news in this section Genentech’s Gazyva snatches anti-CD20 crown
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FDA halts and restores Ariad’s leukemia drug
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The US Food and Drug Administration (FDA) approvals of Gilead’s Sovaldi (sofosbuvir) on December 6 and, to a lesser extent, of Janssen Pharmaceutical’s Olysio (simeprevir) on November 22 ushers in a new era of hepatitis C virus (HCV) therapy. With these latest approvals, most patients will soon be able to avail themselves of treatments that are substantially safer, easier to take and more effective than the current regimens. Gilead’s Sovaldi, the first nucleotide (‘nuc’) polymerase inhibitor approved for treating HCV infection, has aroused high clinical and commercial expectations, on the strength of its favorable safety and efficacy profiles across HCV genotypes (GT) 1, 2, 3 and 4 (Table 1). What’s more, it will enable many patients to clear their infections without needing interferon. For more than two decades, interferon has been a cornerstone of HCV therapy. But it carries a heavy burden of side effects, and current regimens, based on one of two approved protease inhibitors Incivek (telaprevir) or Victrelis (boceprevir), plus ribavirin, all include pegylated interferon-α. The goal of eliminating interferon from HCV drug regimens emerged as a major theme in drug development since the first report of patients achieving a sustained virologic response (SVR) or cure on an interferon-free regimen (Nat. Biotechnol. 29, 963–966, 2011). As yet, however, the first all-oral, interferonfree regimen, comprising Sovaldi and ribavirin (another long-standing cornerstone of therapy), is approved only for people infected with HCV GT2 or 3. It will take at least another year before interferon-free regimens for patients with HCV GT1, the most prevalent and most difficult-to-treat variant of the virus, become routinely available, although the FDA has recommended Sovaldi and ribavirin as a potential option for GT1 patients who are ineligible for interferon therapy. At $84,000 for a 12-week course in the US, Sovaldi does not come cheap, and patient advocates are mobilizing in order to make the drug—or generic equivalents— available in low-to-middle income countries at an affordable price (Box 1).
Gilead
© 2014 Nature America, Inc. All rights reserved.
FDA approvals usher in the post-interferon era in HCV
Sovaldi has the potential to be bigger than Lipitor—some analysts believe.
An SVR 12 weeks after the completion of therapy (SVR12) is now generally accepted as a viral cure, and in clinical trials, some investigational interferon-free regimens have elicited SVR12 rates of 90% and over, often after just 12 weeks of therapy. In contrast, the previously approved regimens (Incivek or Victrelis, plus pegylated interferon-α and ribavirin) required up to 48 weeks of treatment and generally offered worse outcomes. Among patients on Incivek in combination with pegylated interferon-α and ribavirin (PR) cure rates (then defined as SVR24) of 74–79% were reported in phase 3 trials in different patient populations. Among those on Victrelis plus PR, cure rates of 63–66% were achieved. The two drugs, both of which were approved in May 2011 for treating HCV GT1 infections in combination with PR did offer a real improvement over PR therapy alone, which generally results in cure rates below 50%. Each has significant side effects, however, on top of those associated with PR therapy.
nature biotechnology volume 32 NUMBER 1 JANUARY 2014
“Telaprevir and boceprevir will probably become history. It’s difficult to see why anyone would want to use them because of their side effects, complicated treatment algorithms and drug-drug interactions,” says Anna Lok, professor of internal medicine in the University of Michigan Health System, in Ann Arbor, Michigan. US sales of Incivek and Victrelis, marketed, respectively, by Cambridge, Massachusetts–based Vertex Pharmaceuticals, and by Merck, of Whitehouse Station, New Jersey, have already plummeted as patients postpone treatment in anticipation of the new drug combinations. Most interferon-free combinations in development comprise two or three directacting antiviral (DAA) drugs plus ribavirin, a nucleoside analog that inhibits viral replication. The most mature DAA classes include nucleotide viral NS5B RNA polymerase inhibitors, non-nucleotide viral NS5B RNA polymerase inhibitors (which work by an allosteric mechanism), NS3/4a 3
NEWS
npg
© 2014 Nature America, Inc. All rights reserved.
