Posted On: October 31, 2012 - 6:31pm
STANFORD, Calif. — Stanford University School of Medicine scientists have used bioengineered mice with livers composed largely of human cells to characterize a drug about to enter early-stage clinical development for combating hepatitis C.
Tests using the new mouse model accurately predicted significant aspects of the drug's behavior in humans — including its interaction with another drug and the profile of its major breakdown products in the body (called metabolites) — far more accurately than would have been achieved using current methods.
The study will be published online Oct. 31 in the Journal of Pharmacology and Experimental Therapeutics. Its findings hold potentially huge implications for drug development in general, because key aspects of the tested drug's activity and properties would likely have gone unnoticed using the kind of mouse study that is the current standard for preclinical tests of candidate drugs.
Importantly, the results strongly hint that the drug, clemizole, could be both safe and an effective drug-cocktail component in humans infected with HCV, the virus that causes hepatitis C.
"This gives us a new tool for improving the testing of drugs before they are given to people in clinical trials," said the study's senior author, Gary Peltz, MD, PhD, professor of anesthesiology, pain and perioperative medicine.
All too often, drugs showing tremendous promise in preclinical animal assessments fail in human trials because of unforeseen safety problems, said Peltz. "It's often not the drug itself, but one of its metabolites, that is responsible for a drug-induced toxicity."
Unexpected interactions between drugs pose another big problem for drug development. A drug may prolong or attenuate another medication's activity by, for example, affecting how the second drug is metabolized. With more than 30 percent of all people over age 57 taking five or more prescription drugs at any given time, that's no trivial matter.
The drug tested in the study, clemizole, was widely prescribed in the 1950s and 1960s as an antihistamine, but it is no longer used because more effective antihistamines now exist, said Jeffrey Glenn, MD, PhD, associate professor of gastroenterology and hepatology, and of microbiology and immunology. "Moreover, the drug tends to accumulate in the liver, which is not ideal for a general-purpose antihistamine but could be very attractive for a virus like HCV that only infects the liver," he said.
Glenn, who is a hepatitis C expert and a co-author of the new study, recently led a team that discovered clemizole impedes replication of HCV. More than 150 million people are infected with HCV, the leading cause of liver transplant operations in the United States and primary cause of liver cancer. Current HCV treatments are highly expensive and, frequently, harsh.
Clemizole is both cheap and safe. But because it was approved before the advent of some testing requirements now routinely in place for new drugs, little is known about how the compound is metabolized or how it interacts with other drugs in the human body, Glenn said.
These days, before any drug can go into people it must first be rigorously tested in animals, such as rodents, to determine tolerability or adverse effects and whether it interacts with other drugs patients are likely to be taking. But mice metabolize things differently from humans, largely because our livers are different.
The liver is the body's chemistry set. It operates like a set of carefully placed workstations in an assembly line, in which batteries of enzymes (protein machines that do most of the body's work) manufacture substances vital to our survival as well as metabolize ingested substances, including drugs.
Mouse and human livers have different drug-metabolizing enzymes. So the two species will produce different metabolites or different amounts of the same metabolites from the same drug. Attempts to get around this have included bioengineering so-called chimeric mice that have "humanized" livers, in which mouse liver tissue has been at least partly replaced by human cells. These efforts have involved introducing toxins or genetic defects to kill off the intrinsic mouse liver cells to make room for their replacement by human ones. But the organ's ongoing malfunction impaired human-cell growth or made "readouts" from drug testing suspect.
So Peltz and collaborators at the Central Institute for Experimental Animals in Japan built a better mousetrap. In 2011, they produced a genetically engineered mouse in which the liver could be humanized without inducing ongoing liver toxicity. The researchers administered a short-acting, non-toxic dose of a drug to mice that had been bioengineered so that the drug would activate a cell-killing mechanism only within their liver cells. Once this drug was cleared, the implanted human liver cells could develop normally in their new environment, contributing to a reconstituted liver that largely recapitulated the architecture and chemistry of a functioning human liver. The human cells produced human metabolites; the mouse cells continued to produce mouse metabolites.
The chimeric mice used in the new study varied in the extent to which their livers were composed of human cells. Their overall metabolic profiles could be likened to two images projected in juxtaposition on a screen, with the difference between the two images corresponding to the extent that a mouse's liver had been humanized. To determine the extent of liver humanization for each mouse, Peltz and his associates measured blood levels of the human version of albumin, a circulating protein produced in the liver. A mathematical algorithm the researchers developed allowed them to accurately determine which metabolites, and how much of each, could be attributed to mouse and human liver cells, respectively.
