Showing posts with label ledipasvir (GS-5885). Show all posts
Showing posts with label ledipasvir (GS-5885). Show all posts

Wednesday, December 18, 2013

Gilead's Sofosbuvir and Ledipasvir Outstanding Late-stage Hepatitis C Data

Of interest
Feb 10 2014
Gilead Files for U.S. Approval:Ledipasvir/Sofosbuvir Fixed-Dose Combo For Genotype 1 Hepatitis C

Dec 19
Gilead's $1,000 Pill Could Eradicate Hepatitis C, But Ethical And Financial Challenges Loom

Matthew Herper
Forbes Staff
Gilead Sciences' GILD -0.37% two-drug combo pill against hepatitis C is so effective, Wall Street analysts say, that it’s possible that public health officials could begin thinking about eradicating the liver-damaging virus, which may afflict 3.2 million Americans and is spread mostly through sharing needles and needle stick injuries, according to the Centers for Disease Control & Prevention. In some of them, like the musician Lou Reed, it leads to liver failure and death. Gilead’s pill could become one of the best-selling medicines in history.....

Stellar hepatitis C data puts Gilead farther ahead of pack

By Ransdell Pierson and Bill Berkrot

Wed Dec 18, 2013 1:34pm EST

(Reuters) - Gilead Sciences Inc released impressive late-stage data for its once-daily combination pill to treat hepatitis C, advancing its lead in the race to develop new, all-oral treatments for the liver disease, and pushed up its timeline for seeking U.S. approval.

Gilead on Wednesday unveiled initial results from three Phase III studies that demonstrated cure rates well in excess of 90 percent with as little as 8 weeks of treatment for some patients.

The findings were achieved without the use of either injectable interferon, which causes miserable flu-like symptoms, or ribavirin, an antiviral pill that carries its own troublesome side effects.

The tough-to-tolerate older drugs have led thousands of patients to delay treatment for the potentially fatal disease and await new options.

"The results certainly raise the bar and dim the outlook for competitors such as AbbVie, Bristol and Boehringer Ingelheim," Sanford Bernstein analyst Geoffrey Porges has said of rival all-oral programs in development that require more drugs and more pills than Gilead's to achieve similarly high cure rates.

Porges, saying the new data could spell the end of ribavirin use and greatly expand the number of people seeking treatment, raised his peak sales forecast for Gilead's combination to an eye-popping $16 billion in 2016, declining to $6.8 billion by 2020 as the backlog of patients awaiting treatment declines.

Gilead said it would file in the first quarter of 2014 for U.S. approval of the combination treatment that pairs its just-approved Sovaldi (sofosbuvir) and its experimental ledipasvir. The company previously said it would seek marketing approval in the first half of next year.

The Phase III trials tested the combination pill in subjects with the most common, but hardest to treat, genotype 1 strain of the liver virus in both previously untreated patients and those who had failed to be helped by prior treatment. They also included difficult to treat patients with cirrhosis, who tend to be farther along in the liver-destroying disease.

Gilead shares rose more than 2 percent on the favorable new data and the likelihood of a speedier approval from the U.S. Food and Drug Administration.

"We see (trial) results and a more-convenient regimen bolstering Gilead's market prospects over rivals, and expect FDA approval for this regimen before the end of 2014," S&P Capital IQ said in a research report.


Sovaldi, which costs about $84,000 for a course of treatment, belongs to a class of drugs known as nucleotide analog polymerase inhibitors, or "nukes," designed to block an enzyme the hepatitis C virus needs to copy itself. Ledipasvir belongs to a promising new class of drugs that work by blocking the NS5A protein, which the virus also needs to replicate.

Current standard regimens include both interferon and ribavirin and must be taken for 24 to 48 weeks, curing about 75 percent of patients.

Gilead tested its combo pill at a variety of treatment durations both with and without ribavirin. But the high cure rates without ribavirin, which can cause rash, anemia and other side effects, are likely to grab most of the attention of physicians and investors.

In a study of 647 previously untreated patients without cirrhosis called ION-3, 94 percent achieved sustained virologic response (SVR), which is considered cured, after just 8 weeks of treatment, rising to 95.4 percent with a 12-week regimen.

In ION 2 - a trial of 440 more difficult to treat patients who were not cured by prior treatment, including 88 cirrhotics - 93.6 percent were cured by the once daily pill after 12 weeks, while the cure rate rose to 99.1 percent with 24 weeks of treatment.

In ION-1, which looked at 865 previously untreated patients, including 136 with cirrhosis, the Gilead pill cured 97.7 percent with 12 weeks of therapy.

"In general, the data position Gilead to dominate the genotype 1 landscape," ISI Group analyst Mark Schoenebaum said in a research note. He noted that Gilead's ribavirin-free regimen involved one pill once a day, while AbbVie's is six pills a day with ribavirin and four pills without, and includes a medicine that may interact with other drugs.

Genotype 1 accounts for about 70 percent of U.S. infections. Hepatitis C affects an estimated 170 million people worldwide, and if left untreated can lead to cirrhosis, liver cancer, or the need for a new liver.

Bernstein's Porges has said given the convenience and cure rates of the new drugs, the hepatitis C conversation is likely to change from disease management to eradication.

"This is going to be very tempting for people to say, 'We can lick this'," Porges said. But he noted that demand for the drug will eventually decline as patients are cured.

"The long-term economics of curing patients is not good for the drug industry, but it's totally great for society."

(Additional reporting by Caroline Humer; Editing by Gerald E. McCormick, Theodore d'Afflisio and Cynthia Osterman)

Press Release

Gilead Announces SVR12 Rates From Three Phase 3 Studies Evaluating a Once-Daily Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients

-- High Cure Rates Observed with Single Tablet Regimen May Eliminate Interferon and Ribavirin from HCV Therapy for Genotype 1 Patients -- 

 -- U.S. NDA Submission Planned for Q1 2014--
FOSTER CITY, Calif.--(BUSINESS WIRE)--Dec. 18, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced topline results from three Phase 3 clinical trials (ION-1, ION-2 and ION-3) evaluating the investigational once-daily fixed-dose combination of the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg and the NS5A inhibitor ledipasvir (LDV) 90 mg, with and without ribavirin (RBV), for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection.
Across the three studies, 1,952 patients with genotype 1 HCV infection were randomized to receive SOF/LDV with or without RBV for eight, 12 or 24 weeks of therapy. Of these, 1,512 patients were treatment-naïve, 440 were treatment experienced and 224 had compensated cirrhosis.
The intent-to-treat SVR12 rates observed to date in the ION studies are summarized in the table below. Results of the 24-week arms from ION-1 will be available in the first quarter of 2014 and will be presented at a future scientific meeting. 

Of the 1,518 patients randomized to the 12-week arms of ION-1 and to all arms of ION-2 and ION-3, 1,456 patients (95.9 percent) achieved the primary efficacy endpoint of SVR12. Of the 62 patients (4.1 percent) who failed to achieve SVR12, 36 patients (2.4 percent) experienced virologic failure: 35 due to relapse and only one patient due to on-treatment breakthrough (with documented non-compliance). Twenty-six patients (1.7 percent) were lost to follow-up or withdrew consent.  

