Abraxane

1
Abraxanefor the adjuvant treatment of
node-positive breast cancer

• Oncologic Drugs Advisory Committee Meeting
• September 7, 2006

2
Purpose of the Meeting

• To determine if, under the 505(b)(2) pathway, an
  efficacy trial in the adjuvant treatment of
  node-positive breast cancer is required to
  approve Abraxane in this setting

3
505(b)(2) Regulatory Pathway

• 505(b)(1) Typical way most new drugs are
  approved all investigations from sponsor
• 505(b)(2) Used for new formulations of existing
  drugs applicant may rely on investigations to
  which it does not own or have the right of
  reference (e.g. information in the published
  literature or in approved NDAs for the RLD)
• 505(j) For generic drugs that are the same as
  the established drug (the Reference Listed Drug
  RLD)

4
FDA Position Regarding 505(b)(2)

• FDAs longstanding interpretation of section
  505(b)(2) the Agencys approach is to use the
  505(b)(2) drug approval pathway to avoid
  requiring drug sponsors to conduct and submit
  studies that are not scientifically necessary.
• The conduct and review of duplicative studies
  would . slow the process for drug approval with
  no corresponding benefit to the public health.

Source Woodcock 2003 Response to Citizens
Petition regarding 505(b)(2)
5
505(b)(2) Avoids Significant Delays inDrug
Approval

• FDA has approved more than 80 section 505(b)(2)
  applications for drugs for indications ranging
  from cancer pain to attention deficit disorder.
  Many of these drugs would never have reached the
  market, or would have been significantly delayed,
  without the 505(b)(2) pathway.

Source Woodcock 2003 Response to Citizens
Petition regarding 505(b)(2)
6
Unique Set of Circumstances for Abraxane

• Active ingredient, paclitaxel, is identical
• Paclitaxel already approved as Adjuvant Rx(Taxol
  175 mg/m2)
• Abraxane delivers a higher dose of
  paclitaxel(260 mg/m2)
• Superior anti-tumor activity demonstrated in
  metastatic breast cancer
• Tolerability of higher Abraxane dose comparable
  to lower Taxol dose
• Abraxane was approved in metastatic breast cancer
  under 505(b)(2)
• FDA approach is to use 505(b)(2) to avoid.
  studies that are not scientifically necessary

7
Position of Abraxis BioScience

• Abraxis believes that an efficacy trial in the
  adjuvant treatment of breast cancer is not
  scientifically necessary and would
  significantly delay the approval of a
  Cremophor-free paclitaxel alternative
• Abraxis is committed to conduct a comparative
  safety trial of Abraxane vs Taxol for women with
  node-positive breast cancer

8
Reasons that an Efficacy Adjuvant Trial Should
not be Required for Approval of Abraxane
Abraxane is Cremophor-free Formulation of
Paclitaxel
Removing Cremophor Allows Safe Delivery of Higher
Doses of Paclitaxel
Therefore, there is no scientific basis to
hypothesize that Abraxane will be less effective
than Taxol as adjuvant therapy
In Metastatic Breast Cancer Abraxane has Greater
Anti-tumor Activitythan Taxol
Paclitaxel is Approved forAdjuvant Use (Taxol)
The Abraxane Dose of Paclitaxel is Safe and
Higher than that Already Proven Effective in the
Adjuvant Setting
9
Reasons that an Efficacy Adjuvant Trial Should
not be Required for Approval of Abraxane

• Michael J. Hawkins, MD

Abraxane is Cremophor-free Formulation of
Paclitaxel
Removing Cremophor Allows Safe Delivery of Higher
Doses of Paclitaxel

• William J. Gradishar, MD

In Metastatic Breast Cancer Abraxane has Greater
Anti-tumor Activitythan Taxol

• Clifford A. Hudis, MD

Paclitaxel is Approved forAdjuvant Use (Taxol)
The Abraxane Dose of Paclitaxel is Safe and
Higher than that Already Proven Effective in the
Adjuvant Setting
10
Development of Paclitaxel FormulationsHistorical
Background

