Product case study Neorecormon

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Neorecormon (tradename, also known as epoetin beta) is a recombinant human EPO first approved for medical use in the EU in 1997. It is indicated for the treatment of anaemia associated with various medical conditions, most commonly chronic renal failure and cancer patients receiving chemotherapy. Neorecormon is produced by recombinant DNA technology 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. administration 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 efficacy 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. Darbepoetin-alfa is its international non-proprietary name and it is marketed under the tradenames Aranesp (Amgen) and Nespo (Dompe Biotec, Italy). The 165 amino acid protein is altered in amino acid sequence when compared with the native human product. The alteration entails introducing two new N-glycosylation sites so that the recombinant product, produced in an engineered CHO cell line, displays five 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 first used therapeutically in 1989 for the treatment of anaemia associated with chronic kidney failure. This anaemia is largely caused by insufficient endogenous EPO production by the diseased kidneys. Prior to EPO approval this condition could only be treated by direct blood transfusion. 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 receiving 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 sufficient 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 composed 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 defined as the activity that promotes the same level of stimulation of erythropoiesis as 5 mmol of cobalt.

Simply Supported Beam Deflection
Figure 10.5 Schematic overview of the production of the EPO-based product 'Neorecormon'. Refer to text for further details

In addition to enhancing erythropoiesis, EPO treatment also improves tolerance to exercise, as well as a patient's sense of well-being. Furthermore, reducing/eliminating the necessity for blood transfusions also reduces/eliminates the associated risk of accidental transmission of blood-borne infectious agents, as well as the risk of precipitating adverse transfusion reactions in recipients. The therapeutic spotlight upon EPO has now shifted to additional (non-renal) applications (Table 10.8).

Table 10.8 Some non-renal applications of EPO (refer to text for details)

Treatment of anaemia associated with chronic disease Treatment of anaemia associated with cancer/chemotherapy Treatment of anaemia associated with prematurity To facilitate autologous blood donations before surgery To reduce transfusion requirements after surgery To prevent anaemia after bone marrow transplantation

10.2.6.2 Chronic disease and cancer chemotherapy

Anaemia often becomes a characteristic feature of several chronic diseases, such as rheumatoid arthritis. In most instances this can be linked to lower than normal endogenous serum EPO levels (although in some cases a deficiency of iron or folic acid can also represent a contributory factor). Several small clinical trials have confirmed that administration of EPO increases haematocrit and serum haemoglobin levels in patients suffering from rheumatoid arthritis. A satisfactory response in some patients, however, required a high-dose therapy that could render this therapeutic approach unattractive from a cost:benefit perspective.

Severe, and in particular chronic, infection can also sometimes induce anaemia, which is often made worse by drugs used to combat the infection. For example, anaemia is evident in 8 per cent of patients with asymptomatic HIV infection. This incidence increases to 20 per cent for those with AIDS-related complex, and is greater than 60 per cent for patients who have developed Kaposi's sarcoma. Up to a third of AIDS patients treated with zidovudine also develop anaemia. Again, several trials have confirmed that EPO treatment of AIDS sufferers (be they receiving zidovudine or not) can increase haematocrit values and decrease transfusion requirements.

Various malignancies can also induce an anaemic state. This is often associated with decreased serum EPO levels, although iron deficiency, blood loss or tumour infiltration of the bone marrow can be complicating factors. In addition, chemotherapeutic agents administered to this patient group often adversely affect stem cell populations, thus rendering the anaemia even more severe.

Administration of EPO to patients suffering from various cancers/receiving various chemo-therapeutic agents yielded encouraging results, with significant improvements in haematocrit levels being recorded in approximately 50 per cent of cases. In one large US study (2000 patients; most receiving chemotherapy) s.c. EPO administration of an average of 150 IU kg-1, three times weekly, for 4 months, reduced the number of patients requiring blood transfusions from 22 per cent to 10 per cent. Improvement in the sense of well-being and overall quality of life was also noted. The success rate of EPO in alleviating cancer-associated anaemia has varied in different trials, ranging from 32 per cent to 85 per cent.

On a more cautionary note, the EPO receptor is expressed not only by specific erythrocyte precursor cells, but also by endothelial, neural, and myeloma cells. Concern has been expressed that EPO, therefore, might actually stimulate growth of some tumour types, particularly those derived from such cells. To date, no evidence (in vitro or in vivo) has been obtained to support this hypothesis.

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