Fewer adverse events were observed in the RBV-free, fixed-dose combination arms compared to the RBV-containing arms in all ION studies. Adverse events observed in those taking the SOF/LDV tablet were generally mild and included fatigue and headache. In the RBV-containing arms of the ION studies, the most common adverse events were fatigue, headache, nausea and insomnia. Anemia, which is a common side effect associated with RBV, was reported in 0.5 percent of patients in the SOF/LDV arms versus 9.2 percent of patients in the RBV-containing arms. Less than 1 percent of patients in the studies discontinued treatment due to treatment-emergent adverse events.

“The results of the ION studies demonstrate that a simple, safe and short course of therapy with a single tablet regimen of sofosbuvir/ledipasvir can provide high cure rates among patients with genotype 1 HCV infection, while eliminating the need for both interferon and ribavirin,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer. “With the availability of these results, Gilead is finalizing its regulatory filing for sofosbuvir/ledipasvir, with the goal of submitting a New Drug Application in the first quarter of 2014.”    

The FDA has assigned the SOF/LDV fixed-dose combination a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options. Sofosbuvir was approved as Sovaldi™ in the United States on December 6 and in Canada on December 13. Applications are pending in the European Union, Australia and New Zealand, Switzerland and Turkey.    

About the ION Studies

The Phase 3 ION studies are randomized, open-label Phase 3 clinical trials evaluating the efficacy and safety of a once-daily fixed-dose combination of SOF/LDV for 8, 12 or 24 weeks, with and without RBV, among 1,952 genotype 1 HCV patients. The studies included patients who were treatment-naïve or who had failed previous treatment, including protease inhibitor-based regimens. The primary endpoint for each study was SVR12. Complete results from all three studies will be presented at a future scientific conference.    

In ION-1, 865 treatment-naïve genotype 1 HCV patients, including those with cirrhosis, received SOF/LDV with or without RBV for 12 or 24 weeks. In March 2013, a planned review by the study’s Data and Safety Monitoring Board (DSMB) of interim safety and efficacy data from an initial enrollment of patients concluded that the trial should continue without modification. Enrollment of the remaining patients was completed in May 2013. Prior to the DSMB meeting, the statistical analysis plan was amended to allow for the analysis of the primary efficacy endpoint for the two 12-week arms, independent of the 24-week arms. Per the amendment, if SVR12 rates in the 12-week arms were >90 percent (including among those with cirrhosis), early regulatory filings could be pursued, given that longer treatment durations would not be able to show statistically significantly higher SVR12 rates.    

The ION-2 study evaluated 440 treatment-experienced genotype 1 HCV patients who had failed past therapy with regimens containing Peg-IFN (including Peg-IFN plus a protease inhibitor). Patients received SOF/LDV with or without RBV for 12 or 24 weeks.

In ION-3, 647 non-cirrhotic treatment-naïve genotype 1 HCV patients received SOF/LDV with or without RBV for 8 weeks or without RBV for 12 weeks.

The SOF/LDV fixed-dose combination is an investigational product and its safety and efficacy has not yet been established.    

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.    

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that Gilead may be unable to file for U.S. regulatory approval of the SOF/LDV fixed-dose combination in the currently anticipated timelines. In addition, the FDA and other regulatory agencies may not approve the SOF/LDV fixed-dose combination, and any marketing approvals, if granted, may have significant limitations on its use. Additional clinical studies of sofosbuvir and the SOF/LDV fixed-dose combination, including results from the 24-week arms of ION-1, may not produce favorable results. As a result, Gilead may not be able to successfully commercialize the SOF/LDV fixed-dose combination, and may make a strategic decision to discontinue its development if, for example, the market for the product fails to materialize as expected. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Sovaldi is available at

Sovaldi is a trademark of Gilead Sciences, Inc., or its related companies.

For more information on Gilead Sciences, please visit the company’s website at, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

- See more at:

Tuesday, July 9, 2013

2013 Pipeline Report - 28 HCV interferon-free regimens in development

Treatment Action Group 2013 Pipeline Report

At the 7th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention held in Kuala Lumpur, Malaysia the HIV i-Base/Treatment Action Group (Tag) released their comprehensive 2013 Pipeline Report. In the report both organizations advocate a global effort for national leaders and regulatory authorities to work together and expedite research needed to bring safe HIV, HCV and tuberculosis drugs to market.

For the HCV community, there is a particular article written by Tracy Swan from (Tag) which offers an update on the new HCV drugs currently in phases II/III trials.

The author writes:
"An impressive 26  new HCV drugs are being studied in phases II/III in at least 28 interferon-free regimens, which are bringing the potential of  faster, all-oral HCV cures rapidly toward approval for the world’s 185 million people living with HCV"

2013 Pipeline Report - Hepatitis C Drug Development Catapults Onward 

Excerpt from the press release;
In the 2013 “HCV Treatment Pipeline,” Tracy Swan (TAG) notes that the “confluence of a robust HCV drug pipeline, shortened regimens, and [shorter] posttreatment follow-up are extraordinary. The new FDA breakthrough therapy designation may speed things up as well. By the end of 2014, [new HCV drugs] from four different classes and fixed-dose combinations (FDCs) are likely to be approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), offering the potential for off-label mixing and matching.” An impressive 26 new HCV drugs are being studied in phases II/III in at least 28 interferon-free regimens, which are bringing the potential of faster, all-oral HCV cures rapidly toward approval for the world’s 185 million people living with HCV.
Swan notes, however, that not all optimal combinations are being studied, with some sponsors preferring combinations of their own proprietary compounds, while many sponsors take too long to study their new drugs in people coinfected with HIV and HCV, and those with cirrhosis.
In her companion chapter, “Low- and Middle-Income Countries Defuse Hepatitis C, the ‘Viral Time Bomb,’” Karyn Kaplan (TAG) describes how a worldwide movement is forming to ensure that when new all-oral HCV cures are approved, that governments, health systems, and providers will be ready for them. Kaplan points to recent progress instigated by HCV activists in countries such as Egypt, Georgia, Thailand, and Ukraine.
The press release is available here

2013 "HCV Treatment Pipeline" - By Tracy Swan

Hepatitis C Drug Development Catapults Onward 
By Tracy Swan

HCV Treatments in Phase II and Phase III
The Best Combinations
Interferon-Free Regimens in Development for HCV Genotype 1
Interferon-Free Regimens in Development - HCV Genotypes 2, 3, & 4
Cross-company Trials
Next in Line: Simeprevir, Faldaprevir, and Sofosbuvir
Without a PEG to Stand on: The Sofosbuvir Saga Goes on
Biting the (Magic) Bullet
Twinkle, Twinkle, Little (Lone) Star
AbbVie: All Hands on Deck
Bristol-Myers Squibb: All In!
(Genotype) 3 is the new 1
SVR in HCV Genotypes 2 and 3
Cirrhosis: From Frontier to Proving Ground
HIV/HCV Coinfection
Faldaprevir plus PEG-IFN/RBV
Simeprevir plus PEG-IFN and RBV
From Excess to Access
Where Should All the Research Go?

Access the report here.........

Next Chapter:
Low-  and Middle-Income Countries Defuse Hepatitis C, the “Viral Time Bomb” 

2013 SVR Rates

Monday, April 29, 2013

EASL 2013: 'Quad' HCV Tx Works but No More Trials Planned

'Quad' HCV Tx Works but No More Trials Planned

By Michael Smith, North American Correspondent, MedPage Today
Published: April 29, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM – A four-drug regimen was effective in hard-to-treat hepatitis C (HCV) patients who had previously failed therapy, a researcher said here, but the drug combination is not being further developed.