Next, Manhong Wu, PhD, a research associate in the Peltz lab and a study co-author, examined the metabolism of clemizole in both humans and several ordinary mouse strains. Clemizole's metabolic pattern was the same in all of the tested strains, but was quite different from that observed in the blood of 10 human subjects. More than half of the total amount of clemizole plus its metabolites in human blood consisted of a single metabolite, known as M1. In ordinary mice, M1 is a trace product.
However, postdoctoral scholar Yajing Hu, PhD, who shares first authorship with visiting professor Toshiko Nishimura, MD, PhD, found that the chimeric mice did produce M1, roughly in proportion to the extent to which their own liver cells had been replaced by human ones. Further studies showed that M1 itself has antiviral activity that can contribute to clemizole's overall potency in humans — a fact that would have been ignored on the basis of testing clemizole in ordinary mice.
Then Peltz and his colleagues tested the chimeric mice's capacity to predict potential interactions between clemizole and other drugs. They picked a drug called ritonavir, which is known to interfere with a metabolic enzyme that is crucial to the breakdown of many drugs in humans. Chimeric mice were first treated with clemizole alone, and later given a combination of clemizole and ritonavir. Afterward, the scientists measured levels of clemizole and its metabolites in the mice's blood. Co-administering ritonavir caused clemizole's blood level to increase and to remain elevated for longer than was the case with clemizole alone.
To see if this held true in humans, Peltz's group initiated a small pilot study with three HCV-positive individuals. As occurred in the chimeric mice, co-administration of ritonavir caused a substantial increase in the blood levels of clemizole in two subjects and a smaller increase in the third subject.
In lab-dish tests assessing clinical potential, a combination of M1 (clemizole's primary metabolite) and boceprevir, a recently approved anti-HCV drug, proved to have far more anti-viral activity than did either compound alone — a synergy that Glenn called "dramatic."
All of the findings validate the utility of the new mouse model as well as clemizole's clinical potential, said Peltz. Clemizole has a half-life of only about 15 minutes in mice, so on the basis of ordinary mouse studies it might well have been discarded, he said. "You can't commercialize a drug you have to take 10 or 20 times a day." Further, Peltz said, "if clemizole's major human metabolite, M1, did cause toxicity in humans, ordinary mouse tests wouldn't have caught it. Conversely, if a metabolite produced in mice but not in humans had a toxic effect, studies performed on ordinary mice would have sent a false alarm."
Posted On: October 31, 2012 - 6:31pm
- Posted by HCV New Drugs
- File Under Just for fun
Could zombies exist? Should we be preparing for a Zombie Apocalypse? Find out how these ferocious, flesh-eating creatures could become a reality, through a simple scientific pathway.
Written and created by Mitchell Moffit (twitter @mitchellmoffit) and Gregory Brown (twitter @whalewatchmeplz).
AASLD President's Press Conference for The Liver Meeting®, Saturday, November 10, 2012 - 4:00-5:00 pm, Room 313, Hynes Convention Center
SOURCE American Association for the Study of Liver Diseases (AASLD)
BOSTON and Alexandria, Va., Oct. 31, 2012 /PRNewswire/ -- AASLD President Guadalupe Garcia-Tsao, MD, will host a press conference on the first full day of presentations at The Liver Meeting®, the annual meeting of the American Association for the Study of Liver Diseases.
