In Burma, the Wrong Kind of Resistance

Drug-resistant malaria may have spread to Burma and, worse, might now be impervious to current first-line drug defenses. Less than a year into the battle to contain resistance, everything that could go wrong may have.

In Southeast Asia, malaria has overrun--twice--the pharmaceutical defenses erected against it, evolving resistance to previously potent anti-malarial drugs and ultimately rendering them useless worldwide. Last year, portents of a third such performance appeared. In cases  along the Thai-Cambodia border, the first-line drug artemisinin began taking longer to completely clear malaria parasites, suggesting that today's champion had lost a step against a strengthening disease. (See Once again, it's 'Apocalypse Now' in Southeast Asia.)

Plans quickly developed to crush this new threat before it spread globally--again. Efforts to eradicate malaria from the affected areas of Cambodia have markedly reduced prevalence of the disease. But preliminary reports now suggest that  parasites in some regions of Burma and Vietnam may also respond poorly to artemisin, meaning the original lines of containment might already be breached.

In the past, drug-defeating strains originated in Southeast Asia and then spread by human carriers to Africa. Worryingly, researchers are currently working to determine whether artemisinin-resistant malaria has arrived in other parts of the world and if there is a connection to Southeast Asia.

On top of news of a faster-than-expected spread, some evidence suggests that artemisinin is getting slower and slower in some cases. If the trend continues, eventually treatment failure will result, meaning complete resistance to artemisinin when there are no new drugs to take its place.

On the other fronts of the war on malaria, a vaccine candidate, called RTS,S, has moved into final clinical trials. However, the protective effects of the vaccine have varied widely, from 40% to 60%, creating a difficult decision on whether to undertake large and costly vaccination campaigns when RTS,S emerges from clinical trials in 2014. The bright spots at present are insecticide-treated bednets. The bednet campaign has raised awareness, money and most importantly actual usage of the nets in malarial regions of the world.

If heart drugs keep improving, will we be able to tell?

Even under high magnification, new drug benefits are vanishing

By the end of the 20th century, modern medicine was fending off 190,000 deaths a year from otherwise fatal heart conditions. Funding poured into cardiovascular research, more than doubling from $3.8b in 1995 to $8.4b in 2005. Now from this richly oxygenated drug pipeline, two new heart drugs have emerged. Massive clinical trials depict, at IMAX scale, medicines that seem better, faster, stronger. But it still takes squinting to see the improvements.  And even tests in tens of thousands of people aren’t large enough to show that the new drugs actually save lives.

Once, life-saving effects were visible to the naked eye. In the 1980s, a clinical trial of 17,000 people demonstrated unequivocally that aspirin prevented hundreds of deaths. After a heart attack, aspirin cuts the subsequent risk of death, stroke or heart attack by 2.0%. Improving on aspirin took nearly a decade and a trial of over 19,000 people for the faint effects of a new drug, Plavix, to surface.  Plavix surpassed aspirin by a hard to see, Braille-like bump of 0.5%. But the benefits of Plavix and aspirin, taken together, are additive. After Plavix gained FDA approval in 1997, it won for drug-maker Sanofi-Aventis the second largest pharmaceutical franchise in the world.

The scent of that $8 billion market brought competitors loping, ears-back in pursuit. First came Effient from Eli Lilly. Perhaps to magnify small differences between Effient and Plavix, the company-funded study put heart attacks under a microscope. The trial looked not only at heart attacks with chest pain and other classic symptoms, but also those detectable only by a blood test measuring levels of cardiac enzymes. The precise definition of these invisible heart attacks varies and even changed mid-trial. And whether they matter is disputed. But largely because of the tally of non-fatal heart attacks, the Eli Lilly study showed Effient beating Plavix.

Neither drug, however, defeats death. Enter Brilinta, a new antiplatelet drug from AstraZeneca. A recent clinical trial showed Brilinta not only besting Plavix but saving lives—maybe. The study of nearly 19,000 people still wasn’t big enough to attribute the 89 fewer deaths among Brilinta patients to the new drug or to chance.

Chance is not why cardiovascular clinical trials funded by drug companies tend to report results favorable to the funder. AstraZeneca paid for the Brilinta trial, and two of the study’s authors were employees of the company. AstraZeneca also managed the trial data itself, contrary to good practice. Britain’s National Health Service has expressed doubt about the trial’s blinding—which could suggest that the new drug might have been given to patients who were healthier to begin with. Also raising eyebrows, the trial’s 1,800 North American patients fared worse on Brilinta, although that too could owe to chance. (Brilinta is currently wending through the FDA approval process).