Action Points
  • This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • The combination of an NS5A inhibitor, a protease inhibitor, and pegylated interferon plus ribavirin appeared to be effective in treatment experienced, genotype 1 HCV-infected patients.

    In a phase II study, 70% of patients had undetectable HCV virus 12 weeks after ending the so-called "quad regimen," according to Gregory Everson, MD, of the University of Colorado in Aurora.

    The drug protocol consisted of an NS5A inhibitor dubbed ledipasvir and a protease inhibitor, GS-9451, along with pegylated interferon and ribavirin.

    Among those who responded to the four-drug regimen quickly and persistently, the rate was even higher at 87%, Everson reported at the meeting of the European Association for the Study of the Liver.

    But despite the promise of what he called a "re-treatment protocol," Everson said further development of the regimen is not in the cards.

    He did not immediately respond to an email from MedPage Today seeking clarification, but other experts here suggest it may have to do with the perception that pegylated interferon and ribavirin are on the way out.

    Meanwhile, ledipasvir and GS-9451 remain in clinical development, according to a spokesman for the developer, Gilead Sciences of Forest City, Calif.

    The results of the trial "are not entirely unexpected," commented Heiner Wedemeyer, MD, of Hannover Medical School in Hannover, Germany, who was not involved with the study.

    "This specific regimen is not being further developed," he said, but what investigators "learned is that if we add more potent drugs, we can treat more difficult patients. We confirmed that concept."

    It seems likely, he said, that the two drugs will continue to be developed for use without interferon and perhaps ribavirin. "The question will be whether we can shorten treatment," Wedemeyer said.

    Until 2011, standard therapy for HCV genotype 1 was 48 weeks of pegylated interferon with ribavirin, a regimen regarded as difficult to tolerate with a substantial proportion of treatment failures.

    Current standard therapy adds a third drug, one of the protease inhibitors telaprevir (Incivek) or boceprevir (Victrelis), but those medications have their own side effects and risks.

    Patients who fail standard treatment – either relapsing or not responding in the first place – need better options, Everson said here.

    He and colleagues tested the four drugs (ledipasvir, GS-9451, pegylated interferon, and ribavirin) in a response-guided fashion, enrolling 163 patients, including 52 who had not responded to previous therapy, 28 who had a partial response, and 83 who either relapsed or had viral breakthrough on treatment.

    Patients who had undetectable viral RNA at weeks four through 20 of treatment stopped therapy after 24 weeks, while the others stopped ledipasvir and GS-9451 but continued the other two drugs for another 24 weeks.

    The 70% rate of undetectable virus 12 weeks after the end of therapy (SVR12) indicated a "fairly robust antiviral effect," Everson said, and response during therapy was "highly predictive " of treatment success.

    Among those who had a so-called extended rapid virologic response – no detectable virus from weeks four through 20 – the SVR12 rate was 87%, compared with just 28% among those who did not have such a response.

    Everson said that patients with genotype 1b did better than those with genotype 1a, while those with the favorable CC variant of the IL-28B gene did better than those with other versions.

    He added that 5% of patients had a serious adverse event during the study and 7.3% stopped treatment because of adverse events, all attributed to the interferon or ribavirin.

    The overall pattern of adverse events, he said, was "typical" of what is seen with the two older drugs.

    The study was supported by Gilead. Everson reported financial links with the company as well as BMS, Abbott, Roche/Genentech, Vertex, Merck/Schering-Plough Novartis, Janssen/Tibotec, GSK, Eisai, and BioTest.

    Wedemeyer reported financial links with Abbott, Achillion, Biolex, BMS, Gilead, Janssen-Cilag, Merck, Novartis, Roche, Siemens, Transgene, and ViiV.

    Primary source: European Accociation For the Study of the Liver
    Source reference:
    Everson GT, et al "Combination of the NS5A inhibitor, GS-5885, the NS3 protease inhibitor, GS-9451, and pegylated interferon plus ribavirin in treatment experienced patients with genotype 1 hepatitis C infection" EASL 2013; Abstract 13.

  • EASL Conference Coverage @ MedPage Today

    Drug Trio Helps Treat HCV After Transplant
    AMSTERDAM -- Three-drug therapy appears to help liver transplant patients whose hepatitis C (HCV) recurs, a researcher said here. 
    AMSTERDAM -- High levels of hemoglobin may be dangerous in patients with non-alcoholic fatty liver disease (NAFLD), with bleeding a potential remedy, researchers said here. 

    Saturday, April 27, 2013

    EASL 2013 Highlights - CCO's independent conference coverage

    Program Overview
    2013 Annual Meeting of the European Association for the Study of the Liver*
    April 24-28, 2013 | Amsterdam, The Netherlands
    CCO's independent conference coverage of the 2013 Annual Meeting of the European Association for the Study of the Liver includes 2 CME-certified slidesets with faculty analysis and downloadable slidesets that focuses on key issues highlighted at the conference.
    **Free registration required
    Latest Content
    Daclatasvir Plus Asunaprevir Plus BMS-791325 Achieves ≥ 88% SVR Rates in Noncirrhotic Treatment-Naive Patients With Genotype 1 HCV
    The all-oral regimen combining an NS5a inhibitor, a protease inhibitor, and a nonnucleoside polymerase inhibitor was well tolerated at both doses of BMS-791325 studied.
    Date Posted: 5/3/2013

    HBV DNA Seroclearance Significantly Reduces Risk of HCC in Patients With High Baseline Viral Loads
    Seroclearance of HBeAg, HBsAg did not significantly decrease HCC risk in adjusted analysis.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 5/2/2013

    CONCISE: Interim Results Show High SVR Rates With Either 12 or 24 Weeks of Telaprevir Plus Peginterferon/Ribavirin in Patients With HCV Genotype 1 and IL28B CC Genotype
    Among patients who completed 12 weeks of triple therapy, 100% SVR12 rate among patients who continued to receive peginterferon/ribavirin through 24 weeks vs 89% SVR4 rate among patients who stopped all therapy at 12 weeks.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 5/2/2013

    QUEST-1: Simeprevir Plus PegIFN/RBV Significantly Improves SVR12 Rate vs PegIFN/RBV Alone in Treatment-Naive Patients With Genotype 1 HCV
    Triple therapy was well tolerated and 85% of patients were able to shorten treatment to 24 weeks, of whom 91% achieved SVR12.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 5/1/2013

