Cyclosporine Ophthalmic Emulsion, 0.05%

1. Cyclosporine Ophthalmic Emulsion, 0.05% July 21, 1999 William M. Boyd, M.D. Medical Officer

2. Cyclosporine Ophthalmic Emulsion, 0.05% • Pharmacologic Category - immunomodulator • Proposed Indication - treatment of moderate to severe keratoconjunctivitis sicca • Dosage Form and Route of Administration - ophthalmic emulsion for topical administration

3. Clinical Data Sources • Two Phase 3 Protocols • Protocol 192731-002 • Protocol 192731-003 • One Phase 2 Protocol • Protocol 192731-001

4. Protocol 192731-002

5. Clinical Studies Protocol 192731-002 • Design - randomized, multicenter, parallel-group, double-masked, Phase 3 trial • Treatment arms - cyclosporine 0.05%, cyclosporine 0.1% , common vehicle

6. Protocol 192731-002 • Test drug schedule - all subjects received either cyclosporine 0.05%, 0.1% or vehicle bilaterally, BID for six months • Total subjects - 405

7. Protocol 192731-002 • Objective Signs: • corneal staining • conjunctival staining • sum of corneal and interpalpebral conjunctival staining • Schirmer Tear Test • tear break-up time

8. Protocol 192731-002 • Subjective Symptoms: • symptoms of dry eye • Ocular Surface Disease Index Score (OSDI) • Facial Expression Subjective Rating Scale • Investigator’s Global Evaluation of Response to Treatment • Treatment Success

9. Protocol 192731-002 • Criteria for Effectiveness - Sponsor must show a statistically significant difference between the active treatment and the vehicle for one (1) objective sign and one (1) subjective symptom.

10. Protocol 192731-002 • Safety Criteria: • EDTRS visual acuity • intraocular pressure • biomicroscopy • pharmacokinetic parameters for subsets of subjects in selected centers

11. Protocol 192731-002 - Objective Signs

12. Protocol 192731-002 - Objective Signs

13. Protocol 192731-002 - Subjective Symptoms

14. Protocol 192731-002 - Subjective Symptoms

15. Protocol 192731-002 - Subjective Symptoms

16. Protocol 192731-002 - Subjective Symptoms

17. Protocol 192731-002 - Subjective Symptoms

18. Protocol 192731-002 - Subjective Symptoms

19. Protocol 192731-002 - Subjective Symptoms

20. Protocol 192731-002Safety • Adverse Events Monitoring • Most Common Ocular Adverse Events • burning • eye pain • pruritis • stinging • No increase in ocular or systemic infections

21. Protocol 192731-002 - Safety

22. Protocol 192731-002Summary • Statistically Significant Objective Signs • Corneal Staining

23. Protocol 192731-002Summary • Statistically Significant Subjective Symptoms • Blurred Vision, Refresh Use, Sensitivity to Light, Itching, Composite Score, OSDI, Facial Expression Subjective Scale

24. Protocol 192731-003

25. Clinical Studies Protocol 192731-003 • Design - randomized, multicenter, parallel-group, double-masked, Phase 3 trial • Treatment arms - cyclosporine 0.05%, cyclosporine 0.1% , common vehicle

26. Protocol 192731-003 • Test drug schedule - all subjects received either cyclosporine 0.05%, 0.1% or vehicle bilaterally, BID for six months • Total subjects - 472

27. Protocol 192731-003 • Objective Signs: • corneal staining • conjunctival staining • sum of corneal and interpalpebral conjunctival staining • Schirmer Tear Test • tear break-up time

28. Protocol 192731-003 • Subjective Symptoms: • symptoms of dry eye • Ocular Surface Disease Index Score (OSDI) • Facial Expression Subjective Rating Scale • Investigator’s Global Evaluation of Response to Treatment • Treatment Success

29. Protocol 192731-003 • Safety Criteria: • EDTRS visual acuity • intraocular pressure • biomicroscopy

30. Protocol 192731-003 - Objective Signs

31. Protocol 192731-003 - Objective Signs

32. Protocol 192731-003 - Subjective Symptoms

33. Protocol 192731-003 - Subjective Symptoms

34. Protocol 192731-003 - Subjective Symptoms

35. Protocol 192731-003Safety • Adverse Events Monitoring • Most Common Ocular Adverse Events • burning • conjunctival hyperemia • photophobia • stinging • No increase in ocular or systemic infections

36. Protocol 192731-003 - Safety

37. Protocol 192731-003Summary • Statistically Significant Objective Signs • Categorized Schirmer w/ Anesthesia

38. Protocol 192731-003Summary • Statistically Significant Subjective Symptoms • Global Response to Treatment

39. Protocol 192731-003Summary • Global Response to Treatment • Some investigators rated Global Response based on their clinical evaluations of their subjects while other investigators queried subjects directly about their response to treatment.

40. Protocol 192731-003 - Variables Approaching Significance*favoring cyclosporine 0.05% over vehicle

41. Protocol 192731-001

42. Clinical Studies Protocol 192731-001 • Design - randomized, multicenter, parallel-group, double masked, Phase 2 trial • Treatment arms - cyclosporine 0.05%, 0.1%, 0.2%, and 0.4% and vehicle of cyclosporine 0.2%

43. Protocol 192731-001 • Test drug schedule - all subjects received either cyclosporine 0.05%, 0.1%, 0.2%, 0.4% or vehicle bilaterally, BID for 12 weeks • Total subjects - 162

44. Protocol 192731-001 • Primary Efficacy Measures: • Schirmer Tear Test w/o Anesthesia • Corneal Staining (SPK) • symptoms of dry eye (from diaries and CRF queries)

45. Protocol 192731-001 • Secondary Efficacy Measures: • tear film debris • rose bengal staining • tear break-up time • brush cytology • tear meniscus • meibomian gland health

46. Protocol 192731-001 • Secondary Efficacy Measures cont’d: • tear proteins • Facial Expression Subjective Rating Scale • Ocular Surface Disease Index Score (OSDI) • Refresh use • Investigator’s Global Evaluation of Response to Treatment

47. Protocol 192731-001 • Safety Criteria: • vital signs • ETDRS visual acuity • intraocular pressure • biomicroscopy • conjunctival microbiology • CBC, blood chemistry, whole blood cyclosporine concentration

48. Protocol 192731-001 - Primary Efficacy Measures

49. Protocol 192731-001 - Primary Efficacy Measures

50. Protocol 192731-001 - Primary Efficacy Measures