1. Basis for Neulasta® (Pegfilgrastim) Approval
Amgen
Neulasta®
Approved 01/31/02
Jeff Summers
DBOP OODP CDER

2. Mechanism of Action
Both Neulasta® and Neupogen™ function as granulocyte colony stimulating factors
Neulasta® (pegfilgrastim) is a pegylated version of Neupogen™
Neupogen™ (Filgrastim) is a nonglycosylated N-terminal methionine modified recombinant human granulocyte colony stimulating factor (G-CSF) protein

3. Granulocyte Colony Stimulating Factors
G-CSF
Controls proliferation of committed progenitor cells and influences their maturation into mature neutrophils.
Stimulates the release of neutrophils from bone marrow storage pools and reduces their maturation time.
Acts to increase the phagocytic activity of mature neutrophils.
In patients receiving cytotoxic chemotherapy, G-CSF can accelerate neutrophil recovery, leading to a reduction in duration of the neutropenic phase .

4. Studies submitted for Neulasta® Approval
Two randomized, double-blind, non-inferiority studies
Dosing
Study 1 used 100 ug/kg dose
Study 2 used a fixed 6 mg dose
Population
High-risk Stage II or Stage III/IV Breast Cancer patients
Age ≥ 18 years
Receiving Docetaxel and Doxorubicin
Endpoint
Duration of severe neutropenia comparing Neulasta® to Neupogen™

5. STUDY RESULTS Primary Endpoint Neupogen Neulasta Study 0.1 (-0.2,0.4)
1.6
1.7
Study 2
N = 310
0.2
(-0.2,0.6)
1.8
Study 1
n = 157
Difference in means (95% CI)
Mean days of severe neutropenia
Study
Study 1 dose = 6 mg x1; study 2 dose = 100 mcg/kg
Table 1. Mean Days of Severe Neutropenia (in Cycle 1)

6. Study Results ●DSN in cycles 2 through 4
Secondary Endpoints
 In both studies the results for the following were similar for both Neulasta and Neupogen:
●DSN in cycles 2 through 4
●Depth of ANC nadir in cycles 1 through 4
●Rates of FN by cycle and across all cycles
●Time to ANC recovery by cycle and across all cycles

7. Label Indication and Usage
Neulasta® is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive
anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

8. Pediatric Aspects of the Neulasta® Label
PRECAUTIONS
Pediatric Use
The safety and effectiveness of Neulasta™ in pediatric patients have not been established. The 6 mg fixed dose single-use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg.

9. Pediatric Aspects of the Neupogen Label
Neupogen is approved for use in children with severe chronic neutropenia
Studied in patients with Neuroblastoma
Formulation allows for dosing based on mcg/kg

10. Pediatric Research Equity Act
If the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, the Secretary may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults, usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies.

11. Neulasta® Pharmacokinetics
Renal impairment had no influence on PK
Maximum Neulasta® concentration was achieved approximately 30 hours after SC administration
Volume of distribution at steady state approximated plasma volume/central compartment
Elimination is primarily via a neutrophil- mediated clearance mechanism
Half-life variable: chemotherapy setting 33 hrs compared to 3.37 hours for filgrastim

12. Safety
The Controlled Clinical Trial Safety Data Base of Neulasta® contains 932 patients
Bone pain
Post-marketing experience revealed the following SAEs:
Rare incidence of splenic rupture, allergic reactions, and sickle cell crises

13. Issues for a Pediatric Neulasta® PMC Trial
Is there any reason to expect the mechanism of action or efficacy to be different in a pediatric population?
Will establishing PK in pediatric age groups likely to be treated with pegfilgrastim ensure the safe use in pediatric patients?
Is the approved dosage form likely to be useful in the younger pediatric age groups

14. Post Marketing Commitment Pediatric Study
To submit results from an ongoing study evaluating the pharmacokinetics (PK), safety and efficacy of Pegfilgrastim in pediatric sarcoma patients receiving a single dose per cycle of Filgrastim-SD/01 as an adjunct to VadriaC/IE chemotherapy.
Expanded access study.
To develop a pediatric dosage form