A cure, but not for all

Dr Patrick Gladding with a 3D laser etching of a double helix, or DNA. Photo / Paul Estcourt

Chances are, if you're admitted to hospital with chest pain from clogged arteries, you'll rapidly become familiar with a lifesaver called Clopidogrel.

The drug, which also goes by the name Plavix, is used in a range of heart diseases as well as for circulatory conditions and in the treatment of stroke.

It saves lives by stopping blood clots forming and is often used in conjunction with other heart procedures such as angioplasty and stenting.

What's less well known is that the drug has to interact with enzymes from your liver in order to work. Unfortunately, by a quirk of genetic fate, some don't have the ability to make these enzymes and so they don't respond to the drug.

For this group - which can be up to 30 per cent of those given the drug - the chances of recovery are not good. Also not well known is that Maori and Pacific people are much more likely than Europeans to have the genetic variant that causes Plavix not to work.

The answer seems obvious.

Test for the gene before you take the drug. And if you're a "non-responder" pursue an alternative drug treatment. Until recently, such an option was a future science fantasy. But, thanks to groundbreaking New Zealand research, you can have the genetic test done for about $200 and get your results in about 24 hours.

Lamentably, hardly anyone knows about it, and even though such a test could save lives, it's not something you'll be offered in New Zealand hospitals. Not yet.

But as research continues to show positive benefits from tailoring drugs to your genes, it's a situation that may be about to change.

Pharmacogenetics. It's a place where drugs, biology and technology collide. At its frontier is the prospect of the "US$1000 genome" - an individual's entire DNA sequence on a computer chip - a future that some claim is as little as two to three years away. Medicine, but not as we know it.

While it's now possible to know and hold the blueprint of one's fate, having such knowledge isn't always helpful. James Watson, when he was presented with his genome recorded on two DVDs, insisted that the information about his APoE gene, an indicator for Alzheimer's, was removed. Watson reasoned there was little point knowing about such a risk if there was nothing he could do about it.

It's an argument that leads many to question the benefit of direct-to-consumer online services such as deCODE Genetics and 23andMe which encourage people to send in a saliva sample and for around US$1000 ($1458) get a picture of some of their genetic quirks and glitches.

Sometimes knowing one's susceptibility to conditions such as cancer, heart disease, diabetes and mental illness may be useful, but when diagnostic ability outstrips therapeutic ability, all one may end up getting is increased anxiety.

There are privacy problems too - about where and how such information should be kept, plus issues around who should have access to information that could have profound effects on insurance and employment.

Dr Patrick Gladding, a cardiologist at Auckland hospital, stays away from such ethical conundrums by focusing on genetic variants that can make a difference.

The Herald last spoke to Gladding 18 months ago when he had just completed a research study of heart patients' response to Clopidogrel related to a number of genetic markers.

Since then Gladding's findings have been confirmed by several other studies, and it is now well accepted that how well Clopidogrel works does indeed depend on certain genes.

In June the United States Food and Drug Administration changed the way it labels Plavix, adding new pharmacogenetic information. The label now states that patients with a genetic variant of the "CYP2C19" gene have a significantly increased risk of heart attack.

But while the FDA clearly acknowledges the effect of genetic variants, it stops short of the next step - recommending that patients undergo a genetic test - before taking the drug.

The FDA did the same with dosage information for the blood thinning drug Warfarin which it acknowledged in 2007 was dependant on genetic variants.

It has since approved a genetic test which identifies individuals who metabolise Warfarin more slowly than normal, but hasn't put a requirement on the Warfarin label that the test be carried out.

Gladding faces similar frustrations in New Zealand. Working with Linnaeus, a laboratory in Gisborne, he's ready to offer genetic marker tests not just for Clopidogrel, but also for Warfarin and cholesterol-lowering statin drugs used in the treatment of heart disease.

Tests which not only improve the efficacy of the drugs - in the case of statins by predicting adverse effects such as muscle wasting - but which also save lives.

While he's in discussions with New Zealand's drug regulator Pharmac, he's yet to get any official support.

"Anything that targets any pharmaceutical to the right people has got to be looked at very seriously," says Pharmac medical director Peter Moodie. "In principle we continue to be very interested in that technology."

Last year Pharmac funded 27,000 prescriptions of Clopidogrel at a cost of $2.8 million. Moodie says the next step in assessing the new information about Clopidogrel or any other personalised medicine is complex - an analysis of the cost of the genetic test, the benefits both in terms of efficacy and lives saved, and the cost of alternative drugs for non-responders.

In Clopidogrel's case, the likely replacement candidate is Prasugrel, which is yet to have a funding application in New Zealand.

It's also likely to be more expensive - about $150 per month compared to $30 per month for the now "off patent" (generic Clopidogrel) Plavix.

The cost benefit equation is further complicated by Pharmac decision-making criteria to assess the impact of a particular disease or therapy on Maori and Pacific people.

Gladding and others have already done preliminary research which shows the genetic variant affecting Clopidogrel is more prevalent in Maori and Pacific populations. Similar studies have also shown the variant to be more common among African Americans and East Asian populations.

Gladding had also done research which indicates it may be possible to overcome the non-responder effect to Clopidogrel by an increased dose.

"The increased dose showed an effect on the sticky platelets in the blood. But we don't know yet whether upping that dose is a good thing. It could make you bleed more or it could save you from a heart attack. More research needs to be done."

The unfinished research is frustrating for Gladding who is about take up a position either in Australia or the United States to complete his specialist training in cardiology. "Essentially I ran out of funding money to keep the impetus alive."

He's hopeful others will pick up where he left off. In the meantime, Gladding has formed a company, Theranostics, to provide pharmacogenetic tests in New Zealand. Ultimately he'd like to start a DNA "biobank" here to further the research, which he believes could play a significant role in improving heart disease outcomes for Maori and Pacific people.

At present the only routine personalised medicine test done in New Zealand is for azathioprine - used in autoimmune conditions such as rheumatoid arthritis and inflammatory bowel disease.

"That's because one in 300 patients are unable to metabolise the drug and can basically be poisoned if you give them the standard dose," says associate professor Martin Kennedy director of the Carney Centre for Pharmacogenomics in Christchurch.

Kennedy and clinical pharmacologist Professor Evan Begg, also with the centre, agree the latest research on Clopidogrel looks compelling for genetic testing.

But they both stress the importance of detailed analysis of such genetic associations with drugs before proceeding. Drug interactions and a host of other factors can also play a big part.

"There's been a lot of hype and not much return from a clinical point of view," says Kennedy. The centre's research on antidepressants, for example, while useful in explaining the mechanism of the drugs, is yet to uncover genetic variants that make a significant difference to drug response.

The research on azathioprine, on the other hand, has looked at the way the drug is metabolised and found several genetic differences that do impact on patient responses.

The challenge of pharmacogenetic research, says Kennedy, is to prove they can make a difference to patient care.