    COMMAND: Daclatasvir Plus PegIFN/RBV Improves SVR24 Rate vs PegIFN/RBV Alone in Treatment-Naive Patients With Genotype 2/3 HCV
    The triple-drug regimen allowed 83% of patients to receive shorter treatment durations of only 12 or 16 weeks, and safety and tolerability was comparable to pegIFN/RBV alone.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    QUEST-2: Simeprevir Plus PegIFN/RBV Superior to PegIFN/RBV for SVR12 in Treatment-Naive Patients With Genotype 1 HCV
    Triple therapy was well tolerated and enabled most patients (91%) to shorten the duration of therapy to 24 weeks while maintaining a high SVR12 rate of 86% in this subgroup.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    POSITRON: Sofosbuvir/Ribavirin Superior to Placebo With 78% SVR12 Rate in Genotype 2/3 HCV–Infected Patients Intolerant of, Ineligible for, or Unwilling to Receive IFN
    Sofosbuvir plus ribavirin is a safe, effective, IFN-free alternative for patients chronically infected with genotype 2/3 HCV who have no other treatment options available.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    Observed HCC Incidence Lower Than Predicted in Patients With Chronic Hepatitis B Receiving Tenofovir in Phase III Clinical Trials
    The effect of tenofovir was more noticeable in noncirrhotic patients, emerging at 2 years of treatment and reaching statistical significance by 6 years of treatment.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    Prolonged Tenofovir-Based Antiviral Therapy Maintains HBV DNA Suppression in Patients With Chronic HBV, Normal ALT Levels, and High HBV DNA Levels
    HBV DNA suppression was increased with tenofovir plus emtricitabine vs tenofovir alone, but safety profiles of both regimens were favorable through 192 weeks of study.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/30/2013

    Ledipasvir, GS-9451, and Peginterferon/Ribavirin Achieves 70% SVR12 With Good Tolerability in Treatment-Experienced Patients With Genotype 1 HCV Infection
    In this single-arm study, 71% of patients were eligible to received truncated 24-week therapy; safety profile was consistent with that of peginterferon/ribavirin alone.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/28/2013

    FISSION: Sofosbuvir/Ribavirin Noninferior to Peginterferon/Ribavirin for SVR12 in Treatment-Naive Patients With HCV Genotype 2/3
    Efficacy was similar between the 2 treatment arms, but sofosbuvir/ribavirin demonstrated superior safety and tolerability with shorter therapy compared with peginterferon/ribavirin.
    Date Posted: 4/28/2013
    NEUTRINO: Sofosbuvir Plus Peginterferon/Ribavirin Achieves High SVR12 Rate, Well Tolerated in Treatment-Naive Patients With Genotype 1, 4, 5, or 6 HCV
    The triple-therapy regimen yielded 90% SVR12 in the overall population, and all patient subgroups attained at least 80% SVR12 rate, including patients with cirrhosis and those with IL28B non-CC genotype.
    Date Posted: 4/28/2013

    FUSION: Sofosbuvir/Ribavirin Superior to Historical Controls for SVR12 in Treatment-Experienced Patients With Genotype 2/3 HCV
    Significantly better rates of SVR12 with both 12 and 16 weeks of therapy compared with historical controls, with better outcomes with 16 weeks of therapy among patients with genotype 3 HCV
    Date Posted: 4/28/2013
    STARTVerso1: Faldaprevir Plus Peginterferon/Ribavirin Highly Effective, Well Tolerated in Treatment-Naive Patients Infected With Genotype 1 HCV
    Most patients receiving faldaprevir (88%) were able to shorten therapy to 24 weeks total, without compromising sustained virologic response, which was 88% in this subgroup.
    Date Posted: 4/28/2013 

    Daclatasvir Plus Sofosbuvir ± Ribavirin Achieves 95% to 100% SVR12 Rate in Patients With Previous Virologic Failure on Telaprevir or Boceprevir            
    Virologic response rates to all-oral, once-daily 24-week regimen unaffected by baseline NS3 variants conferring protease inhibitor resistance
    Date Posted: 4/28/2013

    QUANTUM: Interferon-Free Sofosbuvir/Ribavirin Regimen Achieves 52% to 72% SVR12 Rate in Treatment-Naive Patients With Chronic HCV Infection
    QUANTUM also identified marked elevations in ALT and/or AST associated with the guanidine nucleotide analog GS-0938, which resulted in GS-0938—containing arms being halted.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/28/2013
    Ledipasvir, GS-9451, and Peginterferon/Ribavirin Achieves 70% SVR12 With Good Tolerability in Treatment-Experienced Patients With Genotype 1 HCV Infection
    In this single-arm study, 71% of patients were eligible to received truncated 24-week therapy; safety profile was consistent with that of peginterferon/ribavirin alone.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/28/2013

    AVIATOR: ABT-450/Ritonavir, ABT-267 and/or ABT-333, and RBV Achieves SVR24 Rates ≥ 90% in Treatment-Naive Patients and Previous Null Responders With Genotype 1 HCV
    The 4-drug peginterferon-free regimens also yielded SVR rates ≥ 89% in treatment-naive patients and previous null responders regardless of sex, HCV subtype, baseline HCV RNA, IL28B genotype, and fibrosis severity.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/26/2013

    High Rate of Advanced Fibrosis in Patients With HBV/HIV Coinfection, Despite HBV Suppression With Antiretroviral Therapy
    Patients with HBV/HIV coinfection treated with HBV-suppressing antiretrovirals continue to demonstrate high rates of advanced fibrosis.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver
    Date Posted: 4/26/2013

    ELECTRON: Addition of Second DAA to Sofosbuvir and Ribavirin Yields Rapid, Sustained Antiviral Suppression in Both Treatment-Naive Patients and Previous Null Responders With Genotype 1 HCV
    Combining ledipasvir with sofosbuvir/ribavirin yielded SVR12 rates of 100% in both treatment-naive patients and previous null responders, lending further support to ongoing development of the sofosbuvir/ledipasvir fixed-dose combination tablet.
    Source: 2013 Annual Meeting of the European Association for the Study of the Liver

    Thursday, April 11, 2013

    Review: NS5A Inhibitors in the Treatment of Hepatitis

    Accepted Manuscript

    Review NS5A Inhibitors in the Treatment of Hepatitis

    C Jean-Michel Pawlotsky PII: S0168-8278(13)00209-2 DOI: Reference: JHEPAT 4652 To appear in: Journal of Hepatology
    Received Date: 28 February 2013 Revised Date: 22 March 2013
    Accepted Date: 27 March 2013
    Please cite this article as: Pawlotsky, J-M.of Hepatitis C, Journal of Hepatology (2013), doi:, NS5A Inhibitors in the Treatment

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    Hepatitis C virus infection is a major health problem worldwide and no vaccine has yet been developed against this virus. In addition, currently approved pharmacotherapies achieve suboptimal cure rates and have side effects that result in noncompliance and premature treatment discontinuation. Significant research has been devoted to developing direct‐acting antiviral agents that inhibit key viral functions. In particular, several novel drug candidates that inhibit the viral nonstructural protein 5A (NS5A) have been demonstrated to possess high potency, pan‐genotypic activity, and a high barrier to resistance. Clinical trials using combination therapies containing NS5A inhibitors have reported results that promise high cure rates and raise the possibility of developing interferon‐free, all‐oral regimens.

