Drugs, money, and glory: Is cancer beating cardiovascular disease? Part 1

Shelley Wood

August 11, 2011

Drugs is the first story in our three - part series Drugs, money, and glory: Is cancer beating cardiovascular disease? examining differences in new therapies, research funding, and public perceptions between cancer and cardiovascular disease. Next up: Money . To read the full series, click here.



New York, NY - If a story could be told in numbers alone, there'd be some twists and turns found in the figures underpinning the quest for new therapies to treat the world's two most lethal diseases. Heart disease is the number-one cause of death in the US and in most high-income countries, followed by cancer, and for years deaths from both diseases have been on the decline. That slope is substantially steeper for cardiovascular diseases than for cancers: according to the Centers for Disease Contro l and Prevention (CDC), age-adjusted deaths from heart disease dropped by almost 31% between 1999 and 2009; by contrast, cancer deaths dropped by just 11.9%.

But if medications alone could cure all that ails, those mortality trends could be on the brink of change. A quick look at new drug approvals over 2010 and the first half of 2011 shows that the cardiovascular sphere got just three new medications: dabigatran etexilate (Pradaxa, Boehringer Ingelheim), azilsartan medoxomil (Edarbi, Takeda Pharmaceutical), and ticagrelor (Brilinta, AstraZeneca). By contrast, 13 new drugs have been approved since January 2010 for different cancers.

Drugs still in development paint an even starker picture: while cancer has over 700 drugs in development, the number of cardiovascular drugs in the pipeline is just 147[1].

Cardiovascular is definitely losing ground in terms of the number of approved new drugs.

According to Dr Christopher Milne, associate director of Tuft University's Center for the Study of Drug Development, the rise of cancer treatments can be traced back several decades. He points to studies conducted at the Tuft's center showing that back in the 1980s, five times more cardiovascular drugs were approved than oncology drugs: 52 vs 11.

"By the 1990s it was only twice as many [38 vs 74]. And now, in the 2000s, it's equal [47 vs 49]," says Milne. "So cardiovascular is definitely losing ground in terms of the number of approved new drugs."

Milne also looked at the top 100 investigational (unapproved) drugs, also compiled by R&D Directions: almost 30% were in cancer, while just 6% were in cardiovascular disease.

Dollars driving development decisions

While the "market" of people with cardiovascular disease may still be greater than the number of people with cancer, for the companies making the products, potential revenues are the bigger driver. Making drugs is an expensive undertaking: ergo, resources are devoted to projects most likely to come to fruition.

Tufts researchers have tracked the actual and probable "success" rates for newly developed drugs and found that of all new drugs first tested in humans between 1993 and 2004, the rate of "successful" approvals for new antineoplastic and immunologic drugs was more than double that of new cardiovascular drugs, at 7% vs 3%[2].

Others have noticed similar trends. In a paper published earlier this summer in Nature Reviews: Drug Discovery, Pammolli et al report that, over time, cancer-medication projects have taken over the lion's share (30%) of total R&D projects—that's up roughly 8% from the 1990s[3]. By contrast, cardiovascular-drug projects have declined by almost 5%, now comprising only 6% of total projects.

It's tough to see this, because it's not like cardiovascular morbidity and mortality h ave been resolved, by any means.

Dr Massimo Riccaboni

In an interview with heartwire , senior author on that paper, economist Dr Massimo Riccaboni (Institutions, Markets, and Technologies Institute for Advanced Studies, Lucca, Italy), explains that drawing on past drug approvals, they were able to estimate annual sales per expected new drug approval and came up with average US sales for cancer drugs that reached almost $200 million per product per year. By contrast, sales of drugs targeting the cardiovascular system would garner, on average, $45.6 million per product per year.

Of note, cancer-drug projects, if looked at as far back as the preclinical work, also had much lower probability of success (POS), according to the Italians, something Riccaboni called highly desirable, if counterintuitive. Low probability of success, he points out, leads to drugs that fill new niches, rather than being me-too drugs: they will fetch a higher price and have little or no competition. For cancer drugs, the average POS ranged from 1.29% to 1.8%; for cardiovascular drugs, the POS was 4.86%.


Regulatory issues

Key to a drug's progression along the drug-development pathway is the regulatory rubber stamp required from the FDA that tells companies what kind of data will be considered sufficient for approval. And here, too, are profound differences between the cancer- and cardiovascular-disease spheres.

Dr Eric Topol

Dr Eric Topol (Scripps Clinic, La Jolla, CA) points to a fundamental difference in the way cancer drugs are now being studied, with cancer researchers turning to pharmacogenetics to develop targeted medications that can be tested in relatively small studies. In the cardiovascular arena, by contrast, companies have persisted in seeking broadly effective agents that yield benefits in almost everyone who takes them.

