A three-ingredient ‘polypill’ for the secondary prevention of cardiovascular disease in people who have already had a heart attack could enter clinical development in the second half of this year.

Backed by the World Heart Federation, the polypill project involves a fixed-dose oral combination of aspirin, an undisclosed statin and an undisclosed ACE-inhibitor. The initiative is being taken forward by the Spanish National Centre for Cardiovascular Research (Centro Nacional de Investigaciones Cardiovasculares/CNIC) in partnership with local pharmaceutical company Laboratorio Ferrer.

According to Dr Francisco de Paula Rodríguez Perera, managing director of the CNIC, the statin and ACE-inhibitor components of the three-in-one polypill are long established in the marketplace, with proven efficacy. Using off-patent ingredients will keep costs down as well. The hope is that the monthly dollar outlay for the new polypill, once it is available, will be in single figures or around one fifth the cost of existing drugs for the prevention of cardiovascular disease.

The aim is to start the clinical programme with pharmacodynamic and pharmacokinetic testing in the second half of this year, then move into Phase II and III clinical trials in at least 600 and no more than 1,200 post-myocardial infarction patients, Rodríguez Perera told PharmaTimes. Trials will initially be in Europe and possibly Canada. Next year they will expand to South America, with the whole programme taking one year or more.

The broader objective is to “go global”, including the US market, noted Rodríguez Perera, who is the managerial and economic leader of the polypill initiative. In February the project partners consulted with the US Food and Drug Administration (FDA) on a suitable trial design for the polypill. They are now putting together a US study proposal on that basis.

The partners hope to have the first approvals for the polypill in the bag by the third or fourth quarter of 2009, with launches to follow in the first half of 2010. The first market would be Spain, followed by other European countries and then perhaps the Americas and Asia, Rodríguez Perera said.

The World Heart Federation originally announced in September 2006 that it would advocate for the development, production and delivery of a polypill for the secondary prevention of cardiovascular disease by 2009/10.

“It has been proven that appropriate stand-alone medications ranging from antihypertensive therapies to statins and including aspirin have had very beneficial effects on premature mortality in Western populations,” the Federation pointed out.

“Many of these medications are now off-patent and as such are available at lower generic prices. However, the complexity of three or more medications would strain developing country health systems both financially and logistically. Patient compliance would be another complicating factor.”

A three-in-one polypill “could save the lives of post-myocardial infarction patients as well as high-risk individuals in low- and middle-income countries as well as low-income patients in more developed economies who would otherwise have limited treatment options,” the Federation stated.

Where it started

The original polypill concept, advanced in June 2003 by Professors Nicholas Wald and Malcolm Law of London’s Wolfson Institute of Preventive Medicine, involved a six-ingredient combination of a statin, aspirin, folic acid and three antihypertensives (a thiazide, a beta-blocker and an ACE-inhibitor), to be given to everyone over the age of 55 years and to people with existing high blood pressure, heart disease or diabetes.

In a much-discussed paper in the British Medical Journal, Wald and Law said taking the polypill daily could reduce the rate of ischaemic heart disease events by 88% and strokes by 80%, with minimal side-effects. The proposal generated a good deal of debate, quite a lot of it hostile. There were concerns about unforeseen adverse reactions from the six ingredients in combination and about people using the polypill as an excuse to continue leading unhealthy lifestyles.

Earlier this month the Wolfson Institute announced that the first samples of a five-in-one polypill manufactured by Indian generics specialist Cipla were now available. The expectation is that, following a small-scale clinical trial programme, this version could be launched within two years at a cost of as little as £1 per day.

According to Professor Wald, “our mission is to make this available to everyone over 55 at an affordable price”. The project has the backing of Professor Roger Boyle, the government’s national director for heart disease and stroke, who would like to see the polypill prescribed on the UK’s National Health Service (NHS).

More polypills

The Wolfson/Cipla polypill contains a statin, three types of antihypertensive and folic acid. Alternative versions are under development in other parts of the world.

For example, in December 2006 India’s Dr Reddy’s Laboratories announced a tie-up with researchers from the University of Aukland, led by Professor Anthony Rodgers, to conduct a clinical trial in New Zealand, India, Australia, Brazil, China, South Africa, the US and the UK with a polypill comprising aspirin, a statin and two antihypertensives.

This initiative, which is supported by the Health Research Council of New Zealand, targets people at increased risk of having a heart attack or stroke. The US National Institutes of Health’s study register ClinicalTrials.gov also lists details of polypill trials in Iran (atorvastatin, aspirin, enalapril, hydrochlorothiazide) and Sri Lanka (aspirin, simvastatin, lisinopril, hydrochlorothiazide) for the prevention of cardiovascular disease.

Explaining the rationale behind a polypill limited to secondary prevention in heart attack patients, Dr Valentin Fuster, immediate past president of the World Heart Federation and scientific president of the CNIC, commented: “Today, within one year of myocardial infarction, between a third and half of all patients are not taking the three drugs they need and are not correcting their risk factors.”

It should be emphasised, he added, that “the FDA will only accept the pill if each individual ingredient is critical for the prolongation of life. Therefore the polypill is aimed only at secondary prevention, helping to prevent heart attack patients suffering a recurrence. It is not intended for primary prevention or daily use by people with no history of heart attack.”

According to Rodríguez Perera, it is too early to talk about potential clinical advantages of the CNIC polypill over the other versions currently in development, as published data on these products are thin on the ground. The overriding philosophy of the CNIC project, though, is to develop a polypill that is not just effective but affordable, he noted.

As such, a point of difference with other polypills may be that the CNIC is 60% funded by the Spanish government, so the need for substantial revenue flows is less acute. “It’s not a business,” and the main focus of the project is low-income countries, Rodríguez Perera said. If the programme can be expanded to developed countries, all the better, he added.