Dr. Garcia-Tsao will highlight individual studies and themes from the 2047 abstracts to be presented at this year's meeting from the leading researchers in the field. She has selected to review 18 abstracts in advance of their actual presentation in scientific sessions for the benefit of the media:
- Active Ingredient Confusion for Acetaminophen-Containing Medications: A Cause of Double Dipping
- Prior Bariatric Surgery Increases the Risk of Acute Liver Failure from Acetaminophen Poisoning
- Maternal Obesity Promotes Offspring Non-Alcoholic Fatty Liver Disease (NAFLD) through Disruption of Molecular Circadian Rhythms
- Survey of nongenetic risk factors suggests that tobacco exposure, coffee consumption, the use of oral contraception and the number of pregnancies could affect disease risk or presentation of primary sclerosing cholangitis
- High Prevalence of Cirrhosis in Young Children with Cystic Fibrosis (CF), Initial Report of the CF Liver Disease Network
- Nonalcoholic fatty liver disease without cirrhosis is an emergent and independent risk factor of hepatocellular carcinoma: A population based study
- Impact of liver fibrosis in development of hepatocellular carcinoma in HBeAg negative genotype D patients with chronic hepatitis B treated with nucleos(t)ide analogues
- Coffee Consumption in NAFLD Patients with Lower Insulin Resistance is Associated with Lower Risk of Severe Fibrosis
- The Stroop Smartphone App is a Short and Valid Screening Tool for Minimal Hepatic Encephalopathy
- Randomized, controlled, double blind study of glycerol phenylbutyrate in patients with cirrhosis and episodic heaptic encephalopathy
- OPTIMIZE trial: Non-inferiority of twice-daily telaprevir versus administration every 8 hours in treatment-naive, genotype 1 HCV infected patients
- High Rate of Sustained Virologic Response with the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients Chronically Infected With HCV Genotype 1, 2, or 3
- A 12-Week Interferon-free Treatment Regimen with ABT-450/r, ABT-267, ABT-333 and Ribavirin Achieves SVR12 Rates (Observed Data) of 99% in Treatment-Naive Patients and 93% in Prior Null Responders with HCV Genotype1 Infection
- An Interferon-free, Ribavirin-free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Yielded SVR4 of 94% in Treatment-Naive Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection
- High Efficacy Of GS-7977 In Combination With Low or Full dose Ribavirin for 24 weeks In Difficult To Treat HCV Infected Genotype 1 Patients : Interim Analysis From The SPARE Trial
- Identification of a New Mechanism of Non-nucleoside Inhibition of HCV RNA-dependent RNA Polymerase by the Flavonoid Quercetagetin
- Randomized Controlled Phase 2 Study (RCT) with Tivantinib in pre-treated hepatocellular carcinoma (HCC): Efficacy, Safety, and MET-analysis
- Developing an RNAi Therapeutic for Liver Disease Associated with Alpha-1-Antitrypsin Deficiency
Dr. Garcia-Tsao is professor of internal medicine at Yale University School of Medicine and staff physician at the Connecticut Veterans Affairs Healthcare System where she is chief of the Section of Digestive Diseases and program director of the Hepatitis C Resource Center, one of four such centers nationwide. She is also director of the Clinical Core of the NIH-funded Liver Center at Yale.
Dr. Garcia-Tsao earned her medical degree from the Universidad Nacional Autonoma de Mexico in Mexico City and completed her internal medicine residency and gastroenterology fellowship at the Instituto Nacional de la Nutricion in Mexico City. She completed training in hepatology at Yale University and joined its faculty in 1989. She has published more than 100 original articles, chapters, and reviews. Dr. Garcia-Tsao's research has been mainly in the area of the complications of cirrhosis, specifically varices, variceal hemorrhage, ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome. She was part of the research team that established the threshold portal pressure level for the development of varices, that performed the only placebo-controlled study of propranolol in the prevention of first variceal hemorrhage and that performed a study defining the cutoff ascites polymorphonuclear cell count in the diagnosis of SBP. Her research has also defined the clinical characteristics and outcome of liver vascular malformations in hereditary hemorrhagic telangiectasia.
She has served as a member of the NIDDK-C Study Section of NIH and served as associate editor of the Journal of Hepatology. She has been a member of various international consensus conference teams that have established current standards in the treatment of portal hypertension and its complications. She was a part of the team that prepared the recent AASLD/ACG guidelines for the management of varices and variceal hemorrhage. Dr. Garcia-Tsao has participated in many AASLD activities and committees. She has served as secretary, chaired the education oversight committee and the membership committee, and served as co-organizer of a research workshop and a single topic conference.
Founded in 1950, AASLD is the leading organization of scientists and health care professionals committed to preventing and curing liver disease. AASLD has grown into an international society responsible for all aspects of hepatology, and the annual meeting attracts 8,500 physicians, surgeons, researchers, and allied health professionals from around the world.
The Liver Meeting® is the premier meeting in the science and practice of hepatology, including the latest findings on new drugs, novel treatments, and the results from pilot and multicenter studies.
When: November 9 - 13, 2012
Where:Hynes Convention Center
ontact: Please click here to obtain a press pass for this event.
Press releases and all abstracts are available online at www.aasld.org.