• Paclitaxel, one of the most active cytotoxic
  agents
• Cremophor required at high concentrations
  (Taxol and generic equivalents)
• In the 1990s, Abraxis developed a paclitaxel
  formulation that replaced Cremophor with Albumin
  (Abraxane)
• Preclinical studies subsequently demonstrated
  that Abraxane significantly improved the
  therapeutic index of paclitaxel with
• Less toxicity due to removal of Cremophor
• Higher paclitaxel dose
• Higher intra-tumoral paclitaxel concentration
• Higher efficacy in multiple tumor types

11
Basis of FDA Approval of Abraxane for Metastatic
Breast Cancer

• 2001 FDA agreed that Abraxane could receive
  approval in MBC (same indication as Taxol)
  provided two issues were satisfied
• That replacement of Cremophor with albumin did
  not result in a decrease in efficacy of
  paclitaxel
• That the higher dose 260 mg/m2 of Abraxane could
  be administered with comparable tolerability to
  Taxol at175 mg/m2
• 2004 Randomized Phase 3 Trial proved superior
  anti-tumor activity of Abraxane with comparable
  tolerability at higherdose than Taxol
• 2005 FDA granted approval for metastatic breast
  cancerunder the 505(b)(2) regulatory pathway for
  new formulationsof existing drugs

12
Reasons that an Efficacy Adjuvant Trial Should
not be Required for Approval of Abraxane
Abraxane is Cremophor-free Formulation of
Paclitaxel
Removing Cremophor Allows Safe Delivery of Higher
Doses of Paclitaxel
Therefore, there is no scientific basis to
hypothesize that Abraxane will be less effective
than Taxol as adjuvant therapy
In Metastatic Breast Cancer Abraxane has Greater
Anti-tumor Activitythan Taxol
Paclitaxel is Approved forAdjuvant Use (Taxol)
The Abraxane Dose of Paclitaxel is Safe and
Higher than that Already Proven Effective in the
Adjuvant Setting
13
Abraxane is Albumin-bound Cremophor-free
Paclitaxel
Albumin
cryo-TEM
Paclitaxel exists in the albumin particle in an
non-crystalline, amorphous state
Mean 130 nm
Concentration dependent dissociation into
individual paclitaxel-bound albumin molecules
Paclitaxel
14
The Active Ingredient in Abraxane and Taxol is
Identical
Abraxane is a Cremophor-free Formulation of
Paclitaxel Received FDA Approval January,
2005 for metastatic breast cancer
Reconstituted Paclitaxel 5 mg/ml Albumin 45
mg/ml No Solvents
Supplied As Paclitaxel 6 mg/ml Cremophor 537
mg/ml Ethanol 396 mg/ml
15
Abraxane was Developed to Eliminate
Cremophor-induced Hypersensitivity Reactions

• Anaphylaxis and severe hypersensitivity
  reactionshave occurred in 2-4 of patients
  receiving Taxol in clinical trials

• Fatal reactions have occurred in patients
  despite premedication

Taxol Package Insert
Common Steroid Side Effects when Given as
Premedication

• Hyperglycemia
• Glucose intolerance in diabetics
• Mood changes
• Insomnia

16
Abraxane was Developed to Eliminate
Cremophor-induced Hypersensitivity Reactions

• Anaphylaxis and severe hypersensitivity
  reactionshave occurred in 2-4 of patients
  receiving Taxol in clinical trials

• Fatal reactions have occurred in patients
  despite premedication

Taxol Package Insert

• No premedication to prevent hypersensitivity
  reactions is required prior to administration of
  Abraxane

Abraxane Package Insert
17
Removal of Cremophor Results in Different PK for
Taxol and Abraxane
Abraxane is Cremophor-free Formulation of
Paclitaxel

• PK linearity
• Alterations in distribution phase

18
Cremophor Entraps Paclitaxel in Micelles in the
Plasma Compartment
Control plasma Plasma Taxol
CremophorMicelle

• Paclitaxel is entrapped in Cremophor micelles
• This results in non-linear paclitaxel PK for Taxol

