The experts agree. Improved results, shorter treatment durations, and, thus, superior tolerability, make sofosbuvir (Sovaldi) and simeprevir (Olysio) breakthrough agents in the fight against the hepatitis C virus (HCV). Their introduction constitutes a major step toward conquering a disease that currently kills more Americans each year than the human immunodeficiency virus (HIV) and, quite possibly, toward easing the chronic shortage of livers available for transplant.
Indeed, doctors prescribed sofosbuvir nearly 5000 times in its first 2 months on the market, putting it on pace for annual revenues well over $5 billion.1 Yet many patients with the most common HCV strain won’t be taking either medication in combinations based on current approvals. Instead, they’ll wait until regulators review experimental regimes that promise to be better still. “The extraordinarily slow progression of hepatitis C gives patients options,” said Fred Poordad, MD, vice president of academic and clinical affairs at The Texas Liver Institute. “Most of my genotype 1 patients can safely wait for next-generation regimes that promise to greatly increase cure rates and greatly reduce side effects, and they are choosing to wait for those interferon-free therapies.”
HCV is a viral disease that attacks the liver very slowly. Infection typically predates symptoms by decades, so the majority of cases remain undiagnosed. Models, however, estimate that HCV currently afflicts more than 3 Americans2 and 150 to 200 million people worldwide.3,4 The disease causes nearly a third of the world’s cirrhosis5 and about a quarter of its hepatocellular carcinomas.6
Here in the United States, almost a third of all liver transplants go to victims of the disease, yet it still kills 16,000 Americans a year, more than HIV or violent crime.2 Until the approval of sofosbuvir and simeprevir, the standard treatment for HCV entailed as many as 48 weeks of pegylated interferon alpha and the antiviral drug ribavirin. Patients with a genotype 1 variant of the disease, which accounts for about 75% of American cases, also received either boceprevir (Victrelis) or telaprevir (Incivek).7
Technically, nothing “cures” HCV, but successful treatment produces sustained virologic response (SVR)—viral levels that are untraceably low after treatment and lifetime relapse rates below 2%. SVR rates for earlier treatments varied among the 6 HCV genotypes, ranging roughly from 65% to 90%.8 For genotype 1 patients, whose regimes included boceprevir or telaprevir, cure rates ranged from 67%9 to 75%10 in trials, depending on patient types. Side effects, primarily from the interferon, begin with flu-like symptoms that, generally, give way to fatigue and mood changes. They are unpleasant for nearly everyone and disabling to some.
Sofosbuvir and simeprevir offer considerable improvements. Phase III trials that combined interferon and ribavirin with simeprevir, an NS3/4A protease inhibitor that has only been approved to treat the genotype 1 variant of HCV, found SVR in 80% of untreated patients.11 Phase III trials that treated patients with genotype 1, 4, 5, and 6 with sofosbuvir, interferon, and ribavirin found SVR of 90%. As an all-oral therapy for genotype 2 and 3, sofosbuvir and ribavirin achieved SVR ranging from 50% to 73%, depending upon patient type and treatment duration.12
Most of those rates represent substantial increases over previous standards of care. Better still, patients using sofosbuvir or simeprevir with interferon and ribavirin achieve those cure rates after shorter treatment periods, saving patients 3 to 6 months of discomfort. Patients with genotype 2 and 3 strains of the disease escape the discomfort of treatment almost entirely. A regime of sofosbuvir and ribavirin (but no interferon) produces only mild side effects in most people. (Patients with genotype 1 cases who are “interferon intolerant” can also skip the interferon and its side effects by doubling treatment time with sofosbuvir and ribavirin, but doing so greatly reduces treatment efficacy.)
With nothing better or milder on the horizon for genotype 2 and 3 patients, many specialists have enthusiastically recommended sofosbuvir to that quarter of their caseload. For the vast majority of cases who have a genotype 1 variant, however, only those with urgent need are being counseled to use one of the new drugs. “If sofosbuvir or simeprevir had been approved for use with interferon and ribavirin for genotype 1 patients a few years ago, they would have had enormous uptake,” said Ira Jacobson, MD, chief of the Division of Gastroenterology and Hepatology at NewYork-Presbyterian Hospital, Cornell Campus. “But from a long-term historical viewpoint, the quantum leap, which has already occurred for patients with certain genotypes, will consist of the use of all-oral antiviral regimens rather than interferon-based regimens for essentially all of our patients,” said Jacobson, who is also a chaired professor at Cornell University’s medical school. “The cure rates from recently reported trials of such oral regimens on genotype 1 patients are truly extraordinary.”
Indeed, in 1 phase III trial of 394 patients who had already failed treatment with interferon and ribavirin, AbbVie’s 3-drug combination (ABT-267, ABT-333, and ABT-450/ritonavir, given with ribavirin) cured 96% of patients with genotype 1a of the virus and 97% of patients with genotype 1b. Another 5 phase III trials showed similar results. AbbVie expects to file a new drug application during the second quarter and, perhaps, to be selling the drugs by year’s end.13 Gilead’s all-oral combination (sofosbuvir plus NS5A inhibitor ledipasvir) posted similar results in its phase III trials. SVR rates ranged from 93.1% to 97.7%14 for the combo, which was submitted to the US Food and Drug Administration (FDA) for approval in early February.