    Recent estimates indicate that there are more than 120‐130 million chronic hepatitis C virus (HCV) carriers worldwide [1], who are at risk of developing cirrhosis and/or hepatocellular carcinoma (primary liver cancer). As many as 4 million persons are thought to be chronically infected in the US [2], 5‐10 million in Europe [2], 12 million in India [2], and 1.2 million in Japan (2004 figure) [3]. Most of these individuals are not aware of their infection. The incidence of acute infection in the US has declined from 7.4/100,000 in 1982 to 0.7/100,000 in recent years, primarily due to screening of blood in transfusion centres and improved safety of intravenous drug use [4]. It is estimated that approximately 150,000 new cases occur annually in the United States and in Western Europe, and about 350,000 in Japan. Only 25% of acute cases are symptomatic, but up to 80% of these acute cases progress to chronic infection and liver disease, and up to 20% of chronic infections progress to cirrhosis [2]. Every year, 4%‐5% of cirrhotic patients develop hepatocellular carcinoma [5]. Despite the decrease in HCV incidence, the number of patients with chronic HCV‐related complications is increasing in those aging patients who have been infected for many years, and chronic hepatitis C infection will continue to be a significant cause of premature mortality, causing at least 200,000‐300,000 deaths per year worldwide [4]. A number of direct‐acting antiviral agents (DAAs) are under development for the treatment of chronic HCV infection. These agents block viral production by directly inhibiting one of several steps of the HCV lifecycle. As shown in Figure 1, the genomic organization of HCV has been elucidated, and several viral proteins involved in the HCV lifecycle, such as the non‐structural (NS) 3/4A serine protease, the NS5B RNA‐dependent RNA polymerase (RdRp), and the NS5A protein,have been targeted for drug development [4]. Two NS3/4A protease inhibitors, telaprevir and boceprevir, which inhibit post‐translational processing of the HCV polyprotein into individual nonstructural proteins, have been approved by the US Food and Drug Administration, the European Medicines Agency, and several other regulatory agencies for the treatment of chronic HCV genotype 1 infection in combination with pegylated interferon (IFN)‐α and ribavirin [6, 7].

    HCV Structure and Lifecycle, and Physiological Role of the NS5A Protein 
    HCV is an enveloped virus with a single‐stranded positive RNA genome of approximately 9.6 kb. At the flanking ends of the genome are 2 highly conserved untranslated regions (UTRs). The 5’ UTR is highly structured and contains the internal ribosome entry site (IRES), which is important for the initiation of the cap‐independent translation of the polyprotein [8]. The 3’ UTR consists of a short genotype‐specific variable region, a tract consisting solely of pyrimidine residues (predominantly uridine) and a conserved 98‐nucleotide sequence, known as X region, containing 3 stem‐loops [9, 10]. The HCV open reading frame is situated between the two UTRs. After entering the bloodstream, HCV binds to a receptor complex at the surface of its target cells, hepatocytes. The envelope glycoproteins E1 and E2 are essential for target cell recognition, binding, and internalization [11]. The bound virus then undergoes clathrin‐mediated endocytosis [12]. Acidification of the endocytosis vesicle frees the genomic RNA from the nucleocapsid for release into the cytoplasm. Along with host RNA molecules, the viral RNA migrates to the endoplasmic reticulum (ER). Binding of the 40S ribosomal subunit to the HCV IRES produces a stable pre‐initiation complex that begins translation of the viral open reading frame to generate an approximately 3000 amino acid polyprotein. Following translation, the polyprotein is cleaved by both cellular and viral proteases to produce at least 10 viral proteins, including structural proteins (core, E1 and E2) and nonstructural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) [13, 14]. Viral replication (ie, the synthesis of new positive RNA genomes that may also serve as messenger RNAs for viral protein synthesis) is catalyzed by the viral RdRp, or NS5B protein. A negative‐strand intermediate of replication is initially produced, which then serves as a template for the synthesis of numerous positive strands. The NS5A viral protein has been shown to play an important role in the regulation of replication. In addition, host cell proteins, such as cyclophilin A, act as necessary cofactors of HCV replication through their interactions with both NS5A and the RdRp in the replication complex [15, 16].

    The nonstructural NS5A protein bears pleiotropic functions, including roles in viral replication and assembly, and complex interactions with cellular functions. The latter include inhibition of apoptosis and promotion of tumorigenesis, both of which may play a role in the triggering of the hepatocarcinogenic process [17‐20]. The protein is comprised of approximately 447 amino acids and localizes to ER‐derived membranes. It basally exists in phosphorylated (p56) and hyperphosphorylated (p58) forms that are implicated in different functions [21‐23]. Its cytoplasmic moiety contains 3 domains, of which Domain I is the most conserved [24]. The mechanism by which NS5A regulates replication regardless of the HCV genotype is still unclear [25]. Considerable information has been gathered on its molecular interactions and role in the viral lifecycle. NS5A and the RdRp directly interact, both in vivo and in vitro [26]. In vitro, this interaction stimulates RdRp‐catalyzed synthesis of the negative RNA strand [27]. It was shown that all 3 domains of NS5A bind to RNA [9]. The interactions of Domain I with the polypyrimidine tract of 3’ UTR suggest it may affect the efficiency of RNA replication by the RdRp; however, their results also suggested the binding of RdRp and NS5A to RNA are mutually exclusive. In addition, Domain II of NS5A interacts with cyclophilin A, a host cell protein required for replication, and this interaction is vital for RNA binding [28]. NS5A also plays a role in viral packaging and assembly. Domain III appears to be essential for this function [29, 30]. This may be due, at least in part, to NS5A recruiting apolipoprotein E, a component of the HCV production process [29, 31]. Indeed, inhibiting apolipoprotein E expression results in marked reduction of infectious particle production without affecting viral entry and replication [31].

    NS5A Inhibitor Mechanism of Action
    Several viral proteins have generated interest as potential targets for specific inhibitory drugs. In addition to the two NS3/4A protease inhibitors already approved for clinical use, numerous other protease inhibitors are being developed as well as inhibitors of viral replication, including nucleoside/nucleotide analogue inhibitors of HCV RdRp, non‐nucleoside inhibitors of RdRp, cyclophilin inhibitors, and NS5A inhibitors. Because of its critical involvement in viral replication and assembly [32], NS5A has been identified as a target for viral inhibition, leading to development of therapeutic agents. In HCV replicon‐containing cells, inhibition of NS5A, but not other HCV proteins, resulted in redistribution of NS5A from the ER to lipid droplets. NS5A‐targeting agents did not cause similar alterations in the localization of other HCV‐encoded proteins, and the transfer of NS5A to lipid droplets coincided with the onset of inhibition of replication [33]. Inhibition of NS5A at picomolar concentrations has been associated with significant reductions in HCV RNA levels in cell culturebased models, which makes these agents among the most potent antiviral molecules yet developed [34‐36].

