NDA 21 174

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NDA 21- 174

• Gemtuzumab Ozogamicin in relapsed acute myeloid
  leukemia
• FDA Review
• ODAC March 17, 2000

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Pharmaceutical Category Immunotoxin

• Recombinant humanized murine anti- CD-33
  antibody (hP67.6) linked to calicheamicin

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Gemtuzumab Ozogamicin

• Proposed indication
• For the Treatment of CD 33 positive acute
  myeloid leukemia in relapse

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Gemtuzumab Ozogamicin

• Proposed indication
• For the Treatment of CD 33 positive acute
  myeloid leukemia in relapse

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Regulatory Issues Accelerated Approval

• Sponsor needs to demonstrate meaningful
  therapeutic benefit over existing treatments.
• In this case, equal efficacy with improved
  safety.
• Benefit must be based on a surrogate endpoint
  which is likely to predict clinical benefit
  (Subpart H)

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Regulatory Issues Accelerated Approval

• In hematologic malignancies, durable complete
  remissions have been considered as adequate
  evidence of clinical benefit.
• Durability was difficult to determine in this
  application so complete response was considered
  to be an acceptable surrogate
• Requires Phase 4 post approval study commitments
  to confirm clinical benefit

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Overview of Review Issues

• Efficacy Issues
• Equivalence of CRs and CRps
• Overall efficacy compared with conventional
  salvage chemotherapy
• Efficacy in Patient Subgroups
• Interpretation of survival data in absence of
  consistent postremission therapy
• Safety Issues
• Safety advantage
• Hepatotoxicity

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Studies submitted for Reviewas of 10/99
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Studies Reviewed

• 41 patients in Phase 1 study
• 104 patients from original NDA
• Updated safety and efficacy data on 142 patients
  1/27/00

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INCLUSION AND EXCLUSION CRITERIA
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Protocol outline

• Single 2 hour infusion 9 mg/M2 given as
  outpatient and repeated in 14 days
• Eligibility determined at site, CD 33 confirmed
  by central flow cytometry lab
• Responses determined by central independent
  pathologist
• Growth Factors not allowed

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Primary Endpoints SafetyComplete Response (CR)

• CR was defined by all of the following
• Leukemic blasts absent from peripheral blood
• Percentage of blasts in the bone marrow lt 5
• Hemoglobin gt9 g/dL, platelets gt 100,000/µL,
  absolute neutrophil count gt 1500/µL
• Red blood cell and platelet-transfusion
  independent

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Morphologic Remission (CRp)

• CRp defined in the same way as Complete
  Remission, except that platelets were not
  required to reach 100,000/µL
• Not a primary endpoint
• Patients required to achieve RBC and platelet
  transfusion independence

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Morphologic Remission (CRp)

• Patients never achieve a platelet count of 100K
• Drug Toxicity vs. residual leukemia?
• Preclinical studies
• Megakaryocyte colony suppression in vitro
• Gene chip expression
• Long term effects on stem cells in vivo?

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Efficacy Results original 104 patients with
relapsed AML
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Original NDA (N104) compared with updated
efficacy data (N142)
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Original NDA (N104) compared with updated
efficacy data (N142)
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CRpCR?Relapse-Free Survival
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Relapse-Free Survival
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Survival data Issues

• Small numbers
• Additional antileukemic therapy in 22/32 (70) of
  overall responders
• 13/32 responders transplanted
• 6/18 (33) CRs (4 Allo)
• 7/14 (50) CRps (6 Allo)
• Survival data not censored for postremission
  therapy

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Prognostic Factors in Relapsed AML

• Age
• Duration of First Remission

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Response Rates vs. Age
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Response Rates vs. Age
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Response Rates vs. Duration of First Remission
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Response Rates vs. Duration of First Remission
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Efficacy Conclusions

• Response rate difficult to compare to
  conventional salvage chemotherapy
• Comparability requires inclusion of CRps
• Efficacy in prognostic subgroups requires further
  study
• Duration of responses are difficult to determine
  because of wide variety of postremission
  treatments

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Safety Issues

• Acute infusion-related symptoms
• Antibodies
• Bleeding
• Infections
• GI Toxicity

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Safety Acute Infusion-Related Events

• Infusion-related symptom complex in 50
• Fever, chills, usually mild
• Outpatient administration feasible
• Occasional hypotension, hypoxia

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Safety Antibodies

• No HAHA anti-idiotype antibodies detected in 104
  patients in phase 2 trials who received 1,2, or 3
  infusions (additional studies requested)
• 2/42 patients in phase 1 trial developed
  antibodies to linker complex, 1 with transient
  symptoms

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Safety Bleeding and Transfusion Events(per
person )
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Safety Bleeding
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Safety Neutropenia, Infections
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Safety GI Toxicity
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Safety Hepatotoxicity

• Calicheamicin (unconjugated) noted to cause liver
  toxicity in preclinical testing
• 14 grade 3-4 elevations of AST and 24 grade
  3-4 elevations in total bilirubin reported in the
  phase 2 trials.
• 13 patients exhibited elevations of both
  transaminases and bilirubin, generally transient
  and reversible

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Hepatic Venoocclusive Disease (VOD)

• 4 patients with transient VOD in study
• 2 with prior Hematopoetic Stem Cell Transplant
  (HSCT)
• 1 patient developed transient VOD, died of
  pulmonary embolism

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Hepatic Venoocclusive Disease (VOD)

• 1 patient developed persistent jaundice and died
  of hepatic failure 156 days after treatment
• 3 died of VOD following HSCT
• 1/15 (6) responder
• 2/12 (17) nonresponders
• 1 pt. died with VOD after treatment of relapse
  post-transplant (hx. previous VOD)

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Safety Summary Advantages

• Outpatient administration feasible
• Antibodies uncommon
• Severe infection, mucositis probably reduced

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Safety Summary Disadvantages

• Markers for hepatotoxicity
• Grade 3-4 elevation in bilirubin in 24
• Grade 3-4 elevations in AST in 14
• Both elevated in 13
• Generally reversible
• Rare persistent jaundice
• VOD especially in HSCT setting

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Issues to Consider

• Is efficacy equivalent to conventional salvage
  regimens?
• Is there adequate demonstration of improved
  safety especially prior to transplant?
• Which patient populations might benefit?
• Elderly?
• Poor prognosis groups?
• Those awaiting transplant?

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Regulatory Options

• Approval based on current interim data with phase
  4 commitment to finish studies
• Approval for limited indications
• Require completion of ongoing studies and
  resubmission of NDA application
• Require randomized clinical trials and
  resubmission

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Review Team