AASLD 2016 Grazoprevir/elbasvir (Zepatier) plus sofosbuvir (Sovaldi) highly effective for hard-to-treat genotype 3 hepatitis C patients

HIVandHepatitis conference coverage includes commentary with interim results from ongoing clinical studies by freelance medical writer, editor, and health educator Liz Highleyman. Additional  conference reports are available at aidsmap and Infohep.

HIVandHepatitis - Reported by Liz Highleyman

Grazoprevir/elbasvir + sofosbuvir highly effective for hard-to-treat genotype 3 hepatitis C patients
A triple regimen of grazoprevir/elbasvir (Zepatier) plus sofosbuvir (Sovaldi) without ribavirin cured 96% of previously untreated and 97% of treatment-experienced people with hepatitis C virus (HCV) genotype 3 and liver cirrhosis, matching
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Coverage reported by Jules Levin the Executive Director of NATAP - National AIDS Treatment Advocacy Project. Coverage at NATAP includes full text articles and slides to review without the hassle of going through a registration process.

NATAP ​- Reported by Jules Levin review slides​
ELBASVIR/GRAZOPREVIR PLUS SOFOSBUVIR ± RIBAVIRIN IN TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 3 INFECTION AND COMPENSATED CIRRHOSIS: THE C-ISLE STUDY

MPR by Bryant Furlow
EBR/GZR+SOF ± RBV is 'Highly Efficacious' for HCV GT3
Elbasvir/grazoprevir (EBR/GZR) and sofosbuvir (SOF) with and without ribavirin (RBV; EBR/GZR + SOF ± RBV) regimen was generally safe and effective for cirrhotic patients with hepatitis C virus (HCV) GT3 infections, according to an author of the UK-based randomized, open-label C-ISLE trial that were presented at The Liver Meeting® 2016.
Additional updates @ MPR

AASLD Updates - On This Website
Sift through highlights from The Liver Meeting arranged by the following topics;
Multimedia
​​Safety Profile
​Reinfection
Sofosbuvir or Daclatasvir-Based Regimens
Key data indexed by pharmaceutical company
Treatment with direct-acting antiviral (DAA) agents; Veterans and Elderly
HCV and Liver Disease; Fibrosis, Cirrhosis, Liver Cancer, Liver Transplant, Liver Failure,​ and Fatty Liver/non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)
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Updates On This Blog: AASLD 2016

Prometheus HepaStem - Therapeutic alternative to liver transplantation could be on horizon in NASH

Nov 11
Therapeutic alternative to liver transplantation could be on horizon in NASH
Kris Gellynck, PhD, manager of research and development at Promethera Biosciences in Brussels, will present data at this year’s annual meeting for the American Association for the Study of Liver Diseases showing that it was possible to decrease nonalcoholic liver disease scores by using what would be marketed as an “off the shelf” product. HepaStem has been classified by the European Medicines Agency as a medicinal product, and is comprised of human adult liver–derived mesenchymal stem cells cryopreserved and reconstituted as needed..
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Nov 14
Prometheus BioScience Inc. Provides Update On Hepastem NASH-Fibrosis Program With Late-Breaking Preclinical Data At 2016 American Association for Study of Liver Diseases Meeting

--HepaStem reduces liver inflammation and improves fibrosis symptoms in a NASH mouse model--

MONT-SAINT-GUIBERT, Belgium--(BUSINESS WIRE)--Promethera Biosciences SA, a world-leading cell therapy and regenerative medicine company targeting liver diseases, today announced the presentation of new preclinical NASH-Fibrosis data from its proprietary HepaStem program, demonstrating a beneficial effect of HepaStem in a nonalcoholic steatohepatitis (NASH) mouse model and confirming Hepastem’s unique and multifaceted mode of action. The results were presented on Sunday, November 13th by the Promethera R&D and Medical Affairs team, in a late-breaking poster presentation titled, “Clinical-grade human liver mesenchymal stem cells for the treatment of NASH-Fibrosis through immunomodulation” at The Liver Meeting® 2016, the 67th Annual Meeting of the American Association for the Study of Liver Disease (AASLD), currently being held in Boston, Massachusetts.

