February 11, 2014

Drug Discovery — Even When You Win, You Still Can Lose

By Josh Bloom | February 11th 2014 03:21 PM

It would be almost impossible to find a better example of the difficulties that face the pharmaceutical industry than the campaign against hepatitis C.

Unfortunately, this example is now at the expense of Vertex Pharmaceuticals, a small, but top-notch drug discovery organization that began as a biotech startup in 1989.

Vertex had the “good” fortune of becoming the first drug company to launch a successful antiviral drug, which had a real impact on hepatitis C—a disease with enormous worldwide public health implications. But, within a year, their fortunes turned sour.

Called “The Silent Killer,” the viral blood-borne disease infects the liver, progressively doing irreversible damage over a two- to three-decade period. Most people who are infected are unaware of this until symptoms of liver disease show up, at which time the resulting cirrhosis or liver cancer are life threatening.  The majority of liver transplants in the U.S. are due to liver failure caused by long-term hepatitis C infection.

Although hepatitis C is much less newsworthy than HIV, the worldwide infection rate is estimated to be four percent—about four-times greater than for HIV. With an estimated 150 million infected people worldwide, the disease became the focus of most infectious disease research beginning in the mid-1990s—surpassing even HIV in research effort.

Virtually every major drug company launched massive research campaigns designed to discover specific antiviral therapies to eradicate the infection. It was far more difficult than anyone could have imagined.

Although researchers used a very similar strategy that was supremely successful for HIV, hepatitis C proved to be a much tougher nut to crack.

Indeed, after a decade of research, and dozens of drug candidates that failed because of toxicity or lack of efficacy, in 2004, scientists at BoehringerIngelheim in Quebec hit the jackpot—or so it seemed. Ciluprevir—the product of arguably one of the most impressive campaigns in the history of medicinal chemistry—was shown to reduce the amount of the virus in the blood to nearly zero after a few doses.

However, unexpected cardiac toxicity forced the discontinuation of the development of the drug. Even though Ciluprevir provided the first proof of principle that a specific antiviral drug could essentially wipe out the virus, this must have been little comfort for Boehringer.

It would be another seven years until the first HCV drugs would be approved. Within two weeks, Vertex Pharmaceuticals and Schering-Plough (now Merck) both launched improved versions of Ciluprevir.

Vertex’s drug, Incivek was superior to Merck’s Victrelis, and it captured essentially the entire anti-HCV market, with sales of an astonishing $457 million in its first full quarter.

But then things went downhill. Given the enormous (and scientifically brilliant) effort that Vertex put forward to discover Incivek, it is perfectly fair to expect them to be financially rewarded. But life is not always fair—especially in the pharmaceutical world.

What went wrong?  The efforts of other companies working in this area (especially AbbVie,Gilead, Johnson and Johnson, and Bristol-Myers Squibb)—although a bit behind Vertex—were beginning to pay off. Clinical results have been astounding, with cure rates approaching 100 percent with certain drug combinations. And aside from the exquisite efficacy of these newer drugs, one enormous advantage is that interferon—an injectable immune stimulant that is still part of the standard of care—can be avoided. This is critical because the side effects of interferon are so brutal that many patients discontinue treatment, essentially committing pharmaceutical suicide.

Now, doctors are advising their patients to wait until some of these second-generation drugs are approved, and this has had a profound impact on Vertex. Sales have plummeted to $86 million this past quarter, and the company just announced a staff reduction of 370 employees—15 percent of its workforce.

This perfectly illustrates two points: 1) Even when a drug goes through a 10-year approval process and makes it out the other end, it still may lose money. In fact 70-80 percent of marketed drugs do just that; 2) Perennial critics of the pharmaceutical industry, such as Marcia Angell of the Harvard Medical School, who maintain that second- and third-generation drugs (often derisively ‘called me-too drugs’) are unnecessary and serve only the companies that make them, must be living on another planet. Because on this planet the first drug for any given disease is rarely the best.

Had research and development ceased after the introduction of Incivek, therapy for hepatitis C would have remained difficult to endure, and less than optimally effective.

There is no tougher business than drug discovery. You can win the race and often still come out the loser.

Update 2/11/14: Gilead is now seeking approval for their drug combo consisting of  Sovaldi and ledipasvir—two potent anti-HCV drugs that work by different mechanisms (like the AIDS cocktail approach). This will be the first non-interferon therapy for the infection. 



  1. The update is misleading. Gilead's Sovaldi/ledipasvir pill will be the third "non-interferon therapy for the infection." It will be the first non-interferon treatment for genotype 1 patients.

    1. What Interferon-free treatment are you referring to other than Sofosbuvir + Ribavirin for Genotypes 2 & 3? Sofosbuvir + Riba was the first and is the only Interferon-free treatment FDA approved to date.