTwice per day

No FoodNo Food FoodFood

Lower ExposureLower Exposure Labeled ExposureLabeled Exposure

182M / 118 F182M / 118 F 174M / 126F174M / 126F

Daily Dosing RegimenDaily Dosing Regimen

12 AM12 AM 12 Noon12 Noon 12 AM12 AM

Accutane Group 1 mg/kgAccutane Group 1 mg/kg

New Formulation Group 0.4 mg/kgNew Formulation Group 0.4 mg/kg

ActiveActive ActiveActive PlaceboPlacebo

PlaceboPlacebo PlaceboPlacebo ActiveActive

BreakfastBreakfast DinnerDinner

Inclusion CriteriaInclusion Criteria

Male or non-pregnant and non-nursing female Male or non-pregnant and non-nursing female patients, 12 years of age or olderpatients, 12 years of age or older

Diagnosed with severe recalcitrant nodular Diagnosed with severe recalcitrant nodular acne, with 10 or more nodular lesions at least acne, with 10 or more nodular lesions at least 5 mm in diameter5 mm in diameter

Clinical Efficacy EndpointsClinical Efficacy Endpoints

PrimaryPrimary– number of patients with 90% reduction in nodulesnumber of patients with 90% reduction in nodules– reduction in total number of nodules from baselinereduction in total number of nodules from baseline

SecondarySecondary– global evaluations by both patients and physiciansglobal evaluations by both patients and physicians– reduction in total number of papules and pustulesreduction in total number of papules and pustules

Safety Evaluations During Trial Safety Evaluations During Trial Laboratory

– CBC, blood lipids, liver enzymesCBC, blood lipids, liver enzymes

Psychiatric evaluationsPsychiatric evaluations– Mood/Depression QuestionnaireMood/Depression Questionnaire– Beck Depression InventoryBeck Depression Inventory

Mucocutaneous adverse eventsMucocutaneous adverse events– Dry or peeling skinDry or peeling skin– Dry or bleeding noseDry or bleeding nose– Dry or irritated eyesDry or irritated eyes– Chapped lipsChapped lips– Rash or erythema of faceRash or erythema of face

Additional EvaluationsAdditional Evaluations

Objective measurements of inflammatory Objective measurements of inflammatory lesions at 8 week and 16 week evaluation lesions at 8 week and 16 week evaluation pointspoints

Subjective measurement of need for Subjective measurement of need for retreatmentretreatment– phone call to patients 16 weeks post therapyphone call to patients 16 weeks post therapy

Results - STD Efficacy AnalysesResults - STD Efficacy AnalysesNew Formulation AccutaneEfficacy

ParameterBaseline

20weeks

Baseline20

weeks

Outcome

Total nodules 20.6 2.4 18.7 1.8Equivalent

Total papulesand pustules 26.1 3.5 26.1 2.6

Equivalent

Patients with>90% clearing 70.9% 78.4% Equivalent

PhysicianGlobal 1 70% 74%

NotStatistically

DifferentNeed for

Retreatment at16 wk post 2

18.3% 13.4%Not

Analyzed

1. Categorized as “cleared” or “excellent response”2. Subjective evaluation

AccutaneAccutaneAccutane NFAccutane NF

Patients with adverse eventPatients with adverse event

Total adverse eventsTotal adverse events

Adverse events leading to Adverse events leading to treatment discontinuationtreatment discontinuation

Serious adverse eventsSerious adverse events

Withdrawals (non AEs)Withdrawals (non AEs)

VariableVariable

296 296

13621362

16 16

2 2

2222

293 293

14501450

16 16

4 4

3030

Overall Comparison of SafetyOverall Comparison of Safety

Accutane (16) New Formulation (16)Appendicitis Depression (3)Chapped lips, dry skin Dizziness/Blurred visionHeadache (3) General body weaknessIrritated eyes Hair lossLFT (3) HeadacheLow white cell count LFT (3)Triglyceride elev (6) Mood swings

PregnancyPustular eruptionTriglyceride elev (3)

Adverse Events Leading to Treatment Adverse Events Leading to Treatment DiscontinuationDiscontinuation

Comparison of Total Adverse Events (>5%)Comparison of Total Adverse Events (>5%)

0

50

100

150

200

250

300

Nu

mb

er

of

Ev

en

ts NF

Accutane

Lipid Profile During TreatmentLipid Profile During Treatment

Abnormal triglyceride levels were observed inAbnormal triglyceride levels were observed in– 48/300 patients on Accutane NF 48/300 patients on Accutane NF – 75/300 patients on Accutane 75/300 patients on Accutane

Mean triglyceride levels increased byMean triglyceride levels increased by– 0.57 0.57 ± 0.87 mmol/L for Accutane NF 0.87 mmol/L for Accutane NF– 0.99 ± 1.44 mmol/L for Accutane0.99 ± 1.44 mmol/L for Accutane

