Hepatitis C, the target of sofosbuvir, is behind what the magazine’s Jerome Groopman described as a “shadow epidemic” of liver disease and cancer: rates of liver cancer are increasing faster than rates for any other type of cancer in the United States. Hepatitis C, which inflames and scars the liver, is thought to account for half of this rise. Worse, up to three quarters of the three million Americans who are infected with hepatitis C are not aware of it. By the time they become symptomatic, they may have been infected for decades. All the while, the hepatitis-C virus has been silently doing its terrible work. About a third of the six thousand Americans who get liver transplants each year now do so as a result of hepatitis C, as the late Lou Reed did.
Hepatitis C is one of a number of viruses that infect the liver. It, along with hepatitis B and D, are transmitted through sex and blood exposure. There is no vaccine for it. In 1998, the Centers for Disease Control and Prevention began recommending screenings for hepatitis C based on risk and exposure. But, because patients don’t always own up to or remember their potential exposures, and because many physicians are embarrassed to ask patients about drug use and sex, the C.D.C. now recommends that all Americans born between 1945 and 1965—the baby boomers, who make up three-quarters of those infected—also be screened. Even so, many clinicians remain reluctant to test patients, because the treatment is so difficult to endure.
The existing treatment regimen involves weekly injections of a substance called interferon combined with other drugs. Interferon is naturally produced by the body to combat viral infections; it’s what makes you feel tired, feverish, and generally miserable when you have the flu. In the treatment of hepatitis C, it boosts the immune system. But the injections have brutal side effects: reduced appetite and hair loss, and, over long periods of time, anemia, fatigue, and depression. If the side effects of interferon don’t sound bad enough, the other drugs often cause more anemia, fatigue, chills, nausea, vomiting, diarrhea, hair loss, and rash.
The months of misery do not guarantee that the patient will emerge cured, either, since some strains of hepatitis C—there are six genotypes—are more responsive to current treatment than others. Because hepatitis C and H.I.V. are transmitted similarly, patients are often infected with both, which further complicates treatment because of toxicities, drug interactions, and difficulties getting the doses right.
Sofosbuvir, on the other hand, is the first hepatitis-C treatment that does not require interferon injections, can be taken simply as a pill with other drugs—like the antiviral ribavirin—and typically works in a fraction of the time of existing treatment cycles. According to Alan Franciscus, the executive director of the Hepatitis C Support Project, a patient-advocacy group that educates patients and clinicians about hepatitis C, “Sofosbuvir has the potential to change the treatment of hepatitis C because of the ease of use—one-pill-a-day therapy, very high cure rates, shorter treatment duration, and fewer side effects.” After enduring his own year and a half of interferon treatment before finally being cured of hepatitis C, “I am a bit envious,” Franciscus admitted.
Sofosbuvir was invented by, and named after, Michael Sofia, the kind of person who daydreams about enzymes metabolizing drugs. Sofia was raised in a rowhouse on the northeastern side of Baltimore. His parents, a barber and a payroll clerk, were both children of Italian immigrants, and born within a block of each other in Baltimore’s Little Italy. Although they instilled an immigrant’s appreciation for education in their three children, who would all go on to work in science, Sofia’s reading skills were so poor as a child that in the fourth grade he was put in a remedial reading class. Sofia credits the nun who taught him with transforming into a “completely different student.”
Sofia eventually enrolled at Cornell and went on to earn his Ph.D. from the University of Illinois, before leaving academia to focus on drug development. Early in his career, at Squibb, he worked on cholesterol-lowering drugs. But he preferred working at small biotech companies, which function more like Internet startups, to Big Pharma. “You have an idea, you discuss it, you make a decision, you move forward,” Sofia explained to me. So, in 2005, Sofia took a risk and joined Pharmasset, then a minor biotech firm.
When Sofia arrived at Pharmasset, the company had already started moving away from the H.I.V.-drug development that it was initially known for, since the market had become saturated with “nucleoside” drugs that worked reliably with manageable side effects. Nucleosides are the building blocks of D.N.A. and R.N.A.; they can be chemically altered to terminate chains of genetic code early, producing something like a defective Lego that can’t be build onto, stopping the growth of the virus. Though this chemistry had been used successfully to treat H.I.V., only a few labs were trying this approach with hepatitis C. Sofia noted that one of the company’s test drugs, PSI-6130, showed activity against hepatitis C.
