Gilead Announces Sofosbuvir Plus GS-5816 SVR12 Rates Across Multiple HCV Genotypes --

Gilead Announces Phase 2 Data for Investigational All-Oral Regimen of Sofosbuvir Plus GS-5816 for the Treatment of Chronic Hepatitis C

-- Once-Daily Combination Achieves High SVR12 Rates Across Multiple HCV Genotypes --

BOSTON--(BUSINESS WIRE)--Nov. 11, 2014-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced data from three Phase 2 open-label studies evaluating the safety and efficacy of an investigational all-oral pan-genotypic regimen containing the nucleotide analog polymerase inhibitor sofosbuvir (SOF), approved as Sovaldi^® by the U.S. Food and Drug Administration in December 2013, and the investigational NS5A inhibitor GS-5816 for the treatment of chronic hepatitis C virus (HCV) infection. These data are being presented this week at the 65th Annual Meeting of the American Association for the Study of Liver Diseases (The Liver Meeting^® 2014) in Boston.

All three studies evaluated SOF 400 mg plus GS-5816 25 or 100 mg, with and without ribavirin (RBV), for eight or 12 weeks. Rates of sustained virologic response (SVR12) ranged from 88 percent to 100 percent among those receiving SOF plus GS-5816 100 mg for 12 weeks - the regimen selected for Phase 3 studies. Patients who achieve SVR12 are considered cured of HCV infection.

"There continues to be a need for simple, interferon- and ribavirin-free treatment regimens that are effective for all hepatitis C patients, regardless of genotype," said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Gilead Sciences. "These data demonstrate the high efficacy and tolerability of sofosbuvir plus GS-5816 among patients with varying genotypes and disease progression and we look forward to providing Phase 3 data on the combination across all six genotypes."

The first study, GS-US-342-0109 (Oral #197), evaluated 12 weeks of SOF plus GS-5816 with and without RBV in treatment-experienced genotype 1 and 3 patients with and without cirrhosis. The genotype 1 patients had all failed a prior treatment course that included a protease inhibitor. The number and proportion of patients achieving SVR12 are summarized in the table below.

The second study, ELECTRON 2 (Oral #79), evaluated the same combination of SOF plus GS-5816, with and without RBV, for eight weeks in non-cirrhotic, treatment-naïve genotype 3 patients. Patients receiving SOF with GS-5816 100 mg achieved SVR12 rates of 100 percent (n=26/26) with RBV and 96 percent (n=26/27) without RBV.

The third study, GS-US-342-0102, evaluated SOF plus GS-5816, with and without RBV, among non-cirrhotic treatment-naïve patients. The results of Part A of the study evaluating 12 weeks of therapy were presented at the 49th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress 2014) in April 2014.

The results of Part B, presented at the Liver Meeting this week (Oral #80), evaluated eight weeks of SOF plus GS-5816, with and without RBV, in patients with genotype 1 or 2 HCV infection. Among genotype 1 patients receiving SOF plus GS-5816 100 mg, SVR12 rates were 81 percent (n=25/31) and 90 percent (n=26/29), with and without RBV, respectively. Genotype 2 patients achieved SVR12 rates of 88 percent (n=23/26) with RBV and 88 percent (n=23/26) without RBV.

SOF plus GS-5816 was well tolerated in over 800 patients with HCV infection evaluated in these three studies. There was a low incidence of serious adverse effects and few discontinuations due to adverse events. The most frequently reported adverse events (>10%) were fatigue, headache, nausea and insomnia. The most frequently observed hematologic abnormality was hemoglobin decrease in the RBV-containing treatment groups.

GS-5816 is an investigational product and its safety and efficacy have not been established.

Additional information about these studies can be found at www.clinicaltrials.gov.

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 possibility of unfavorable longer-term results from these studies and other ongoing and subsequent clinical trials involving sofosbuvir plus GS-5816, alone or in combination with other products, for the treatment of HCV. In addition, Gilead may make a strategic decision to discontinue development of GS-5816 if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. 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, 2014, 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 www.gilead.com.

Also View:
AASLD Conference Reports: HCV Data, slide presentations categorized by genotype and pharmaceutical company

AASLD Conference Reports: HCV Data, slide presentations categorized by genotype and pharmaceutical company

65th Annual Meeting of the American Association for the Study of Liver Diseases

Comprehensive data investigating HCV interferon-free, ribavirin-free regimens presented at the liver meeting is now available on the website.

Updated daily, categorized by genotype and pharmaceutical company, with links to breaking news, clinical data, commentary and slide-sets from premier Hepatitis C websites.