Media Contact: Ann Haran
Press Room: November 10 – November 13, 2012
Hynes Convention Center, Room 208
This release was issued through The Xpress Press News Service, merging e-mail and satellite distribution technologies to reach business analysts and media outlets worldwide. For more information, visit http://www.XpressPress.com.
High prevalence of antibiotic-resistant bacterial infections with cirrhosis
The latest issue of the Clinical Gastroenterology & Hepatology reports a high prevalence of antibiotic-resistant bacterial infections among patients with cirrhosis at a liver center in the USA.
-47% were found to be antibiotic resistant
There are limited data on the prevalence or predictors of antibiotic-resistant bacterial infections in hospitalized patients with cirrhosis in North America.
Exposure to systemic antibiotics is a risk factor for antibiotic-resistant bacterial infections.
However, little is known about the effects of the increasingly used oral nonabsorbed antibiotics.
Dr Guadalupe Garcia–Tsao and colleagues from Connecticut, USA analyzed data from patients with cirrhosis and bacterial infections hospitalized in a liver unit at a US hospital between 2009 and 2010.
Multivariate logistic regression was used to determine predictors of antibiotic-resistant bacterial infections.
Data were analyzed on the first bacterial infection of each patient, and a sensitivity analysis was performed on all infectious episodes per patient.
The researchers found that 30% of infections were nosocomial.
The team noted that urinary tract infections, and spontaneous bacterial peritonitis were most common.
Of the 70 culture-positive infections, 47% were found to be antibiotic resistant.
The research team found that exposure to systemic antibiotics within 30 days before infection was associated independently with antibiotic-resistant bacterial infections, with an odds ratio of 14.
The team observed that exposure to only nonabsorbed antibiotics (rifaximin) was not associated with antibiotic-resistant bacterial infections.
In a sensitivity analysis, exposure to systemic antibiotics within 30 days before infection and nosocomial infection was associated with antibiotic-resistant bacterial infections.
Dr Garcia-Tsao's team concluded, "The prevalence of antibiotic-resistant bacterial infections is high in a US tertiary care transplant center."
"Exposure to systemic antibiotics within 30 days before infection, but not oral nonabsorbed antibiotics, is associated with development of an antibiotic-resistant bacterial infections."
|Clin Gastroenterol Hepatol 2012: 10(11):
30 October 2012
Gilead's Once-Daily Novel Prodrug for the Treatment of HIV Meets 24-Week Primary Objective in Phase 2 Study
Compared to Stribild, the TAF-based regimen demonstrated statistically significantly smaller reductions from baseline to week 24 in bone mineral density at the lumbar spine and hip (p<0.005). In addition, small, statistically significant differences were seen in serum creatinine and in calculated creatinine clearance between the two arms in favor of the TAF-containing regimen (p<0.02). No patient discontinued study drug for renal adverse events. There were no statistically significant differences in the frequency of laboratory abnormalities and the frequency and nature of adverse events were generally similar between the two arms. Both regimens were generally well tolerated. Gilead plans to submit these data for presentation at a scientific conference next year.
“These interim findings are encouraging and warrant advancing this TAF-containing single tablet regimen into Phase 3 development,” said
TAF is also being studied in a second ongoing Phase 2 trial evaluating a single tablet regimen containing TAF, Janssen R&D Ireland’s protease inhibitor Prezista® (darunavir), cobicistat and emtricitabine compared to Truvada® (emtricitabine and tenofovir disoproxil fumarate) plus Prezista and cobicistat, dosed as individual components. The study is fully enrolled and 24-week results will be available in the first half of 2013.
About the Study
The Phase 2 study is a randomized, double-blind 48-week clinical trial among HIV-1 infected adults with HIV RNA levels (viral load) greater than or equal to 5,000 copies/mL and CD4 cell counts greater than 50 cells/mm3. A total of 170 patients were randomized (2:1) to receive a once-daily tablet containing TAF 10 mg/elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg (n=112) or Stribild (n=58). Bone mineral density was assessed in all patients by DEXA scans at baseline and at week 24.
The study is ongoing. Secondary endpoints will include the proportion of patients who achieve viral load of less than 50 copies/mL at 48 weeks of therapy, and changes in HIV-1 RNA and in CD4 cell count from baseline to Weeks 24 and 48. After week 48, patients will continue to take their blinded study drug until treatment assignments have been unblinded, at which point all will be given the option to participate in an open-label rollover extension and receive the TAF-based single tablet regimen.