    NS5A inhibitors have pan‐genotypic activity, i.e. they suppress replication of all HCV genotypes, but their antiviral effectivenesses against genotypes other than 1 may vary from one molecule to another [35]. Use of multiple DAAs including an NS5A inhibitor in replicon systems in cell culture has resulted in additive/synergistic inhibition of viral production and an increased barrier to resistance [37]. The exact mechanism of antiviral action of NS5A inhibitors is unknown. Available evidence suggests that they have multiple effects, which contribute to their potency [32]. One putative mechanism is the inhibition of hyperphosphorylation. Phosphorylation of NS5A seems required for viral production [38], but the relative roles of the phosphorylated and hyperphosphorylated forms are unclear, and conflicting results have been reported suggesting that reduced hyperphosphorylation may either enhance or reduce replication [21, 39]. It is thought that a tightly regulated control of phosphorylation versus hyperphosphorylation is required for efficient viral function. It was also shown that NS5A acts in two different pathways in RNA replication, and one of them likely requires hyperphosphorylation [23]. However, other mechanisms may also play a role. For instance, NS5A inhibitors alter the subcellular localization of NS5A, which may cause faulty viral assembly [33, 40

    Resistance to NS5A Inhibitors
    HCV displays a large degree of genomic variability, resulting in its quasispecies distribution [41]. Variants that confer resistance to NS5A inhibitors pre‐exist within HCV quasispecies populations in the absence of any previous exposure to these drugs. These variants generally replicate at low levels and are thus undetectable by currently available techniques. However, they can be selected if an NS5A inhibitor is administered and may be grown to high levels. Clinically significant resistance is usually associated with an escape pattern whereby viral replication returns to pretreatment levels and the dominant virus harbours amino acid substitutions that confer high levels of drug resistance without impairing fitness of the virus. Very high levels of the drug may be required to suppress highly resistant viruses, which may not be achievable without compromising safety [42]. At present, only genotype 1, the most prevalent HCV genotype, has been studied in detail for resistant variants. Table 1, adapted from Fridell et al [43], describes the resistance profile of the NS5A inhibitor daclatasvir in genotype 1a and 1b replicons. The barrier to resistance is lower for genotype 1a than for genotype 1b. Substitutions at positions L31 and Y93 have the greatest ability to confer resistance to daclatasvir, and double mutations may increase the EC50 to a far greater extent (Table 1).

    These substitutions also confer resistance to other first‐generation NS5A inhibitors. In addition, studies with daclatasvir have shown that double and triple inhibitor combinations in replicon systems can generate resistance pathways that differ from those observed during NS5A inhibitor monotherapy [37]. Agents without cross‐resistance with NS5A inhibitors should thus be used in combination with this class of drugs.

    NS5A Inhibitors Undergoing Clinical Trials 
    Although no NS5A inhibitor has yet been approved for therapeutic use, these agents are viewed with optimism due to their favourable characteristics, including the requirement for low dosing to inhibit HCV replication; pan‐genotypic activity; once‐daily dosing; resistance profiles that do not overlap with those of other DAAs in development; and successful suppression of HCV replication with an acceptable safety profile in early clinical trials [34].

    Daclatasvir (BMS790052) 
    Daclatasvir is an oral, once‐daily, highly selective NS5A inhibitor with broad coverage of HCV genotypes in vitro developed by Bristol‐Myers Squibb. Daclatasvir currently is in Phase III clinical trials. Its inhibitory target maps to Domain I, and it has been shown to block hyperphosphorylation of NS5A [23], as well as alter the subcellular localization of the viral protein [33, 40]. Daclatasvir has an EC50 of 50 pM against genotype 1a, 9 pM against genotype 1b, and 28 pM against genotype 2a [35]. Daclatasvir has been tested in Phase II clinical trials in combination with pegylated IFN‐α and ribavirin; in quadruple combination with asunaprevir, an NS3/4A protease inhibitor, and pegylated IFN‐α/ribavirin; and with asunaprevir, the nucleotide analogue sofosbuvir and the non‐nucleoside inhibitor of HCV RdRp BMS‐791325 in IFN‐free regimens. In a randomized, parallel‐group, double‐blind, placebo‐controlled, dose‐finding Phase IIa trial of treatment‐naïve patients infected with HCV genotype 1, 5 of 12 patients who received 3 mg daclatasvir with pegylated IFN‐α and ribavirin for 48 weeks achieved extended rapid virologic response (eRVR), compared with 10 of 12 who received 10 mg daclatasvir, 9 of 12 who received 60 mg daclatasvir, and 1 of 12 who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across treatment groups [44]. In another Phase IIa trial in genotype 1‐infected patients who were nonresponders to a prior course of pegylated IFN‐α and ribavirin, all 10 patients who received quadruple therapy with daclatasvir, asunaprevir, and pegylated IFN‐α/ribavirin showed a sustained virologic response (SVR) after 12 weeks, as opposed to 4 of 11 who received daclatasvir and asunaprevir only [45]. A higher incidence of viral breakthrough due to resistance was observed in genotype 1a patients who weregiven only the 2 DAAs without pegylated IFN‐α/ribavirin versus genotype 1b patients receiving the same treatment regimen, as a result of the lower barrier to resistance in genotype 1a [45].

    Among patients who experienced virologic failure, the most common variants harboured Y93H and L31M, two substitutions well known for conferring resistance to daclatasvir. In a 24‐week dual‐oral Phase II trial with daclatasvir and asunaprevir in genotype 1binfected patients, 90.5% of null responders and 63.6% of patients ineligible for or intolerant to pegylated IFN‐α/ribavirin achieved SVR 24 weeks after the end of treatment (SVR24) [46]. Interestingly, many patients in this study with pre‐existing resistance‐associated NS5A polymorphisms were cured of their chronic HCV infection. In a Phase IIb study with daclatasvir, pegylated IFN‐α, and ribavirin, 100% of genotype 4‐ infected patients achieved SVR at 12 weeks post‐treatment (SVR12) [47]. A combination of daclatasvir and sofosbuvir (formerly GS‐7977), a nucleotide analogue inhibitor of HCV RdRp developed by Gilead Sciences, given for 24 weeks achieved SVR in 100% (44/44) of treatmentnaïve patients infected with HCV genotype 1, and 91% (40/44) of patients infected with HCV genotypes 2 and 3 at 4 weeks post‐treatment (Figure 3).

    Addition of ribavirin had no effect on SVR rates [48]. Finally, the triple combination of daclatasvir, asunaprevir and BMS‐791325, a nonnucleoside inhibitor of HCV RdRp, resulted in an SVR12 in 15 of 16 patients (94%) treated for 12 weeks (data missing in the remaining patient) [49].

    This drug candidate, developed by AbbVie, is in Phase II clinical trials. It is an oral, oncedaily NS5A inhibitor that significantly reduces HCV RNA levels in vitro and in vivo. In a study of treatment‐naïve genotype 1‐infected patients, ABT‐267 in combination with pegylated IFN‐α andribavirin produced a rapid virologic response (RVR) at 4 weeks in 22 of 28 patients as compared with 2 of 22 who received placebo; after 12 weeks, 25 of 28 patients receiving the NS5A inhibitor in combination with pegylated IFN‐α and ribavirin showed complete early virologic response (cEVR) compared with 6 of 9 patients in the placebo group. A recently presented Phase IIb clinical trial, which used a 4‐drug combination of ABT‐267, ritonavir‐boosted ABT‐450 (a protease inhibitor), ABT‐333 (a non‐nucleoside inhibitor of HCV RdRp), and ribavirin achieved SVR12 in 97.5% of treatment‐naïve patients and in 93.3% of prior null‐responders infected with genotype 1 [50, 51]. In treatment‐naïve patients, the SVR rates were 87.5% when the three drugs and ribavirin were administered for 8 weeks, 89.9% when ABT‐267 was administered with ABT‐450 and ribavirin for 12 weeks, and 87.3% when the three DAAs were administered without ribavirin for 12 weeks. In null responders, the SVR rate was 88.9% with the combination of ABT‐450, ABT‐ 267 and ribavirin. Based on these results, Phase III trials with the 3 DAAs with and without ribavirin are planned [51].