The key to the outstanding cure rates for both combinations—along with other combinations that have undergone smaller trials—lies both in the individual medications themselves and in the way they are used. “It appears that much of the power comes simply from using antivirals in combination and thus attacking the disease on multiple fronts,” said Eric Lawitz, MD, vice president of scientific and research development at the Texas Liver Institute. “None of the medications produced such dramatic results when tried as monotherapies. It was only when trials began putting complementary antivirals together—an idea that had never been tried before against HCV—that the cure rates surpassed 90%.” Of course, better results and less discomfort come at high prices.
Johnson & Johnson charges $66,36015 for a 12-week supply of simeprevir. Gilead, meanwhile, charges $84,000 for a 12-week supply of sofosbuvir16 and twice that for the 24-week supply needed by patients who want to avoid interferon. Still, doctors interviewed for this story have yet to encounter a third-party payer that refused to cover either of the medications, or even one that made them expensive enough or inaccessible enough to make patients consider using older, cheaper regimens. Even with simeprevir’s high price and wide coverage, analysts expect its sales to top out around $500 million annually, 17,18 not only because its numbers generally lag behind those of sofosbuvir in currently approved regimens, but also because it only treats genotype 1 cases and the experimental all-oral therapies look to be so much better.
Sofosbuvir, on the other hand, is predicted to be even more of a blockbuster than the early sales would indicate, thanks to its place in Gilead’s all-oral treatment for genotype 1. Analysts believe those high cure rates and mild side effects will spell huge profits for Gilead and AbbVie. The only big differentiator they see, the one they think will determine which company emerges the big winner, is convenience. The AbbVie combination requires patients to take up to 6 pills a day. The Gilead “combination” comes in a single pill, taken once per day.
Observers expect that consumers, other things being equal, will choose the 1-pill option, which may be good for cure rates. Studies show that pill aversion or memory lapses keep patients from following multi-pill regimes as rigorously as they adhere to 1-pill regimes. As a result, analysts think Gilead’s combination will score a decisive win that would push annual sofosbuvir sales to $9.5 billion.19
But cost may end up trumping convenience and prevent Gilead from scoring the easy victory that many expect. Several of the nation’s largest pharmacy benefits managers, including CVS Caremark Corp, Catamaran Corp, and ExpressScripts Holding Co, are already pushing back against high prices.19 ExpressScripts says that if the combination treatments from Gilead and AbbVie are both approved and if an independent committee finds them medically equivalent, it may only cover whatever alternative comes cheaper.
“We are firmly committed to this clinical-based formulary approach, which drives down the nation’s prescription drug costs while also ensuring patients retain access to the medications they need,” said ExpressScripts spokesman David Whitrap. ExpressScripps says it will not enact any formulary exclusions in HCV in 2014. The company has not announced any plans for 2015, but, Whitrap noted, “This approach makes the most sense when applied to therapy classes that are both high cost and increasingly competitive.”
And HCV will almost certainly become a more competitive area for pharmaceutical companies. Bristol-Myers Squibb and Merck & Co appear likely to bring out their own all-oral treatments for HCV in the coming years, as effective and well tolerated as anything else. Some observers think that Johnson & Johnson may get into the market too, by finding a partner drug for simeprevir.
Insurers, thus, may be in a strong position to announce plans to cover only 1 treatment—ask companies to submit bids and pick only the lowest. (Industry observers generally doubt that insurers would refuse to cover any of the new all-oral treatments as a first-line therapy and force patients to first try older, cheaper treatments.)
Absent steep discounts, the prices for the new treatments will be extremely high. Given that Gilead’s wholesale price for a 12-week course of sofosbuvir alone is $84,000, a full course of the combination drug could be more than $100,000. (Neither Gilead nor AbbVie has made any public announcement about combination pricing.) The aggregate numbers are even more striking.
Multiply $100,000 by the 150,000 patients that Gilead expects will seek treatment each year once the all-oral regimes hit the market and the total yearly tab is $15 billion.
However, if the economics work out, the new medications appear to be a transformative moment in the history of HCV. They might even be the beginning of the end, at least in wealthier countries where patients have access to expensive treatments. “We’ve already reached the point where insurers pay for the test, and we’re just about at the point where we will be able to offer a reasonably easy cure to the vast majority of people who test positive. If we can get the word out about who needs to be tested and convince those people to actually take the test, then we may just reach the point where we can start talking seriously about eradicating strains of this disease entirely,” said Tom Nealon, national board chair at the American Liver Foundation.
The elimination of any disease as widespread and as deadly as HCV—even just the genotype 1 strain—would represent a major medical triumph, of course, but Nealon says the benefits of that triumph would extend not just to those spared the ravages of HCV but to all 30 million Americans with liver disease. “Right now, a third of all the livers we have available for transplant go to the victims of HCV. If we succeed in eliminating or greatly reducing that 1 disease, we can eliminate or at least greatly reduce the chronic shortage of transplant livers that has existed since we started transplanting livers,” Nealon said. “People with all sorts of liver disease, diseases that have nothing to do with HCV, will live on because of these new treatments that are coming to market. They are a tremendous breakthrough.