“These first data support that HepaStem has the strong potential to modulate and decrease inflammation and fibrosis, opening the route to promising clinical trials in NASH and other severe inflammatory conditions of the liver”

In the study, HepaStem was administered in a single and repeated dose setting with or without immunosuppression in a NASH STAMTM cell mouse model. HepaStem significantly reduced inflammation and Nonalcoholic Fatty Liver Diseases (NAFLD) Activity score (NAS), as well as fibrotic collagen deposition in liver sections at 9 weeks of age. In addition, Promethera’s in-house R&D could further elucidate the underlying immunomodulatory effect of HepaStem cells. In in vitro co-culturing systems with T-lymphocytes or dendritic cells, HepaStem was shown to decrease T-cell activation and dendridic cell generation and activation in vitro. HepaStem cells were also shown to secrete high levels of HGF (Hepatocyte Growth Factor), a growth factor known to inhibit stellate cells, the key in-situ players in liver fibrosis development.

“These first data support that HepaStem has the strong potential to modulate and decrease inflammation and fibrosis, opening the route to promising clinical trials in NASH and other severe inflammatory conditions of the liver,” said Prof. Dr. Etienne Sokal, Founder and CI and CSO of Promethera Biosciences. He added that Promethera is further investigating preclinical studies in various liver inflammatory and fibrotic models.

“Promethera is in the process of building on results such as these that firmly support our expansion to the larger indications of NASH, liver inflammation and fibrosis,” said Dr. John Tchelingerian, CEO of Promethera Biosciences. “With the good safety profile shown in the pediatric patients from our initial clinical studies, HepaStem cells offer a unique product profile which we believe will differentiate Promethera’s approach as a novel and impactful cell therapy platform in a highly-competitive environment as our industry seeks therapies for devastating liver diseases.”

HepaStem is a cell suspension constituted of heterologous human adult liver-derived mesenchymal stem cells isolated from ethically donated healthy adult human liver tissue. HepaStem treatment has been shown to be safe in a phase I/II study in 20 pediatric patients suffering from inherited metabolic disorders.

About Promethera Biosciences
Promethera Biosciences is a clinical stage biopharmaceutical company and the global leader in cell therapy and regenerative medicine for the treatment of inborn and acquired liver diseases with no effective therapeutic cure. Promethera uses allogeneic progenitor cells, stem cells and mature hepatocytes that are harvested and purified from non-transplantable, healthy human livers (Heterologous Human Adult Liver-derived Progenitor Cells, HHALPC and Heterologous Human Liver Cells, HHLivC). These technologies have resulted in the development of three different cell products, HepaStem and H2Stem (progenitor/stem cells) and Heparesc® (mature hepatocytes). Promethera specializes in the development of therapeutic options for the treatment of a broad variety of liver diseases. These range from orphan indications, such as rare inborn metabolic diseases including urea cycle disorders (UCD) to large indications such as acute-on-chronic liver failure (ACLF), and nonalcoholic steatohepatits (NASH)/fibrosis.

Promethera Biosciences is a spin-off of the Walloon Region-based Université catholique de Louvain (UCL) and was founded in 2009 by Prof. Dr. Etienne Sokal and Sopartec, the tech transfer office (TTO) of UCL. Promethera is headquartered in Mont-Saint-Guibert, Belgium with a U.S. based operation and a GMP compliant manufacturing facility in Durham, NC, US. For more information, visit www.promethera.com.

AASLD 2016 Study eyed zinc for slowing progression of chronic liver disease

Study eyed zinc for slowing progression of chronic liver disease

BOSTON – Oral zinc supplementation was associated with maintenance of liver function and suppression of hepatocellular carcinoma in a retrospective cohort study of 267 patients with chronic liver disease.

Additional analyses revealed stepwise inverse relationships between serum zinc levels and rates of de novo liver failure, hepatocellular carcinoma, and death, Atsushi Hosui, MD, PhD, said at the annual meeting of the American Association for the Study of Liver Diseases. No patients stopped zinc therapy because of adverse events, and there were no serious adverse events, although some patients experienced nausea, which can occur with zinc supplementation, noted Dr. Hosui of Osaka-Rosai Hospital, Japan.