Sparreboom A et al. Cancer Research,
19995914541457. van Tellingen O et al
British Journal of Cancer, 1999 81330-35.
19
Paclitaxel PK for Abraxane are Linear
Abraxane
Taxol
(1) Kearns, C. M., Pharmacotherapy, 1997 (2)
Taxol Package insert (3) Mross et al, Cancer
Chemother Pharm 2000
Source Abraxane NDA
20
Cremophor Alters the Distribution PhasePK of
Paclitaxel
Source Abraxane NDA and Sparreboom et al., 2005,
CCR
21
Reasons that an Efficacy Adjuvant Trial Should
not be Required for Approval of Abraxane
Abraxane is Cremophor-free Formulation of
Paclitaxel
Removing Cremophor Allows Safe Delivery of Higher
Doses of Paclitaxel
Therefore, there is no scientific basis to
hypothesize that Abraxane will be less effective
than Taxol as adjuvant therapy
In Metastatic Breast Cancer Abraxane has Greater
Anti-tumor Activitythan Taxol
Paclitaxel is Approved forAdjuvant Use (Taxol)
The Abraxane Dose of Paclitaxel is Safe and
Higher than that Already Proven Effective in the
Adjuvant Setting
22
Reasons that an Efficacy Adjuvant Trial Should
not be Required for Approval of Abraxane
Abraxane is Cremophor-free Formulation of
Paclitaxel
Removing Cremophor Allows Safe Delivery of Higher
Doses of Paclitaxel
Therefore, there is no scientific basis to
hypothesize that Abraxane will be less effective
than Taxol as adjuvant therapy
260 mg/m2 Q3W Phase 3 MBC
260 mg/m2 Q2W Adjuvant setting
23
Abraxane can Deliver Higher Paclitaxel Dosewith
Comparable Tolerability to Taxol
CA012 Randomized Phase 3 Trial in Metastatic Breast Cancer Abraxane 260 mg/m2n 229 Taxol 175 mg/m2 n 225

Median cycles/patient 6 5
Percentage of planned dose 98 98
Mean paclitaxel dose intensity q3w 255 mg/m2 171 mg/m2
The tolerability of Abraxane was equivalent to
that of Taxol at a 50 higher DELIVERED dose.
24
Abraxane and Taxol have Comparable Overall
Toxicity Profiles
Abraxane 260 mg/m2 Taxol 175 mg/m2n 229 n 225
Percentage of Patients
All Cycles
After 4 Cycles
25
Tolerable GI Toxicities for Abraxane and Taxol
Adverse Event Drug Percentage of Patients by Grade Percentage of Patients by Grade Percentage of Patients by Grade Percentage of Patients by Grade P-value
Adverse Event Drug 1 2 3 4 P-value
Nausea Taxol 12 8 lt1 0 0.039
Nausea Abraxane 19 7 3 0 0.039
Vomiting Taxol 4 4 1 0 0.022
Vomiting Abraxane 10 4 3 lt1 0.022
Diarrhea Taxol 11 3 1 0 0.006
Diarrhea Abraxane 17 9 lt1 0 0.006
Cochran-Mantel-Haenszel test
26
Taxane and Cremophor Related Toxicities
Adverse Event Drug Percentage of Patients by Grade Percentage of Patients by Grade Percentage of Patients by Grade Percentage of Patients by Grade P-value
Adverse Event Drug 1 2 3 4 P-value
Neutropenia Taxol 10 19 32 22 lt 0.001
Neutropenia Abraxane 21 25 32 9 lt 0.001
Hypersensitivity Reactions Taxol 8 3 2 0 0.001
Hypersensitivity Reactions Abraxane 3 lt1 0 0 0.001
Peripheral Neuropathy Taxol 43 10 2 0 lt 0.001
Peripheral Neuropathy Abraxane 41 20 10 0 lt 0.001
Cochran-Mantel-Haenszel test
27
Improvement from Grade 3 Sensory Neuropathy and
Resumption of Treatment with Abraxane (n 24)
1.00 0.75 0.50 0.25 0.00


10/14 patients resumed Abraxane at a lower dose


Median 22 days
Proportion not resolved
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Days since grade 3 to improvement
Source Abraxane NDA. Censored (n 10 patients)
28
Reasons that an Efficacy Adjuvant Trial Should
not be Required for Approval of Abraxane
Abraxane is Cremophor-free Formulation of
Paclitaxel
Removing Cremophor Allows Safe Delivery of Higher
Doses of Paclitaxel
Therefore, there is no scientific basis to
hypothesize that Abraxane will be less effective
than Taxol as adjuvant therapy
260 mg/m2 Q3W Phase 3 MBC
260 mg/m2 Q2W Adjuvant setting
29
Results of a Pilot Adjuvant Trial of Dose Dense
Abraxane

