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CANCIDAS  (caspofungin acetate) for intravenous injection

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

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CANCIDAS  (caspofungin acetate) for intravenous injection

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

  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. 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. 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. 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. 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… CANCIDAS35 mg daily is recommended” • No dosage adjustment is necessary for patients with renal insufficiency.

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

  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. 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. 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. Clinical Studies:Invasive Aspergillosis • Clinical trials Study 019 Open label N = 69 Study 024 Compassionate use N = 3 • Historical control Study 028/029 N = 229

  13. Clinical Studies:Mucosal Candidiasis

  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. Study 019: Study Procedures

  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. Exclusion Criteria

  18. 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) Study 019 and Study 028/029:Exclusion Criteria

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

  20. Disease Definition

  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. 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. 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. Expert Panel Assessment

  25. Expert Panel Assessment

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

  28. Study 019: Patient Accounting(May 1998- April 2000) N Enrolled 69 Excluded - 6 Evaluable 63 Reason for Exclusion: protocol violation 1 another pathogen identified 3 unevaluable 2

  29. Study 028: Patient Accounting1995-1998

  30. Baseline Characteristics

  31. Baseline Characteristics (cont.)

  32. Baseline Characteristics (cont.)

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

  34. Duration of Prior/Standard Therapy

  35. Total Treatment Duration for Current Aspergillosis Infection

  36. Applicant Clinical Efficacy Rates Study 019 Study 028/029 Expert Panel Investigator Population n/N (%) n/N (%) All patients 26/63 (41.3) 35/206 (17.0) Response to prior therapy Refractory 19/53 (35.8) 27/188 (14.4) Intolerant Only 7/10 (70.0) 3/5 (60.0) Site of infection Pulmonary 21/45 (46.7) 32/154 (20.8) All other sites 5/18 (27.8) 3/52 (5.8)

  37. Complete Responses and Relapse

  38. Complete Response to Caspofungin Identifier 219 330 366 065 Extent of IA pulmonary pulmonary skull+ pulmonary* Underlying disease allo BMT lymphoma diabetes leukemia Prior treatment AmB/ ABLC Itraconazole AmB ABLC, Itra lobectomy resection Caspofungin Rx (days) 8 28 27 90 Death yes no no no Relapse N/A no no no + possible brain abscess * CT nodules without cavitation, (-) BAL cultures with suggestive direct examination

  39. Clinical Efficacy Rates by Baseline Risk

  40. Clinical Efficacy Rates by Geographic Region

  41. Clinical Efficacy Rates by Total Duration of Treatment

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

  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. 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. 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. 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. Summary of Comparability • All of these biases could act to predispose the historical control to have a lower success rate and the CANCIDASTM-treated group to have a higher success rate, independent of treatment with CANCIDASTM • 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 CANCIDASTM, and it is difficult to quantify the potential effect of these biases

  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. Safety Database Clinical Pharmacology 12 Studies 274 Clinical Studies 338 3 comparative Candida 263 1 variable dose Candida 14 1 Aspergillus study 58 1 compassionate use 3 Total 612

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