Hepatitis C New Drug Research:  Conference Reports 

AASLD - AbbVie Results PEARL-I Study in Genotype 4 Chronic Hepatitis C Patients

AbbVie to Present Results from Phase 2 PEARL-I Study in Genotype 4 Chronic Hepatitis C Patients at The Liver Meeting® 2014

- Results demonstrated high response rates in adult chronic hepatitis C genotype 4 patients without cirrhosis

- Data underscore AbbVie's commitment to evaluating treatments across a range of patients with chronic hepatitis C virus infection

BOSTON, Nov. 11, 2014 /PRNewswire/ -- AbbVie (NYSE:ABBV) announced detailed results from its open-label Phase 2b study, PEARL-I, which demonstrated that 100 percent of genotype 4 (GT4) patients who were new to therapy (n=42/42) or who had failed previous treatment with pegylated interferon (pegIFN) and RBV (n=49/49) achieved sustained virologic response rates at 12 weeks post-treatment (SVR12) after taking AbbVie's investigational treatment with ribavirin (RBV). Additionally, 90.9 percent of patients who were new to therapy achieved SVR12 (n=40/44) after taking the treatment without RBV. These data will be presented today during a poster session at The Liver Meeting® 2014.

"As many as 34 million people around the world are living with genotype 4 chronic hepatitis C, a population that is common in the Middle East and Africa, where it accounts for more than 80 percent of all hepatitis C cases,[i]" said Barry Bernstein, M.D., vice president, infectious disease development, AbbVie. "The data from PEARL-I represent another important step forward in realizing our commitment to advancing scientific knowledge in hepatitis C with the ultimate goal of providing treatment options to as many patients as possible."

PEARL-I studied AbbVie's all-oral, interferon-free investigational treatment combining two direct-acting antivirals (ABT-450/ritonavir and ombitasvir) with and without RBV for 12 weeks in non-cirrhotic adult patients with chronic genotype 1b (GT1b) and GT4 hepatitis C virus (HCV) infection.

There were no discontinuations due to adverse events in PEARL-I. The most commonly reported treatment-emergent adverse events (greater than 15 percent in any group) were headache (29-33 percent), asthenia (weakness) (24-33 percent), fatigue (7-18 percent), nausea (9-17 percent) and insomnia (5-16 percent). One patient had a grade 3 liver function test elevation (AST> five times the upper limit of normal), which was asymptomatic and resolved during continued dosing. Four patients with hemoglobin decreases (anemia) required RBV dose reductions; however, none of these patients required blood transfusions or medication to boost their red blood cell production. In the treatment-naïve group without RBV, on-treatment virologic breakthrough was reported in one patient (2 percent) and two patients (5 percent) experienced post-treatment relapse. There were no virologic failures in the other treatment arms.

About AbbVie's Investigational Two Direct-Acting Antiviral HCV Treatment
AbbVie's proposed all-oral antiviral treatment consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ombitasvir (25mg) dosed once daily, co-administered with weight-based ribavirin (1000mg or 1200mg in divided doses twice daily). The combination of two direct-acting antivirals, each with distinct mechanisms of action, targets and inhibits specific HCV proteins in the viral replication process.

About AbbVie's HCV Clinical Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating interferon-free, all-oral treatments with and without ribavirin with the goal of achieving high sustained virologic response rates in as many patients as possible. AbbVie's development programs combining two direct-acting antivirals are studying additional hepatitis C virus (HCV) genotypes.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score =6.

AASLD - AbbVie Results Hepatitis C Patients with HIV-1 Co-Infection (TURQUOISE-I) and Liver Transplant Recipients (CORAL-I)

AbbVie to Present Results from Studies in Chronic Hepatitis C Patients with HIV-1 Co-Infection (TURQUOISE-I) and Liver Transplant Recipients (CORAL-I) at The Liver Meeting® 2014

- In adult patients co-infected with genotype 1 (GT1) hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) type 1 infection, TURQUOISE-I demonstrated sustained virologic response rates 12 weeks post-treatment (SVR(12)) of 93.5 percent after 12 weeks of treatment and 90.6 percent after 24 weeks of treatment, respectively

- In adult liver transplant patients with recurrent chronic GT1 HCV infection and new to treatment after transplantation, CORAL-I demonstrated 97.1 percent SVR rates at 12 and 24 weeks post-treatment after 24 weeks of treatment

- CORAL-I results published online today in The New England Journal of Medicine

BOSTON, Nov. 11, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced results from studies in chronic hepatitis C patients with human immunodeficiency virus type 1 (HIV-1) co-infection (TURQUOISE-I) and liver transplant recipients (CORAL-I) at The Liver Meeting®2014.

New, detailed results from part one of the Phase 2 portion of AbbVie's Phase 2/3 open-label study, TURQUOISE-I, showed patients co-infected with genotype 1 (GT1) hepatitis C virus (HCV) and HIV-1 receiving AbbVie's investigational treatment and ribavirin (RBV) for 12 weeks or 24 weeks achieved sustained virologic response rates 12 weeks post-treatment (SVR12) of 93.5 percent (n=29/31) and 90.6 percent (n=29/32), respectively. These data were presented today, November 11, as a "Poster of Distinction."

