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Abraxane for the adjuvant treatment of node-positive breast cancer

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. . 505(b)(2) Regulatory Pathway. 505(b)(1):

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Abraxane for the adjuvant treatment of node-positive breast cancer

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    1. Abraxane® for 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) “FDA’s longstanding interpretation of section 505(b)(2) ……… the Agency’s 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.”

    5. 505(b)(2) Avoids Significant Delays in Drug 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.’

    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

    9. Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane William J. Gradishar, MD

    10. Development of Paclitaxel Formulations: Historical Background Paclitaxel, one of the most active cytotoxic agents Cremophor® required at high concentrations (Taxol® and generic equivalents) In the 1990’s, 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. 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 at 175 mg/m2 2004: Randomized Phase 3 Trial proved superior anti-tumor activity of Abraxane with comparable tolerability at higher dose than Taxol 2005: FDA granted approval for metastatic breast cancer under the 505(b)(2) regulatory pathway for new formulations of existing drugs Basis of FDA Approval of Abraxane for Metastatic Breast Cancer

    12. Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

    13. Abraxane is Albumin-bound Cremophor-free Paclitaxel

    14. The Active Ingredient in Abraxane and Taxol is Identical

    15. Abraxane was Developed to Eliminate Cremophor-induced Hypersensitivity Reactions Hyperglycemia Glucose intolerance in diabetics Mood changes Insomnia

    16. Abraxane was Developed to Eliminate Cremophor-induced Hypersensitivity Reactions

    17. Removal of Cremophor Results in Different PK for Taxol and Abraxane PK linearity Alterations in distribution phase

    18. Cremophor Entraps Paclitaxel in Micelles in the Plasma Compartment

    19. Paclitaxel PK for Abraxane are Linear

    21. Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

    22. Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

    23. Abraxane can Deliver Higher Paclitaxel Dose with Comparable Tolerability to Taxol

    24. Abraxane and Taxol have Comparable Overall Toxicity Profiles

    25. Tolerable GI Toxicities for Abraxane and Taxol

    26. Taxane and Cremophor Related Toxicities

    27. Improvement from Grade 3 Sensory Neuropathy and Resumption of Treatment with Abraxane (n = 24)

    28. Reasons that an Efficacy Adjuvant Trial Should not be Required for Approval of Abraxane

    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* from Peripheral Neuropathy within 8 Months Following Dose Dense Abraxane at 260 mg/m2

    31. Ongoing Adjuvant Safety Trials

    32. Design of Proposed Comparative Safety Study using the Approved Dosing Schedules of Abraxane and Taxol

    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

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