Hepatitis C: Move Over Interferon (Nature Biotechnology)

Nature Biotechnology, November 2011.

Following approval of hepatitis C virus protease inhibitors Incivek and Victrelis, companies are partnering to devise all-oral combination antiviral regimens without interferon a.  But the virus is a long way from vanquished.  Ken Garber investigates.

The mid-May approval of the first two hepatitis C virus (HCV) protease inhibitors by the US Food & Drug Administration, a foregone conclusion for more than a year, still made headlines worldwide. That’s understandable. The drugs, Incivek (telaprevir) (ref. 1) from Vertex Pharmaceuticals in Cambridge, Massachusetts, and Victrelis (boceprevir) from Merck in Whitehouse Station, New Jersey, each combined with polyethelyene glycol–decorated (pegylated; PEG) interferon (IFN)a and ribavirin in clinical trials almost doubled the cure rate compared with the standard of care, subcutaneous PEG-IFNa plus ribavirin alone.  Analysts predict that Incivek will approach $2 billion in sales in its first full calendar year on the market, which would make it the most successful drug launch in history.

But an even more important milestone went largely unmentioned by the press. On April 2, at an international HCV meeting in Berlin, an academic hepatologist presented interim results for a phase 2a trial of two direct-acting antivirals (DAAs) from Bristol-Myers Squibb (BMS) in Princeton, New Jersey (2). (DAAs target specific viral proteins, as opposed to promotiong a general antiviral immune response or other nonspecific antiviral effects.)  In one arm of the trial, 4 out of 11 patients treated with just the two drugs for 24 weeks achieved a sustained virologic response (SVR)—a cure. These were the first reported cures in humans from a regimen of DAAs that did not include IFN.Impressively, these patients had previously failed to respond to PEG-IFNa and ribavirin, and thus represented the hardest-to-treat patient population.

The Berlin report instantly transformed the idea of an all-oral regimen from a theoretical goal to a virtual certainty and has triggered a mad scramble in pharma and biotech to get such a regimen on the market as soon as possible. “The BMS experiment absolutely worked,” says Norbert Bischofberger, chief scientific officer of Gilead Sciences in Foster City, California. “When we saw that, we thought, ‘Now we know that this is the thing to do.’”

Greatest launch ever?

Given that roughly 170 million people worldwide are infected with HCV (five times the number with HIV), including perhaps  four million in the US and five million in Europe, the potential market for such an all-oral regimen is enormous. Companies are heavily invested, with at least 29 DAAs in clinical trials (Fig. 1). Incivek and Victrelis, the first two approved DAAs, are almost certain to be superseded fairly soon by agents with better pharmaceutical properties and fewer side effects.

But there is concern that the trials to date have tested drugs in only select groups of individuals and that certain patient subgroups may not benefit nearly as much. Unfortunately, companies may already be trimming some early-stage discovery and development programs now that three well-validated viral protein targets exist. “You don’t really want to say it’s over until it’s over, in terms of having all the compounds that we need to treat everybody that needs treatment,” says virologist Charles Rice at Rockefeller University in New York.

In the meantime, thousands of HCV patients who have been waiting for up to three years to start treatment with the new protease inhibitors are flocking to clinics. Since the drugs hit the market, “you’re seeing virtually 100% conversion of patients from the old standard of care to the new,” says Geoffrey Porges, a biotech analyst at Sanford C. Bernstein, a broker-dealer in New York. Porges expects about 30,000 HCV patients to receive treatment in the US in the second half of 2011, rising to 100,000 for full-year 2012, with Incivek taking about 75% of market share. The greater complexity of the Victrelis regimen, which includes four weeks of lead-in treatment with PEG-IFNa and ribavirin followed by variable lengths of Victrelis treatment, is giving Incivek the edge, says Porges. With a billion dollars in sales likely in the first year on the market, he says, Incivek is experiencing “a breathtaking launch.” For the full 2012 year, Wall Street consensus is very close to $2 billion, says J.P. Morgan biotech analyst Geoffrey Meacham in New York.