"Patients living with both chronic HCV and HIV have been historically considered more difficult to treat," said Barry Bernstein, M.D., vice president, infectious disease development, AbbVie. "TURQUOISE-I is one of the few dedicated studies looking specifically at this population, who are seen in everyday clinical practice. These data will help us gain a better understanding of how our investigational treatment works in this subpopulation of genotype 1 patients."

Additionally, results from the first cohort of AbbVie's ongoing open-label Phase 2 study, CORAL-I, were presented today during an oral session and published online in The New England Journal of Medicine. Results showed that non-cirrhotic liver transplant patients with recurrent GT1 HCV and new to treatment after transplantation achieved a SVR12 rate of 97.1 percent (n=33/34) and a sustained virologic response rate 24 weeks post-treatment (SVR24) of 97.1 percent (n=33/34) after 24 weeks of treatment.

"Recurrence of HCV infection in the new graft post-liver transplantation is universal in those that have the virus prior to transplantation, and can be associated with an aggressive disease course," explained Dr. Paul Kwo, medical director of liver transplantation and professor of medicine, Indiana University School of Medicine. "The high SVR rates seen in CORAL-I are promising and offer valuable information as we continue to assess this regimen within this specific patient population."

About TURQUOISE-I

TURQUOISE-I is an ongoing Phase 2/3, multi-center, randomized, open-label study evaluating the efficacy and safety of AbbVie's all-oral, interferon-free investigational treatment combining three direct-acting antivirals (ombitasvir/ABT-450/ritonavir and dasabuvir) with RBV (weight based dosing of 1000 mg or 1200 mg per day divided twice daily) for 12 or 24 weeks in adult patients with chronic GT1 HCV infection with or without compensated liver cirrhosis who are also infected with HIV-1. Study patients were either new to therapy (treatment naïve) or had failed previous treatment with pegylated interferon and RBV (treatment-experienced), had a stable immune status (CD4+ counts of ≥200 cells/mm3 or CD4+ % ≥14%) and had HIV-1 ribonucleic acid levels suppressed on a stable atazanavir- or raltegravir-based antiretroviral HIV therapy.

No patients discontinued treatment due to adverse events in either the 12-week or 24-week arm. In the 12-week arm, no virologic breakthroughs were observed while on treatment. One patient (3.3 percent) experienced post-treatment relapse after 12 weeks of treatment. In the 24-week treatment arm, one virologic breakthrough was observed (3.1 percent). Two patients in the 24-week treatment group were believed to have been re-infected post-treatment by a different strain of HCV than the original infection. The most commonly reported adverse events (greater than 15 percent in both treatment arms combined) were fatigue (47.6 percent), insomnia (19 percent), nausea (17.5 percent), and headache (15.9 percent). Elevations in total bilirubin were the most common laboratory abnormality (68.3 percent), were mainly composed of indirect bilirubin, and were not associated with aminotransferase elevations. Reductions in RBV dose because of anemia or reduced hemoglobin occurred in 9.5 percent of patients (n=6/63); all six patients achieved SVR12.

About CORAL-I

CORAL-I is an ongoing Phase 2, multi-center, two-cohort, open-label study evaluating the efficacy and safety of AbbVie's all-oral, interferon-free investigational treatment combining three direct-acting antivirals (ombitasvir/ABT-450/ritonavir and dasabuvir) with RBV (RBV dosing left up to the discretion of the investigator) for 24 weeks in adult non-cirrhotic (screening biopsy Metavir score ≤F2) liver transplant recipients with recurrent chronic GT1 HCV infection. Patients in the study initiated therapy at least 12 months after receiving a liver transplant, had not received other HCV therapy since their liver transplant, and were on a stable immunosuppressant regimen based on either tacrolimus or cyclosporine, for which dose adjustments were advised. Enrollment in the second cohort of the study is ongoing.

One patient (2.9 percent) discontinued the study due to adverse events but still achieved SVR12. Two patients experienced serious adverse events. The most commonly reported treatment-emergent adverse events (greater than 20 percent) were fatigue (50 percent), headache (44.1 percent), cough (32.4 percent), anemia (29.4 percent), diarrhea (26.5 percent), insomnia (26.5), asthenia (23.5 percent), nausea (23.5 percent), muscle spasms (20.6 percent), and rash (20.6 percent). No patients experienced virologic breakthrough while on treatment; however, one patient experienced post-treatment relapse. Nine patients had a grade 2 reduction in hemoglobin, and one patient had a grade 3 reduction. Five patients with hemoglobin decreases (anemia) received a medication to boost their red blood cell production at the investigator's discretion. No patients discontinued study drugs because of anemia, required a blood transfusion, or experienced a rejection of their transplanted liver.