Table 1 Selected trials of interferon-free HCV drug regimens Drug combinations
Developer
Description
Current status
Latest data
Sovaldi/ledipasvir, without ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, NS5A inhibitor, nucleoside analog viral RNA replication inhibitor
Ongoing phase 3 trial (Ion-3) in treatment-naive patients with HCV genotype 1 (GT1)
Study based on phase 2 (Lonestar) trial: 8 weeks therapy SVR8 98%; 12 weeks therapy (without ribavirin) SVR4 100%
Sovaldi/ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Completed phase 3 trial (Fission) in treatment-naive patients with GT2 or GT3 on 12 weeks of therapy
SVR12 67% in all patients treated (n = 256) vs. SVR12 67% in patients on interferon + ribavirin (n = 243); SVR12 90% in GT2 patients
Sovaldi + ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Completed phase 3 trial (Positron) SVR12 78% (n = 207) vs. 0% placebo (n = 71) in interferon-intolerant patients with GT2 or GT3
Sovaldi + ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Completed phase 3 trial (Fusion) in patients with GT2 or GT3 who had previously failed interferonbased therapies
Sovaldi + ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Interim data: SVR12 attained by 85% Phase 3 ongoing (Valence) in cirrhotic and non-cirrhotic patients of patients with GT3 on 24 weeks of therapy
Sovaldi + ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Phase 3 ongoing in patients coinfected with HIV
Interim data: SVR12 attained by 76% of GT1 patients, 88% of GT2 patients, 67% of GT3 patients
Daclatasvir + asunaprevir
Bristol-Myers Squibb NS5A replication complex inhibitor, NS3 protease inhibitor
Filed (Japan)
SVR24 84.7% in Japanese patients with GT1b (n = 222)
ABT-450/ra + ABT-267 + ABT-333
AbbVie, Enanta Pharmaceuticals (Watertown, Massachusetts)
Phase 3
Sapphire-1 96% of treatment-naive GT1 patients attained SVR12; Sapphire-2 96% of treatment-experienced GT1 patients attained SVR12
Faldaprevir + deleobuvir + ribavirin
Phase 3 in GT1b patients Boehringer Ingelheim NS3/4A protease inhibitor, nonnucleoside NS5B RNA polymerase inhibitor, nucleoside analogue viral RNA replication inhibitor
MK-5172 + MK-8742 +/ribavirin
Merck
Phase 2b ongoing in treatment NS3/4A protease inhibitor, NS5A replication complex inhibitor, nucleoside naive non-cirrhotic patients with GT1a or GT1b infection analog viral RNA replication inhibitor
Interim phase 2 data SVR12 attained by 100% in two dose arms (n = 22, n = 12) and by 96% in one dose arm (n = 24)
Olysio + Sovaldi
Johnson & Johnson, Medivir
Protease inhibitor, nucleotide NS5B RNA polymerase inhibitor,
SVR4 >90% across two cohorts, including treatment-naive patients & prior null responders to interferon + ribavirin
aABT-450/r,
Protease inhibitor + ritonavir, NS5A inhibitor, non-nucleoside polymerase inhibitor
Phase 2a
12 weeks therapy SVR12 50%; 16 weeks therapy SVR12 71%
Data due Q2 2014
ABT-450 formulated with ritonavir to support once-daily dosing.
Source: company websites.
