Growth factors - Pharmaceutical Biotechnology: Concepts and Aapplications - page 287

Box 10.3

Product case study: Kepivance

Kepivance (tradename, also known as palifermin) is a keratinocyte growth factor produced
by recombinant means in E. coli . It was fi rst approved in the USA in 2004 and is indicated
to decrease the incidence and duration of severe oral mucositis in patients with haematologic
malignancies receiving myelotoxic therapy requiring haematopoietic stem cell support. Oral
mucositis, characterized by ulcerative lesions of the mouth, is a common and debilitating side
effect of high-dose chemotherapy or radiotherapy. It is particularly common (incidence of
70-80 per cent) and severe in the indication patient grouping.
Keratinocyte growth factor is a 140 amino acid, 16.3 kDa member of the FGF family. It dif-
fers f rom native keratinocyte g rowt h factor in t hat t he fi rst 23 N-terminal amino acids have been
deleted, which improves its stability. After cell growth the product is recovered and purifi ed by
a multistep chromatographic protocol. It is presented in lyophilized format in single-use vials
and containing mannitol, sucrose, polysorbate 20 and histidine as excipients. It is administered
by daily i.v. injection, usually for several days.
The cell surface keratinocyte growth factor receptor is present in a wide variety of tissues,
including the tongue, buccal mucosa and oesophagus, but also additional tissues including the
liver, kidneys and bladder. Keratinocyte growth factor receptor binding triggers proliferation,
differentiation and migration of epithelial cells.
After single-dose i.v. administration, total body clearance appears two- to four-fold higher in
cancer patients than in healthy subjects, although elimination half-life (3.3-5.7 h) was similar
in both groups.
The initial trial establishing safety and effi cacy was a randomized, placebo-controlled study
involving 212 patients. The treated group received 60 g kg 1 day 1 of the product for 6 days.

The primary end-point measured was the number of days during which the patients experienced
severe oral mucositis, which treatment reduced from 9 to 3 days. The incidence of mucositis
was also reduced from 98 per cent to 63 per cent.
Side effects noted included rash, erythema, tongue thickening and discoloration, as well as
alteration of taste. Kepivance is manufactured and marketed by Amgen Inc.

µ

3. Although the product of distinct
genes, all exhibit close homology. In the mature form, they exist as homodimers, with each
subunit containing 112 amino acid residues. Most body cells synthesize TGF-

consists of t h ree sepa rate g rowt h factors: TGF- β 1, - β 2 and - β

β , singly or in

combination.
TGF- s are pleiotrophic cytokines. They are capable of inhibiting the cell cycle and, hence,

cell growth of several cell types, most notably epithelial and haematopoietic cells. These factors,
however, stimulate the growth of other cell types, most notably cells that give rise to connective
tissue, cartilage and bone. They induce the synthesis of extracellular matrix proteins and modulate
the expression of matrix proteases. They also serve as a powerful chemoattractant for monocytes

β