About AbbVie's Investigational Three Direct-Acting Antiviral Treatment

AbbVie's investigational treatment consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ombitasvir (25mg), dosed once daily, and dasabuvir (250mg) dosed twice daily with or without ribavirin. The combination of three direct-acting antivirals, each with a distinct mechanism of action, targets and inhibits specific hepatitis C virus proteins in the viral replication process.

About AbbVie's HCV Clinical Development Program

The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating interferon-free, all-oral treatments with and without ribavirin with the goal of achieving high sustained virologic response rates in as many patients as possible. AbbVie's multinational program using an investigational treatment combining three direct-acting antivirals includes more than 2,300 patients in over 25 countries. The program is designed to identify ways to maximize response rates in a broad spectrum of patient populations, including those with compensated cirrhosis, liver transplant recipients and those with human immunodeficiency virus type 1 co-infection.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

AbbVie's New Drug Application to the U.S. Food and Drug Administration (FDA) and Marketing Authorization Applications to the European Medicines Agency (EMA) for its investigational, all-oral, interferon-free regimen for the treatment of adult patients with chronic genotype 1 HCV infection have been accepted and granted priority review by the FDA and validated and granted accelerated assessment by the EMA.

Safety Information for Ribavirin and Ritonavir

Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ≥6.

See approved product labels for more information.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvieon Twitter or view careers on our Facebook or LinkedIn page.

SOURCE AbbVie

AASLD - BMS Announces High Cure Rates With daclatasvir (DCV) in combination with sofosbuvir (SOF)

BMS Announces High Cure Rates for Hepatitis C Drug
Mon, 11/10/2014 - 10:42am

Bristol-Myers Squibb announced late-breaking data from the landmark ALLY Trial investigating a ribavirin-free 12-week regimen of daclatasvir (DCV) in combination with sofosbuvir (SOF) in genotype 3 hepatitis C (HCV) patients, a patient population that has emerged as one of the most difficult to treat. The results of the study, which showed sustained virologic response 12 weeks after treatment (SVR12) in 90% of treatment-naïve and 86% of treatment-experienced patients, will be presented at The Liver Meeting, the Annual Meeting of The American Association for the Study of Liver Diseases (AASLD), in Boston, MA, November 7 – 11.

“Both treatment naïve and treatment experienced patients in the ALLY-3 study achieved high SVR rates. These results are encouraging given that patients with genotype 3 have emerged as among the hardest to treat,” said David R. Nelson, M.D., professor of Medicine, Molecular Genetics and Microbiology Director, UF Clinical and Translational Science Institute, and assistant Vice President of Research for the University of Florida. “Genotype 3 is associated with a more rapid progression of disease and remains a challenge to the efficacy of even newer regimens. The ALLY-3 results demonstrate the possibility of bringing a cure to genotype 3 patients in an all-oral, 12-week regimen.”

These results build upon the existing body of data on the daclatasvir and sofosbuvir combination. Data from an open-label, randomized study of daclatasvir with sofosbuvir in genotypes 1, 2, and 3 demonstrated that the 24-week regimen of daclatasvir and sofosbuvir achieved SVR12 in 89% of patients with genotype 3. The ALLY study presented at The Liver Meeting investigates the regimen for 12 weeks, halving the previous treatment duration. Other ongoing ALLY studies examine diverse HCV populations across all genotypes: cirrhotic and post-liver transplant patients, as well as treatment-naïve and treatment-experienced patients who are co-infected with HIV.

“HCV is a complex disease, and the treatment community needs multiple options to address the remaining unmet medical needs,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “Daclatasvir has shown pan-genotypic activity in bench research, a factor which is becoming increasingly important as we learn more about the complexity of HCV. Further, daclatasvir’s potential to be combined with many other agents, including sofosbuvir, is significant in continuing to develop additional treatment options that may help patients of all genotypes achieve cure.”

In the ALLY-3 study, the daclatasvir and sofosbuvir combination regimen was well tolerated, with no deaths, treatment-related serious adverse events, or discontinuations due to adverse events. The most frequent side effects were headache (19.7%), fatigue (19.1%), nausea (11.8%), diarrhea (8.6%), insomnia (5.9%), abdominal pain and arthralgia (both 5.3%). Additionally, there were 17 (11.2%) treatment failures, with 16 relapses post-treatment and 1 rebound at the end of treatment. There were no viral breakthroughs in this ribavirin-free regimen.

