Isegoria

Why are so few blockbuster drugs invented today?

On Sept. 25, 1990, James D. Watson, the Nobel Prize-winning co-discoverer of the double-helix structure of DNA, and at the time the director of the National Center for Human Genome Research, wrote a letter to this paper making a prediction: “The ability to sequence DNA quickly and cheaply will also provide the technological basis for a new era in drug development.”

At that moment, the idea that the human genome would lead to a multitude of cures for diseases seemed inevitable and irresistible. DNA is, after all, nature’s instruction booklet for building living things; open that book and read its instructions, the thinking ran, and the botched instructions that result in diseases would be revealed. From there, a logical series of steps would arrive at a cure. Once a malfunctioning gene was isolated, scientists would find the protein coded by that gene. Then they’d use that protein as a target. Finally, they’d run tests of tens of thousands of unique chemical entities that drug companies have stockpiled over the years, to find one that fit the target like a key in a lock, to correct its function.

But this golden road to pharmaceutical riches, known as target-based drug discovery, has often proved to be more of a garden path. The first disappointment has been that most diseases affecting large numbers of people are not caused by a handful of mutations that can be unearthed as easily as digging potatoes in a field. Geneticists have called this the problem of “missing heritability,” because despite what they promised in the 1990s, they have found no single genetic variants that are necessary and sufficient to cause most forms of widespread diseases like diabetes, heart disease, Alzheimer’s or cancer.

The second disappointment is that even when a genetic variation can be plainly linked to a disease, the process for figuring out what to do about it rarely works as efficiently as advertised. Compounds that appear to hit a designated target right between the eyes still often fail to be safe and effective in animal and human studies. Biology is just way too complicated.

“If you read them now, the claims made for genomics in the 1990s sound a bit like predictions made in the 1950s for flying cars and anti-gravity devices,” Jack Scannell, an industry analyst, told me. But rather than speeding drug development, genomics may have slowed it down. So far it has produced fewer returns on greater investments. Scannell and Brian Warrington, who worked for 40 years inventing drugs for pharmaceutical companies, published a grim paper in 2012 that showed the plummeting efficiency of the pharmaceutical industry. They found that for every billion dollars spent on research and development since 1950, the number of new drugs approved has fallen by half roughly every nine years, meaning a total decline by a factor of 80. They called this Eroom’s Law, because it resembled an inversion of Moore’s Law (the observation, first made by the Intel co-founder Gorden E. Moore in 1965, that the number of transistors in an integrated circuit doubles approximately about every two years).

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So far, most drug companies have continued to devote a vast majority of their funding to target-based research, even as more traditional methods of drug discovery have proved more productive. A study published last year by David Swinney found that only 17 of 50 novel drugs approved by the F.D.A. between 1999 and 2008 came from target-based research, compared with 28 from what Swinney calls “phenotypic” discovery, made by studying living cells in Petri dishes, animals and humans. Many of the drugs in this latter category — Alamast for allergies, Amitiza for constipation, Abreva for herpes cold sores, Ranexa for angina, Veregen for genital warts and Keppra, Excegran and Inovelon for seizures — were discovered by chemists who didn’t set out knowing what the drugs’ targets were, or even how they worked. In one now well known case of nontargeted research, scientists developed a drug for angina and found that while it wasn’t effective for relieving chest pain, it did cause erections in the study’s male volunteers. The researchers changed course, and Viagra was born.

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