But there are drawbacks to both new regimens. Obviously, they still include the much-dreaded IFNa, which has numerous side effects, including extreme fatigue and severe flu-like symptoms, headaches, muscle aches as well as psychiatric problems, including depression and, in rare cases, suicide. Now patients must also cope with the additional side effects of the protease inhibitors—mainly rash for Incivek and anemia for Victrelis. These drugs only work in patients with genotype 1 HCV, not in the other five genotypes, which infect 30–35% of the patient population. Even in genotype 1, neither drug works very well in patients who did not respond to the previous standard of care. And though the regimen for Incivek is simpler than Victrelis’s, they’re both complex. Many drug interactions and intricate treatment algorithms ensure that doctors will make errors, and the need to take the protease inhibitors every eight hours with food (fatty food, in Incivek’s case) means that patient compliance, and thus efficacy, will suffer. “Obviously you worry that people can’t follow those regimens,” says Anna Lok, a hepatologist at the University of Michigan in Ann Arbor. “Even for 12 weeks [with Incivek]. I mean, 12 weeks is a long time.”

Newer protease inhibitors promise better. Although resistance mutations in the NS3 protease inevitably arise—a chronically infected person churns out about a trillion particles a day, so mutant variants are present even before treatment starts—these drugs could have several advantages. “When you have low drug concentration transiently in a patient, that’s when you have the greatest probability of outgrowth of resistant variants,” says Rob Ralston, a virologist at the University of Missouri in Columbia. One reason for low trough concentration is that patients often miss a dose, but pharmaceutical qualities also matter. “Having less frequent dosing, and better pharmacokinetics and higher [in vitro] potency, all of those things together help build a barrier to resistance that’s important to the [protease inhibitor] class,” says Ralston. And most newer protease inhibitors have serum half-lives that permit daily dosing.

At least 11  protease inhibitors are in clinical development, most of them macrocyclics, which bind more tightly to the target than linear inhibitors like Incivek and Victrelis. Of these, TMC435, a macrocyclic inhibitor from Tibotec in Beerse, Belgium, part of Johnson & Johnson, is the most advanced. The drug has once-daily dosing, and so far has been well tolerated in trials, with adverse event incidence similar to control arms. In phase 2b data to be reported at this year’s annual meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco in early November, TMC435 treatment at its high dose, combined with PEG-IFNa2a plus ribavirin for 24 weeks, led to an 85% SVR rate at 72 weeks.  By contrast, the SVR rate was 65% for controls receiving PEG-IFNa2a plus ribavirin alone for 48 weeks (3). TMC435 is being developed jointly by Tibotec and by Medivir in Huddinge, Sweden. Barring any toxicity surprises for TMC435 in phase 3, “they’re going to be on the market [by] the end of 2013 probably, beginning of 2014,” predicts Porges. “No one else has actually started their pivotal trials yet.”

Eliminating interferon

Companies must now decide whether, like Tibotec, to include PEG-IFNa in their own phase 3 protocols, or to go with an all-oral regimen. It’s a crucial decision. PEG-IFNa, albeit for shorter durations of treatment, was considered a necessity until the all-oral BMS results stunned the field in April. Although DAAs halt viral replication, they don’t eliminate existing viral genomes, and boosting the immune system with IFN—according to orthodox thinking—may be necessary to clear infected hepatocytes. (Unlike with HIV, merely suppressing HCV has not been shown to improve clinical outcomes; eradication is needed.) “I don’t think we’ll ever find a day when we’re not using interferon in hepatitis C, one way or another,” Lawrence Blatt, then chief science officer of InterMune in Brisbane, California, told Nature Biotechnology in 2007 (4). Blatt, currently president and CEO of Alios BioPharma in So. San Francisco, California, now thinks differently. “I was most likely wrong in my opinion that we wouldn’t be able to eliminate interferon from the HCV treatment regime,” he said in an e-mail, citing the BMS trial reported in April. “The bottom line is that the data wins the day.” Alios, in fact, recently licensed two nucleoside inhibitors of the HCV NS5B polymerase to Vertex for a future all-oral combination therapy.