Mean cholesterol levels increased byMean cholesterol levels increased by– 0.4 0.4 ± 0.56 mmol/L for Accutane NF 0.56 mmol/L for Accutane NF– 0.6 ± 0.69 mmol/L for Accutane0.6 ± 0.69 mmol/L for Accutane

Treatment GroupTreatment Group

Comparison of Psychiatric EventsComparison of Psychiatric Events

Accutane NF Accutane NF Accutane Accutane N = 300 N = 300 N =300N =300

Patients reporting AEsPatients reporting AEs 1111 11

Positive Mood AssessmentsPositive Mood Assessments 3737 3838

Patients with BDI >13 (not BL) Patients with BDI >13 (not BL) 99 1010

Pts with Baseline BDIPts with Baseline BDI131311 66 7 7

Prior history (medications)Prior history (medications) 1313 1515

Additional BDIAdditional BDI11 22 22

1. Subgroup of prior category1. Subgroup of prior category

Mucocutaneous Adverse Events (MAEs)Mucocutaneous Adverse Events (MAEs)

MAEs were fewer and less intense in Accutane MAEs were fewer and less intense in Accutane NF-treated patients NF-treated patients

At several time points, differences were At several time points, differences were statistically significantstatistically significant

Subgroup analysis showed no imbalance among Subgroup analysis showed no imbalance among age, sex, race, or body weight categoriesage, sex, race, or body weight categories

Mucocutaneous Event:Mucocutaneous Event:Dry or Bleeding NoseDry or Bleeding Nose

0%

10%

20%

30%

40%

50%

0 5 10 15 20

Weeks

Pe

rce

nt

of

Pa

tie

nts

Accutane NF

Accutane

** *

* *

Mucocutaneous Event: Dry or Irritated Mucocutaneous Event: Dry or Irritated EyesEyes

0%

10%

20%

30%

40%

50%

0 5 10 15 20

Weeks

Pe

rce

nt

of

Pa

tie

nts

Accutane NF

Accutane

**

* * *

Isotretinoin / Hormonal Contraceptives Isotretinoin / Hormonal Contraceptives ProgramProgram

To assure that isotretinoin does not alter the To assure that isotretinoin does not alter the clinical pharmacology of hormonal clinical pharmacology of hormonal contraceptivescontraceptives

Two components of program:Two components of program:– in vitro studies with hepatocytes and in vitro studies with hepatocytes and

microsomes microsomes – clinical programclinical program

In Vitro Human Hepatocytes ExperimentsIn Vitro Human Hepatocytes ExperimentsExperiment Completion DatesExperiment Completion Dates

ProgestinCompound

InhibitionStudy*

InductionStudy†

Medroxyprogesterone No inhibition Dec 2000Progesterone No inhibition Jan 2001Norethindrone Oct 2000 Apr 2001Norgestimate Jan 2001 May 2001Levonorgestrel Mar 2001 Aug 2001

*Initiated January 2000: 5-6 months to complete each study*Initiated January 2000: 5-6 months to complete each study††Initiated January 2000: 11 months to complete each studyInitiated January 2000: 11 months to complete each study

Oral Contraceptive Clinical StudiesOral Contraceptive Clinical Studies

Two studies to determine if isotretinoin affects oral Two studies to determine if isotretinoin affects oral contraceptives (Ortho-Novum 7/7/7)contraceptives (Ortho-Novum 7/7/7)– pharmacokinetics (ethinyl estradiol and pharmacokinetics (ethinyl estradiol and

norethindrone) norethindrone) – pharmacodynamics (LH/FSH/progesterone) pharmacodynamics (LH/FSH/progesterone)

Females with severe recalcitrant nodular acneFemales with severe recalcitrant nodular acne

Accutane 1.0 mg/kg/day in two divided dosesAccutane 1.0 mg/kg/day in two divided doseswith foodwith food

Accutane NF 0.4 mg/kg/day as a single dailyAccutane NF 0.4 mg/kg/day as a single dailydose fasteddose fasted

Oral Contraceptive Studies: Pharmacokinetic (PK) Oral Contraceptive Studies: Pharmacokinetic (PK) and Pharmacodynamic (PD) Assessmentsand Pharmacodynamic (PD) Assessments

Study Month 1 Study Month 2OC Stabilization OC Pill Cycle 2

Study Month 3OC Pill Cycle 3 + Isotretinoin

Day 6

Day 6

Day 20

Day 20

PK and PDAssessments

Study Month 4

IsotretinoinInitiated

OC Pill Cycle 4 + Isotretinoin

Oral Contraceptive StudiesOral Contraceptive StudiesCurrent StatusCurrent Status

No pregnanciesNo pregnancies

No serious or unexpected adverse eventsNo serious or unexpected adverse events

Timelines:Timelines:

