1. 1 Kepivance™ (Palifermin) Basis for Approval and Pediatric Studies Kepivance™ (Amgen) Approved 12/15/04 Joseph E. Gootenberg, M.D. Office of Oncology Drug Products Division of Biological Oncology Products Food and Drug Administration

2. 2 Kepivance™ (Palifermin) Keratinocyte Growth Factor Kepivance™ (Palifermin) is a recombinant human Keratinocyte Growth Factor (KGF) manufactured in E. coli. Endogenous KGF is a member of the fibroblast growth factor family that binds to the unique KGF receptor and stimulates proliferation of epithelial cells.

3. 3 KGF Receptor The KGF receptor is expressed on epithelial cells. Found in many tissues including the gastrointestinal tract (for example tongue, buccal mucosa, salivary gland) and skin.

4. 4 Mechanism of Action Kepivance™ reduces chemotherapy and radiotherapy-induced injury to epithelium by increasing epithelial thickness and enhancing recovery after injury.

5. 5 Major Study Supporting Approval Randomized placebo-controlled trial comparing Kepivance™ to placebo in patients with hematologic malignancies undergoing autologous Hematopoietic Stem Cell Transplant Primary endpoint: duration of severe oral mucositis 212 patients randomized 1:1 to Kepivance™ versus placebo

6. 6 Study Population Diagnoses – Hematologic malignancies (Non-Hodgkin Lymphoma, Hodgkin Disease, Leukemia, Multiple Myeloma ) Age 18 to 69 years Autologous Peripheral Blood Stem Cell Transplant utilizing a uniform preparative regimen of TBI / VP-16 / Cy and post transplant G-CSF

7. 7 Study 1 Trial Schema

8. 8 Results of Pre-specified Oral Mucositis Endpoints EndpointPlaceboKepivance™ Statistical Significance Mean Duration Grade 3 or 4 Mucositis (Days) 10.43.7p < 0.001 Incidence Grade 4 Mucositis 62.2%19.8%p < 0.001 WHO Grade 1234 Oral Toxicity Soreness and erythema Erythema, ulcers Can swallow solid diet Ulcers, extensive erythema Cannot swallow solid diet Mucositis to the extent that alimentation is not possible

9. 9 Label: Indication and Usage Kepivance™ is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. The safety and efficacy of Kepivance™ have not been established in patients with non-hematologic malignancies.

10. 10 Pediatric Aspects of Label Special Populations The pharmacokinetic profile in pediatric populations (see PRECAUTIONS: Pediatric Use) has not been assessed. Pediatric Use The safety and effectiveness of Kepivance™ in pediatric patients have not been established.

11. 11 Pharmacokinetics PK Data Available Only In Adults: Mechanism of elimination not known –Possibly receptor binding and internalization Terminal half-life 4.5 hours No accumulation with 3 daily doses Renal impairment: Insignificant influence on PK

12. 12 Safety The Kepivance™ Transplant Safety Pool included 650 patients (all adults): 409 Kepivance™ and 241 placebo Most adverse events were attributable to the underlying malignancy, cytotoxic chemotherapy, or TBI and occurred at similar rates in patients receiving Kepivance™ and those receiving placebo.

13. 13 Safety Most of the Kepivance™ related adverse events were consistent with the known pharmacologic action of Kepivance™ on skin and oral epithelium (for example: skin rash, pruritus, erythema, or edema; mouth and tongue thickness or discoloration; and taste disorders).

14. 14 PREA Goals for Pediatric Trial Major focus: Safety evaluation Determine pharmacokinetics in pediatric age groups likely to be treated with Kepivance™ Evaluation of pharmacodynamic effect (reduction in oral mucositis)

15. 15 Anti-cancer regimen associated with a high incidence of severe mucositis. To increase ability to characterize Kepivance™ related adverse events: –Randomized trial –Uniform underlying disease, clinical status and treatment FDA Considerations: Pediatric Trial

16. 16 FDA Considerations: Pediatric Trial Avoid allogeneic hematopoietic stem cell transplant regimens: high levels of baseline toxicity could confound detection and analysis of Kepivance™ related toxicity. Tumor stimulation in cancers of epithelial origin of concern in adult oncology patients is less an issue in pediatric malignancies

17. 17 Amgen Kepivance™ Initial Post Marketing Commitment Stages 1 and 2 B-cell NHL Children age 3 to 16 Multi-center dose escalation study Placebo controlled Evaluate safety, pharmacokinetics, and efficacy of Kepivance™ 174 pediatric patients