A decades-long search for better treatments for a debilitating liver disorder is finally coming to fruition. Later this year the U.S. Food and Drug Administration is expected to approve a new pill that can cure hepatitis C—a chronic infection that afflicts about 170 million people worldwide and annually kills 350,000 people, including 15,000 in the U.S.—faster and with fewer side effects than current remedies.
The breakthrough treatment comes, however, at a price that may place it out of reach for all but the wealthiest or best-insured patients. It will contain two drugs, one of which is already available at $1,000 per dose, or $84,000 for a complete 12-week course. The dual-drug combination will likely cost even more, which has prompted outrage from physicians and patient advocates alike, as well as plans from insurers to ration the combination when it becomes commercially available.
Over the coming months, physicians, patients, economists and insurance companies will no doubt hotly debate whether the treatment is worth the full asking price. There is little doubt, however, that the medication's effectiveness is unprecedented and that its development is a significant achievement. A closer look at the complex chemical problems that needed to be solved to develop the cure shows why.
Fast and Invisible
Cures sometimes result from happy accidents—think penicillin mold growing in an overlooked petri dish. More often they require years of research into what is causing the problem in the first place. Understanding the science behind the new hepatitis C treatment starts with deciphering the meaning of the virus's name.
“Hepatitis” is a general term that refers to severe swelling or inflammation of the liver in response to certain drugs, toxins, excessive alcohol or infections—whether from bacteria or viruses. The letter C refers to the third in a series of viruses that researchers have isolated that specifically target and damage the liver. By the mid-1970s investigators had developed blood tests to identify hepatitis A, which typically spreads when infected individuals improperly handle food or water, and hepatitis B, which is often transmitted during sexual intercourse, the sharing of needles or contact with contaminated blood.
Soon after, researchers realized that a third form of viral hepatitis was silently spreading around the globe and that it was more likely than hepatitis A or B to result in permanent liver damage. By 1989 they had identified the virus that caused the condition. They also determined that the virus's genes mutate very fast—a process that has generated several equally successful varieties, called genotypes, and rendered an effective vaccine impossible to create so far. Hepatitis B virus, in contrast, does not evolve as quickly, and a vaccine against it has been available since the 1980s. Infection with hepatitis A virus, which usually causes symptoms within days, can also be prevented with a vaccine.
Standard treatment for hepatitis C has long been a synthetic, injectable version of interferon, one of the immune system's most powerful proteins, plus the antiviral drug ribavirin. The combination helps 25 to 75 percent of patients, depending on the genotype of the virus. But the side effects, including severe flulike symptoms, fatigue, depression and anemia, are often intolerable. In addition, the virus often becomes resistant to medication, allowing the disease to worsen.
Toward a Cure
Developing effective treatments against the virus required researchers to understand the structure of the various proteins that formed its outer shell, as well as the precise sequence of its genetic material, which is made up of RNA—a process that took the better part of the 1990s and involved researchers working around the globe in government, academia and industry.
With this information in hand, scientists still faced a long and costly phase of trial and error. They chose what looked like a promising target for treatment: an enzyme known as a protease that the virus depends on to make copies of itself. After several false starts, researchers at Vertex Pharmaceuticals, in collaboration with others, developed a protease inhibitor known as telaprevir, while scientists at Schering-Plough (which merged with Merck in 2009), created one called boceprevir. In clinical trials, 60 to 75 percent of patients receiving the standard treatment—ribavirin and interferon—as well as the two new drugs had no detectable signs of the virus in their bloodstream, compared with 44 percent or fewer patients receiving the typical treatment alone.
The FDA approved the new drugs in 2011, but the sense of triumph felt by many in the medical community soon gave way to disappointment. The medications had harsh side effects and worked only for those patients with a particular genetic variant of the virus known as genotype 1, which is the most common type in the U.S. and Canada but rare in many other countries with hepatitis C epidemics. Moreover, the continued need for interferon and ribavirin, with their attendant side effects, was a huge drawback.
As enthusiasm for telaprevir and boceprevir waned, other viral proteins emerged as promising drug targets. What scientists had learned from their earlier research, however, was that inactivating an enzyme or protein was not enough. To stop hepatitis C, any effective drug also had to incorporate itself into the virus's genetic code, where it would need to halt the virus's ability to make new copies of its genes and thus to make new virus. In addition, to avoid potentially debilitating side effects, the medication had to get to the liver quickly and directly, bypassing as many other organs as possible.