September 2000: last patient visit scheduled September 2000: last patient visit scheduled for both studiesfor both studies

1st Quarter 2001: final study reports to FDA1st Quarter 2001: final study reports to FDA

Rationale for New Formulation of IsotretinoinRationale for New Formulation of Isotretinoin

New Formulation Development ProgramNew Formulation Development Program

Dose/Exposure Response RelationshipDose/Exposure Response Relationship

Risk Management of Two FormulationsRisk Management of Two Formulations

Benefit of New FormulationBenefit of New Formulation

Isotretinoin Dose Efficacy StudiesIsotretinoin Dose Efficacy Studies

Publication N DoseEfficacy

Rank (mg/kg)

Conditions

Farrell 1980 14 1.0 0.5 0.1 FedJones 1981 22 1.0=0.5>0.1 FedPlewig 1981 127 1.0>0.5>0.2 FedStrauss 1984 150 1.00.50.1 FedPeck 1979 14 2.0=1.0 FastedNF Study 600 1.0 0.4 NF Fed/Fasted

Plasma Concentrations of Isotretinoin After Single Dose of Plasma Concentrations of Isotretinoin After Single Dose of Accutane (80 mg), Accutane NF (30 mg) Under Fed or Accutane (80 mg), Accutane NF (30 mg) Under Fed or Fasted Conditions (n=74)Fasted Conditions (n=74)

IsotretinoinIsotretinoinng/mLng/mL

Time, (hrs)Time, (hrs)

0

100

200

300

400

500

600

700

0 6 12 18 24

Accutane, 80 mg, Fasted

Accutane, 80 mg, Fed

Accutane NF, 30 mg, Fasted

Accutane NF, 30 mg, Fed

Effect of Food on ExposureEffect of Food on Exposure Accutane has a significant food effect:Accutane has a significant food effect:

– 2.5 : 1 ratio between Accutane (fed) and Accutane 2.5 : 1 ratio between Accutane (fed) and Accutane (fasted)(fasted)

– inconsistent eating habits lead to large within subject inconsistent eating habits lead to large within subject variabilityvariability

– between subject variability is less when administered with between subject variability is less when administered with food food

Taking Accutane without food significantly increases Taking Accutane without food significantly increases the risk of under exposure to isotretinoin, which the risk of under exposure to isotretinoin, which could result in sub-optimal therapy (decreased could result in sub-optimal therapy (decreased efficacy)efficacy)

Effect of Food on Exposure (cont’d)Effect of Food on Exposure (cont’d)

Accutane NF has minimal food effectAccutane NF has minimal food effect– 30% greater exposure when administered with food30% greater exposure when administered with food– between subject variability is similar when between subject variability is similar when

administered with or without foodadministered with or without food– reduced within subject variability (versus Accutane) reduced within subject variability (versus Accutane)

even with inconsistent eating habits even with inconsistent eating habits

Risk of sub-optimal therapy is minimized with Risk of sub-optimal therapy is minimized with Accutane NFAccutane NF

Method for Simulating the Steady State Method for Simulating the Steady State Plasma Concentrations of IsotretinoinPlasma Concentrations of Isotretinoin

Data from the Fed/Fasted PK Accutane - NF Data from the Fed/Fasted PK Accutane - NF study were usedstudy were used

Principle of superpositioning for linear Principle of superpositioning for linear pharmacokinetics was used to simulate pharmacokinetics was used to simulate plasma concentrations of isotretinoin for plasma concentrations of isotretinoin for different dosage regimens of NF and Accutane different dosage regimens of NF and Accutane under fed or fasted conditionsunder fed or fasted conditions

Figure 1 - Simulated Steady-State Exposure to Isotretinoin Figure 1 - Simulated Steady-State Exposure to Isotretinoin Following Administration of Accutane* & Accutane NFFollowing Administration of Accutane* & Accutane NF††

Nominal Time, hrNominal Time, hr

0

100

200

300

400

500

600

0 4 8 12 16 20 24

Accutane, 35 mg BID, Fed (545, 9209)

Accutane, 17.5 mg BID, Fed (272, 4605)

Accutane NF, 28 mg QD, Fasted (332, 4161)

*1.0 mg/kg and 0.5 mg/kg†0.4 mg/kg NF 414, 9/17/00

IsotretinoinIsotretinoinng/mLng/mL

Nominal Time, hrNominal Time, hr

Simulated Steady State Exposure to Isotretinoin Following the Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Administration of Accutane and Accutane NF under Fed and

Fasted ConditionsFasted Conditions

Isotretinoin Dose Efficacy StudiesIsotretinoin Dose Efficacy Studies

Publication N DoseEfficacy

Rank (mg/kg)