Source: Bristol-Myers Squibb

AASLD- Achillion Reports 100% SVR12 With ACH-3102 and Sovaldi

Achillion Reports 100% SVR12 in a Phase 2 Combination Study With ACH-3102 at the Liver Meeting 2014 (AASLD)

Achillion Achieves 100% SVR12 in Eight-Week Phase 2 Trial Evaluating a Ribavirin-Free Regimen of ACH-3102 and Sofosbuvir for Genotype 1 HCV ("Proxy Study") Including Nine of 12 Patients With Viral Loads Higher Than 6 Million IU/ml at Baseline -

- Reports Additional Preclinical Results for ACH-3422, Uridine-Analog Nucleotide NS5B Polymerase Inhibitor -

Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced the presentation of results from the ongoing Phase 2 study of ACH-3102 in a late breaker poster and data in three preclinical posters on ACH-3422. The poster presentations are being made at the 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), The Liver Meeting 2014, which takes place through November 11, 2014 in Boston, MA.

Late Breaker Poster Presentation: Phase 2 pilot study evaluating eight week treatment of ACH-3102 in combination with sofosbuvir for genotype 1 treatment-naïve HCV

In a late breaker poster presentation, Achillion reported updated interim results from an ongoing interferon-free, ribavirin-free, Phase 2 open-label, randomized, partial-crossover study to evaluate the efficacy, safety, and tolerability of eight weeks or six weeks of ACH-3102 and sofosbuvir, a marketed nucleotide polymerase inhibitor, without ribavirin, in treatment-naïve genotype 1 HCV-infected patients. The primary objective of the study is determination of sustained viral response 12 weeks (SVR12) after the completion of therapy. Eighteen patients were enrolled, including six observational patients. Twelve patients completed eight weeks of treatment consisting of 50 mg of ACH-3102 and 400 mg of sofosbuvir administered once daily while observational patients received no drug during this phase of the trial.

Of the 12 patients treated, 100 percent (n=12/12) achieved SVR12. Of the 12 patients treated in this study, nine of 12 patients had a baseline viral load substantially greater than 6 million IU/ml at baseline. No on-treatment viral breakthrough or post-treatment viral relapse has been observed.

Preclinical poster presentations on ACH-3422

Achillion presented three posters at AASLD which reported updated preclinical results on ACH-3422. The in vitro results demonstrated that this nucleotide pro-drug has improved potency against genotype 3 HCV as compared to sofosbuvir. In addition, in a separate poster presentation, Achillion reported that ACH-3422 displays additive to synergistic activity when combined with ACH-3102 or sovaprevir, Achillion's Phase 2 NS3/4A protease inhibitor, in vitro. Furthermore, the high barrier to resistance for ACH-3422 was supported with the ability of the agent to block, in vitro, the appearance of resistant colonies in combination with other direct-acting antiviral agents.

"The antiviral activity and safety profile observed to date for ACH-3422 both in preclinical studies and in the ongoing 422-001 Phase 1 trial support further development with this nucleotide in combination with Achillion's other direct-acting antivirals, and represents an exciting treatment option for HCV," commented Professor Edward Gane, M.D., Deputy Director and Hepatologist, New Zealand Liver Transplant Unit, Auckland City Hospital in New Zealand, and Lead Investigator in the ACH-3422 Phase 1 proof-of-concept study and Phase 2 proxy study of ACH-3102 and sofosbuvir.

Reprints of the posters are available on the Company's website at www.achillion.com/resources.

AASLD - Aspirin Might Protect Against Liver Fibrosis

Medscape Medical News from: The Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD)

Good Old Aspirin Might Protect Against Liver Fibrosis

Neil Osterweil

November 10, 2014

BOSTON — Will wonder drugs never cease? Aspirin, already touted for its cardiovascular and anti-inflammatory prowess, seems to be flexing its muscles against liver fibrosis, particularly in people at risk for chronic liver disease, according to new research.

"Clinical equipoise is emerging that may justify prospective randomized trials of aspirin and, potentially, other antiplatelet drugs such as antifibrotic agents," Gordon Jiang, MD, a gastroenterology fellow at the Beth Israel Deaconess Medical Center in Boston, and colleagues state in a scientific poster here at The Liver Meeting 2014.

In a population-based cross-sectional study of more than 14,000 adults, there was "a consistent association between aspirin use and less liver fibrosis," Dr. Jiang and colleagues report.

The team drew on the National Health and Nutrition Examination Survey (NHANES) III to look at the association between aspirin, ibuprofen, and liver fibrosis. Fibrosis was measured with four validated noninvasive indices: Fibrosis-4, the nonalcoholic fatty liver disease fibrosis score, the aspartate aminotransferase/platelet ratio index, and the Forns Index.

To see if the association between aspirin and fibrosis protection is stronger in patients most at risk for fibrosis, they did additional analyses in patients with viral hepatitis, heavy drinkers, and patients with fatty liver disease.