Companies now worry that regimens that include IFN will be rendered obsolete before phase 3 is even complete. “Things are moving so fast,” says Gilead’s Bischofberger. Six months ago, Gilead changed strategic direction. “Our intent [now] is to move into phase 3 with an all-oral regimen,” says Bischofberger.

With limited phase 2 data available, the eventual winning combination or combinations are anyone’s guess. The landmark BMS trial combined a protease inhibitor with an inhibitor of the NS5A protein. The exact function of NS5A in the viral life cycle has long been a mystery, but NS5A inhibitors have the potential to become mainstays of future all-DAA regimens. That’s due to their astonishing potency. Last year, BMS reported low picomolar potency for its NS5A inhibitor, BMS-790052—a rarity in medicinal chemistry (5). “I was absolutely shocked when I saw some of this data,” says Tim Tellinghuisen, a virologist at the Scripps Research Institute in Jupiter, Florida. In patients, a single dose of BMS-790052 led to an almost 2,000-fold decrease in mean blood levels of HCV RNA, with levels remaining low for more than a week. At least two ongoing DAA phase 2 combination trials include NS5A inhibitors (Table 1).

The potency mystery

NS5A, one of six nonstructural proteins that coordinate the intracellular processes of the viral life cycle, was first isolated in 1994. But it remains an enigma. NS5A exists only in HCV and a few related viruses, and it has no known enzymatic activity. “It’s a very strange protein,” says Tellinghuisen, who worked out the structure of NS5A amino terminus in 2005 (ref. 6). That structure revealed multiple surfaces that might interact with other proteins, as well as RNA. But exactly which proteins bind NS5A functionally, and how NS5A affects RNA replication, remains poorly understood. “If you ask me what the protein does, I can’t tell you,” says Tellinghuisen, who has been working on NS5A for 11 years. Since 2008, it has been clear that NS5A is important for viral assembly as well as RNA replication, which may account, at least in part, for the great potency of NS5A inhibitors.

But that’s probably not the whole story. BMS scientists have calculated the relative concentrations of its drug and the target, concluding that a single molecule of drug inhibits 5,000 NS5A dimers. That implies some kind of amplification or ripple effect. BMS scientists postulate that NS5A dimers assemble into a polymer that wraps around the viral RNA, protecting it from degradation and perhaps also presenting the RNA to the polymerase during RNA replication. “One of our [inhibitor] molecules is binding to this 5A polymeric form in a fashion that is sufficient to disrupt the activity of the entire polymer,” speculates Nicholas Meanwell, head of virology chemistry at BMS R&D. Assuming NS5A is presenting the RNA genome to the polymerase, “one can imagine that as the polymerase zips along the surface, reading the genetic code and synthesizing a copy, that if there’s an imperfection in the road, or a spike in the railroad track…it might fall off.” The result:  RNA replication is halted.

Regardless of mechanism, NS5A inhibitors should be relatively nontoxic, because nothing like NS5A exists in humans, and their extreme potency should work to rapidly drive down viral load. In a Japanese study to be presented at this month’s AASLD meeting, ten HCV genotype 1b patients, all prior null-responders to PEG-IFNa plus ribavirin, were treated with BMS’s NS5A inhibitor and protease inhibitor. All ten were cured, including one who left the study early, due to an adverse event (7).

The main drawback of NS5A inhibitors is the emergence of spectacularly resistant variants that suffer little or no loss of replication fitness. “It’s definitely going to be important to pair those kinds of compounds with those that have higher barrier to resistance, in terms of genetic barrier to resistance and also [reduced] fitness of resistant variants,” says Rice.

The hottest biotech on the planet?

