C-1 Pegfilgrastim (Neulasta  ) Oncologic Drugs Advisory Committee Pediatric Subcommittee October 20, 2005 Amgen Inc.

C-2 Pegfilgrastim  Approved in January 2002 to decrease febrile neutropenia in patients with non ‑ myeloid malignancies receiving myelosuppressive therapy  To date, approximately 3,800 adult patients have been treated in clinical trials and approximately 517,000 patients have been treated worldwide since commercial introduction

C-3 Primary Goals of Pediatric Development of Pegfilgrastim  To determine an appropriate dose of pegfilgrastim for use in the pediatric population  Introduce a pediatric dosage form to ensure coverage for all age and weight groups – Current dosage form  6mg syringe (10mg/ml)  Fixed dose for patients  45kg

C-4 Common Challenges of Pediatric Oncology Drug Development  Limited patient population  Majority of pediatric patients enter clinical studies  Limited study centers  Need for pharmacokinetic and pharmacodynamic data – Intensive monitoring and blood sampling

C-5 Pegfilgrastim-Specific Challenges in Pediatric Development  Availability of filgrastim  Competition with therapeutic agent trials  Study of tumor and associated chemotherapy regimen across pediatric age ranges

C-6 Pediatric Study Tumor Type: Sarcoma  Challenge – Higher incidence in older ages  Predominantly Ewing’s sarcoma enrolled into study *Per 1,000,000 pediatric population SEER Cancer Statistics Review, , National Cancer Institute. Incidence*

C-7 Pediatric Study Summary  Primary objective – To determine an appropriate pediatric dose  Clinical hypothesis – At the identified dose, pegfilgrastim will provide Absolute Neutrophil Count (ANC) recovery and safety profile similar to filgrastim  Parameters to be measured – Duration of severe neutropenia – Rates of febrile neutropenia – Pharmacokinetic profile of pegfilgrastim – Incidence of adverse events

C-8 Pediatric Sarcoma Study Schema Cycle 1 VAdC VAdC Pegfilgrastim Filgrastim Day 1 to 21 Pegfilgrastim Cycle 2 IE IE Filgrastim Day 22 to 42 Cycle 3 VAdC VAdC Pegfilgrastim Filgrastim Day 43 to 63 Cycle 4 IE IE Pegfilgrastim Filgrastim Day 64 to 84 Daily ANC and PK samples Doses: Vincristine 2 mg/m 2 ; Adriamycin 75 mg/m 2 ; Cyclophosphamide 1200 mg/m 2 ; Ifosphamide 1800 mg/m 2 ; Etoposide 100 mg/m 2 Multi-center, randomized (6:1), open-label, using VAdriaC/IE ClinicalTrials.gov identifier NCT

C-9 Age Groups Defined in Study Protocol 0 to 5 years 6 to 11 years 12 to 21 years Dose selection for each age group is done independently

C-10 Dose Selection Algorithm Requires Two Successive Cohorts Showing ANC Recovery ANC recovery in  5 patients Cohort 2 Dose 1.5 x A Cohort 3 Dose 1.5 x A ANC recovery in  5 patients Cohort 2 Dose A ANC recovery in  5 patients Cohort 1 Dose A ANC recovery in  5 patients Scenario A ANC recovery in <5 patients Cohort 1 Dose A Scenario B All numbers refer to the 6 patients treated with pegfilgrastim

C-11 Rationale for Selection of Pediatric Starting Dose of 100  g/kg  Pharmacokinetics and mechanism of action are expected to be similar in adults and pediatric patients – Neutrophil-mediated clearance  This dose is safe and effective in adults  Commonly-used filgrastim pediatric dose (5  g/kg/day) is same as adult dose

C-12 Pediatric Study Status 0 to 5 years 3 enrolled 4 more needed 6 to 11 years 3 enrolled 4 more needed 12 to 21 years ENROLLMENT AND TREATMENT COMPLETED 12 to 21 years ENROLLMENT AND TREATMENT COMPLETED 0 to 5 years ENROLLMENT AND TREATMENT COMPLETED 6 to 11 years ENROLLMENT AND TREATMENT COMPLETED Cohort 1 Cohort 2

C-13 Challenges to Completing the Pediatric Study  Filgrastim available and commonly used  Accrual issues – Low incidence of sarcoma in younger patients – Therapeutic protocols have higher priority than supportive care – Daily monitoring / blood draws may keep children in hospital or clinic

C-14 Addressing Current Accrual Challenges  Maintained contact with pediatric community to advise on ways to improve enrollment  Competing therapeutic trials have recently completed accrual resulting in a small window of opportunity – Expand site numbers – Enroll more patients at existing sites

C-15 Lessons Learned for the Future  Whenever possible, integrate into therapeutic protocols  Design more efficient studies by continued collaboration with pediatric community and regulatory authorities (e.g. targeted collection of data)

C-16 Summary and Conclusions  Pediatric patients, like adult patients, are expected to benefit from the addition of pegfilgrastim as a supportive care option  Significant progress has been made in determining the appropriate dose for pegfilgrastim in pediatric patients  Amgen looks forward to continued collaboration with cooperative groups and FDA to expedite pediatric drug development