Sofia realized that any effective hepatitis-C drug not only needed to get into the liver, where the virus was replicating, but stay there, to avoid unintended side effects elsewhere in the body. It is relatively easy to transport a drug to the liver: when you eat or drink something, it is absorbed into the bloodstream by the stomach and intestines, and in turn flows directly to the liver, the body’s metabolic engine. The problem is that, in their active form, nucleoside drugs don’t enter liver cells. Sofia hypothesized that if he could shroud a nucleoside with an “invisibility cloak” to get it into liver cells he could then count on the liver’s enzymes to break down the cloak and activate the drug. Once the cloak has been shed, the nucleoside would be trapped inside, protecting the rest of the body from exposure. “A lot of people were telling me when I had this idea that this is never going to work,” he told me. “People have been trying to do this for a long time, this is a hopeless cause.”
Sofia explicitly engineered sofosbuvir with this and a number of other goals in mind—that the drug would be taken orally, ten times more potent than PSI-6130, and effective against all six genotypes of hepatitis C. Beginning with a modified version PSI-6130, after three years of development, Sofia and his colleagues arrived at sofosbuvir in 2007. What’s remarkable, according to Sofia, is that it was not in fact a happy accident, but a product of explicit engineering. “It does exactly what we designed it to do, which is one of those things that hardly ever happens,” he said.
Sofia’s clinical colleagues at Pharmasset began testing sofosbuvir in human patients between 2010 and 2011. When Pharmasset’s medical advisory group reviewed the data, they realized for the first time that sofosbuvir could potentially treat hepatitis patients without interferon—considered a heresy at the time. Since then, others have conducted larger trials of sofosbuvir—studies named POSITRON, FUSION, FISSION, NEUTRINO, and VALENCE, playing on the idea that sofosbuvir is a nucleotide—which showed that the drug is effective against all six genotypes of hepatitis C, with minimal side effects. Last month, at The Liver Meeting in Washington, D.C., scientists presented studies showing that sofosbuvir could also help cure hepatitis C in harder-to-treat patients, like those who also have H.I.V. or more advanced liver disease. There will be more studies of sofosbuvir to come, including post-marketing trials that will look for previously undetected side effects—as well as research on how sofosbuvir can best be used in combination with other new drugs in the pipeline.
Sofosbuvir does have limits, however. The first genotype of hepatitis C has always been the most difficult to treat, and remains so, even with the advent of sufosbuvir. Most patients infected with that genotype still need a combination of interferon injections and ribavirin, at least until other, new drugs hit the market, which is anticipated to happen in the next year or two. More problematically for the hundred and fifty million people worldwide who suffer from hepatitis C, Franciscus and other advocates are worried that sofosbuvir and other new drugs in the pipeline may be too expensive. Gilead announced that the wholesale cost of sofosbuvir will be a thousand dollars a pill, with the total cost of treatment easily exceeding a hundred thousand dollars per patient. Insurance companies, meanwhile, may only cover treatment for hepatitis-C patients who already have liver damage.
Following the acquisition in 2011, Sofia worked with Gilead for about a year to manage the transition process, a time he doesn’t recount fondly. “When you develop something and you take very personal ownership of it, and see it move on to where you’re no longer involved in a direct way to what’s happening to that drug,” Sofia said, “well, it’s very difficult to go through that.”
Afterward, Sofia and some of his old Pharmasset colleagues started a new company, OnCore BioPharma, to develop cures for hepatitis B. Hepatitis B is another leading cause of liver cancer, and is far more transmissible from mother to child, during pregnancy and birth, than hepatitis C; many who succumb to hepatitis B were infected as infants. Currently, we only have drugs that suppress hepatitis B, but you may have to take them for the rest of your life to keep the virus in check.
I asked Sofia what he’d be calling his next drug. “I consider myself very lucky to have one drug, he replied. “When I was doing undergraduate research at Cornell, I was told that I had to be comfortable with failure because eighty per cent of what you’re going to do is going to fail.”
Celine Gounder is a physician, public-health specialist, and medical journalist.
Photograph: David Paul Morris/Bloomberg via Getty