Growth factors - Pharmaceutical Biotechnology: Concepts and Aapplications - page 278

Box 10.2
Product case study: Neorecormon
Neorecormon (tradename, also known as epoetin beta) is a recombinant human EPO fi rst
approved for medical use in the EU in 1997. It is indicated for the treatment of anaemia as-
sociated with various medical conditions, most commonly chronic renal failure and cancer
patients receiving chemotherapy. Neorecormon is produced by recombinant DNA tech-
nology in a CHO cell line and is manufactured as outlined in Figure 10.5. It is presented
in lyophilized format at various strengths (500-10 000 IU/vial) and contains phosphate
buffer, sodium chloride, calcium chloride, urea, polysorbate and various amino acids as
excipients.
The product displays a terminal half-life of 4-12 h and 8-22 h after i.v. and s.c. administra-
tion respectively. Dosage regime is dependent upon the exact disease condition, but generally
involves administration once/several times weekly. Various clinical trials investigating various
indications proved product effi cacy in the treatment and prevention of anaemia, with increased
haemocrit values observed.
Common side effects include increased blood pressure, increased respiratory infections and
increased platelet counts. Serious (rare) side effects were most often related to cardiovascular
complications. Neorecormon is marketed by Roche.
Neorecormon is one such product (Box 10.2), an overview of whose production is provided
in Figure 10.5. More recently, an engineered form of EPO has gained marketing approval. Dar-
bepoetin-alfa is its international non-proprietary name and it is marketed under the tradenames
Aranesp (Amgen) and Nespo (Dompé Biotec, Italy). The 165 amino acid protein is altered in
amino acid sequence when compared with the native human product. The alteration entails intro-
ducing two new N-glycosylation sites so that the recombinant product, produced in an engineered
CHO cell line, displays fi ve glycosylation sites as opposed to the normal three. The presence of
two additional carbohydrate chains confers a prolonged serum half-life on the molecule (up to
21 h, compared with 4-6 h for the native molecule).
EPO was fi rst used therapeutically in 1989 for the treatment of anaemia associated with chronic
kidney failure. This anaemia is largely caused by insuffi cient endogenous EPO production by the
diseased kidneys. Prior to EPO approval this condition could only be treated by direct blood trans-
fusion. It responds well, and in a dose-dependent manner, to the administration of recombinant
human EPO (rhEPO). The administration of EPO is effective, both in the case of patients receiv-
ing dialysis and those who have not yet received this treatment.
Administration of EPO doses ranging from 50 to 150 IU kg 1 three times weekly is normally
suffi cient to elevate the patient's haematocrit values to a desired 32-35 per cent. (Haematocrit
refers to 'packed cell volume', i.e. the percentage of the total volume of whole blood that is com-
posed of erythrocytes.) Plasma EPO concentrations generally vary between 5 and 25 IU l 1 in
healthy individuals. One IU (international unit) of EPO activity is defi ned as the activity that
promotes the same level of stimulation of erythropoiesis as 5 mmol of cobalt.