For this reason, inhibitors of NS5B polymerase will be part of most future combinations, either with NS5A inhibitors or protease inhibitors—or all three together. NS5B is responsible for the synthesis of viral RNA, a fundamental and critical step in replication. NS5B inhibitors fall into two classes: nucleosides (or nucleotides) , which target the active site; and nonnucleoside allosteric inhibitors. Resistance occurs less often for nucleosides than nonnucleosides and therefore they have become a coveted commodity.  Nucleosides act as chain terminators, and it’s hard for the viral polymerase to mutate around the inhibitor and still permit the natural nucleoside to attach. Crucially, nucleoside-resistant NS5B variants show reduced viral fitness.

Reduced fitness is important because all-DAA therapies attack processes in the viral life cycle, but not the viruses themselves. So eradication becomes a race between the drugs and the resistant viruses. “These direct-acting antivirals, while they inhibit production of new virus genomes, don’t directly destroy existing viruses,” says Ralston. But eradication should still be possible. In the presence of nucleoside NS5B inhibitors, “at some point, you should be able to push the threshold of replication down low enough so that it just can’t sustain itself even at the infected cell level,” says Rice. “The RNA is just turning over faster than it amplifies, so it just dies out…. Theoretically that should be doable, if the resistant virus is unfit enough.”

The disadvantage of nucleosides, however, is toxicity. Humans use RNA polymerases for synthesis of several kinds of RNA, so nucleoside NS5B inhibitors can interfere with important human biology. Toxicity has led several companies, including , Merck and Roche in Basel, Switzerland, to discontinue nucleoside NS5B inhibitors in recent years.

Pharmasset, in Princeton, New Jersey, is the best-positioned survivor and is poised to reap the benefits. “If you had to pick any one asset right now, let’s say among the nucs [nucleoside inhibitors], that’s Pharmasset’s 7977: extremely potent and great resistance profile,” says J.P. Morgan’s Meacham. Two IFN-free phase 2 combination trials of PSI-7977 are underway, with a third set to begin. Investor expectations are almost off the charts. In the year ending in September 2011, the company’s share price rocketed from $14.40 to $81.15, giving the company a market capitalization of $6.2 billion, even though Pharmasset has no products—and no drugs beyond phase 2.

The versatility of nucleosides accounts for the great interest, says Meacham.  “Nucs are so valuable: they’re pan-genotypic, so you can be [HCV genotype] one through six,” he says.”   “It doesn’t matter what the BMI [body mass index] of the patient is, it doesn’t matter if they’re African-American, if they’re Caucasian. It doesn’t matter if they’re CC versus TT genotype [for the IL28B predictive marker]. That’s the theory, anyway—that the nuc class, if it’s a backbone, will treat everyone. We just don’t know the right dose and the right duration.”  A safety problem could emerge in phase 3, of course, he acknowledges. But “so far…touch wood, they’ve been pretty clean.”

Speed dating and strange bedfellows

Pharmasset is testing the limits of nucleosides with a trial pairing PSI-7977, a pyrimidine nucleoside analog, with its PSI-938, a purine. To be active, nucleoside analogs must first be metabolized to the 5¢ triphosphate form by cellular kinases in the target cell. Because the two Pharmasset nucleosides go down different phosphorylation pathways, they shouldn’t interfere with each other. But can hitting the virus with just  two polymerase inhibitors eliminate viral RNA fast enough to overcome resistant variants and thus eradicate the virus? “I do worry that that might not be good enough,” says Rice. “But you never know, it might be.”

Pharmasset is not revealing its phase 3 strategy. “We’re trying to collect as much data as possible to get a sense of what the next step will be,” says Richard Smith, the company’s vice president for investor relations and media communications. “We don’t need to tell the competition what we might be doing.” Meacham predicts that Pharmasset, by itself or with a partner, will have an IFN-free regimen on the market by 2015 or 2016.