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AASLD 2016 Gilead Phase 2 Data for Selonsertib in Nonalcoholic Steatohepatitis (NASH)

Phase 2 Data for Selonsertib in Nonalcoholic Steatohepatitis (NASH) Presented at The Liver Meeting® 2016
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-- Results Demonstrate Improvement in Fibrosis Stage among NASH Patients with Moderate to Severe Fibrosis --

BOSTON--(BUSINESS WIRE)--Nov. 14, 2016-- Gilead Sciences (Nasdaq:GILD) today announced detailed results from an open-label Phase 2 trial evaluating the investigational apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib (formerly GS-4997) alone or in combination with the monoclonal antibody simtuzumab (SIM) in patients with nonalcoholic steatohepatitis (NASH) and moderate to severe liver fibrosis (fibrosis stages F2 or F3). The data demonstrate regression in fibrosis that was, in parallel, associated with reductions in other measures of liver injury in patients treated with selonsertib for 24 weeks. These data were presented in a late-breaking abstract session at The Liver Meeting® 2016 in Boston (#LB-3).

Patients receiving selonsertib demonstrated improvements in several measures of liver disease severity, including fibrosis stage, progression to cirrhosis, liver stiffness (measured by magnetic resonance elastography, MRE) and liver fat content (measured by magnetic resonance imaging (MRI)-proton density fat fraction, PDFF). Data for these efficacy endpoints are summarized in the table below. As no differences were observed between combination and monotherapy, results are presented for selonsertib (18 mg and 6 mg) with/without SIM and for SIM alone. Additionally, patients with fibrosis improvement demonstrated reductions in hepatic collagen content, liver biochemistry (e.g., serum ALT) and the apoptosis marker, cytokeratin-18, supporting the biological activity of selonsertib.

Endpoint (Week 24)			Selonsertib 18 mg ± SIM			Selonsertib 6 mg ± SIM			SIM
Fibrosis Improvement ≥1 Stage from Baseline*			43% (n=13/30)			30% (n=8/27)			20% (n=2/10)
Progression to Cirrhosis			3% (n=1/30)			7% (n=2/27)			20% (n=2/10)
≥15% Reduction in Liver Stiffness by MRE			20% (n=5/25)			32% (n=7/22)			0% (n=0/7)
≥30% Reduction in Liver Fat by MRI-PDFF			26% (n=8/31)			13% (n=3/24)			10% (n=1/10)
*Fibrosis staged according to the NASH Clinical Research Network (CRN) classification by a central pathologist blinded to treatment group.

Selonsertib demonstrated no dose-related increases in treatment-emergent adverse events or serious adverse events. Headache, nausea and sinusitis were the most common adverse events in patients receiving selonsertib.

“Currently, no approved treatments exists for NASH, and patients with advanced fibrosis would potentially benefit from new options to halt and/or reverse the progression of their disease,” said Rohit Loomba, MD, MHSc, lead study author and Director, NAFLD Research Center, Director of Hepatology, Professor of Medicine, Vice Chief, Division of Gastroenterology, University of California San Diego School of Medicine. “After only 24 weeks of therapy, selonsertib exhibited promising anti-fibrotic activity in this study, which was the first known multi-center NASH clinical trial to use centrally-assessed MRE, MRI-PDFF, in addition to liver biopsy as endpoints. Based on these data, selonsertib represents an important investigational drug candidate for further clinical trials in patients with NASH and significant fibrosis.”

Other Gilead NASH data being presented at The Liver Meeting include results from Phase 1 studies evaluating the investigational selective, non-steroidal Farnesoid X receptor (FXR) agonist GS-9674. Data from a Phase 1 study demonstrated the biological activity and safety profile of GS-9674 in healthy volunteers and support the evaluation of this compound in patients with NASH and cholestatic liver disorders (#1077 and #1140). Phase 2 studies with GS-9674 are ongoing in patients with NASH, primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Additionally, preclinical data for the combination of selonsertib and GS-9674 in a rodent model of advanced fibrosis suggested that the combination of selonsertib and GS-9674 resulted in greater anti-fibrotic activity than either agent alone (#1588). These preclinical data support clinical evaluation of combination approaches with selonsertib and GS-9674 in patients with NASH and advanced fibrosis.

Selonsertib, GS-9674 and simtuzumab have not been determined to be safe or efficacious.

About Selonsertib and the Study

Selonsertib is an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis (cell death) and fibrosis in settings of oxidative stress. Oxidative stress can be increased in many pathological conditions including liver diseases such as NASH.