On the four measures, the use of aspirin was consistently associated with lower stages of liver fibrosis. In contrast, there was virtually no link between ibuprofen use and liver fibrosis.

Similarly, in an analysis of patients with and without chronic liver disease (hepatitis B or C infection, more than 5 alcoholic drinks per day, or suspected nonalcoholic steatohepatitis), aspirin but not ibuprofen was consistently associated with lower stages of fibrosis.

For patients with or at risk for liver disease, compared with those without risk factors, there was about a 5-fold increase in the negative coefficient for the interaction between aspirin use and liver fibrosis. This suggests that the protective effect of aspirin is much larger in patients with chronic liver disease, said researcher Yury Popov, MD, PhD, assistant professor of medicine at the Beth Israel Deaconess Medical Center.

The researchers acknowledge that the study was limited by the observational design, and by that fact that the NHANES III data were limited to 1 month of drug use, "whereas the protection against liver fibrosis likely requires long-term use."

They speculate that the antiplatelet activity of aspirin, rather than its anti-inflammatory properties, likely account for its positive effects on fibrosis.

"Our observations support emerging experimental and clinical evidence for a pathologic link between platelet activation and liver fibrosis," they write.

In a separate study, also presented here, another group of researchers report that "platelets drive liver fibrosis through the direct activation of hepatic stellate cells in chronically injured liver."

"We also found that aspirin in the long term, at the low dose — the antiplatelet dose — is reducing — well actually, preventing — fibrosis in the mouse model," Dr. Popov, who was involved in both studies, told Medscape Medical News.

More potent antiplatelet agents — such as clopidogrel (Plavix), prasugrel (Effient), and others currently in the pipeline — could have an even stronger effect against fibrosis, said Athan Kuliopulos, MD, PhD, professor of medicine at the Tufts University Sackler School of Biomedical Sciences in Boston, who was not involved with the study.

"And this is just liver fibrosis," he told Medscape Medical News. "What does it mean for outcome?"

He said that if, as he and his colleagues theorize, platelet activation or action is a primary cause of fibrosis, it might be possible to "bypass the platelet entirely," and target the factor Xa protease.

Dr. Jiang has disclosed no relevant financial relationships. Dr. Popov reports consulting for and receiving research grants from Gilead Sciences. Dr. Kuliopulos is the CEO of Oasis Pharmaceuticals.

The Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract 449, presented November 8, 2014; abstract 778, presented November 9, 2014.

Medscape 

Also View:

AASLD Conference Reports: HCV Data, slide presentations categorized by genotype and pharmaceutical company

UPDATED: Merck's hepatitis C cocktail drug fails a 4-week challenge

UPDATED: Merck's hepatitis C cocktail drug fails a 4-week challenge

November 10, 2014 | By John Carroll

After sending out signals that it might be running into trouble with a short-duration study of a new triple combination drug for its hepatitis C regimen, Merck ($MRK) investigators hailed the clear success of an 8-week test but confirmed analysts' fears in a batch of 4-week data released at the meeting of the American Association for the Study of Liver Diseases.

A mix of grazoprevir/elbasvir (MK-5172/MK-8742, MK-5172A)--the company's investigational NS3/4A protease inhibitor and NS5A inhibitor, in combination with Gilead's Sovaldi (sofosbuvir), an NS5B nuc inhibitor, clearly hit the mark with a 94.7% cure rate for treatment naïve cirrhotic patients at 8 weeks. But the combination fell well short of the goal line on efficacy at 4 weeks, with a cure rate of 38.7%. At 6 weeks the triple hit an 80% cure rate in the treatment-naïve group of cirrhotic patients while the non-cirrhotic cohort hit 86.7%--shy of the 90% level some analysts believe Merck is likely to face as a competitive hurdle cleared by rivals. All the patients in the study were genotype 1.

Continue Reading.... 

Merck’s Four-Week Hepatitis C Regimen Fails to Top Gilead
Merck & Co. (MRK) won’t move forward with an ultra-short hepatitis C regimen that attempted to cut treatment durations in half by combining two of its drugs with another from Gilead Sciences Inc.

Patients in the mid-stage, 102-person trial got Merck’s experimental drugs grazoprevir and elbasvir, along with Gilead’s Sovaldi, for as little as four weeks, with the length of treatment based partly on how severe their infection was.

In patients whose livers weren’t already badly damaged by the virus, 38.7 percent were cured in four weeks and 86.7 percent were cured in six weeks, according to data to be presented at the American Association for the Study of Liver Diseases conference in Boston.

That’s well below the 90 percent-plus cure rates seen with longer treatments. Merck won’t take the four-week course into a new round of testing, said Eliav Barr, the company’s vice president of infectious diseases...