    Ledispasvir (GS5885) 
    This oral, once‐daily drug candidate, developed by Gilead Sciences, is a potent NS5A inhibitor against genotypes 1a, 1b, 4a, and 5a in vitro, but has lower activity against genotypes 2a and 3a [52]. In a randomized, placebo‐controlled study of 14 days of ledipasvir monotherapy in genotype 1‐infected patients, significant HCV RNA reductions (up to 1000‐fold) were observed. Several resistance‐associated substitutions were selected, including the aforementioned Y93H and L31M. In patients infected with HCV genotype 1b, daclatasvir has been reported to be more active than ledipasvir, whereas ledipasvir has been found to be 4‐5 times more active than daclatasvir for the M28T and Q30H substitutions in HCV genotype 1a infection. In addition, daclatasvir has been demonstrated to be 2‐fold more active against the L31M substitution as compared with ledipasvir [53].

     Ledipasvir is now in a Phase II trial as a component of a 4‐drug regimen with tegobuvir (a non‐nucleoside inhibitor of HCV RdRp), GS‐9451 (an NS3/4A protease inhibitor), and ribavirin [52]. Recent results from the ELECTRON Phase II trial have shown SVR rates 12 weeks after the end of treatment of 100% in 25 treatment‐naïve and 10 null responder patients infected with HCV genotype 1 with the combination of sofosbuvir, ledipasvir and ribavirin [54]. A Phase III trial with a fixed‐dose combination of sofosbuvir and ledipasvir, with or without ribavirin, is in progress in treatment‐naïve patients infected with HCV genotype 1 [55]. A recent presentation also showed that ledipasvir, in combination with GS‐9451, pegylated IFN‐α, and ribavirin achieved SVR at 4 weeks post‐treatment in 100% of CC IL28B patients infected with HCV genotype 1 [56].

    This oral, once‐daily drug candidate is being developed by GlaxoSmithKline. 
    Preliminary studies show that GSK‐2336805 is particularly effective against HCV genotype 1b, and has potent antiviral activity against other genotypes as well. A placebo‐controlled Phase I study of treatment naïve patients with chronic genotype 1 infection found a reduction in HCV RNA level of up to 1000‐fold following 14 days of monotherapy. This NS5A inhibitor is currently in Phase II clinical trials in treatment‐naïve patients infected with HCV genotype 1 in combination with pegylated IFN‐α, ribavirin, and telaprevir [57]. Resistance to GSK‐2336805 maps to NS5A [58].

    This oral, once‐daily drug candidate, developed by Achillion Pharmaceuticals, displays highly potent activity in vitro against genotype 1a replicons as well as chimeric replicons of genotypes 2‐6. ACH‐2928 has demonstrated in vitro synergistic activity in combination with sovaprevir (formerly ACH‐1625), an HCV NS3/4A protease inhibitor, which is further enhanced by ribavirin [59]. In Phase I trials, ACH‐2928 monotherapy for 3 days produced up to a 3.7 log10 reduction in HCV RNA levels in patients with chronic HCV genotype 1 infection [60].

    This NS5A inhibitor is being developed by Bristol‐Myers Squibb. It has shown strong in vitro potency against genotypes 1a and 1b. In a Phase I study in which this agent was used as a monotherapy for 3 days in genotype 1‐infected patients, a decline of up to 3.9 log10 was observed [61].

    This drug candidate, developed by Idenix Pharmaceuticals, has shown greater potency in vitro than daclatasvir against HCV genotypes 1a, 1b, 2a, 3a, 4a, and 5a [62]. In Phase I studies, HCV RNA levels declined by more than 3 log10 in single‐dose trials for all genotype 1, 2, and 3 patients after 24 hours. Similar reductions in HCV RNA levels (over 3 log10) were observed for genotype 1, 3, and 4 patients, and reductions of 2 log10 for genotype 2, in 3‐day monotherapy studies [63, 64]. However, evidence indicates that the Y93H substitution confers resistance to this NS5A inhibitor [62]. A Phase II clinical trial using IDX719, simeprevir (a protease inhibitor developed by Janssen and Medivir), and TMC647055, a non‐nucleoside polymerase inhibitor developed by Janssen, has been announced [65].

    This oral drug candidate is under development by Presidio Pharmaceuticals. A Phase Ib trial of monotherapy for 3 days in patients with HCV genotype 1 infection showed a decrease of HCV RNA level of up to 3.6 log10. However, widespread resistance emerged rapidly, mapping to amino acids 28, 30, 31, and 93 [66].

    Also under development by Presidio Pharmaceuticals, this NS5A inhibitor has been shown to possess high efficacy against HCV genotype 1, with up to 3.7 log10 mean HCV RNA reductions, in a Phase Ib clinical trial [67, 68]. Activity was demonstrated against variants harbouring the L31M substitution. In an added genotype‐2/3 cohort, the first 2 patients achieved mean 3.0 log10 RNA level reductions [68]. PPI668 will be studied in combination with two DAAs developed by Boehringer‐Ingelheim, faldaprevir, an NS3/4A protease inhibitor, and BI207127, a non‐nucleoside inhibitor of HCV RdRp.

    This NS5A inhibitor, developed by Achillion Pharmaceuticals, has a modified structure designed to have a higher pharmacologic barrier to resistance. Pharmacokinetic studies support once‐daily oral dosing with this agent. ACH‐3102 has shown potent antiviral activity against all genotypes in preclinical studies. In replicon studies, ACH‐3102 has shown the smallest difference in potency between genotype 1a and 1b replicons, compared with daclatasvir and ACH‐2928 [69]. ACH‐3102 is potent against mutants harbouring substitutions that confer resistance to firstgeneration NS5A inhibitors (Figure 2), such as those at positions Y93 and L31 [69]. Antiviral efficacy is also strong against double mutants that are highly resistant to other NS5A inhibitors (unpublished data). In addition, this inhibitor has shown very low potential for emergence of resistant variants in genotype 1b replicons (unpublished data). For theses reasons, ACH‐3102 is considered a “second‐generation” NS5A inhibitor. A recently reported preclinical study using ACH‐3102 and ACH‐2684 (an NS3/4A protease inhibitor) has shown an additive to synergistic antiviral effect against genotypes 1a and 1b without the emergence of resistance variants [70].

    Recently announced results from a Phase Ia trial in patients infected with HCV genotype 1 show that a single dose of ACH‐3102 produces a mean HCV RNA level reduction of up to 3.9 log10, with an upper range of 4.6 log10, with inhibition lasting for 4 days after dosing. Also, ACH‐3102 has a half‐life of approximately 250 hours (unpublished data), compared with 13‐15 hours for daclatasvir [71], 22‐50 hours for ledipasvir [53], and 25‐32 hours for ABT‐267 [72]. A single Phase II trial has been initiated in genotype 1b patients using ACH‐3102 in combination with ribavirin [73].

