Two drugs or three? Ribavirin or not? What is the role of interferon? These will be the questions physicians will be asking as they consider a rather dizzying set of new hepatitis C agents likely to be launched in the next couple of years.
While it has always been assumed that the virus would be targeted with the same “cocktail” approach that has transformed HIV treatment, the speed with which so many hep C agents have proceeded through the clinic has been surprising, and this is certainly a good problem to have. The difficulty will be differentiating between products that all seem to be able to generate the same high viral suppression rates of 90% or more.
Interferon still needed
One certainty from the AASLD meeting in Washington, DC, is that while interferon and ribavirin will probably fade from the mainstay of treatment, neither is going away. So far, genotype 1 patients – who represent the biggest population in western markets – are the biggest target for treatment exclusively with new agents like Gilead Sciences’ sofosbuvir; regimens structured for genotypes 2 and 3, in particular, will still rely on the older drugs.
Experts reviewing clinical trials were fairly blunt on this point. Gilead’s clinical programme in genotype 2 patients has achieved impressive 80-90% viral suppression rates only with an assist from ribavirin. “It’s a very simple story: genotype 2 will become a curable disease, and there’s probably not a lot of interest in pursuing new regimens,” said David Nelson, a professor of medicine at the University of Florida. “12 weeks and a safe regimen look pretty good.”
In genotype 3, now emerging as a vexing patient population, those same levels could be achieved with longer treatment cycles of 16-24 weeks. In more difficult-to-treat patients like those who have failed on other regimens or with liver disease, there could be a need for more potent assistance from the viral clearing power of interferon, Dr Nelson said.
“We have some fairly simple approaches, but almost always with combinations of either interferon or non-interferon containing regimens,” he said of the genotype 3 population.
Even though more treatment options are emerging, or perhaps because of this, genotype 1 is set to become more complicated for physicians attempting to choose a regimen. Two-drug combinations have shown impressive progress – witness the reaction to data indicating that sofosbuvir and Johnson & Johnson’s simeprevir, which could be on the market within weeks, can achieve 90% viral suppression rates – yet drugmakers plough ahead with clinical trials including three or more different agents.
Nearly every big pharma company in the game – not just Gilead and J&J, but also Bristol-Myers Squibb, Boehringer Ingelheim, Merck & Co and AbbVie – are plugging a variety of molecules with different mechanism of actions into experimental protocols. A big challenge, of course, is to reduce how many agents – or at least individual pills – are necessary to achieve viral suppression and improve patient adherence and reduce the risk of side effects.
Should the FDA approve simeprevir, now known as Sovriad, and sofosbuvir on schedule in a few weeks, their use will become the new standard of care in combination with interferon and ribavirin as labelled – the former just in genotype 1 and the latter in 1-4. Off-label use in combination, without interferon and perhaps without ribavirin, is expected, particularly in patients with few treatment options (AASLD – Sofosbuvir-simeprevir pairing scores big, November 5, 2013).
As with HIV, multiple mechanisms of action are necessary to combat viral resistance, which is why the cocktail approach is favoured. The three mechanisms are protease inhibitors, and inhibition of the NS5A and NS5B polymerases.
Sofosbuvir, a nucleoside NS5B polymerase inhibitor, has passed nearly every test thrown at it, so much so that it was hoped that, in combination with ribavirin and Gilead's NS5A polymerase inhibitor ledipasvir, it might even cure some of the easier patients, the non-cirrhotic genotype 1s who have never been treated before, with just a six-week course. This attempt generated a disappointing 68% sustained viral response 12 weeks after the end of treatment in an early phase trial, but an eight-week course achieved 100%, according to data outlined at AASLD.
It is on that sofosbuvir-ledipasvir combination that so much expectation has been placed, not the least because of the $11bn Gilead spent to acquire sofosbuvir when it bought Pharmasset. A pivotal trial of a fixed-dose combination with and without ribavirin will read out next year, revealing whether it will be able to suppress the infection without the aid of another antiviral.
If Gilead is perhaps most advanced in getting a two-drug regimen to phase III, it is not alone in trying, although all of the data so far are earlier stage. AbbVie has completed a phase IIb trial of its protease inhibitor ABT-450 and NS5B inhibitor ABT-267 that the Illinois group has managed to formulate into a single pill.
This showed that the combination could achieve sustained viral responde 12 weeks after the end of treatment in 95% of patients who had never sought treatment, and 90% in patients who had failed to respond to interferon-based therapy.
Merck & Co is another company that released data from a two-drug combination, again a protease inhibitor in MK-5172 and an NS5A inhibitor in MK-8742. Without ribavirin, this achieved 100% viral suppression in genotype 1b patients, the only population in which it was attempted.
Even if satisfactory results can be achieved from a two-drug combination, as with HIV multiple agents might still be necessary because of individual patient needs, Dr Nelson said. “I don’t know that we can clarify exactly what the approach is for every patient,” he said.
“But clearly there will be multiple regimens, some simple and some subtype-specific. I still believe interferon will be used in a minority of patients. We fortunately will have lots of options to choose from.”