1. A New Once-Daily Formulation of Isotretinoin Accutane NF
John McLane, PhD Roche Medical Science and Safety David Young, PharmD, PhD GloboMax LLC
Test 1

2. Rationale for New Formulation of Isotretinoin
New Formulation Development Program
Dose/Exposure Response Relationship
Risk Management of Two Formulations
Benefit of New Formulation
Test 2

3. Accutane Dose Efficacy Studies

4. Variability in Accutane Exposure
Dosing without food results in a significant reduction in exposure
Physician Survey
68% of patients instructed to take Accutane with food
21% of patients instructed to take Accutane once a day (approximately 1 mg/kg)
Prescribers report that 33% of patients do not take Accutane consistently with food
Prescribers report that 22% of patients do not consistently take the second dose in a BID regimen
Overall Effect: significant patient variability in exposure
Efficacy of alternative dosing regimens has not been fully evaluated

5. Accutane Dosing Issues
Inconsistency in dosing recommendations
once a day or twice a day
with or without food
Individual tolerability Prescriber survey shows that the principal reasons for patients withdrawing from therapy are:
mucocutaneous effects (19%)
triglyceride elevations (17%)
Compliance
Noncompliance would result in under/over dosing which may affect efficacy and safety

6. The New Formulation (NF) of Isotretinoin is as Safe and Efficacious as Accutane
Simplifying dosing recommendations
The NF can be given with or without food
The NF can be given QD
Individual tolerability
The NF has fewer and less intense mucocutaneous events
The NF has fewer patients with elevated triglycerides
Compliance with dosing regimen
More predictable exposure from NF decreases the impact of individual noncompliance

7. Rationale for New Formulation of Isotretinoin
New Formulation Development Program
Dose/Exposure Response Relationship
Risk Management of Two Formulations
Benefit of New Formulation

8. Clinical Development Program for NF
Pivotal Clinical Program
efficacy and safety trial
Pharmacokinetic Program
food effect on bioavailability
bioequivalence
dose proportionality
Hormonal Contraceptive Interaction Program
in vitro studies
clinical evaluations

9. Clinical Study Objective
Compare the efficacy and safety:
New Formulation vs. Accutane
Once per day Twice per day
No Food Food
Lower Exposure Labeled Exposure
182M / 118 F 174M / 126F

10. Daily Dosing Regimen Accutane Group 1 mg/kg
Active
Active
Placebo
12 AM
12 Noon
12 AM
Breakfast
Dinner
Placebo
Placebo
Active
New Formulation Group 0.4 mg/kg

11. Inclusion Criteria
Male or non-pregnant and non-nursing female patients, 12 years of age or older
Diagnosed with severe recalcitrant nodular acne, with 10 or more nodular lesions at least 5 mm in diameter

12. Clinical Efficacy Endpoints
Primary
number of patients with 90% reduction in nodules
reduction in total number of nodules from baseline
Secondary
global evaluations by both patients and physicians
reduction in total number of papules and pustules

13. Safety Evaluations During Trial
Laboratory
CBC, blood lipids, liver enzymes
Psychiatric evaluations
Mood/Depression Questionnaire
Beck Depression Inventory
Mucocutaneous adverse events
Dry or peeling skin
Dry or bleeding nose
Dry or irritated eyes
Chapped lips
Rash or erythema of face

14. Additional Evaluations
Objective measurements of inflammatory lesions at 8 week and 16 week evaluation points
Subjective measurement of need for retreatment
phone call to patients 16 weeks post therapy

15. Results - STD Efficacy Analyses

16. Overall Comparison of Safety
Variable
Accutane NF
Accutane
Patients with adverse event
Total adverse events Adverse events leading to treatment discontinuation Serious adverse events
Withdrawals (non AEs)
296 2 22
293 4 30

17. Adverse Events Leading to Treatment Discontinuation
Accutane (16) New Formulation (16)
Appendicitis Depression (3)
Chapped lips, dry skin Dizziness/Blurred vision
Headache (3) General body weakness
Irritated eyes Hair loss
LFT (3) Headache
Low white cell count LFT (3)
Triglyceride elev (6) Mood swings
Pregnancy
Pustular eruption
Triglyceride elev (3)

