ChemGenex aims to lend Gleevec a helping hand

Melbourne-based drug-development company ChemGenex (ASX:CGX) has begun a Phase II trial of its developmental drug Ceflatonin to re-sensitise late-stage chronic myeloid leukaemia (CML) who have developed resistance to the Novartis 'miracle' drug Gleevec.

Ceflatonin, or homoharringtonine (HHT), has shown promise in preclinical trials as an adjuvant therapy to Gleevec, particularly for patients in the late, or blastic phase of CML.

ChemGenex president and director Dr Dennis Brown said Gleevec was very effective in patients in the chronic (early) and accelerated phases of the disease, but benefited only 15 per cent of patients in late-stage CML.

Brown said CML had a complex course of development -- the chronic phase typically lasts five to seven years, the accelerated phase lasts up to two years, but the median survival time for blast-phase CML is only three to six months.

The new multi-centre trial in the US aims to determine whether Ceflatonin and Gleevec have synergistic effects in the 85 of blast-phase CML patients who have become refractory to Gleevec.

Gleevec is a potent, orally administered tyrosine kinase inhibitor which prevents leukaemic cells dividing.

ChemGenex said about 20 per cent of newly diagnosed CML patients experience primary resistance to Gleevec, and another 20 per cent become resistant after 20 months.

CML is a relatively rare form of leukaemia, resulting from a chromosomal fracture that apposes segments of two genes, resulting in production of a fusion protein, Bcr-Abl. Expression of Bcr-Abl is the hallmark of Gleevec resistance in CML patients.

Prof Greg Collier, CEO and MD of ChemGenex, said Ceflatonin was an attractive prospect for a combination therapy with Gleevec, because, during pre-clinical trials, it exhibited some activity against CML in its own right.

Combined with Gleevec, it has a synergistic mode of action -- it reduces expression of the Bcr-Abl fusion protein. Collier said that if it fulfilled its promise, it would be offered to patients who showed signs of becoming refractory to Gleevec in the chronic and accelerating phases of the disease.

The aim would be to prevent such patients entering the more dangerous blastic phase, or even to convert them back to the more favourable, chronic phase of the disease.

"I think our agent will be valuable to maintain opportunities for patients to remain stable or even disease-free as long as possible," Brown said.

In a recent Phase I trial at the MD Anderson Cancer Centre in Houston, Texas, sponsored by the National Cancer Institute, 10 patients in the advanced stages of CML were treated with Ceflatonin alone; five showed significant responses.

The new Phase II trial will be an open-label study for patients in the chronic, accelerated or blast phases of CML. Each patient will receive a daily dose of Gleevec (400mg for chronic-phase and, 600mg for accelerated- and blastic-phase patients), and all will be given a continuous 2.5mg/day intravenous infusion of Ceflatonin for five days at four-weekly intervals.

The trial's principal investigator is the Anderson Centre's professor of leukaemia, Jorges Cortes.