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

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 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 Study 1 Trial Schema

8 Results of Pre-specified Oral Mucositis Endpoints EndpointPlaceboKepivance™ Statistical Significance Mean Duration Grade 3 or 4 Mucositis (Days) p < Incidence Grade 4 Mucositis 62.2%19.8%p < 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 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 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 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 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 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 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 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 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 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