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

19. Lipid Profile During Treatment
Abnormal triglyceride levels were observed in
48/300 patients on Accutane NF
75/300 patients on Accutane
Mean triglyceride levels increased by
0.57 ± 0.87 mmol/L for Accutane NF
0.99 ± 1.44 mmol/L for Accutane
Mean cholesterol levels increased by
0.4 ± 0.56 mmol/L for Accutane NF
0.6 ± 0.69 mmol/L for Accutane

20. Comparison of Psychiatric Events
Treatment Group
Accutane NF Accutane N = 300 N =300
Patients reporting AEs 11 1
Positive Mood Assessments 37 38
Patients with BDI >13 (not BL)
Pts with Baseline BDI
Prior history (medications) 13 15
Additional BDI1 2 2
1. Subgroup of prior category

21. Mucocutaneous Adverse Events (MAEs)
MAEs were fewer and less intense in Accutane NF-treated patients
At several time points, differences were statistically significant
Subgroup analysis showed no imbalance among age, sex, race, or body weight categories

22. Mucocutaneous Event: Dry or Bleeding Nose* * * * *

23. Mucocutaneous Event: Dry or Irritated Eyes* * * * *

24. Isotretinoin / Hormonal Contraceptives Program
To assure that isotretinoin does not alter the clinical pharmacology of hormonal contraceptives
Two components of program:
in vitro studies with hepatocytes and microsomes
clinical program

25. In Vitro Human Hepatocytes Experiments Experiment Completion Dates
*Initiated January 2000: 5-6 months to complete each study
†Initiated January 2000: 11 months to complete each study

26. Oral Contraceptive Clinical Studies
Two studies to determine if isotretinoin affects oral contraceptives (Ortho-Novum 7/7/7)
pharmacokinetics (ethinyl estradiol and norethindrone)
pharmacodynamics (LH/FSH/progesterone)
Females with severe recalcitrant nodular acne
Accutane 1.0 mg/kg/day in two divided doses with food
Accutane NF 0.4 mg/kg/day as a single daily dose fasted

27. OC Pill Cycle 3 + Isotretinoin OC Pill Cycle 4 + Isotretinoin
Oral Contraceptive Studies: Pharmacokinetic (PK) and Pharmacodynamic (PD) Assessments
Study Month 1
Study Month 2
Isotretinoin
Initiated
OC Stabilization
OC Pill Cycle 2
Day 6
Day 20
PK and PD
Assessments
Day 6
Day 20
Study Month 3
Study Month 4
OC Pill Cycle 3 + Isotretinoin
OC Pill Cycle 4 + Isotretinoin

28. Oral Contraceptive Studies Current Status
No pregnancies
No serious or unexpected adverse events
Timelines:
September 2000: last patient visit scheduled for both studies
1st Quarter 2001: final study reports to FDA

29. Rationale for New Formulation of Isotretinoin
New Formulation Development Program
Dose/Exposure Response Relationship
Risk Management of Two Formulations
Benefit of New Formulation

30. Isotretinoin Dose Efficacy Studies

31. Plasma Concentrations of Isotretinoin After Single Dose of Accutane (80 mg), Accutane NF (30 mg) Under Fed or Fasted Conditions (n=74)
Isotretinoin ng/mL
Time, (hrs)

32. Effect of Food on Exposure
Accutane has a significant food effect:
2.5 : 1 ratio between Accutane (fed) and Accutane (fasted)
inconsistent eating habits lead to large within subject variability
between subject variability is less when administered with food
Taking Accutane without food significantly increases the risk of under exposure to isotretinoin, which could result in sub-optimal therapy (decreased efficacy)

33. Effect of Food on Exposure (cont’d)
Accutane NF has minimal food effect
30% greater exposure when administered with food
between subject variability is similar when administered with or without food
reduced within subject variability (versus Accutane) even with inconsistent eating habits
Risk of sub-optimal therapy is minimized with Accutane NF

34. Method for Simulating the Steady State Plasma Concentrations of Isotretinoin
Data from the Fed/Fasted PK Accutane - NF study were used
Principle of superpositioning for linear pharmacokinetics was used to simulate plasma concentrations of isotretinoin for different dosage regimens of NF and Accutane under fed or fasted conditions

35. Figure 1 - Simulated Steady-State Exposure to Isotretinoin Following Administration of Accutane* & Accutane NF†
Isotretinoin ng/mL
*1.0 mg/kg and 0.5 mg/kg
Nominal Time, hr
Nominal Time, hr
†0.4 mg/kg
NF 414, 9/17/00

36. Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Fasted Conditions

37. Isotretinoin Dose Efficacy Studies

38. AUC Exposure to Isotretinoin for Accutane and Accutane NF
Dose AUC Condition
Fed
,842 Fed
0.4NF 4,161 Fasted
,605 Fed
,209 Fed
,310 Fasted

39. Rationale for New Formulation of Isotretinoin
New Formulation Development Program
Dose/Exposure Response Relationship
Risk Management of Two Formulations
Benefit of New Formulation

40. Risk of Confusion with Two Formulations
Taking Accutane with or without food
Misunderstanding about QD administration for NF and BID for Accutane
Concurrent administration of NF and Accutane
Potential for substitution at the pharmacy

41. Simulated Steady State Exposure to Isotretinoin Following Administration of Accutane and Accutane NF Under Fed and Fasted Conditions

42. Simulated Steady State Exposure to Isotretinoin Following Administration of Accutane and Accutane NF Under Fed and Fasted Conditions

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

44. New Formulation Product Differentiation
Differences in dosing
once per day vs twice per day
taken with or without food
Unique packaging
pouches versus prescription packs
packaging shape and color
Capsule appearance
contrasting capsule color schemes
different identification marks on capsules
different capsules strengths (7.5, 15, 22.5 mg for Accutane NF)
Distinct, unique brand name for NF
trade name submitted to FDA July 2000

45. The New Formulation of Isotretinoin is as Safe and Efficacious as Accutane
Simplifying dosing recommendations
The NF can be given with or without food
The NF can be given QD
Individual tolerability
The NF has fewer and less intense mucocutaneous events
The NF has fewer patients with elevated triglycerides
Compliance with dosing regimen
More predictable exposure from NF decreases the impact of individual noncompliance

46. Labeling for the New Formulation
Once per day
Can be taken with or without food
All safety issues and programs carried over from Accutane
Indication remains the same

47. End of presentation

48. Benefit of New Formulation
Equivalent clinical efficacy
Increased tolerability and comparable safety profiles
mucocutaneous adverse events
lipid adverse events
Decreased variability in exposure
Once daily dosing
Can be taken with or without food

50. Dosing variability issues with Accutane
Rationale for new formulation for isotretinoin
Program for assessing new formulation
efficacy
safety
drug interaction program
pharmacokinetics of dosing
Risk management issues

52. The new formulation is designed to address:
acceptability
inconsistency in dosing recommendations
compliance

53. Psychiatric Adverse Event Reports
Self-reporting of adverse events
Other tools to evaluate psychiatric conditions do not demonstrate disparity in formulations
Not substantiated by BDI-II scores of individuals or population
Formulation with most AE reports had lowest exposure to isotretinoin
Based on utility of other tools expected more reports in Accutane arm

54. Frequency Distribution of Triglycerides

55. Outcomes from Accutane Therapy
Accutane Treatment
Incomplete clearance
Incomplete Therapy
Effective Therapy

56. Triglyceride Level Categorized at Baseline
Accutane NF
mg/dL
Weeks
NF 038, (65), 9/5/00

57. Improved Safety Profile of Accutane NF Adverse Events
Fewer total adverse events
Fewer moderate or severe adverse events
Fewer adverse events in most body systems
NF 133, (255), 8/1/00

58. In Vitro Human Hepatocytes Program Experiment Completion Dates
*Initiated January 2000: 5-6 months to complete each study
†Initiated January 2000: 11 months to complete each study

59. Therapeutic Dose Range for Isotretinoin

60. Rationale for Evaluating Accutane NF
Provide a new micronized formulation of isotretinoin that reduces variability in exposure
taken with or without food
administered once daily
Retain the efficacy and safety of Accutane
Enhance patient compliance and convenience
Achieve a lower but effective exposure

61. Psychiatric Adverse Event Reports
Treatment Group
Accutane NF Accutane Adverse Event N = 300 N =300
Depression NOS 6 (2.0%) -
Mood swings 2 (0.7%) -
Panic reaction 1 (0.3%) 1 (0.3%)
Anxiety 1 (0.3%) -
Mood alteration NOS 1 (0.3%) -
NF 049, (76), 9/5/00

62. Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Fasted Conditions

63. Simulated Steady State Exposure to Isotretinoin Following the Administration of Accutane and Accutane NF under Fed and Fasted Conditions