A company called Pharmasset had been looking at a group of drugs known as nucleotide analogues, which met some of these criteria, since the mid-2000s. Constructed by stitching molecules that resemble the building blocks of DNA and RNA with a molecule made of phosphorus plus oxygen (known as a phosphate), these compounds inserted themselves into the virus's genes, where they promptly fell apart, interfering with viral replication.
Researchers then ran into a few big biochemical problems. Because the nucleotide analogues were water-soluble, they could not traverse the fatty lining of the intestine (fats and water do not mix) to reach the bloodstream and then the liver. In addition, the phosphate group carried a double negative electrical charge, further restricting its ability to move across the intestine's electrically neutral membrane. Finally, other enzymes in the liver easily dislodged the phosphate group from the nucleotide analogue, rendering the compound ineffective.
Michael Sofia, then at Pharmasset, solved the problems by adding two compounds known as esters to the analogue. This addition both shielded the negative charges and made the drug greasy, enabling it to leave the gut. Once inside liver cells, the enzymes that had initially interfered with the phosphate group hit the ester molecules instead, leaving the active drug free to do its job. The new formulation was named sofosbuvir in Sofia's honor; the company was purchased, in 2011, by Gilead for $11 billion.
In a large study, 295 out of 327 patients treated with sofosbuvir, as well as ribavirin and interferon, showed no signs of the virus in their blood after 12 weeks. In a more advanced trial, 12 weeks of sofosbuvir plus ribavirin yielded the same results as 24 weeks of interferon plus ribavirin: 67 percent of patients had no evidence of the virus in their blood (although side effects such as fever and depression were fewer among patients who did not receive interferon). The FDA approved sofosbuvir in late 2013 as a treatment for hepatitis C in combination with ribavirin.
Still, investigators pushed to make further improvements. During sofosbuvir's development, they had studied other drugs that inhibited different viral proteins and that might eliminate the need for continued use of interferon and ribavirin. So they ran another study of sofosbuvir plus one such complementary drug, daclatasvir, made by Bristol-Myers Squibb. The result: nearly all patients were cured of the disease, with far fewer side effects than before. Since then, Gilead has run three additional studies of sofosbuvir paired with a different drug, ledipasvir. The combination cured at least 94 percent of patients with genotype 1 disease.
It is this combination, mixed in a single daily pill, that industry watchers expect the FDA to approve by October 2014. It heralds a new era of curative treatment for patients with hepatitis C. Similar drugs that work equally well for all genotypes are now in the final stages of clinical development.
Because the soon to be released combination pill cures hepatitis in just 12 weeks—eliminating the need for and the expense of treating an otherwise chronic illness—it may end up costing less overall than previous treatments. (Gilead is not expected to announce the retail price of the pill until it receives FDA approval.) Of course, that does not mean that patients will be to afford it.
David Thomas, director of the division of infectious diseases at Johns Hopkins University, considers the price an impediment to health care around the globe, despite the potential savings. Many people in the U.S. with hepatitis C are poor, and several hundred thousand are incarcerated. “Medication that costs more than $100,000 won't make a big impact in prisons in Russia or for drug users in Pakistan,” Thomas says. Within the U.S., copayments may put the treatment out of reach.
The price tag has also struck a nerve among insurers and other third-party payers. “We've never had such a high-cost drug for such a large population,” says Brian Henry, a spokesperson at Express Scripts, which manages benefits for more than 3,500 companies. “Treatment for one hepatitis C patient now can take up a huge portion of a small business's budget for drug spending.”
The manufacturer insists that cost will not prevent access. As it has for its HIV drugs, Gilead plans to provide patient assistance within the U.S., to license the drug (for a fee) to select generic manufacturers outside the U.S., and to lower prices in low- and middle-income countries. In Egypt, which has the world's highest rate of hepatitis C, sofosbuvir costs $300 for a 28-day supply.
At the FDA meeting to review sofosbuvir for approval, Sofia listened to testimony from a patient who had been cured by the new drugs at practically the last minute. “Stories like this,” Sofia says, “put everything one does in perspective.” How many other patients get to tell such stories remains to be seen.