Merck's Shortened Hep C Regimens Fall Short of Cure-Rate Goal

Merck's hepatitis C regimen is only disappointing because improvements in treatments for the viral liver disease have progressed at a rapid and remarkable rate. Five years ago, the best treatment for hepatitis C required weekly injections and twice-daily pills for one year. At best, about half of hepatitis C patients were cured but only after enduring debilitating side effects, including flu-like symptoms and anemia.

Reuters

Merck 4-week hep C regimen with Gilead's Sovaldi comes up short

By Bill Berkrot

Nov 9 (Reuters) - An attempt by Merck & Co to shorten hepatitis C treatment to just four weeks by adding Gilead Sciences Inc's huge selling Sovaldi to its own oral two-drug combination came nowhere near the desired efficacy due to a high rate of relapses, according to interim data from a midstage study.

Several companies have been working to find ways to further reduce the number of weeks of treatment needed, while keeping cure rates above 90 percent.

A just approved pill called Harvoni that combines Sovaldi with another Gilead drug requires eight weeks of treatment for many patients, and longer for tougher to treat patients.

In the ongoing Merck trial of previously untreated patients, only 38.7 percent had no detectable sign of the liver destroying virus after four weeks of treatment with Sovaldi and Merck's grazoprevir/elbasvir combination. Nineteen of the 31 patients in the four-week treatment arm relapsed prior to the planned end of the study, which is 12 weeks after completion of dosing.

The preliminary data was set to be presented on Monday at the American Association for the Study of Liver Diseases (AASLD) meeting in Boston.

The best result so far in the multi-arm, three-drug study called C-Swift was observed with eight weeks of treatment of patients with cirrhosis in which 94.7 percent had no detectable virus. They will be deemed cured if the virus has not reappeared 12 weeks after stopping treatment.

With a six-week regimen in non-cirrhotics, 86.7 percent of patients had no sign of virus up to 8 weeks after completing treatment, according to the interim results.

"These findings will inform the design of larger studies aimed at understanding the potential of short-duration triple therapy across multiple patient types," Dr. Eric Lawitz, the study's lead investigator, said in a statement.

The three drugs each work in a different way to help prevent the virus from replicating. But following failure of the 4-week experiment, Merck said it will turn its attention to studying a combination of three of its own drugs in development rather than involving the Gilead medicine in future studies.

The hepatitis C field has been moving at a lightning pace. Only a handful of years ago, patients needed 48 weeks of treatment with drugs that had harsh side effects and only cured about 40 percent of patients.

The new all-oral treatments eliminate the need for injectable interferon and its flu-like side effects, as well as another older drug called ribavirin that caused anemia and other problems, while dramatically increasing cure rates and reducing treatment duration.
(Reporting by Bill Berkrot; Editing by Chris Reese)

Interim Data from Proof-of-Concept Study of Merck’s Investigational Hepatitis C Treatment Grazoprevir/Elbasvir in Combination with a Nucleotide Inhibitor (C-SWIFT study) Presented at The Liver Meeting®

BOSTON--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of interim data from the C-SWIFT study exploring the potential of a candidate triple-therapy regimen consisting of the fixed-dose combination of grazoprevir/elbasvir (MK-5172/MK-8742, MK-5172A), the company’s investigational NS3/4A protease inhibitor and NS5A inhibitor, in combination with sofosbuvir, a nucleotide (NS5B) inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. Preliminary findings in treatment-naïve HCV genotype 1- (GT1) infected non-cirrhotic patients, following six and four weeks of treatment, and patients with cirrhotic disease, following eight and six weeks of treatment, will be presented by Dr. Eric Lawitz, vice president, scientific and research development, The Texas Liver Institute, San Antonio, TX and C-SWIFT lead investigator. This poster presentation is part of a late-breaking abstract session at the 65th American Association for the Study of Liver Diseases (AASLD) Annual Meeting, also known as The Liver Meeting®.

“These interim data provide a compelling proof-of-concept for the potential of an eight- or six-week triple therapy course in treatment-naive patients with genotype 1 disease, including cirrhotic patients,” said Dr. Lawitz. “These findings will inform the design of larger studies aimed at understanding the potential of short-duration triple therapy across multiple patient types.”

To date, the investigational triple therapy has shown response rates (sustained virologic response1 [SVR] at 4/8 weeks following therapy) ranging from 80 percent to 94.7 percent in cirrhotic and non-cirrhotic patients following six and eight weeks of treatment in this study, as shown in table 1. The four-week regimen resulted in sub-optimal efficacy.

Table 1
Treatment duration (weeks)		Treatment-Naïve Cirrhotic				Treatment-Naïve Non-Cirrhotic
		8		6		6		4
SVR4/8		18/19** 94.7%**		16/20 80%		26/30 86.7%		12/31 38.7%
Virologic Failure*		1		4		4		19
*All treatment failures were due to relapses. **21 patients enrolled; two patients discontinued; 18/19 (modified intent-to-treat). Data includes week 8 follow up data for 99/102 patients (excludes 2 cirrhotic patients who discontinued).