Additional information about the study can be found at www.clinicaltrials.gov.
About Tenofovir Alafenamide Fumarate
Tenofovir alafenamide fumarate (TAF) is a nucleotide reverse transcriptase inhibitor and a novel prodrug of tenofovir, the active agent in Viread® (tenofovir disoproxil fumarate). Phase 1b dose-ranging studies identified a dose of TAF that is ten times lower than Viread and provides greater antiviral efficacy. The smaller milligram size of TAF may enable the development of new fixed-dose combinations and single tablet regimens for HIV therapy that are not feasible with Viread.
As an integrase inhibitor, elvitegravir interferes with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir was licensed by Gilead from
Cobicistat is Gilead’s proprietary potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body. Unlike ritonavir, cobicistat acts only as a pharmacoenhancing or “boosting” agent and has no antiviral activity. Gilead submitted an NDA to
TAF, elvitegravir and cobicistat are investigational products and their safety and efficacy have not yet been established.
Important Safety Information about Stribild
Stribild contains four Gilead compounds in a complete once-daily, single tablet regimen: elvitegravir 150 mg; cobicistat 150 mg; emtricitabine 200 mg; and tenofovir disoproxil fumarate 300 mg. Stribild is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve. Stribild does not cure HIV-1 infection.
BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (“tenofovir DF”), a component of Stribild, in combination with other antiretrovirals.
- Stribild is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Stribild have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Emtriva or Viread, which are components of Stribild. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Stribild. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
- Coadministration: Do not use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Do not use with drugs that strongly induce CYP3A as this may lead to a loss of virologic response and possible resistance to Stribild. Use with the following drugs is contraindicated: alfuzosin, rifampin, dihydroergotamine, ergotamine, methylergonovine, cisapride, lovastatin, simvastatin, pimozide, sildenafil for pulmonary arterial hypertension, triazolam, oral midazolam, and St. John’s wort.
- New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir DF and Stribild. Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent.
- Use with other antiretroviral products: Stribild should not be coadministered with products containing any of the same active components; with products containing lamivudine; with adefovir dipivoxil; or with products containing ritonavir.
- Decreases in bone mineral density (BMD) and cases of osteomalacia have been seen in patients treated with tenofovir DF. Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss.
- Fat redistribution and accumulation have been observed in patients receiving antiretroviral therapy.
- Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported.
- Common adverse drug reactions in clinical studies (incidence greater than or equal to 5%; all grades) were nausea, diarrhea, abnormal dreams, headache and fatigue.
- CYP3A substrates: Stribild can alter the concentration of drugs metabolized by CYP3A or CYP2D6.
- CYP3A inducers: Drugs that induce CYP3A can decrease the concentrations of components of Stribild. Do not use with drugs that strongly induce CYP3A as this may lead to loss of virologic response and possible resistance to Stribild.
- Antacids: Separate Stribild and antacid administration by at least 2 hours.
- Prescribing information: Consult the full prescribing information for Stribild for more information on potentially significant drug interactions, including clinical comments.
- Adult dosage: One tablet taken orally once daily with food.
- Renal impairment: Do not initiate in patients with CrCl below 70 mL/min. Discontinue in patients with CrCl below 50 mL/min.
- Hepatic impairment: Not recommended in patients with severe hepatic impairment.
- Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk. An Antiretroviral Pregnancy Registry has been established.
- Breastfeeding: Emtricitabine and tenofovir have been detected in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed.
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 risks related to the possibility of unfavorable 48-week results from this or other clinical trials involving TAF, including the trial evaluating the single tablet regimen of TAF, darunavir, cobicistat and emtricitabine. Further, Gilead may be unable to obtain clinical trial results in the timelines currently anticipated and may need to modify or delay the clinical trials or to perform additional trials. Further, Gilead may make a strategic decision to discontinue development of TAF if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. There is also risk of failing to obtain approvals from regulatory authorities for TAF, alone or in combination with other products, and the New Drug Applications for elvitegravir and cobicistat may not be approved by the
Prezista is a registered trademark of Janssen R&D Ireland
Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)
Return to Press Releases
Black cohosh liver warning
It follows a serious case of liver failure resulting in a liver transplant suspected to have been caused by a herbal product containing black cohosh.
Richard Woodfield, the MHRA’s Head of Herbal Policy, says in a press release: "It is important that people with a history of liver problems do not use black cohosh herbal products."
