1. CANCIDAS  (caspofungin acetate) for intravenous injection NDA 21-227 Merck & Co., Inc.

2. 2 Safety and Efficacy of CANCIDAS  (caspofungin acetate) in Invasive Aspergillosis Eileen Navarro, M.D., Medical Officer Division of Special Pathogen and Immunologic Drug Products CDER/FDA

3. 3 FDA Review Team for NDA 21-227 Regulatory Project Manager:L. Chan, R.Ph. Chemistry:G. Holbert, Ph.D. D. Matecka, Ph.D. Microbiology:S. Bala, Ph.D. Pharmacokinetics/Biopharmaceutics:H. Mahayni, Ph.D. Pharmacotoxicologist:O. McMaster, Ph.D. Biostatistician:C. Dixon, Ph.D. Clinical:E. Navarro, M.D. L. Sacks, M.D. OPDRA consultant:J. Staffa, Ph.D.

4. 4 Outline 1. CANCIDAS  proposed labeling, microbiology, pharmacokinetics 2. Efficacy of CANCIDAS  as therapy for refractory or intolerant invasive aspergillosis 3. Safety of CANCIDAS  in healthy subjects and in patients with fungal infections

5. 5 Proposed Labeling Indication –“CANCIDAS  is indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies.” Dosage –A single 70-mg loading dose... administered on Day 1, followed by 50 mg daily.

6. 6 Proposed Dosage Adjustments Increase –“...available safety data suggests an increase to 70 mg daily...in patients without evidence of clinical response…” Decrease –“In patients with moderate hepatic insufficiency… CANCIDAS 35 mg daily is recommended” No dosage adjustment is necessary for patients with renal insufficiency.

7. 7 Microbiology Gene inhibition  cell membrane enzyme modulation  cell wall glucan reduction Time kinetics studies: slower kill rate for C. albicans (7 hours caspofungin vs 1 hour Amphotericin B ) Activity specific for actively growing hyphae Activity for Aspergillus spp not “fungicidal” ? activity against Fusarium, Trichosporon, Mucor spp

8. 8 Comparative Efficacy of Caspofungin and Amphotericin B in Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

9. 9 Pharmacokinetics Concentrations are more variable in patients Trough levels >1  g/ml are immediately achieved with a 70 mg loading dose CNS distribution low in rodents; unknown in humans

10. 10 Pharmacokinetics No adjustment for itraconazole, amphotericin B, and mycophenolate mofetil Reduces tacrolimus levels Cyclosporine increases caspofungin AUC by 35% NOT an inhibitor or a substrate of CYP isoenzymes Potential metabolic inducers: nelfinavir, CYP 3A4 inducers (rifampin, phenobarbital…)

11. 11 Outline 1. CANCIDAS  proposed labeling, microbiology, pharmacokinetics 2. Efficacy of CANCIDAS  as therapy for refractory or intolerant invasive aspergillosis 3. Safety of CANCIDAS  in healthy subjects and in patients with fungal infections

12. 12 Clinical Studies: Invasive Aspergillosis Clinical trials Study 019 Open labelN = 69 Study 024 Compassionate useN = 3 Historical control Study 028/029 N = 229

13. 13 Clinical Studies: Mucosal Candidiasis

14. 14 Protocol Summary Highlights for Studies 019 and 028/029 Procedures Disease definition Response to prior therapy Timing of assessments Outcome definitions Study design and analysis

15. 15 Study 019: Study Procedures

16. 16 Study 028: Study Procedures Case finding: pathology/microbiology department, subspecialty consultation and hospital discharge registries Sites: 4/10 participated in Study 019 Data: chart abstraction Outcome assessment: site investigator

17. 17 Exclusion Criteria

18. 18 Study 019 and Study 028/029: Exclusion Criteria Severity of underlying disease: a) Abnormal Lab values –Hemoglobin <8 gm/dL –Platelet count <25,000/  L –INR > 1.6 –Bilirubin >3 times the upper limit of normal –AST or ALT > 5 times the upper limit of normal b) Patients who were not expected to survive at least 5 days (after 7 days of prior therapy)

19. 19 Disease Definition DEFINITE Pulmonary: histopathology OR tissue cultures Extrapulmonary: histopathology (invasion of affected tissue)

20. 20 Disease Definition

21. 21 Response to Prior Therapy Refractory –progression or failure to improve despite AmB, lipid formulation AmB, itraconazole, or investigational azole Intolerance –renal baseline doubling or creatinine >2.5 mg/dL –other infusion toxicities Study 028: intolerance (creatinine >2.5 mg/dL)

22. 22 Study 019 and 028/029: Timing of Assessments Response to prior therapy: Refractory:  7 days Intolerance: undefined Study 019: Response to caspofungin therapy: EOT Relapse: 4 weeks post EOT

23. 23 Study 019 and 028/029: Outcome Definitions Favorable –Complete response: resolution of IA –Partial response: improvement clinical, x-ray, bronchoscopic findings Unfavorable –Stable: non-progressive disease –Failure: progression or death

24. 24 Expert Panel Assessment

25. 25 Expert Panel Assessment

26. 26 Study 019: Study Design Efficacy: estimation study response rate 30% Population:Primary MITT 1 dose Secondary CE > 7days Expert Panel superceded MITT Safety: 95% probability of detecting at least 1 DRAE if the incidence is  5.8%

27. 27 Study 019 and 028/029: Data Analysis Primary: proportion of success at EOT Secondary: logistic regression analysis Adjusted for predictive/baseline risk variables

28. 28 Study 019: Patient Accounting (May 1998- April 2000) N Enrolled 69 Excluded- 6 Evaluable63 Reason for Exclusion: protocol violation 1 another pathogen identified 3 unevaluable2

29. 29 Study 028: Patient Accounting 1995-1998

30. 30 Baseline Characteristics

31. 31 Baseline Characteristics (cont.)