All 28 patients not achieving SVR4/8 relapsed following the end of therapy. Of these patients, 25 (89%) were genotype 1a (GT1a) and three (11%) were genotype 1b (GT1b) [82% of enrolled subjects were infected with HCV GT1a at baseline]. Sequence analysis of virologic failures is so far available for 23 patients. Wild type virus was determined to be the cause in 12 of the relapsed patients. In the other relapsed patients, 10 had elbasvir-resistant viral variants and one had a variant resistant to both grazoprevir and elbasvir.

In this study, the co-administration of grazoprevir/elbasvir and sofosbuvir was generally well-tolerated. The most common adverse events associated with the triple regimen were: headache (4%), fatigue (2%) and nausea (2%). One patient withdrew from the study for reasons unrelated to treatment.

“Our goal is to establish a simple, effective, well-tolerated regimen that is applicable across the diverse population of patients with HCV,” said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories. “The preliminary data provide us with the confidence to initiate our C-CREST study to evaluate a triple combination comprising Merck’s investigational candidates from three major therapeutic classes of HCV medicines.”

About C-SWIFT

The C-SWIFT study enrolled a total of 102 treatment-naïve patients with HCV genotype 1 (GT1a and GT1b) infection at The Texas Liver Institute, San Antonio, TX. Treatment-naïve, non-cirrhotic patients were randomized to receive the fixed-dose combination of grazoprevir/ elbasvir (one pill containing 100 mg, 50 mg respectively) plus the nucleotide inhibitor sofosbuvir (400 mg) once daily for eight, six or four weeks. Similarly, treatment-naïve, cirrhotic patients were randomized to receive the investigational combination for either eight or six weeks. The primary endpoint of the study is the percentage of patients achieving sustained virologic response 12 weeks after the completion of therapy (SVR12). An additional analysis of patients with genotype 3 (GT3) HCV enrolled in the C-SWIFT study will be presented at a future scientific congress.

About C-CREST

Based upon the interim findings from C-SWIFT and data from the Phase 1 clinical trial for MK-3682, also presented at The Liver Meeting®, Merck plans to initiate Phase 2 clinical trials evaluating the efficacy and safety of two short-duration triple therapy regimens: MK-3682 in combination with grazoprevir/elbasvir; and MK-3682 in combination with grazoprevir and Merck’s investigational early-stage NS5A inhibitor MK-8408, in non-cirrhotic HCV patients. Part A of the Phase 2 studies is planned to evaluate eight weeks of therapy among non-cirrhotic HCV-infected patients, and Part B studies may evaluate shorter courses of treatment based on findings from Part A.

MK-3682 (formerly IDX21437) Data Presentation at AASLD Annual Meeting

MK-3682 is an investigational oral prodrug HCV nucleotide analogue NS5B polymerase inhibitor. Phase 1/2a clinical trial results for MK-3682 are scheduled to be presented in a poster session (Abstract #1974) at The Liver Meeting®. HCV infected subjects (24 GT1 and 20 GT2/3) were randomized to receive placebo or 50, 150 or 300 mg of MK-3682 daily for seven days. Following initial pharmacokinetic and pharmacodynamic analysis, enrollment into the 50 mg and 150 mg treatment groups was discontinued due to a small reduction in viral load. In the 300 mg arms, the mean maximum viral load reductions from baseline for 7-day dosing were 4.6 and 4.1 log10 IU/mL in GT 2 (n=3) and GT 3 subjects (n=7), respectively. In GT1a (n=3) and GT1b subjects (n=5), the mean maximum viral load reductions from baseline for 7-day dosing were 4.8 and 3.9 log10 IU/mL respectively.

To date, no discontinuations due to an adverse event and no drug-related serious adverse events have been reported. Most adverse events were mild or moderate in intensity, with no apparent dose effect. There were no clinically significant abnormalities reported in routine blood and urine biomarker panels and physical examinations. Initial results from this study were previously announced by Idenix Pharmaceuticals in April 2014.

About Grazoprevir/Elbasvir

Grazoprevir/elbasvir (MK-5172/MK-8742, MK-5172A) is an investigational, oral, once-daily, fixed-dose combination chronic HCV treatment, consisting of grazoprevir, an investigational oral, once-daily HCV NS3/4A protease inhibitor, and elbasvir, an investigational oral, once-daily HCV NS5A replication complex inhibitor. In October 2013, Merck announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to grazoprevir/elbasvir for treatment of chronic HCV infection. Breakthrough therapy designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

AASLD - Media Updates