• CA030 U.S. Oncology (P.I. Nicholas Robert)
• Dose Dense AC x 4 ? Abraxane x 4 (all cycles q2w)
• Abraxane dose 260 mg/m2
• 30 received AC 29 received Abraxane
• 27/29 (93) received all 4 Abraxane cycles
• Comparable to Taxol q 3 weeks
• Mean cumulative dose 962 mg/m2
• Well tolerated without unexpected toxicity
• Peripheral neuropathy prospectively monitored and
  followed to resolution
• 28/29 (97) patients asymptomatic 8 months
  following treatment

30
28/29 (97) Patients were Asymptomatic
fromPeripheral Neuropathy within 8 Months
Following Dose Dense Abraxane at 260 mg/m2

• 59 asymptomatic at end of 4 cycle RX
• 75 2 months p Rx
• 97 8 months p Rx

Proportion Asymptomatic
Grade 0 or 1 per NCI CT CAE
Months
31
Ongoing Adjuvant Safety Trials
Institution P.I. Design N
US Oncology JohnPippen dd AC x 4 cycles?dd Taxol or Abraxane x 4 cyclesRandomized, with Bevacizumab N 4 of 200 (Accrual ongoing)
Dana Farber (DFCI) Harold Burstein dd AC x 4? dd Abraxane 260 mg/m2 x 4 N 39 of 50(Accrual ongoing)
MSKCC and UCSF Maura Dickler and Hope Rugo dd AC x 4 Bevacizumab ?dd Abraxane 260 mg/m2 x 4 Bevacizumab? Bevacizumab N 12 of 75(Accrual ongoing)
University of Washington Georgiana Ellis Wkly Doxorubicin oral Cy?Wkly Abraxane 100 mg/m2 x 12 /- Trastuzumab N 1 of 60(Accrual ongoing)
NSABP André Robidoux ABX 100 mg/m2 wkly x12?FEC x 4 /- Trastuzumab? surgery N 67 of 67(Accrual completed)
32
Design of Proposed Comparative Safety Study using
the Approved Dosing Schedules of Abraxane and
Taxol

• Objective
• Describe safety profiles of Abraxane and Taxol in
  Adjuvant Breast Cancer following AC x 4

Abraxane 260 mg/m2 IV over 30 min q 3 wk No
Standard Premedication
AC x 4 cycles
x 4 cycles
Randomization
Taxol 175 mg/m2IV over 3 hrs q 3 wk Standard
Premedication with Dexamethasone and
Anti-histamines
Final design to be agreed upon with FDA
33
How Similar or Dissimilar are Taxol and Abraxane?

• The active ingredient in both formulations is
  paclitaxel
• Administration Differences
• Cremophor-related HSRs are eliminated with
  Abraxane
• No steroid premedication required with Abraxane
• Standard IV tubing with shorter infusion time
• Differences in PK due to paclitaxel sequestration
  by Cremophor
• The removal of Cremophor permits delivery of a
  50 higher dose of paclitaxel than that of Taxol
• Despite higher dose the tolerability of Abraxane
  is comparable to that of Taxol
• Abraxane demonstrated higher anti-tumor activity
  than Taxol in metastatic breast cancer

34
Reasons that an Efficacy Adjuvant Trial Should
not be Required for Approval of Abraxane
Abraxane is Cremophor-free Formulation of
Paclitaxel
Removing Cremophor Allows Safe Delivery of Higher
Doses of Paclitaxel
Therefore, there is no scientific basis to
hypothesize that Abraxane will be less effective
than Taxol as adjuvant therapy
In Metastatic Breast Cancer Abraxane has Greater
Anti-tumor Activitythan Taxol
Paclitaxel is Approved forAdjuvant Use (Taxol)
The Abraxane Dose of Paclitaxel is Safe and
Higher than that Already Proven Effective in the
Adjuvant Setting