NZ's billion-dollar man aims to mend diabetes' broken hearts

Prof Garth Cooper's ambition to build his second -- and new Zealand's first -- billion-dollar biotech company appears to be on track, with his Auckland-based biopharma company Protemix announcing remarkable results from a Phase IIa clinical trial of an oral drug that reverse heart disease in type 2 diabetics.

In a paper 'Regeneration of the heart in diabetes by selective copper chelation', published this month in the journal Diabetes, Cooper and long-time collaborator Dr John Baker report that a six-month course of Protemix' Laszarin reverses chronic enlargement of the heart in diabetic patients, regenerating heart muscle to near normal.

Laszarin is a copper chelator, a small-molecule drug that removes excess copper from the body. Patients in the trial exhibited increased urinary excretion of copper.

Heart enlargement (cardiomegaly) and dysfunction are major cause of death in the estimated 194 million patients around the world with non-insulin dependent diabetes. More than 65 per cent of diabetics develop premature heart disease, and die of heart failure or stroke.

In a statement, Protemix said the study was the first to implicate defective copper metabolism in heart disease in diabetics.

Cooper said heart failure in diabetes appeared to be mediated by an accumulation of toxic copper 2 ions within the extracellular matrix of the cardiovascular system.

Cooper said copper 2 was the primary form in which copper is present in the extracellular environment of the body, whereas intracellular copper is usually present as copper 1. He said copper 2 was the most electrochemically active ion in the body. It catalyses the production of hydrogen peroxide, which decomposes to water and toxic hydroxyl radicals that damage tissue.

Australian biotech Prana Biotechnology (ASX:PBT) is developing novel copper-chelating drugs to treat Alzheimer's disease, based on a hypothesis developed by Prana co-founder Prof Ashley Bush that by copper ions in amyloid plaques in the brain spawn hydroxyl radicals that kill off neurons in the brains of Alzheimer's patients.

Cooper said copper 2 was normally tightly regulated by a network of copper-binding proteins. Protemix researchers have experimental evidence that, in diabetes, an abnormal accumulation of loosely bound copper 2 ions in the extracellular matrix causes major free-radical stress, resulting in localised accumulations of glycated end-products that damage the heart and other cardiovascular tissue.

Fortunately, in their loosely bound form, copper 2 ions were readily extractable by a copper chelator like Laszarin.

Asked if Laszarin's copper-chelating activity might provide a therapeutic benefit to diabetics' brains, as well as their hearts, Cooper said, "We've thought about that. It just might fix up Alzheimer's as well."

Commenting on the latest findings, Prof Norman Sharpe, medical director of the New Zealand Heart Foundation, said it had always been assumed that damaged heart muscle could not regenerate.

"This work refutes that," he said. "We hear the word 'breakthrough' all too often, but this is a significant finding for diabetes research, which provides insight into the mechanisms of the disease. There is a distinct possibility for intervention and treatment."

Prof Harvey White, director of coronary care and cardiovascular research at Greenlane Cardiovascular Service, Auckland Hospital, said the drug "could have a major impact on the management of diabetes, high blood pressure and coronary artery disease".

In earlier trials in an animal model of heart enlargement, researchers found that a seven-week course of Laszarin significantly alleviated heart failure.

The company is about to begin a phase 2b clinical trial in diabetic patients at nine hospitals in New Zealand and Australia. Monash University heart expert Prof Henry Krum will be co-lead investigator.

Cooper said Protemix was also submitting an Investigational New Drug application to the US Food and Drug Administration for an extended, Phase III trial of Laszarin in human volunteers.

If the trials are successful, Cooper said, Laszarin would have a potential worldwide market of more than 2 million people with diabetic heart failure. Last year, he told Australian Biotechnology News that if Laszarin were to be given fast-track status from the FDA, Laszarin could reach clinical use in four years, and achieve annual sales of US$750 million.

As a PhD at Oxford University in 1986-87, Cooper discovered the hormone amylin, which when co-administered with insulin, markedly reduces the adverse side-effects of chronic insulin therapy in diabetics.

He founded Amylin Pharmaceuticals to commercialise an amylin analogue, Pramlintide. In 1988 he moved Amylin to California, where it is now capitalised at more than $4 billion.

Cooper returned to New Zealand in 1993, with the intention of creating a major biotech company to provide a focal point for international investment in his home country's biotech industry.

Renowned in the NZ biotech industry both for his self-belief and his formidable research skills, Cooper has stated his intention to make Protemix the first NZ company to take a new drug all the way from discovery to clinic without help from big pharma.