protease inhibitors and NS5A viral replication complex inhibitors. Each has varying levels of genotypic coverage, but Sovaldi and other nucleotide polymerase inhibitors appear to be active against all genotypes (Ann. Rev. Pharmacol. Toxicol. 53, 427–492, 2013). They also appear to have very high barriers to resistance. “This is an example where maybe the field got a little lucky,” says Charles Rice, professor of virology at the Rockefeller University, in New York. “We can select for resistance in culture,” he says. “It appears to give rise to a virus that is very unfit in vivo.” The landscape for HCV therapies has shifted so rapidly since 2011 that some regimens that are still in clinical development will—in Western markets at least—no longer be competitive by the time they gain approval. A case in point is the recently approved Olysio. Discovered by Stockholmbased Medivir and inlicensed by the Janssen Therapeutics arm of New Brunswick, 4
New Jersey–based Johnson & Johnson, Olysio faces major challenges in making significant headway in the short term, as it still needs to be combined with PR. Interim data from an interferon-free combination of Olysio and Sovaldi have been impressive, but Gilead is not planning to pursue development of this combination regimen any further. In its approved indication, the Johnson & Johnson drug attained SVR12 rates of 80% and 79% in treatment-naive and relapsed HCV GT1 patients, respectively. Its advantages over the first two protease inhibitors Incivek and Victrelis include once-daily as opposed to three-times daily dosing and a better safety profile. Its potential has been hobbled, however, as Olysio does not appear to be active in patients infected with HCV GT1a strains that carry a polymorphism called Q80k, which is found in over 40% of US GT1a isolates (or about 25% of all GT1 strains) and in about 30% of European GT1a isolates. “Most of us recognize it’s going to be
a tough sell to tell patients to take simeprevir [Olysio],” Lok says. Johnson & Johnson may attempt that task in non-Western markets. “You have to realize the world is not just the US or Europe,” says Gaston Picchio, hepatitis disease area leader at Janssen. “It’s going to take time before these regimens reach every corner of the world, especially those regions which are most severely impacted by hepatitis C virus.” It will also take some time to understand what kind of cure rates the new generation of drug combinations will achieve in real-world settings, as opposed to the artificial environment of clinical trials. “In general we should always assume in clinical practice that the results are not going to be replicated,” Lok says. Economics will be an issue as well. “I think cost is going to drive a lot of these decisions,” says Jerry Stern, vice president and head of virology at Ingelheim, Germany– based Boehringer Ingelheim. “Cost for some
volume 32 NUMBER 1 JANUARY 2014 nature biotechnology
news
npg
© 2014 Nature America, Inc. All rights reserved.
Initiative for Medicines, Access & Knowledge (I-Mak), a New York–based advocacy group, has fired the opening salvo of what is likely to be a lengthy battle with Gilead and other companies over access to HCV drugs in low- and middle-income countries. I-Mak has filed a pre-grant opposition in India to one of Gilead’s key patents for Sovaldi, known in India as Application Number 3658/KOLNP/2009. Others are in the offing. “It’s not just going to be in India—it’s going to go wider than India,” I-Mak cofounder and director of intellectual property Tahir Amin says. “There’s probably going to be action on some of the other direct-acting antivirals as well.” (In the US, Merck and Cambridge, Massachusetts–based Idenix are also opposing Gilead’s Sovaldi patents.) Most of the world’s HCV-infected population, which is estimated at around 185 million people, lives outside of the wealthy regions of North America and Europe, as do most of the estimated 350,000 people who die every year from liver diseases associated with HCV infection. India has 10–12 million HCV patients. Egypt has the world’s highest prevalence rate, with an estimated 7 million cases in a population of 85 million, a legacy of poorly conducted anti-schistosomiasis campaigns over several decades. I-Mak, whose donors include the Open Society Foundation, founded by investor and philanthropist George Soros, is attempting to use India’s patent laws as a lever to force Western pharmaceutical firms to cut their prices to affordable levels. “India has laws that are more stringent in terms of what is regarded as new or novel,” Amin says. Its initial opposition concerns Sovaldi, which is administered as a prodrug but which, according to I-Mak, is based on claims that are covered or anticipated by an earlier application concerning the base uridine analog to which Sovaldi gives rise. “Technically they’re trying to double dip and get another four to five years patent life,” he says. Moreover, he claims the same compound was disclosed in a paper (J. Med. Chem. 50, 1840–1849, 2007) published electronically on March 17, immediately before the patent application filing in India, which was completed on March 30, 2007. I-Mak will also contest the previous patent, on the basis that the compound was already known. The initial patent application has already been refused by the Indian Patent Office, Amin says, despite Gilead’s objections. “Once we file our opposition and evidence, we believe it will only solidify the patent office’s refusal,” he says. Although still in its infancy, the dispute is strongly reminiscent of the ongoing struggle between HIV patient advocates and the pharmaceutical industry—except it is likely to get even bigger, given the scale of the global HCV pandemic, which dwarfs that of the HIV pandemic. CS
