Roche's anaemia therapy trial gets underway worldwide

Swiss pharmaceutical giant Roche has begun a massive, 484-centre Phase III trial of its new drug for anaemia associated with chronic kidney disease.

Roche's CERA (continuous erythropoietin receptor activator) is a semi-synthetic form of the natural red blood-cell booster erythropoietin (EPO), which continuously activates the EPO receptor.

Chemists were able to stabilise the native EPO molecule by integrating polymers into its amino acid chain. Melbourne-trained John Michaeilidis, who heads Roche's global anaemia franchise, said the modified molecule had a half-life of 133 hours in the bloodstream, almost 15-fold improvement on the 9-hour half-life of native EPO.

Michailidis said CERA had a unique mode of action, rapidly and repeatedly attaching and dissociating from the erythropoietin receptor to trigger bursts of red blood-cell formation.

Its persistence in the bloodstream should avoid the need to dose patients frequently with EPO -- CERA needs to be administered only once a month, where conventional EPO is administered between one and three times a week.

Michailidis said a further advantage of CERA is that its slow, even release profile results in a rapid rise in haemoglobin levels in the blood, followed by steady, controlled erythropoiesis throughout the month-long lifetime of the dose.

In contrast, anaemic patients on conventional EPO therapy require repeated haemoglobin tests and dose adjustments to prevent their red blood cell counts over-shooting or under-shooting.

If CERA fulfils its early clinical promise, Roche expects it to become one of the world's biggest selling drugs. There are 400,000 potential patients in the US alone, and several hundred thousand more in other developed nations.

A number of Australian and New Zealand hospitals are involved in the Phase III multi-centre trials. Michailidis said Australia and New Zealand played an important role in the pre-clinical and Phase I trials.

Because the kidneys are the primary source of EPO, anaemia is a common consequence of chronic renal disease. CERA is being investigated for managing anaemia associated with chronic kidney disease in both pre-dialysis patients, and patients on dialysis.

Kidney disease is also a common consequence of type 2 diabetes. Failing kidneys send EPO levels into decline, triggering programmed cell death in the bone-marrow stem cells that give rise to red blood cells and sending patients into a worsening spiral of anaemia. Michailidis said CERA had been found to protect erythroid progenitor cells against apoptosis.

Before the advent of EPO therapies like Roche's own NeoRecormon in the early 1990s, patients with chronic renal disease, or recovering from cancer therapy, required repeated blood transfusions. Michailidis said CERA should take further pressure off blood supplies.

Roche is also investigating CERA as a therapy for managing anaemia in cancer patients who undergo chemotherapy after surgery to remove solid tumours. Chemotherapy causes anaemia by killing blood stem cells.

CERA is also being investigated as an anaemia therapy in patients with leukaemias and lymphomas, which dramatically skew blood cell production towards lymphoid lineages.

Michailidis warns that athletes in endurance sports who attempt to exploit CERA's sustained activity to enhance their performance will be readily detected -- a mass spectrometer will quickly detect the telltale presence of the polymer in the modified molecule.