"Basically the CVD field got into this 'megatrial' world, enrolling tens of thousands patients testing a drug that would be good for all people—things like statins—and it kind of got stuck in this approach," says Topol. "We see this now with the anticoagulants—apixaban and dabigatran—and all the -prils and -sartans. That mentality, that strategy, just isn't sustainable, because the drug companies don't want to go there anymore."

Facing the prospect of multibillion-dollar drug-development costs, companies are getting out of the business of cardiovascular medicine and are turning to therapeutic areas where smaller, more focused research can bring a drug to market, he says.

"There's just not the drive in cardiology to identify root-cause variations in the genome or to use other means, like wireless sensors, to individualize treatment and prevention and better strategies," says Topol. "There's not a lot of that going on right now. . . . It's tough to see this, because it's not like cardiovascular morbidity and mortality have been resolved, by any means."

A double standard?

Dr Clyde Yancy

Dr Clyde Yancy (Northwestern University, Chicago, IL), who serves on the FDA's Circulatory System Devices Committee, points to another difference in how drug efficacy is viewed by the FDA.

In cardiovascular medicine, he says, "we insist on meaningful mortality benefits and minimal side effects/morbidity, while cancer is comfortable with much more modest gains and a higher tolerance for drug toxicity/side effects/etc."

For example, he continues, "We willingly accept and prescribe without hesitation chemotherapy agents that we recognize will put a patient at risk of developing heart failure, and I wouldn't advocate against that because those drugs, those Adriamycin-type compounds, are critical in the fight against certain types of cancers. . . . But if there is any cardiovascular drug for which there is even a hint that a contribution to malignancies might occur, it would be totally unacceptable to allow a drug on the market, even if it had a clinical experience of being beneficial."

If there is any cardiovascular drug for which there is even a hint that a contribution to malignancies might occur, it would be totally unacceptable to allow a drug on the market.

And whereas an approach that Yancy calls "poison, cut, or burn" has long dominated—and been deemed acceptable—in cancer therapy, the approach to heart-disease treatments has "always been more measured and conservative," he says, in part because of the huge number of patients who may end up getting the kind of cardiovascular drugs approved in recent years. "Even an infinitesimally small side-effect profile in clinical trials will be realized in clinical practice."

Dr Thomas Bersot (University of California, San Francisco) has also served as an FDA advisor—on the agency's Endocrinologic and Metabolic Drugs advisory committee—and he points to the fact that most people diagnosed with heart disease have many more years of life ahead of them, something that can't be said for many cancers. And the "acceptable" level of risk for a cardiovascular drug expected to extend life by at least a decade will be lower than that of a drug for a cancer that kills within months.

The gap widens even further for metabolic conditions like obesity and diabetes, Bersot adds. "You have to decide whether or not the issue of safety is a critical one," especially if it's a disease that's not lethal in the short term.

Dr Donna Arnett

"When you have a drug that is basically going to be taken indefinitely, the FDA's position is that you need to know over a long period of time what the adverse effects might be, because if you're obese, you're not going to die in five years, whereas if you have lung cancer, you're probably going to be dead in five years."

But Dr Donna Arnett (University of Alabama at Birmingham), a scientist and epidemiologist, points out that while the lethality of certain cancers is widely feared, it's not the case that there are no parallels in heart disease.

"Heart failure has a shorter life expectancy than almost every cancer, with the exception of maybe pancreatic," she says. "Heart failure is one of those conditions that's really lethal," and it's by no means rare.

Hot or not

But medical need doesn't drive up stock prices; successful drugs do. And all signs suggest: cancer is hot; heart disease is not. Milne cites a survey by consulting company Decision Resources, which asked a panel of experts across science and business to pick the 12 most promising therapeutic areas for drug development: eight out of 12 were cancer subtypes; none were forms of cardiovascular disease.

There are some encouraging signs. Arnett and Topol are quick to agree that the cardiovascular-drug research lags far behind cancer in terms of pharmacogenomics and individualized therapy, but at the same time, this also represents a huge area for growth. Many of the most basic discoveries in cancer research, including the strides made in immunomodulating therapies, microRNAs, and epigenetics, may one day prove transferable to the cardiovascular arena, they say—presuming, of course that there is funding, passion, public support, and political will for this kind of knowledge transfer to occur.

Just how those different factors stack up in both the cancer and cardiovascular fields, however, is a different numbers game altogether.

Topol is editor in chief of theheart.org .






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