countries will be a large factor in deciding who gets treated.” An added complication for physicians and patients is the sheer profusion of combination therapies now in late-stage trials, which will shortly become available. Gilead, of Foster City, California, which acquired Sovaldi through its $11.2-billion cash acquisition of Princeton, New Jersey– based Pharmasset in 2012 (Nat. Biotechnol. 30, 122, 2012), may be leading the race right now, but others, including AbbVie, of North Chicago, Illinois, and Bristol-Myers Squibb, of New York, are not far behind. “There are others who have developed other regimens, which will be effective as well. It’s not a onehorse race,” says John McHutchison, Gilead’s senior vice president for liver disease therapeutics. As Nature Biotechnology went to press, AbbVie had reported data from two of six phase 3 trials, with more results imminent. “We’re looking to file in the second quarter of 2014,” says Barry Bernstein, AbbVie’s vice president for infectious diseases. Choosing the optimum regimen for an individual patient will not be a straightforward
task, given pharmaceutical companies’ opposition to head-to-head trials of different combinations. The Hepatitis C Therapeutic Registry and Research Network (HCVTarget), an initiative led by the University of Florida, in Gainesville, and the University of North Carolina at Chapel Hill, will collate real-world data from over 100 treatment centers across the US, Europe and Israel, which will offer physicians some insights into which patients do best on which regimens. Eliminating the virus completely remains, for now, a long-term aspiration rather than a tangible goal. “Remember three-quarters of patients with HCV infection don’t know they have it at this point in time,” says AbbVie’s Bernstein. Moreover, those who do clear their infections successfully still carry a risk of liver disease. “It ain’t over completely, even if you completely eliminate the virus,” says Rice. Despite the advent of vastly improved new therapies, the public health burden associated with HCV infection will be with us for a long time to come. Cormac Sheridan Dublin
nature biotechnology volume 32 NUMBER 1 JANUARY 2014
in brief Sequenom falls after judge invalidates Down’s patent A US federal judge in October invalidated patent claims for a noninvasive prenatal test marketed by San Diego–based Sequenom. The decision is part of an anti-patent trend in the courts that has left everyone in the biotech community unclear on which diagnostic method claims are patent-eligible. Sequenom’s patent covers methods to detect cell-free fetal DNA (cffDNA) in a pregnant woman’s bloodstream. The technology gives women a noninvasive way to test their unborn children for chromosomal defects such as Down syndrome. Older methods are less accurate or carry a slight risk of miscarriage because they involve sampling tissue or fluid from the womb (Nat. Biotechnol. 31, 595–601, 2013). Sequenom was first to the market with the test, in 2011, and has been trying to lock out its numerous competitors by claiming they infringe on the test’s central patent. In the ruling, Judge Susan Illston of the US District Court in Northern California said Sequenom’s patent was invalid because cffDNA is a natural phenomenon, and because the company’s methods for detecting it involve routine DNA amplification and detection techniques. Illston also said the patent posed a risk of preempting other uses of cffDNA because there is no commercially viable alternative for detecting it. The judge cited several US Supreme Court decisions, including a June 2013 decision involving Myriad Genetics in which the court ruled that naturally occurring DNA segments are a product of nature that cannot be patented (Nat. Biotechnol. 31, 663–665, 2013). She also cited a 2012 decision involving Prometheus Laboratories, in which the court ruled against another diagnostics patent, this one a method for determining the optimal dosage of a drug (Nat. Biotechnol. 30, 373–374, 2012). The Sequenom ruling is “not good news” for the biotech community, says attorney David Resnick at Nixon Peabody in Boston. “But it’s not a surprise either,” he says. Resnick’s advice to diagnostics makers: “Don’t panic. It’s a district court decision that is being appealed and hopefully the Federal Circuit will provide more clarity.” But taken together, the Myriad, Prometheus and Sequenom cases present a confusing and decidedly anti-patent landscape that may lead to trade secrecy in lieu of patenting, say attorneys. “If a client comes in and asks about patenting a test for detecting abnormalities during pregnancy, I may tell them not to patent,” says attorney Kevin Noonan at McDonnell Boehnen Hulbert & Berghoff in Chicago. Emily Waltz Scott Camazine / Alamy
