Polypills: Are Miracle Treatments Being Overlooked?

Cardiovascular diseases (CVD), a group of conditions that can result in heart attacks and strokes, is the world’s number one killer, accounting for one-third of deaths throughout the world, according to research released recently (17 May) by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington.

Stroke victim with the family he is reliant on in shantytown São Paulo, Brazil. Effects of high blood pressure ignored.

Alarmingly, much of the burden falls on low- and middle-income countries where people without access to strong health systems die younger from CVDs – tragically most often in their most productive years.

That’s why a fixed dose combination therapy, or polypill, proposed 15 years ago by a couple of academics in the British Medical Journal has been pushed by many in the global health community from the Wellcome Trust to the Public Foundation of India.

The idea of such a pill would be to simplify treatment, reduce costs, overcome physician inertia and enhance patient adherence over the long term, say its proponents.

It would join a number of extremely successful combination treatments that include treatments for HIV, malaria, asthma, and migraines.

A polypill for CVDs might include a statin, as well as one or more antihypertensive (blood pressure lowering) drugs and a few also contain aspirin.

And because they generally contain generic components, the theory is they could be produced cheaply to patients in need within low- and middle-income countries.

To that end, numerous studies – at least 13 involving thousands of patients in 32 countries – have been funded to assess their effectiveness.

Proponents want their widespread use. “Polypills have been demonstrated effective in improving use of and adherence to essential CVD preventive medications,” said Ruth Webster of the George Institute for Global Health in Australia, who has led some of the large studies. “Failure to include them in the wider strategy to reduce heart attacks and strokes (currently responsible for millions of deaths globally each year) means that effective treatments will have been left on the table.”

Cardiologists from New Zealand to Iran and Mexico have been so impressed with the pills, they are supporting their inclusion into the WHO’s next version of its Essential medicines list. That would ensure a polypill could be recommended for use in every country of the world. The decision on whether to include them will be made imminently.

Despite this, the market for polypills has moved at a glacial rate. Just a handful of products have been registered in India by companies such as Cadila Pharmaceuticals and Mumbai’s USV.

It’s perhaps unsurprising that branded companies are not interested in creating polypills – given their generic content and potential customer base. They are unlikely to be blockbusters.

But it is uncertainty over intellectual property that may have deterred manufacturers, says Webster. “There is little clarity around the ability to patent the combination of various drugs,” she said.

The problem is, although active ingredients are largely off-patent, quite a few patents have been taken out around the world on the combinations of the drugs that make up polypills. “To my knowledge no one has challenged these and no one really knows if they will stand up in court,” she added.

Certainly, there have been rumours that a few of the patent holders might even consider defending a patent.

The extent to which there are patents is perhaps surprising. A group of researchers carried out a patent landscape analysis.

last year and confirmed that many original patents on these active ingredients have expired and that generic alternatives are usually available.

But looking at patents in Canada, the United States, Europe and elsewhere, they found that patents covering novel (co-) formulations are far more complex. There are patents on everything from co-formulations and method of treatments to manufacturing processes, which are far more prevalent and can carry on for years after the expiration of the original patents on the active ingredients. They found that of 48 drugs, only 19 were totally patent-free and most of the drugs – 40 of 48 – could be found on co-formulation patent applications filed through the World Intellectual Property Organization.

“You can see how companies might be patent-averse,” said one of the authors, Mark Huffman, a cardiologist, assistant professor of preventive medicine and medicine-cardiology at Northwestern University’s Feinberg School of Medicine (US) and a spokesperson for the World Heart Federation.

But he reckons it’s highly unlikely that many of these patents will stand up in court. “There really can be an obviousness to this,” he said. “But just putting the drugs together itself doesn’t have that much intellectual value. You could infringe upon the patent but you would probably lose that case.”

On the other hand, a patent related to a non-obvious process of manufacture – say on a substance that allows different medicines to coexist in the same pill or capsule, may be something a company could defend.

The fact is, the business case for polypills has been fraught with difficulty. “Large companies tend to avoid it as there is limited perception for exclusivity. Smaller generics companies don’t have the R&D budget to go out on a limb with new developments,” said Webster of the George Institute. There are more problems: some companies view regulatory pathways in some countries as impenetrable and manufacturing has not been straightforward. Creating a single pill, where the individual components do not react together, is not as easy as it sounds.

Certainly, the George Institute ended up having to secure an exclusive global license from Indian firm Dr Reddy’s in December 2012. It had not wanted to proceed with taking its polypills to market because of what it termed “uncertainty in regulatory requirements”.

That’s despite the subsequent use of its Red Heart pills on thousands of patients in three trials that spanned Australia, New Zealand, India and the EU principal investigators including the then head of intellectual property at Dr Reddy’s. The company says it still has no intention to produce a pill. “Polypill is no longer a part of our current active product portfolio,” said Aparna Tekuri, corporate communications manager at Dr Reddy’s.

The lack of interest shows something interesting, said Reed Beall, a researcher at Brigham & Women’s Hospital in Boston, who also contributed to the polypills patent paper. “This implies there is skepticism from industry about the existence of solid and sustainable market for it,” he said. “If there weren’t, I’m sure the companies would find a way to overcome those challenges to a certain extent.”

Huffman, Beall and the other researchers have suggested that to accelerate polypill development, it’s probably wiser to consider partnerships with patent holders – particularly those with patents on the ideal combinations – because patents flag the most innovative and promising products.

Any progress made thus far, however, has been a result of public–private partnerships between academic groups and generics companies, and funded by institutions such as the Wellcome Trust and the EU.

Take the Spanish Centro Nacional de Investigaciones Cardio-vasculares (CNIC), for example. It has collaborated in a private–public partnership with manufacturer Ferrer since 2007 to create the most successful polypill to date. Trinomia, created with a major statin that has just come off patent in 2014, has been registered in well over 30 countries.

And if polypills reach the essential medicines list, the market will be boosted further, say researchers including Huffman. Today, Trinomia is licensed for use in just one Latin American public health system – Mexico’s – and is not part of many reimbursement systems where it is registered. That means it is available in countries, but patients may not be reimbursed for the cost.

Even if these other problems were solved, more doctors will still need to be encouraged to prescribe polypills. It turns out that although public health officials and even many patients like them, specialist physicians don’t. They prefer prescribing individual drugs, because they can better control dosing of the individual components.

 

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