1

Kepivance™ (Palifermin) Basis for Approval and

Pediatric StudiesKepivance™ (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

Endpoint Placebo Kepivance™Statistical

Significance

Mean Duration Grade 3 or 4 Mucositis (Days)

10.4 3.7 p < 0.001

Incidence Grade 4 Mucositis

62.2% 19.8% p < 0.001

WHO Grade

1 2 3 4

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™ InitialPost 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