This Phase 2, randomized, open-label trial evaluated the safety, tolerability and efficacy of selonsertib alone or in combination with SIM in 72 patients with NASH and fibrosis stages F2 (n=25) or F3 (n=47). Eligible patients were randomized (2:2:1:1:1) to receive selonsertib 6 mg (n=20), selonsertib 18 mg (n=22), selonsertib 6 mg plus SIM 125 mg (n=10), selonsertib 18 mg plus SIM 125 mg (n=10) or SIM 125 mg alone (n=10) for 24 weeks. Selonsertib was administered orally once daily and SIM was administered via weekly subcutaneous injection.

About Gilead’s Clinical Programs in NASH

Gilead is advancing a pipeline of novel investigational therapies for the treatment of NASH with advanced fibrosis. Gilead is currently planning or conducting Phase 2 and Phase 3 clinical trials evaluating single-agent and combination therapy approaches against multiple core pathways associated with NASH – metabolic dysfunction, inflammation and fibrosis. Compounds in development include the ASK1 inhibitor, selonsertib; the FXR agonist, GS-9674; and an inhibitor of acetyl-coA carboxylase (ACC), GS-0976, currently being evaluated in a Phase 2 study in patients with NASH.

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. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

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 Gilead’s ability to initiate or complete its Phase 2 and Phase 3 clinical trial programs evaluating selonsertib, GS-9674 and GS-0976 in patients with NASH in the currently anticipated timelines or at all. In addition, there is the possibility of unfavorable results from further clinical trials involving these compounds. Further, it is possible that Gilead may make a strategic decision to discontinue development of selonsertib, GS-9674 and GS-0976 if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. As a result, selonsertib, GS-9674 and GS-0976 may never be successfully commercialized. 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, 2016, 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.

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

AASLD 2016 IFN-free DAA Regimens Found Safe and Effective for Elderly Patients

IFN-free DAA Regimens Found Safe and Effective for Elderly Patients
By Da Hee Han, PharmD
BOSTON, MA—Interferon (IFN)-free direct-acting antiviral agent (DAA) regimens are “as safe and effective” for elderly patients with hepatitis C virus (HCV)-related cirrhosis or severe fibrosis as they are for younger patients, according to research presented at The Liver Meeting® 2016.

“The lifetime utility of HCV eradication in the elder in terms of reduction of events and overall survival needs evaluation in long-term observational cohorts,” however, cautioned senior study author Vincenza Calvaruso, MD, PhD, of the University of Palermo, in Palermo, Italy.
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DAAs Effective for Chronic HCV, Even in Very Elderly
By Da Hee Han, PharmD November 14, 2016
BOSTON, MA—“Advanced age in and of itself should not be considered a barrier to direct-acting antiviral (DAA) treatment” in patients with chronic hepatitis C virus (HCV) infection, a study in more than 17,000 veterans presented at The Liver Meeting® 2016 concluded.

“DAAs are equally highly effective for the treatment of chronic HCV in all age groups, including very elderly patients,” added Feng Su, MD, University of Washington, Seattle, WA and Veterans Affairs Puget Sound Healthcare System, Seattle, WA, and colleagues.
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Additional updates @ MPR
Updates On This Blog: AASLD 2016

AASLD 2016 Merck's HCV Triple-Combination High Rates of SVR In Genotypes 1, 2 or 3 Infection

Related
AASLD - Slides available @ NATAP
Safety and Efficacy of the Fixed-Dose Combination Regimen of MK-3682/Grazoprevir/MK-8408 (Ruzasvir) With or Without Ribavirin in Non-cirrhotic or Cirrhotic Patients with Chronic HCV GT1, 2 or 3 Infection (Part B of C-CREST-1 & -2)

High Sustained Virologic Response Rates in Patients with Chronic HCV GT1, 2 or 3 Infection Following 16 Weeks of MK-3682/Grazoprevir/MK-8408 (Ruzasvir) Plus Ribavirin After Failure of 8 Weeks of Therapy (Part C of C-CREST-1 & 2) 

Safety and Efficacy of the Fixed-Dose Combination Regimen of MK-3682 / Grazoprevir / MK-8408 (Ruzasvir) in Cirrhotic or Non-cirrhotic Patients with Chronic HCV GT1 Infection who Previously Failed a Direct-acting Antiviral Regimen (C-SURGE) 

View all conference coverage at NATAP

Merck Announces Findings for Investigational Triple-Combination Chronic Hepatitis C Therapy Showing High Rates of Sustained Virologic Response in People with Genotypes 1, 2 or 3 Infection

Phase 2 Data Presentations at The Liver Meeting® Detail SVR12 Rates from Two Studies as Well as SVR8 Rates in Patients for Whom Direct-Acting Antiviral Treatment Previously Failed

November 13, 2016 08:00 AM Eastern Standard Time
KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced the presentation of results from three Phase 2 clinical trials evaluating MK-3682B (MK-3682/grazoprevir/ruzasvir1), the company’s investigational all-oral, triple-combination regimen for the treatment of chronic hepatitis C (HCV) infection (informally referred to as MK3). Results from Part B of C-CREST 1 & 2 demonstrated high rates of sustained virologic response2 (SVR) 12 weeks after the completion of therapy (SVR12, considered virologic cure) in patients with chronic HCV genotype (GT) 1 or GT3 infection who received eight weeks of treatment with MK-3682B. Findings from C-CREST 1 & 2 Part B also demonstrated high rates of SVR12 in GT1, GT2 and GT3-infected patients who received MK3 for 12 or 16 weeks. Findings from Part C of C-CREST 1 & 2 and interim results from the ongoing C-SURGE study showed high rates of SVR12 and SVR8, respectively, in chronic HCV patients who had failed prior treatment with investigational or approved direct-acting antiviral regimens. These results will be announced in oral presentations at The Liver Meeting® 2016 today (C-CREST 1 & 2 Parts B and C) and tomorrow (C-SURGE).

“Across the chronic hepatitis C treatment landscape, incredible progress has been made in a remarkably short amount of time, but there remains a need for more options, particularly for patients who do not achieve sustained virologic response with treatment regimens available today,” said Dr. Eliav Barr, senior vice president, global clinical development, infectious diseases and vaccines, Merck Research Laboratories. “The strong findings observed following treatment with MK-3682B are an encouraging step towards Merck’s goal of developing and delivering a shorter-duration, pan-genotypic next-generation treatment regimen for more patients with chronic hepatitis C infection.”

C-CREST 1 & 2 Part B Overview and Findings

Part B of C-CREST 1 & 2 – ongoing, open-label Phase 2 clinical trials – was designed to evaluate the safety and efficacy of MK-3682B in patients with chronic HCV GT1, GT2 or GT3 infection, with or without cirrhosis. Patients with GT2 or GT3 infection received MK-3682B with or without RBV. All patients with GT1 or GT2 infection were treatment-naïve. Fifty six percent (189/337) of patients with GT3 infection were treatment naïve and 44 percent (148/337) were previously treated with peginterferon/ribavirin (RBV). The primary endpoint of the study was the proportion of patients in each treatment arm who achieved SVR12.

Eight weeks of treatment with MK-3682B resulted in SVR12 rates of 95 percent, 86 percent and 95 percent in GT1, GT2 and GT3 patients, respectively. A 12-week treatment duration resulted in high SVR12 rates in all genotypes (GT1, 99%; GT2, 97%; GT3, 97%). Efficacy was comparable in patients with and without cirrhosis. There were no virologic failures in the patients with GT1 or GT2 infection who received 12 weeks of MK-3682B. Efficacy results are presented in the table below. Results from Part A of C-CREST 1 & 2 were previously reported at The Liver Meeting® in November 2015.   

Summary of SVR12 Findings

Population

N

MK-3682B +/- RBV 8 weeks

MK-3682B +/- RBV 12 weeks

MK-3682B +/- RBV 16 weeks

GT1a

90

93% (39/42)

98% (47/48)

-

GT1b

86

98% (45/46)

100% (40/40)

-

GT2

151

86% (54/63)

97% (60/62)

100% (26/26)

GT3*

337

95% (98/103)

97% (155/159)

96% (72/75)

*28 percent (29/103), 36 percent (58/159) and 81 percent (61/75) of patients with GT3 infection receiving eight, 12 or 16 weeks of therapy, respectively, were previously treated with peginterferon/RBV

  
Among patients who received at least one dose of MK-3682B with or without RBV, the overall most common adverse events (AEs) reported (greater than 10% incidence in either treatment arm) were headache (22%), fatigue (19%) and nausea (13%). There were two drug-related serious AEs, both considered related to RBV only. Nine patients discontinued study drug due to AEs, four of whom discontinued RBV only. One patient died due to AEs not related to the study drug.

“As a scientist and physician who regularly treats patients with chronic hepatitis C, the importance of continuing to research this complex disease and its many complications is evident,” said Dr. Eric Lawitz, vice president, scientific and research development, The Texas Liver Institute and clinical professor of medicine, The University of Texas Health Science Center, San Antonio. “The virologic cure rates observed in Part B of C-CREST 1 & 2 clearly demonstrate the potential for MK3 and support further study of this investigational regimen.”

C-SURGE Overview and Preliminary Findings

C-SURGE is an ongoing, open-label Phase 2 clinical trial designed to evaluate MK-3682B with or without RBV in chronic HCV GT1 patients who previously failed therapy with either ledipasvir/sofosbuvir (LDV/SOF) or ZEPATIER™ (elbasvir and grazoprevir). The study enrolled 94 patients randomized to receive 16 weeks of MK-3682B plus RBV (n=45) or 24 weeks of MK-3682B without ribavirin (n=49); one patient in the 16 week arm withdrew prior to starting treatment. Of the 93 patients who received treatment in this study, 61 percent (57/93) had previously received 12 to 24 weeks of treatment with LDV/SOF; 15 percent (14/93) had received 8 weeks of LDV/SOF; and 24 percent (22/93) had received 12 weeks of ZEPATIER. A majority of patients (84%, 78/93) had at least one baseline NS5A resistance-associated variant (RAV) at positions 28, 30, 31 or 93.

Interim results from the modified full analysis set (mFAS), which excludes one patient in the 16-week arm who withdrew due to administrative reasons after receiving three doses of study medication, show all patients (43/43) who have completed treatment with MK-3862B plus RBV for 16 weeks achieved SVR8. All patients (49/49) in the mFAS who received MK-3682B for 24 weeks have completed treatment and remain subject to follow-up; the interim results show of those in the 24-week arm who have reached follow-up weeks four and eight, 100 percent have achieved SVR4 (38/38) and SVR8 (30/30), respectively. SVR12 is the primary outcome measure of this ongoing trial. Final results will be presented at a future scientific congress.

Among patients who received at least one dose of MK-3682B with or without RBV, the overall most common AEs reported were fatigue (35%), headache (13%), diarrhea (9%), rash (9%) and pruritus (5%). There were no drug-related serious AEs, and no patients discontinued due to a drug-related AE.

C-CREST 1 & 2 Part C Overview and Findings

Part C of C-CREST 1 & 2 was designed to evaluate retreatment with MK-3682B plus RBV for 16 weeks among patients who previously failed an investigational triple-therapy regimen (MK-3682/grazoprevir/ruzasvir or MK-3682/grazoprevir/elbasvir). The study enrolled 24 patients with GT1 (n=2), GT2 (n=14) or GT3 (n=8) infection. All patients (23/23) who completed treatment achieved SVR12. One GT2 patient discontinued treatment after a single dose due to drug-related serious AEs. Among patients who received at least one dose of MK-3682B plus RBV, the most common AEs reported (greater than 20% incidence) were headache (33%), fatigue (25%), nausea (25%), rash (21%) and insomnia (21%).

About MK-3682B

MK-3682B (informally referred to as MK3) is Merck’s investigational triple-combination therapy in Phase 2 development for the treatment of chronic HCV infection. MK-3682B combines an HCV nucleotide analogue NS5B polymerase inhibitor (MK-3682), an HCV NS3/4A protease inhibitor (grazoprevir, MK-5172) and an HCV NS5A inhibitor (ruzasvir, MK-8408).

About ZEPATIER™ (elbasvir and grazoprevir) 50 mg/100mg tablets

ZEPATIER is a fixed-dose combination product containing elbasvir, an HCV NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. ZEPATIER is indicated with or without ribavirin (RBV) for treatment of chronic HCV genotypes 1 or 4 infection in adults.

Selected Safety Information about ZEPATIER

ZEPATIER is not for use in patients with moderate or severe hepatic impairment (Child Pugh B or C). ZEPATIER is also not for use with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors (e.g., atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine), strong cytochrome P450 3A (CYP3A) inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s Wort), and efavirenz. If ZEPATIER is administered with RBV, healthcare professionals should refer to the prescribing information for RBV as the contraindications, warnings and precautions, adverse reactions and dosing for RBV also apply to this combination regimen.

Elevations of alanine transaminase (ALT) to greater than 5 times the upper limit of normal (ULN) occurred in 1% of subjects, generally at or after treatment week 8. These late ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Healthcare professionals should perform hepatic lab testing on patients prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, additional hepatic lab testing should be performed at treatment week 12.

Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces. Healthcare providers should consider discontinuing ZEPATIER if ALT levels remain persistently greater than 10 times ULN. ZEPATIER should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalized ratio.

The concomitant use of ZEPATIER with certain drugs may lead to adverse reactions or reduced therapeutic effect due to drug interactions. Certain strong CYP3A inhibitors may increase the plasma concentration of ZEPATIER, leading to possibly clinically significant adverse reactions. Moderate CYP3A inducers may decrease the plasma concentration of ZEPATIER, leading to reduced therapeutic effect and possible development of resistance. Coadministration of ZEPATIER with these drugs is not recommended. Physicians should consult the Prescribing Information for potential drug interactions.

In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache and nausea. In subjects receiving ZEPATIER with RBV for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (greater than or equal to 5%) were anemia and headache.

Selected Dosage and Administration Information for ZEPATIER (elbasvir and grazoprevir)

ZEPATIER is a single tablet taken once daily. The recommended dosing is 12 or 16 weeks with or without RBV, depending on HCV genotype, prior treatment history and, for patients with genotype 1a infection, presence of certain baseline NS5A resistance-associated polymorphisms. See Prescribing Information for ZEPATIER for specific dosage regimens and durations. Refer to RBV prescribing information for RBV dosing and dosage modifications when ZEPATIER is given with RBV. To determine dosage regimen and duration of ZEPATIER for genotype 1a patients, testing for the presence of virus with one or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, or 93 is recommended prior to initiating treatment.

http://www.businesswire.com/news/home/20161113005036/en/Merck-Announces-Findings-Investigational-Triple-Combination-Chronic-Hepatitis

AASLD 2016 Liver Cancer Rare After HCV Therapy

Liver Cancer Rare After HCV Therapy

by Michael Smith Michael Smith
North American Correspondent, MedPage Today

But some patients develop aggressive form of the disease

BOSTON -- For patients with advanced liver disease owing to hepatitis C (HCV), treatment with direct-acting antiviral agents did not increase the risk of hepatocellular carcinoma, a researcher said here.

The risk of liver cancer in the first year after such therapy was pretty much the same as it is in untreated patients, according to Alfredo Alberti, MD, of the University of Padua in Italy.

On the other hand, the rare patients who developed cancer after HCV treatment were more likely to have an aggressive form of the disease, Alberti told reporters at the American Association for the Study of Liver Diseases (AASLD) annual meeting.

The findings, from a large prospective cohort of patients in northern Italy, should help to settle what has been a "controversial and confusing issue," Alberti said, with small studies yielding conflicting results on the issue.
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Additional Reading @ MedPage Today

Fibrosis Risk High in Kids With Transplanted Livers

Those with cirrhosis at risk of liver failure and graft loss

Marked Sex Difference Seen in Drug-Induced Liver Failure

Brain damage, polypharmacy more common in women with ALF

AASLD: HCV Outcomes Under Scrutiny

Treatment now 'predictably' good in trials but what about real world?

AASLD: Focus on Liver Broadens

Fatty liver disease expected to get lion's share of spotlight

Elsewhere
Current updates: Conference Reports
Updates On This Blog: AASLD 2016

AASLD 2016 Glecaprevir/Pibrentasvir: High SVR Rates in HCV GT 2, 4, 5, 6 Without Cirrhosis

Nov 13
Glecaprevir/Pibrentasvir: High SVR Rates in HCV GT 2, 4, 5, 6 Without Cirrhosis
By Debra Hughes, MS
Patients with chronic hepatitis C virus (HCV) genotypes (GT) 2, 4, 5, or 6 infection without cirrhosis had SVR12 rates of 97% after 8 weeks of treatment with co-formulated glecaprevir/pibrentasvir, investigators from the SURVEYOR-II, Part 4, concluded at The Liver Meeting® 2016.​

Press Release
Nov 11
Update AbbVie's Glecaprevir/Pibrentasvir (G/P) Acheive High SVR12 Rates at 8 Wks Genotypes 1-6
- 97.5 percent of chronic HCV infected patients without cirrhosis and new to treatment across all major genotypes (GT1-6) achieved SVR12 with 8 weeks of G/P
- Across the 8-week arms of three registrational studies, no patients discontinued treatment due to adverse events
- G/P is an investigational, pan-genotypic, once-daily, ribavirin-free regimen for the treatment of chronic HCV

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