Alemtuzumab BLA committee

CD52 Expression Leukocytes B- lymphocytes T- lymphocytes Monocytes Macrophages Thymocytes Granulocytes (<5%)

Expression on Other Cell Types Male reproductive tract Skin Tested on a range of tissues, absent on –Erythrocytes –Platelets –Hematopoietic stem cells

Antibody History CAMPATH-1Mrat IgM CAMPATH-1Grat IgG2b CAMPATH-1Hhumanized IgG1

CAMPATH-1H (Alemtuzumab) FOR THE TREATMENT OF PATIENTS WITH CLL WHO HAVE BEEN TREATED WITH ALKYLATING AGENTS AND WHO HAVE FAILED FLUDARABINE

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

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

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 ~ hours

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

Supporting Trials Study 009: single arm study conducted by B- W in the US from 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 by B-W with last F/U for survival in March, 1997

Study Design

Demographics

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

Rai Stage

Eligibility

Disposition

Efficacy Information Studies 211, 009, and 005

Responses, Response Rate

Response Measures

Responder Characteristics

Other Efficacy Parameters

Resolution in Symptoms in Responders

Safety Data Study 211, 009, and 005

Dose Delays: > Seven Days

Reasons for Dose Delays > Seven Days

Mortality

Drug Related Causes of Death

Discontinuations

Serious Adverse Events

211: Analysis of Heme / Infectious SAEs, Stage I / II

211: Analysis of Hem and Infectious SAEs, Stage III / IV

Opportunistic Infections

Types of Serious OIs

Infusional Toxicities:All Grades

Infusional Toxicities: Gr. 3/4

Premedications

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

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

211 Heme Toxicity: Hgb

211 Heme Toxicity: Hemoglobin

211Hem Toxicity : Neutrophils

211 Heme Toxicity : Platelets

Heme Toxicity: 211- Platelets

211 Hem Toxicity: Two Month Follow-Up

Blood Product Usage

CD4+ Counts < 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%)

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

SUMMARY CAMPATH Related Mortality: % Discontinuations for Treatment Related AEs: % SAE Incidence: % of population Drug related SAEs: % of all SAEs Opportunistic Infections: % study; 50% serious in nature

SUMMARY Hematological toxicity > 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%

SUMMARY Prolonged CD4+ recovery: 27% < 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

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