    Progress Toward All Oral Combination Therapies for HCV and the Role of NS5A Inhibitors
    Currently, the standard of care for chronic HCV genotype 1 infection is a combination of pegylated IFN‐α, ribavirin, and an NS3/4A protease inhibitor (ie, boceprevir or telaprevir), whereas patients infected with other HCV genotypes continue to be treated with pegylated IFN‐α and ribavirin. The SVR rates observed with the triple combination in patients infected with HCV genotype 1 range from 67% to 75% in clinical trials [74, 75], though probably lower in the real‐life setting, indicating that a significant proportion of patients will still experience virologic failure and that improved therapeutic regimens are needed. In addition, patients receiving pegylated IFN‐α and ribavirin experience a plethora of adverse effects, some of which are aggravated by the protease inhibitor [6, 7, 76]. Clinical trials of NS5A inhibitors in combination with pegylated IFN‐α and ribavirin have shown promising results. However, the trials conducted thus far have included only small numbers of patients, and more studies are needed before the efficacy of such 3‐drug combinations can be fully ascertained. In this respect, the results of a Phase III trial with daclatasvir, pegylated IFN‐α, and ribavirin are awaited. Quadruple therapies including an NS5A inhibitor, pegylated IFN‐α, ribavirin, and another DAA also appear promising. However, recent reports of very high SVR rates, over 90%, in the vast majority of patients treated with all‐oral, IFNfree regimens with or without ribavirin clearly indicate that the IFN era is coming to an end. It is also noteworthy that NS5A inhibitors developed by one company have been used with different classes of DAAs developed by other companies [48]; as such, a highly potent NS5A inhibitor may find uses in combinations with various other DAAs to achieve high cure rates.

    Due to their specificity, potency, and low EC50, NS5A inhibitors will likely be a critical component of future all‐oral, IFN‐free combinations. It is interesting to note that the most attractive all‐oral combinations presented at the last annual meetings of the American and European liver societies all contained an NS5A inhibitor, combined either with a nucleotide analogue or a protease inhibitor and a non‐nucleoside inhibitor of HCV RdRp, with or without ribavirin. Fixed‐dose combinations (ie, 2‐drug combinations in 1 pill) including an NS5A inhibitor are already available in Phase II and III clinical trials. The advent of second‐generation NS5A inhibitors with a modified structure and near‐equal efficacy against variants known to resist firstgeneration NS5A inhibitors, is also promising.

    Summary and Conclusion 
    Although blood screening and other preventive measures have reduced the incidence of HCV in some parts of the world, infection with this virus remains a significant worldwide health concern. The multiple genotypes of HCV, as well as rapid development of mutations, have complicated the development of effective drugs. Until recently, a nonspecific antiviral combination, pegylated IFN‐α and ribavirin, was the mainstay of HCV therapy. The approval of two NS3/4A protease inhibitors has allowed the addition of a DAA to this treatment regimen. Although the first‐generation protease inhibitors, telaprevir and boceprevir, in combination with pegylated IFN‐α and ribavirin, have improved treatment of chronic HCV genotype 1 infection, response rates remain suboptimal. In addition, many patients are unable to tolerate this therapy and, among those who can, adverse events associated with the drugs can compromise patient compliance and lead to premature treatment discontinuations. Thus, there has been a strong desire to develop alloral, IFN‐free therapies with high efficacy. The discovery of the multiple roles of the NS5A protein in viral replication has been paralleled by the development of specific NS5A inhibitors. Evidence gathered thus far indicates that these agents are potent and possess antiviral activity against multiple HCV genotypes with acceptable safety profiles. In addition, clinical trial data support the efficacy of NS5A inhibitors with and without pegylated IFN‐α and ribavirin, suggesting an important role for these agents as a component of all‐oral therapeutic regimens for the treatment of HCV.

    Acknowledgments The author would like to thank Amlan RayChaudhury, PhD, of ACCESS Medical, LLC, for editorial assistance in preparing the manuscript. ACCESS Medical obtained funding from Achillion Pharmaceuticals for editorial assistance with this manuscript.

    Disclosure Statement The author has received research grants from Gilead. He has served as an advisor for Abbott, Abbvie, Achillion, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Gilead, Idenix, Janssen‐ Cilag, Madaus‐Rottapharm, Merck, Novartis, and Roche.

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    Monday, March 4, 2013

    Ledipasvir (GS-5885), Extra Drug Hikes HCV Regimen's Efficacy

    Extra Drug Hikes HCV Regimen's Efficacy

    By Michael Smith, North American Correspondent, MedPage Today
    Published: March 04, 2013

    Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

    ATLANTA – Adding an extra drug to a promising hepatitis C (HCV) regimen increased its efficacy – especially in patients who had failed previous standard therapy, a researcher said here.

    The addition of the third drug meant that all patients, regardless of previous treatment, were free of the virus 12 weeks after the end of therapy, according to Edward Gane, MD, of Auckland City Hospital in Auckland, New Zealand.

    Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • Note that this small trial of three antiviral medications demonstrated a 100% sustained virologic response rate at 12 weeks in patients with Hepatitis C, regardless of prior treatment outcome.
  • Be aware that the study excluded patients with existing cirrhosis.

    The combination did not give rise to any new safety or tolerability issues, Gane told reporters in a press conference here at the Conference on Retroviruses and Opportunistic Infections.

    The new drug is ledipasvir, previously known as GS-5885, which blocks the action of the viral nonstructural protein 5A. Gane and colleagues added it to the nucleotide analogue sofosbuvir (GS-7977) and ribavirin, long a part of standard therapy.

    An advantage of the combination is that it avoids pegylated interferon, long part of the standard HCV therapy but regarded as both hard to tolerate and dangerous to use. Another benefit: All three drugs in the combination are taken orally, while interferon is given by injection.

    The earlier results showed that 84% of patients who had never been treated for chronic HCV infection were free of the virus 12 weeks after the end of 12 weeks of therapy – the so-called 12-week sustained virologic response (SVR12).

    But, Gane noted, patients who had not had a successful response to standard therapy with interferon and ribavirin – so-called null responders -- did much worse, with only 10% reaching an SVR12.

    The researchers had two choices to improve efficacy, he told reporters – increase the length of treatment or add an extra medication. They opted for the second choice, enrolling 25 treatment-naïve patients and 10 null-responders, all with the relatively hard-to-treat genotype 1 of the virus.

    As in the previous trial, response was quick, with all but one patient having no detectable virus after 4 weeks of therapy and all patients undetectable at the end of treatment.

    All patients in both groups also achieved an SVR12, Gane reported.

    There were two serious adverse events, both among the treatment-naïve group, but they were considered not related to treatment. One of the patients, with a diverticular perforation, stopped therapy after 8 weeks, but later was shown to be free of virus 24 weeks after the end of treatment.

    Gane commented that future study will use a co-formulated version of sofosbuvir and ledipasvir and will evaluate patients with cirrhosis who were excluded from this trial or had shorter durations of treatment. It will also look at the possibility of eliminating ribavirin.

    Although the results overcome the surprising findings of the earlier trial, they were achieved in a relatively easy-to-treat population, commented Juergen Rockstroh, MD, of the University of Bonn, who was not involved in the study but who moderated the session at which it was presented.

    "They got a 100% cure rate, but they had no cirrhotics," Rockstroh told MedPage Today. "They didn't give us an answer in a really difficult-to-treat population."

    Taken with other research presented here, the findings suggests that a one-size-fits-all approach may not be valid for future HCV treatment, he said – those who have advanced liver disease or have previously failed therapy may need more intensive therapy than other patients.

    The regimen has the advantage, however, that it does not include interferon, commented David Thomas, MD, of Johns Hopkins University, who was not involved in the study but who moderated a press conference at which some details were presented.

    "Interferon has been the workhorse," he told reporters, "but now we are moving into automobiles."