Not only are the benefits of these drugs diminishing and arguable. The number of new drugs is plummeting. From eight in 1995, the number of novel chemical entities approved for heart conditions crashed to zero in 2005. All newly-approved drugs tumbled, from 53 in 1996 to just 18 by 2005.

Surprisingly, it’s not the drug companies’ fault. Huge updrafts of research funding did little to arrest the drug free fall. Not only did cardiovascular research funding double, government funding of all biomedical research ballooned, also doubling between 1998 and 2003. The biomedical research engine now gulps $100 billion annually in the United States. Reassuringly, it powers more scientists than ever and generates 200,000 research papers a year, nearly twice the output of 1995. But research and funding have clearly broken away from drug production. Why?

Research has dived deeper and deeper in search of the fundamental causes of disease. This fantastic voyage ever downward in scale was expected to conclude with the sequencing of the human genome and the molecular pinpointing of the genes that cause disease. Instead, the search is still on. Only 3% of the heritable, genetic basis for early heart attack has been discovered. Scrutinizing the DNA of nearly 3,000 sufferers turned up just nine genes in common, suggesting that there are hundreds more. Worse, early heart attacks have a stronger genetic basis than those occurring after age 65 which represent 90% of all heart attacks.

The research odyssey continues deeper and gets murkier. The genes with the strongest influence on early heart attack don’t, say, produce artery-blocking plaque. Instead they appear to control other, unidentified genes of unknown function. Disentangling this self-referential interplay of genes with each other and genes with environment is the daunting task of epigenetics. Like drug trials, research projects are becoming enormous. Inevitably, there is a Human Epigenome Project, vaster in scope than even its parent, the Human Genome Project.

But as research dives deeper, the medical payoff has become fainter. The tether connecting research to new drugs and health benefits began stretching a quarter century ago. In 1984, a group at Oxford quietly and presciently called for megatrials in the 10,000- to 20,000-person range because most trials were “too small to be of much independent value.” In other words, drug benefits had become too small to be detected without a large trial. In 1985, new drug approvals climbed to record heights. They held there, helped by the arrival of the last key heart medication, the statins, which began lowering cholesterol in 1987. In 1988, the Oxford team published the 17,000-person study of aspirin’s antiplatelet credentials. The era of megatrials began. In 1989, as if on cue, new drug approvals began dropping from their all time highs and have not recovered.

In the realm of heart medications, only modest refinements have ensued. Plavix and other antiplatelet drugs improved very slightly on venerable aspirin but lifesaving benefits have vanished even from megatrials. Similarly, new anticoagulants (with names like bivalirudin and fondaparinux) mostly burnished the achievements of heparin which began saving lives in its first, tiny 1960 trial of 35 patients.

A similar pattern holds for cancer, the number two killer in the United States after heart disease. For breast cancer, the 1960s delivered the biggest breakthrough ever: chemotherapy. It cut mortality by 14% and finally displaced 19th-century radiation treatment as front line therapy. Every therapeutic discovery for breast cancer since chemotherapy has produced only smaller benefits. In the 1970s, modified chemotherapy pared mortality just another 3.1% by employing more toxic drugs developed in the 1950s. Those treatments remain front line to this day. The biggest news since has been tamoxifen, which reduces mortality by 9.2% but only for about three quarters of patients with a particular type of breast cancer. Tamoxifen dates to 1977. The more recent aromatase inhibitors marginally improve on tamoxifen but not in a life-saving way.

The latest generation of cancer drugs, “targeted agents” like Tykerb, approved in 2007, exploit the new, high-definition molecular knowledge. But targeted agents, while higher in precision, have generally lost even the occasional power to cure wielded by older, cruder chemotherapy.

Seemingly the last thing to decouple from new drugs is expectations. In 1998, on the 50th anniversary of the first clinical trial, the Oxford trialists looked ahead to the next half century. They called once again for “greatly increasing” trial size. The reason, they said gently and soberly, is simple: “when it comes to major outcomes it is generally unrealistic to hope for large therapeutic effects.” Instead expectations, like new drug prices, continue to soar, high above shrinking health benefits below.

Photo credit: Buttersweet on Flickr

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