Alemtuzumab BLA committee

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Alemtuzumab BLA committee
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CD52 Expression

• Leukocytes
• B- lymphocytes
• T- lymphocytes
• Monocytes
• Macrophages
• Thymocytes
• Granulocytes (lt5)

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Expression on Other Cell Types

• Male reproductive tract
• Skin
• Tested on a range of tissues, absent on
• Erythrocytes
• Platelets
• Hematopoietic stem cells

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Antibody History

• CAMPATH-1M rat IgM
• CAMPATH-1G rat IgG2b
• CAMPATH-1H humanized IgG1

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CAMPATH-1H(Alemtuzumab)

• FOR THE TREATMENT OF PATIENTS WITH CLL WHO HAVE
  BEEN TREATED WITH ALKYLATING AGENTS AND WHO HAVE
  FAILED FLUDARABINE

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History of Submission

• September 12, 1997
• Response rate is a surrogate endpoint
• Commitment to a post-marketing randomized trial
  (CAMPATH-1H vs. Fludarabine) trial should be
  ongoing at time of accelerated approval
• March 25, 1999
• Conventional approval possible if the response
  rate is so compelling and indicative of benefit
  and the toxicities so low that no need for a
  confirmatory trial

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History of Submission

• December 23, 1999 Application filed
• June 23, 2000 Completed review letter issued
  Request for more information, revision of study
  reports, update and audit of the efficacy and
  safety information
• August 18, 2000 Revised study reports and data
  tables including updated, audited safety and
  efficacy information submitted

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Pharmacokinetics Comment

• PK is heavily influenced by tumor burden.
  Increase in half-life as tumor burden diminishes.
  Blood levels continue to increase with repeated
  dosing as receptors are saturated.
• At the end of four weeks estimated half-life is
  100 hr.
• At twelve weeks estimated half-life is 400 -
  900 hours

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Clinical Trials

• Study 211 (Pivotal)
• Single arm study conducted by L I Partners in
  1998 at 22 centers in the US and Europe
• Enrollment 93 patients previously treated with
  alkylators and refractory to fludaradine
• Last follow-up July 26, 2000

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Supporting Trials

• Study 009 single arm study conducted by B-W in
  the US from 1993 -1995 at six centers in the US
  enrolling 24 patients Last F/U for survival in
  March, 1997
• Study 005 study population of thirty-two CLL
  patients selected from a 125 patient study
  conducted in Europe between 1993-1995 by B-W with
  last F/U for survival in March, 1997

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Study Design
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Study Design
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Study Design
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Study Design
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Study Design
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Study Design
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Demographics
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Rai Staging System

• Stage 0 Lymphocytosis
• Stage I Lymphocytosis, adenopathy
• Stage II Lymphocytosis, adenopathy,
  and organomegaly
• Stage III Lymphocytosis, adenopathy,
  organomegaly, and anemia
• Stage IV Lymphocytosis, adenopathy,
  organomegaly, anemia, thrombocytopenia

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Rai Stage
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Eligibility
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Disposition
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Efficacy Information

• Studies 211, 009, and 005

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Responses, Response Rate
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Response Measures
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Responder Characteristics
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Other Efficacy Parameters
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Other Efficacy Parameters
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Other Efficacy Parameters
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Resolution in Symptoms in Responders
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Safety Data

• Study 211, 009, and 005

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Dose Delays gt Seven Days
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Reasons for Dose Delays gt Seven Days
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Mortality
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Drug Related Causes of Death
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Discontinuations
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Serious Adverse Events
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211 Analysis of Heme / Infectious SAEs, Stage I
/ II
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211 Analysis of Hem and Infectious SAEs, Stage
III / IV
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Opportunistic Infections
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Types of Serious OIs
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Infusional ToxicitiesAll Grades
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Infusional Toxicities Gr. 3/4
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Premedications
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New Malignancies / Transformations

• Study 211
• Higher Grade Lymphoma 4
• PLL 1
• Plasma Cell Dyscrasia 1
• Prostatic Cancer (Gleason 6) 1
• Study 009
• Higher Grade Lymphoma 2
• Study 005 none

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Hematological Toxicity

• Autoimmune Phenomena
• Study 211 3 AIT (1fatal) 1 AIHA
• Study 009 none
• Study 005 none
• Pancytopenia
• Study 211 8 patients, 3 deaths
• Study 009 3 patients
• Study 005 1 patient

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211 Heme Toxicity Hgb
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211 Heme Toxicity Hemoglobin
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211Hem Toxicity Neutrophils
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211 Hem Toxicity Neutrophils
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211 Heme Toxicity Platelets
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Heme Toxicity 211- Platelets
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211 Hem Toxicity Two Month Follow-Up
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Blood Product Usage
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CD4 Counts lt 200/?l

• Baseline 11/89 (12)
• Thirty Days on Study 84/86 (98)
• 2 Mo. Follow-up 23/55 (42)
• 4 Mo. Follow-up 8/30 (27)

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SUMMARY

• Data from three single arm studies 149 patients
• Response Rate 33 (22, 29)
• Complete Response Rate 2
• Median Duration Response 6.9 (7.1, 10.8) mos.
• Improvement / resolution of symptomatology and
  hematological parameters in responders

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SUMMARY

• CAMPATH Related Mortality 13 - 15
• Discontinuations for Treatment Related AEs 21 -
  25
• SAE Incidence 66 -80 of population
• Drug related SAEs 73- 88 of all SAEs
• Opportunistic Infections 28 - 42 study 50
  serious in nature

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SUMMARY

• Hematological toxicity gt 50
• Pancytopenia / Aplasia 8 pts. (3 fatal)
• Autoimmune toxicities 5 pts.
• Delayed recovery of neutrophils
• 38 at two months of follow-up
• 25 at 4 months
• Increased / new transfusion requirement during
  therapy 68

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SUMMARY

• Prolonged CD4 recovery 27 lt 200/ul at 4 months
• Infusion related toxicities
• Need for premedication
• Absolute requirement for gradual dose escalation
  on initial treatment / post dosing interruptions
• Maximal safe dose 30 mg TIW

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SUMMARY

• Potential for induction of a second malignancy?
• Potential for a decrease in survival due to
  infections /hematological toxicity?