Black cohosh is the second most popular herbal ingredient in the UK. It's also known as Cimicifuga racemosa, Black snakeroot, Bugbane, Macrotys or Squaw root and it's used for the relief of hot flushes, night sweats, poor sleep, mood changes and irritability.
Some studies have found evidence it does help with menopause symptoms. However, many experts consider the evidence is unclear and more research is needed. The NHS doesn't recommend the use of black cohosh for treating the symptoms of menopause because it may interact with other medications and cause side effects.
- Posted by HCV New Drugs
- File Under clinical trials
Click below to view all updates:
ClinicalTrials.gov: hepatitis c | "Hepatitis C Virus" | updated in the last 30 days
Month Of October 2012
A Study of the Combination Regimen MK-5172, MK-8742, and Ribavirin in Participants With Chronic Hepatitis C (MK-5172-035)
Friday, October 26, 2012, 9:00:00 AM
Condition: Hepatitis C
Interventions: Drug: MK-5172; Drug: MK-8742; Drug: Placebo; Drug: Ribavirin
Sponsors: Merck; Merck
Not yet recruiting - verified October 2012
A Study to Evaluate Chronic Hepatitis C Infection in Treatment Experienced Adults
Thursday, October 25, 2012, 9:00:00 AM
Condition: Chronic Hepatitis C Infection
Interventions: Drug: ABT-450/r/ABT-267; Drug: ABT-333; Drug: ribavirin (RBV)
Sponsors: Abbott; Abbott
Not yet recruiting - verified October 2012
A Study of Different Durations of Treatment With MK-5172 in Combination With Ribavirin in Participants With Chronic Hepatitis C (MK-5172-039)
Thursday, October 25, 2012, 9:00:00 AM
Condition: Hepatitis C
Interventions: Drug: MK-5172; Drug: Ribavirin
Sponsors: Merck; Merck
Not yet recruiting - verified October 2012
A Study to Evaluate Chronic Hepatitis C Infection
Thursday, October 18, 2012, 9:00:00 AM
Condition: Chronic Hepatitis C Infection
Interventions: Drug: ABT/450/r/ABT-267; Drug: ABT-333; Drug: Ribavirin (RBV); Drug: Placebo for ABT-450/r/ABT-267; Drug: Placebo for ABT- 333; Drug: Placebo for Ribavirin (RBV)
Sponsors: Abbott; Abbott
Not yet recruiting - verified October 2012
A Study of Different Doses of MK-5172 Given With Pegylated Interferon Alfa-2b and Ribavirin to Treatment-Naïve Participants With Chronic Hepatitis C (MK-5172-038)
Wednesday, October 17, 2012, 9:00:00 AM
Condition: Chronic Hepatitis C (CHC)
Interventions: Drug: MK-5172; Biological: PegIFN-2b; Drug: Ribavirin; Drug: Placebo
ponsors: Merck; Merck
Not yet recruiting - verified October 2012
Sofosbuvir Plus Ribavirin Administered for Either 12 or 24 Weeks in Treatment-Naïve and Treatment-Experienced Egyptian Adults With Chronic Genotype 4 Hepatitis C Virus (HCV) Infection
Wednesday, October 17, 2012, 9:00:00 AM
Condition: Hepatitis C Virus
Interventions: Drug: Sofosbuvir; Drug: Ribavirin (RBV)
Sponsors: Gilead Sciences; Gilead Sciences
Recruiting - verified October 2012
Pharmacokinetic Study of BMS-914143 in Participants With Normal Renal Function and Mild, Moderate, Severe and End-stage Renal Dysfunction
Tuesday, October 16, 2012, 9:00:00 AM
Conditions: Chronic Hepatitis B Virus Infection; Chronic Hepatitis C Virus Infection
Intervention: Biological: BMS-914143 (Peginterferon Lambda-1a)
Sponsors: Bristol-Myers Squibb; Bristol-Myers Squibb
Recruiting - verified October 2012
A Study to Assess the Absolute Bioavailability and Pharmacokinetics of Simeprevir (TMC435) Administered as Single Oral Doses of TMC435 and an Intravenous Microdose of [3H]-TMC435 in Healthy Male Patients
Friday, October 12, 2012, 9:00:00 AM
Condition: Healthy Male Participants
Intervention: Drug: Simeprevir (TMC435)
Sponsors: Janssen R&D Ireland; