The re-invention game

Big Pharma executives are searching desperately for a way of 'evergreening" the world's most lucrative drugs, the cholesterol-lowering statins, before they run out of patent protection in a few years time.

Melbourne drug-discovery company Phosphagenics (ASX:POH) might have just what the doctor ordered. Its lead compound, APA-01, not only exhibits promising activity against cardiovascular disease in its own right, it enhances the activity of the statins when they are co-administered to animals.

And for good measure, APA-01 also shows potential as an inhibitor of amyloid plaque formation the brain - the cause of Alzheimer's disease.

Phosphogenics has recently begun an international, pre-clinical trial of its lead compound in animal models of cardiovascular disease, after earlier in vitro studies at Johns Hopkins University in Maryland confirmed promising activity in preventing and treating cardiovascular disease.

Phosphagenics managing director Ian Patterson said the company was exploring two potential markets for APA-01: as a stand-alone therapeutic to prevent cardiovascular disease, and to enhance the efficacy of statin-family anti-cholesterol drugs.

Global sales of the statins are running at US$26 billion annually, with Pfizer's Lipitor dominating the market. Lipitor and Merck's Zocor were Australia's two top-selling drugs last year, with sales of $336 million and $311 million respectively.

Patterson said the statins were approaching their patent expiry dates - the Lipitor patent expires in 2007, and Zocor and Pravachol will follow soon after.

For all their phenomenal commercial success, the statins are notoriously inefficient drugs. Their bioavailability ranges from only 5 per cent to 14 per cent. Much of the expensive active ingredient goes to waste, and the high dosages required to compensate for low absorption can cause unpleasant side effects, including muscle pain.

Patterson said attempts to reformulate the drugs to improve their activity have failed, and at least one of the companies has stopped research aimed at 'evergreening' its drug to prolong its commercial life.

If APA-01 is successful, the companies could co-formulate it with statins to improve their activity. They would also qualify for 'evergreening' protection for their proprietary drugs.

The US Food and Drug Administration's 'evergreening' provision, allows it to grant multi-year extensions on the patent life of an existing drug, where a manufacturer can demonstrate improved activity.

'Evergreening', which was a contentious issue during Australia's recent Federal election, aims to prolonging the commercial life of proven drugs.

Phosphogenics' animal studies are running on three continents - at Monash University, the University of Bern in Switzerland, and at the University of California, Sacramento, in preparation for planned Phase I trial in human volunteers before the middle of next year.

Professor Angelo Azzi, Director of the Institute of Biochemistry and Molecular Biology at the University of Bern, Switzerland, said APA-01 inhibits the development of the fatty, atherosclerotic plaques that trigger heart attack and stroke by blocking major arteries in the heart or brain.

Azzi, a member of Phosphagenics' scientific advisory board, visited Melbourne this week this week for discussions with the company, and researchers at Monash University who are also involved in the animal trials trial. Professor Ishwarlal Jialal, another member of Phosphagenics scientific advisory board, heads a third group involved in the study, at the University of California, Sacramento.

Azzi said bis-phosphonate tocopherol, which occurs naturally in cells, has a longer half-life than standard alpha-tochpherol, or Vitamin E.

Six years ago his research group published a paper showing that the molecule inhibits the transformation of smooth-muscle cells in artery walls into foam cells, which accumulate oxidized lipoproteins and form the fatty plaques that narrow and clog major blood vessels. It also prevents macrophages from entering artery walls and forming foam cells.

Azzi said APA-01 not only acted as an anti-oxidant, it inhibited a signalling pathway that causes healthy cells to transform into foam cells.

Studies in knockout mice have shown that the drug works by chemically blocking expression of a cell-surface receptor called CD36, which mediates the uptake of oxidized lipoprotein Apo E.

As lipid levels increase in the bloodstream, smooth-muscle cells and macrophages ramp up expression of the CD36 scavenger receptor, and sequester oxidized Apo E as they begin transforming into foam cells.

Azzi said recent research in a rabbit model of atherosclerosis had shown that APA-01 actually reduces the expression of the CD36 scavenger receptor, preventing the cells accumulating Apo E.

In a different role, the drug has been shown to facilitate the removal of beta amyloid from the bloodstream - the toxic peptide aggregates in the brain, forming the amyloid plaques that cause the chronic neurodegenerative disorder, Alzheimer's disease.

Azzi said if this anti-amyloid activity could be also demonstrated in an animal model, Phosphogenics might be successful in gaining approval from the FDA to fast-tracking the drug through clinical trials - there are currently no effective drugs for preventing or treating Alzheimer's disease, which affects 1 person in 4 over the age of 70.