32. 32 Baseline Characteristics (cont.)

33. 33 Baseline Characteristics: Prior Therapy in Study 019 and 028/029

34. 34 Duration of Prior/Standard Therapy

35. 35 Total Treatment Duration for Current Aspergillosis Infection

36. 36 Applicant Clinical Efficacy Rates Study 019Study 028/029 Expert Panel Investigator Populationn/N (%)n/N (%) All patients26/63 (41.3)35/206 (17.0) Response to prior therapy Refractory19/53 (35.8) 27/188 (14.4) Intolerant Only 7/10 (70.0) 3/5 (60.0) Site of infection Pulmonary21/45 (46.7)32/154(20.8) All other sites5/18 (27.8) 3/52(5.8)

37. 37 Complete Responses and Relapse

38. 38 Complete Response to Caspofungin Identifier 219330 366 065 Extent of IApulmonarypulmonaryskull+ pulmonary* Underlying disease allo BMTlymphomadiabetes leukemia Prior treatmentAmB/ ABLCItraconazoleAmB ABLC, Itra lobectomyresection Caspofungin Rx (days)8 2827 90 Deathyesnono no RelapseN/Anono no + possible brain abscess * CT nodules without cavitation, (-) BAL cultures with suggestive direct examination

39. 39 Clinical Efficacy Rates by Baseline Risk

40. 40 Clinical Efficacy Rates by Geographic Region

41. 41 Clinical Efficacy Rates by Total Duration of Treatment

42. 42 Central nervous system involvement in patients with IA Success in CNS involvement 2/6 CNS aspergillosis emerging on treatment*2 *Day 16 and 58 of therapy

43. 43 Post-Caspofungin Therapy Patient #Initial RXFinal treatment Outcome 0002 AmB, ABCD AmBisome + surgery died 0056AmBisome AmBisomefailure 0057ABLC, azolelipid AmB failure 0059Itra, ABLC, AmBisome + surgery failure lipid AmB 0186ABLC ABLC failure 0187AmB, ABLC, ABLC died 0246Itra, AmB AmBisome died 0296AmB, Itra ABLC failed 0412azole, Itra AmB failed 0446lipid AmB, Itra Itraconazole + surgery improved 0507AmB azole not known

44. 44 Comparability of the Historical Control (028/029) and the Cancidas™-treated Patients (019) Comparison is subject to several potential biases –Information bias –Bias from secular trends in diagnosis and/or treatment –Selection bias

45. 45 Information Bias Assessment of outcome was not as rigorous with the control group, due to lower quality of available information –retrospective review of medical records –incomplete information on concomitant medications and underlying disease –Expert assessment varied greatly between the two studies

46. 46 Bias from Secular Trends in Diagnosis and/or Treatment Historical control success rate by year of enrollment increased from 1995 (12.0%) to 1998 (20.6%) Improved ability to manage the underlying disease from 1995 to 2000 –Transplantation (new immunosuppressants) –Oncology (earlier diagnoses, improved therapy)

47. 47 Selection Bias Differences in distribution and success rates of US and foreign patients between studies Differences in distribution of duration of therapy for current infection between studies Differences in the exclusion criteria between studies

48. 48 Summary of Comparability All of these biases could act to predispose the historical control to have a lower success rate and the CANCIDAS TM -treated group to have a higher success rate, independent of treatment with CANCIDAS TM Notable differences between 019 and 028/029 may provide alternative explanations for at least part of the treatment effects seen Therefore, it is not clear that all the observed treatment effect is due to treatment with CANCIDAS TM, and it is difficult to quantify the potential effect of these biases

49. 49 Outline 1. CANCIDAS  proposed labeling, microbiology, pharmacokinetics 2. Efficacy of CANCIDAS  as therapy for refractory or intolerant invasive aspergillosis 3. Safety of CANCIDAS  in healthy subjects and in patients with fungal infections

50. 50 Safety Database Clinical Pharmacology12 Studies274 Clinical Studies338 3 comparative Candida263 1 variable dose Candida 14 1 Aspergillus study 58 1 compassionate use 3 Total612

51. 51 Drug Exposure

52. 52 Overall Caspofungin Safety in Clinical Studies

53. 53 Drug-Related Adverse Events

54. 54 LFT Elevations : Clinical Studies Relative Elevation > 3x ULN Phase I N = 257, excluding subjects with impaired hepatic function 4 subjects w/ ALT or AST >3x ULN (these 4 patients had normal bilirubin levels) Comparative Phase II and Phase III Patients w/ ALT or AST >3x ULN and Bilirubin > ULN Caspofungin vs. Fluconazole 6/263 2/93 (2.3%) (2.2%)

55. 55 Potential Safety Issues Elevations in serum calcium / creatinine –056hypercalcemia Respiratory adverse events –186pulmonary infiltrates –220pulmonary infiltrates Possible histamine reactions –1338rash, pruritus, tachypnea –0683fever, wheeze, rash

56. 56 Summary 1. CANCIDAS  proposed labeling, microbiology, pharmacokinetics 2. Efficacy of CANCIDAS  as therapy for refractory or intolerant invasive aspergillosis 3. Safety of CANCIDAS  in healthy subjects and in patients with fungal infections

57. 57