Condition

Farrell 1980 14 1.0 0.5 0.1 FedJones 1981 22 1.0=0.5>0.1 FedPlewig 1981 127 1.0>0.5>0.2 FedStrauss 1984 150 1.00.50.1 FedPeck 1979 14 2.0=1.0 FastedNF Study 600 1.0 0.4 NF Fed/Fasted

AUC Exposure to Isotretinoin for AUC Exposure to Isotretinoin for Accutane and Accutane NFAccutane and Accutane NF

DoseDose AUCAUC ConditionCondition

0.10.1 921 921 FedFed

0.20.2 1,842 1,842 FedFed

0.4NF0.4NF 4,161 4,161 FastedFasted

0.50.5 4,605 4,605 FedFed

1.01.0 9,209 9,209 FedFed

2.02.0 7,310 7,310 FastedFasted

Rationale for New Formulation of IsotretinoinRationale for New Formulation of Isotretinoin

New Formulation Development ProgramNew Formulation Development Program

Dose/Exposure Response RelationshipDose/Exposure Response Relationship

Risk Management of Two FormulationsRisk Management of Two Formulations

Benefit of New FormulationBenefit of New Formulation

Risk of Confusion with Two FormulationsRisk of Confusion with Two Formulations

Taking Accutane with or without food Taking Accutane with or without food

Misunderstanding about QD administration for Misunderstanding about QD administration for NF and BID for Accutane NF and BID for Accutane

Concurrent administration of NF and AccutaneConcurrent administration of NF and Accutane

Potential for substitution at the pharmacyPotential for substitution at the pharmacy

Simulated Steady State Exposure to IsotretinoinSimulated Steady State Exposure to IsotretinoinFollowing Administration of Accutane and Accutane Following Administration of Accutane and Accutane NFNFUnder Fed and Fasted Conditions Under Fed and Fasted Conditions

Simulated Steady State Exposure to IsotretinoinSimulated Steady State Exposure to IsotretinoinFollowing Administration of Accutane and Accutane NFFollowing Administration of Accutane and Accutane NFUnder Fed and Fasted Conditions Under Fed and Fasted Conditions

Simulated Steady-State Exposure to Isotretinoin Following Simulated Steady-State Exposure to Isotretinoin Following Administration of Accutane (1.0 mg/kg) Given As Divided Doses & Administration of Accutane (1.0 mg/kg) Given As Divided Doses & As a Single Daily Dose Compared With Accutane NF (0.4 mg/kg)As a Single Daily Dose Compared With Accutane NF (0.4 mg/kg)

0

100

200

300

400

500

600

700

800

900

0 4 8 12 16 20 24

Accutane, 70 mg QD, Fed, (777, 9210)

Accutane, 35 mg BID, Fed (545, 9209)

Accutane, 70 mg QD, Fasted (281, 3655)

IsotretinoinIsotretinoinng/mLng/mL

Time, hrTime, hr

New Formulation Product DifferentiationNew Formulation Product Differentiation Differences in dosingDifferences in dosing

– once per day vs twice per day once per day vs twice per day – taken with or without foodtaken with or without food

Unique packagingUnique packaging– pouches versus prescription packspouches versus prescription packs– packaging shape and colorpackaging shape and color

Capsule appearanceCapsule appearance– contrasting capsule color schemescontrasting capsule color schemes– different identification marks on capsulesdifferent identification marks on capsules– different capsules strengths (7.5, 15, 22.5 mg for Accutane NF)different capsules strengths (7.5, 15, 22.5 mg for Accutane NF)

Distinct, unique brand name for NFDistinct, unique brand name for NF– ttrade name submitted to FDA July 2000rade name submitted to FDA July 2000

The New Formulation of Isotretinoin is The New Formulation of Isotretinoin is as Safe and Efficacious as Accutaneas Safe and Efficacious as Accutane Simplifying dosing recommendationsSimplifying dosing recommendations

– The NF can be given with or without foodThe NF can be given with or without food– The NF can be given QD The NF can be given QD

Individual tolerabilityIndividual tolerability– The NF has fewer and less intense mucocutaneous eventsThe NF has fewer and less intense mucocutaneous events– The NF has fewer patients with elevated triglycerides The NF has fewer patients with elevated triglycerides

Compliance with dosing regimen Compliance with dosing regimen – More predictable exposure from NF decreases the impact of More predictable exposure from NF decreases the impact of

individual noncomplianceindividual noncompliance

Labeling for the New FormulationLabeling for the New Formulation

Once per day Once per day

Can be taken with or without foodCan be taken with or without food

All safety issues and programs carried over All safety issues and programs carried over from Accutane from Accutane

Indication remains the sameIndication remains the same