Unfortunately for patients, IFN will remain a part of the treatment equation at least until then. Some companies are even testing ‘quad therapy’—two DAAs, plus PEG-IFNa2a and ribavirin. Vertex, for example, is pairing Incivek with its nonnucleoside polymerase inhibitor, VX-222. “This could bring us down to a 12-week treatment, which fundamentally changes the game for how patients would be treated,” said Vertex CEO Matthew Emmens at the J.P. Morgan healthcare conference in San Francisco  in January. “If you can get it down to 12 weeks with a high SVR, it’s going to be a very high bar to beat.” But clinicians dread adding yet another drug on top of PEG-IFNa2a plus ribavirin, making a barely manageable regimen even more complex while increasing toxicity. Quad therapy  therefore may  only play a temporary role or will be reserved for very hard-to-treat populations.

Meanwhile, companies are scrambling to assemble the components of their all-oral phase 3 trials. “There’s ‘speed dating’ going on across the industry,” says Porges. “Everyone is sort of looking at each others’ molecule and saying, ‘Is this a good fit with my molecule?’ and ‘How much will it cost me to get access to it, can we do a trial together?’ and…‘Maybe we go on a couple of dates and see if we like each other.’” But removing IFN from the equation may not prove simple. Vertex discontinued the PEG-IFNa–free arms of its combination protease inhibitor–polymerase inhibitor trial due to high rates of viral breakthrough in patients. Most companies are now hedging their bets by including ribavirin in their experimental DAA regimens. Pharmasset’s Smith considers ribavirin “a weak antiviral, doesn’t protect against resistance and in the presence of two potent antivirals has very little effect…so we don’t think you need it.” But, he says, it makes sense to add for the moment, if only to prove it’s superfluous.

Market saturation—or expansion?

But in the rush to move all-oral regimens forward, it’s easy to forget that very few of them have been tested in hard-to-treat populations, much less shown efficacy. Patients with cirrhosis (scarring of the liver) do fairly well on Incivek and Victrelis with PEG-IFNa and ribavirin, but that may not be true for all-DAA combinations. In patients with cirrhosis, compared with less sick patients, DAAs “could have very different properties with respect to…penetrating through the scar tissue and [then] compromising the virus,” says Rice. “Certainly, we’re not going to know how these combinations perform in the most difficult populations until we actually do the clinical experiments.” Patients co-infected with HIV and liver-transplant patients are almost certainly going to be hard to cure.

Rice thinks improved IFN therapies could play an important future role, including BMS’s IL-29, a lambda IFN. Lambda and alpha IFNs have similar (but not identical) antiviral effects and signal through different receptor complexes. Because the receptor for lambda IFNs is less widely distributed within the human body, BMS’s IL-29 (PEG-IFN-l) should have fewer side effects than the standard PEG-IFNa. Unexpected validation came in 2009 when three independent genome-wide association studies in HCV patients identified polymorphisms in or near the gene encoding IL28B. IL28B codes for a slightly different lambda IFN than IL-29 and the polymorphisms are strong predictors of response to PEG-IFNa2a treatment (8), as well as for spontaneous resolution of HCV infection (9). Although no one knows the mechanism, “this has really heightened interest in what these [IFNs] are doing in terms of…virus biology,” says Rice. BMS’s IL-29 is in phase 2, with plans to combine it soon with protease inhibitors and NS5A inhibitors.

Non-DAAs that target host factors might also make an impact. Furthest along is the nonimmunosuppresive cyclosporine analog, Debio 025, from Debiopharm in Lausanne, Switzerland. It is in phase 3, sponsored by Novartis. Debio 025 targets the host protein cyclophilin B, which interacts with NS5B to stimulate its RNA binding activity.

But the overwhelming industry focus remains on DAAs, specifically inhibitors of the protease, the polymerase and NS5A. But it’s possible that by the time an all-oral therapy reaches market—2015 at the earliest—most willing and available patients will have been treated and cured by Incivek and Victrelis triple therapy (with PEG-IFNa and ribavirin). An estimated 350,000 of them will have received triple therapy by then, Porges estimates. “Maybe the patients who are most inclined to be treated will have been treated by 2015,” he says. “That’s a real question about the long run…return on investment for companies that are madly pursuing drugs in this category.” Porges points out that only about half of HIV patients in the US, a much more motivated patient population, are receiving treatment. “How many of the 1.1–1.2 million treatment eligible in [hepatitis C] can we get to?” he asks.