Box 1 Patient advocates oppose Gilead patents
5
23andMe designer baby patent controversy
FDA halts and restores Ariad’s leukemia drug
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The US Food and Drug Administration (FDA) approvals of Gilead’s Sovaldi (sofosbuvir) on December 6 and, to a lesser extent, of Janssen Pharmaceutical’s Olysio (simeprevir) on November 22 ushers in a new era of hepatitis C virus (HCV) therapy. With these latest approvals, most patients will soon be able to avail themselves of treatments that are substantially safer, easier to take and more effective than the current regimens. Gilead’s Sovaldi, the first nucleotide (‘nuc’) polymerase inhibitor approved for treating HCV infection, has aroused high clinical and commercial expectations, on the strength of its favorable safety and efficacy profiles across HCV genotypes (GT) 1, 2, 3 and 4 (Table 1). What’s more, it will enable many patients to clear their infections without needing interferon. For more than two decades, interferon has been a cornerstone of HCV therapy. But it carries a heavy burden of side effects, and current regimens, based on one of two approved protease inhibitors Incivek (telaprevir) or Victrelis (boceprevir), plus ribavirin, all include pegylated interferon-α. The goal of eliminating interferon from HCV drug regimens emerged as a major theme in drug development since the first report of patients achieving a sustained virologic response (SVR) or cure on an interferon-free regimen (Nat. Biotechnol. 29, 963–966, 2011). As yet, however, the first all-oral, interferonfree regimen, comprising Sovaldi and ribavirin (another long-standing cornerstone of therapy), is approved only for people infected with HCV GT2 or 3. It will take at least another year before interferon-free regimens for patients with HCV GT1, the most prevalent and most difficult-to-treat variant of the virus, become routinely available, although the FDA has recommended Sovaldi and ribavirin as a potential option for GT1 patients who are ineligible for interferon therapy. At $84,000 for a 12-week course in the US, Sovaldi does not come cheap, and patient advocates are mobilizing in order to make the drug—or generic equivalents— available in low-to-middle income countries at an affordable price (Box 1).
Gilead
© 2014 Nature America, Inc. All rights reserved.
FDA approvals usher in the post-interferon era in HCV
Sovaldi has the potential to be bigger than Lipitor—some analysts believe.
An SVR 12 weeks after the completion of therapy (SVR12) is now generally accepted as a viral cure, and in clinical trials, some investigational interferon-free regimens have elicited SVR12 rates of 90% and over, often after just 12 weeks of therapy. In contrast, the previously approved regimens (Incivek or Victrelis, plus pegylated interferon-α and ribavirin) required up to 48 weeks of treatment and generally offered worse outcomes. Among patients on Incivek in combination with pegylated interferon-α and ribavirin (PR) cure rates (then defined as SVR24) of 74–79% were reported in phase 3 trials in different patient populations. Among those on Victrelis plus PR, cure rates of 63–66% were achieved. The two drugs, both of which were approved in May 2011 for treating HCV GT1 infections in combination with PR did offer a real improvement over PR therapy alone, which generally results in cure rates below 50%. Each has significant side effects, however, on top of those associated with PR therapy.
nature biotechnology volume 32 NUMBER 1 JANUARY 2014
“Telaprevir and boceprevir will probably become history. It’s difficult to see why anyone would want to use them because of their side effects, complicated treatment algorithms and drug-drug interactions,” says Anna Lok, professor of internal medicine in the University of Michigan Health System, in Ann Arbor, Michigan. US sales of Incivek and Victrelis, marketed, respectively, by Cambridge, Massachusetts–based Vertex Pharmaceuticals, and by Merck, of Whitehouse Station, New Jersey, have already plummeted as patients postpone treatment in anticipation of the new drug combinations. Most interferon-free combinations in development comprise two or three directacting antiviral (DAA) drugs plus ribavirin, a nucleoside analog that inhibits viral replication. The most mature DAA classes include nucleotide viral NS5B RNA polymerase inhibitors, non-nucleotide viral NS5B RNA polymerase inhibitors (which work by an allosteric mechanism), NS3/4a 3
NEWS
npg
© 2014 Nature America, Inc. All rights reserved.
Table 1 Selected trials of interferon-free HCV drug regimens Drug combinations
Developer
Description
Current status
Latest data
Sovaldi/ledipasvir, without ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, NS5A inhibitor, nucleoside analog viral RNA replication inhibitor
Ongoing phase 3 trial (Ion-3) in treatment-naive patients with HCV genotype 1 (GT1)
Study based on phase 2 (Lonestar) trial: 8 weeks therapy SVR8 98%; 12 weeks therapy (without ribavirin) SVR4 100%
Sovaldi/ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Completed phase 3 trial (Fission) in treatment-naive patients with GT2 or GT3 on 12 weeks of therapy
SVR12 67% in all patients treated (n = 256) vs. SVR12 67% in patients on interferon + ribavirin (n = 243); SVR12 90% in GT2 patients
Sovaldi + ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Completed phase 3 trial (Positron) SVR12 78% (n = 207) vs. 0% placebo (n = 71) in interferon-intolerant patients with GT2 or GT3
Sovaldi + ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Completed phase 3 trial (Fusion) in patients with GT2 or GT3 who had previously failed interferonbased therapies
Sovaldi + ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Interim data: SVR12 attained by 85% Phase 3 ongoing (Valence) in cirrhotic and non-cirrhotic patients of patients with GT3 on 24 weeks of therapy
Sovaldi + ribavirin
Gilead
Nucleotide NS5B RNA polymerase inhibitor, nucleoside analog viral RNA replication inhibitor
Phase 3 ongoing in patients coinfected with HIV
Interim data: SVR12 attained by 76% of GT1 patients, 88% of GT2 patients, 67% of GT3 patients
Daclatasvir + asunaprevir
Bristol-Myers Squibb NS5A replication complex inhibitor, NS3 protease inhibitor
Filed (Japan)
SVR24 84.7% in Japanese patients with GT1b (n = 222)
ABT-450/ra + ABT-267 + ABT-333
AbbVie, Enanta Pharmaceuticals (Watertown, Massachusetts)
Phase 3
Sapphire-1 96% of treatment-naive GT1 patients attained SVR12; Sapphire-2 96% of treatment-experienced GT1 patients attained SVR12
Faldaprevir + deleobuvir + ribavirin
Phase 3 in GT1b patients Boehringer Ingelheim NS3/4A protease inhibitor, nonnucleoside NS5B RNA polymerase inhibitor, nucleoside analogue viral RNA replication inhibitor
MK-5172 + MK-8742 +/ribavirin
Merck
Phase 2b ongoing in treatment NS3/4A protease inhibitor, NS5A replication complex inhibitor, nucleoside naive non-cirrhotic patients with GT1a or GT1b infection analog viral RNA replication inhibitor
Interim phase 2 data SVR12 attained by 100% in two dose arms (n = 22, n = 12) and by 96% in one dose arm (n = 24)
Olysio + Sovaldi
Johnson & Johnson, Medivir
Protease inhibitor, nucleotide NS5B RNA polymerase inhibitor,
SVR4 >90% across two cohorts, including treatment-naive patients & prior null responders to interferon + ribavirin
aABT-450/r,
Protease inhibitor + ritonavir, NS5A inhibitor, non-nucleoside polymerase inhibitor
Phase 2a
12 weeks therapy SVR12 50%; 16 weeks therapy SVR12 71%
Data due Q2 2014
ABT-450 formulated with ritonavir to support once-daily dosing.
Source: company websites.
protease inhibitors and NS5A viral replication complex inhibitors. Each has varying levels of genotypic coverage, but Sovaldi and other nucleotide polymerase inhibitors appear to be active against all genotypes (Ann. Rev. Pharmacol. Toxicol. 53, 427–492, 2013). They also appear to have very high barriers to resistance. “This is an example where maybe the field got a little lucky,” says Charles Rice, professor of virology at the Rockefeller University, in New York. “We can select for resistance in culture,” he says. “It appears to give rise to a virus that is very unfit in vivo.” The landscape for HCV therapies has shifted so rapidly since 2011 that some regimens that are still in clinical development will—in Western markets at least—no longer be competitive by the time they gain approval. A case in point is the recently approved Olysio. Discovered by Stockholmbased Medivir and inlicensed by the Janssen Therapeutics arm of New Brunswick, 4
New Jersey–based Johnson & Johnson, Olysio faces major challenges in making significant headway in the short term, as it still needs to be combined with PR. Interim data from an interferon-free combination of Olysio and Sovaldi have been impressive, but Gilead is not planning to pursue development of this combination regimen any further. In its approved indication, the Johnson & Johnson drug attained SVR12 rates of 80% and 79% in treatment-naive and relapsed HCV GT1 patients, respectively. Its advantages over the first two protease inhibitors Incivek and Victrelis include once-daily as opposed to three-times daily dosing and a better safety profile. Its potential has been hobbled, however, as Olysio does not appear to be active in patients infected with HCV GT1a strains that carry a polymorphism called Q80k, which is found in over 40% of US GT1a isolates (or about 25% of all GT1 strains) and in about 30% of European GT1a isolates. “Most of us recognize it’s going to be
a tough sell to tell patients to take simeprevir [Olysio],” Lok says. Johnson & Johnson may attempt that task in non-Western markets. “You have to realize the world is not just the US or Europe,” says Gaston Picchio, hepatitis disease area leader at Janssen. “It’s going to take time before these regimens reach every corner of the world, especially those regions which are most severely impacted by hepatitis C virus.” It will also take some time to understand what kind of cure rates the new generation of drug combinations will achieve in real-world settings, as opposed to the artificial environment of clinical trials. “In general we should always assume in clinical practice that the results are not going to be replicated,” Lok says. Economics will be an issue as well. “I think cost is going to drive a lot of these decisions,” says Jerry Stern, vice president and head of virology at Ingelheim, Germany– based Boehringer Ingelheim. “Cost for some
volume 32 NUMBER 1 JANUARY 2014 nature biotechnology
news
npg
© 2014 Nature America, Inc. All rights reserved.
Initiative for Medicines, Access & Knowledge (I-Mak), a New York–based advocacy group, has fired the opening salvo of what is likely to be a lengthy battle with Gilead and other companies over access to HCV drugs in low- and middle-income countries. I-Mak has filed a pre-grant opposition in India to one of Gilead’s key patents for Sovaldi, known in India as Application Number 3658/KOLNP/2009. Others are in the offing. “It’s not just going to be in India—it’s going to go wider than India,” I-Mak cofounder and director of intellectual property Tahir Amin says. “There’s probably going to be action on some of the other direct-acting antivirals as well.” (In the US, Merck and Cambridge, Massachusetts–based Idenix are also opposing Gilead’s Sovaldi patents.) Most of the world’s HCV-infected population, which is estimated at around 185 million people, lives outside of the wealthy regions of North America and Europe, as do most of the estimated 350,000 people who die every year from liver diseases associated with HCV infection. India has 10–12 million HCV patients. Egypt has the world’s highest prevalence rate, with an estimated 7 million cases in a population of 85 million, a legacy of poorly conducted anti-schistosomiasis campaigns over several decades. I-Mak, whose donors include the Open Society Foundation, founded by investor and philanthropist George Soros, is attempting to use India’s patent laws as a lever to force Western pharmaceutical firms to cut their prices to affordable levels. “India has laws that are more stringent in terms of what is regarded as new or novel,” Amin says. Its initial opposition concerns Sovaldi, which is administered as a prodrug but which, according to I-Mak, is based on claims that are covered or anticipated by an earlier application concerning the base uridine analog to which Sovaldi gives rise. “Technically they’re trying to double dip and get another four to five years patent life,” he says. Moreover, he claims the same compound was disclosed in a paper (J. Med. Chem. 50, 1840–1849, 2007) published electronically on March 17, immediately before the patent application filing in India, which was completed on March 30, 2007. I-Mak will also contest the previous patent, on the basis that the compound was already known. The initial patent application has already been refused by the Indian Patent Office, Amin says, despite Gilead’s objections. “Once we file our opposition and evidence, we believe it will only solidify the patent office’s refusal,” he says. Although still in its infancy, the dispute is strongly reminiscent of the ongoing struggle between HIV patient advocates and the pharmaceutical industry—except it is likely to get even bigger, given the scale of the global HCV pandemic, which dwarfs that of the HIV pandemic. CS
countries will be a large factor in deciding who gets treated.” An added complication for physicians and patients is the sheer profusion of combination therapies now in late-stage trials, which will shortly become available. Gilead, of Foster City, California, which acquired Sovaldi through its $11.2-billion cash acquisition of Princeton, New Jersey– based Pharmasset in 2012 (Nat. Biotechnol. 30, 122, 2012), may be leading the race right now, but others, including AbbVie, of North Chicago, Illinois, and Bristol-Myers Squibb, of New York, are not far behind. “There are others who have developed other regimens, which will be effective as well. It’s not a onehorse race,” says John McHutchison, Gilead’s senior vice president for liver disease therapeutics. As Nature Biotechnology went to press, AbbVie had reported data from two of six phase 3 trials, with more results imminent. “We’re looking to file in the second quarter of 2014,” says Barry Bernstein, AbbVie’s vice president for infectious diseases. Choosing the optimum regimen for an individual patient will not be a straightforward
task, given pharmaceutical companies’ opposition to head-to-head trials of different combinations. The Hepatitis C Therapeutic Registry and Research Network (HCVTarget), an initiative led by the University of Florida, in Gainesville, and the University of North Carolina at Chapel Hill, will collate real-world data from over 100 treatment centers across the US, Europe and Israel, which will offer physicians some insights into which patients do best on which regimens. Eliminating the virus completely remains, for now, a long-term aspiration rather than a tangible goal. “Remember three-quarters of patients with HCV infection don’t know they have it at this point in time,” says AbbVie’s Bernstein. Moreover, those who do clear their infections successfully still carry a risk of liver disease. “It ain’t over completely, even if you completely eliminate the virus,” says Rice. Despite the advent of vastly improved new therapies, the public health burden associated with HCV infection will be with us for a long time to come. Cormac Sheridan Dublin
nature biotechnology volume 32 NUMBER 1 JANUARY 2014
in brief Sequenom falls after judge invalidates Down’s patent A US federal judge in October invalidated patent claims for a noninvasive prenatal test marketed by San Diego–based Sequenom. The decision is part of an anti-patent trend in the courts that has left everyone in the biotech community unclear on which diagnostic method claims are patent-eligible. Sequenom’s patent covers methods to detect cell-free fetal DNA (cffDNA) in a pregnant woman’s bloodstream. The technology gives women a noninvasive way to test their unborn children for chromosomal defects such as Down syndrome. Older methods are less accurate or carry a slight risk of miscarriage because they involve sampling tissue or fluid from the womb (Nat. Biotechnol. 31, 595–601, 2013). Sequenom was first to the market with the test, in 2011, and has been trying to lock out its numerous competitors by claiming they infringe on the test’s central patent. In the ruling, Judge Susan Illston of the US District Court in Northern California said Sequenom’s patent was invalid because cffDNA is a natural phenomenon, and because the company’s methods for detecting it involve routine DNA amplification and detection techniques. Illston also said the patent posed a risk of preempting other uses of cffDNA because there is no commercially viable alternative for detecting it. The judge cited several US Supreme Court decisions, including a June 2013 decision involving Myriad Genetics in which the court ruled that naturally occurring DNA segments are a product of nature that cannot be patented (Nat. Biotechnol. 31, 663–665, 2013). She also cited a 2012 decision involving Prometheus Laboratories, in which the court ruled against another diagnostics patent, this one a method for determining the optimal dosage of a drug (Nat. Biotechnol. 30, 373–374, 2012). The Sequenom ruling is “not good news” for the biotech community, says attorney David Resnick at Nixon Peabody in Boston. “But it’s not a surprise either,” he says. Resnick’s advice to diagnostics makers: “Don’t panic. It’s a district court decision that is being appealed and hopefully the Federal Circuit will provide more clarity.” But taken together, the Myriad, Prometheus and Sequenom cases present a confusing and decidedly anti-patent landscape that may lead to trade secrecy in lieu of patenting, say attorneys. “If a client comes in and asks about patenting a test for detecting abnormalities during pregnancy, I may tell them not to patent,” says attorney Kevin Noonan at McDonnell Boehnen Hulbert & Berghoff in Chicago. Emily Waltz Scott Camazine / Alamy
Box 1 Patient advocates oppose Gilead patents
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