But companies are counting on all-oral regimens to bring in patients who now refuse to take IFN. “Once you get rid of IFN the market should expand dramatically,” said Pharmasset CEO P. Schaefer Price at the J.P. Morgan healthcare conference in January.  Price cited studies showing that 70–90% of people who go to clinics seeking HCV treatment end up refusing it. And then there are the millions who don’t even know they have the disease (only 20–25% of infected people are overtly symptomatic). “We still have this vast collection of people who were infected in the sixties, seventies and eighties who are unaware that they’ve been infected,” says Rice. Many received blood transfusions before the 1989 identification of the virus. Because of the long period of infection, and its silent nature, this population is at greatest risk for severe liver disease. “Their clock is ticking,” says Rice. Finally, there are developing countries, where the incidence of HCV is usually much higher.

Although all-DAA regimens, which will likely cost more than even Incivek and Victrelis triple therapy (roughly $80,000 list price each) will not be widely used in poor countries—even the old standard of care is often unaffordable there—they might find a expanded market in North America and Europe. If treatments can be made effective enough and nontoxic enough, the asymptomatic population could theoretically be brought in for treatment. “As the treatments get better, we really need to institute an effort to screen populations that are at high or even medium risk [for past infection], and treat them and get rid of it before it causes real trouble,” says Rice. Possible consequences of untreated infection include end-stage liver disease and liver cancer. If even asymptomatic patients can be treated, then Incivek’s spectacular drug launch will pale next to that of a future all-in-one combination pill that’s taken once daily for three months and cures 90% of patients. But though that dream has suddenly entered the realm of the possible, a lot needs to go right in the coming years and decades to make it come true.

Ken Garber, Ann Arbor, Michigan

  1. 1.       Kwong A.D. et a., Nat. Biotechnol. 29, XX-XX. (2011).
  2. 2.       Lok A. et al. J. Hepatol. 54, Suppl. 1, S536, abstract 1356 (2011).
  3. 3.       Fried M. et al.  AASLD annual meeting abstract LB-5 (2011).
  4. 4.       Garber, K.  Nat. Biotechnol. 25, 1379-1381 (2007).
  5. 5.       Gao M. et al.  Nature 465, 96-102 (2010).
  6. 6.       Tellinghuisen T.L. et al.  Nature 435, 374-379 (2005).
  7. 7.       Chayama K. et al.  AASLD annual meeting abstract LB-4 (2011).
  8. 8.       Ge D. et al. Nature 461, 99-101 (2009).
  9. 9.       Thomas, D.L. et al. Nature 461, 798-801 (2009).
  10. 10.    Murray, C.L. & Rice, C.M. Nature 465, 42-44 (2010.)

Table 1 IFN-free DAA phase 2 combination trials for hepatitis C

Sponsors DAAs Targets
Roche Danoprevir, RO5024048 (RG7128) NS3-4A and NS5B
Pharmasset PSI-7977, PSI-938 NS5B
BMS, Pharmasset BMS-790052, PSI-7977 NS5A and NS5B
Boehringer Ingelheim (Ingelheim, Germany) BI2071287, BI201335 NS3-4A and NS5B
Gilead Sciences GS 9451, GS 5885, GS 9190 (tegobuvir) NS3-4A, NS5B, NS5A
Abbott Laboratories (Abbott Park, IL, USA) ABT-450, ABT-072 NS3-4A and NS5B
Tibotec, Pharmasset TMC435, PSI-7977 NS3-4A and NS5B

Figure 1 [Not shown.] Hepatitis C life cycle. HCV replicates using a series of nonstructural proteins, which provide targets for drug development, including the NS3-4A protease and the NS5B polymerase. A third target, NS5A, has no known enzymatic activity. (Reprinted from ref. 10.)


Comments are closed.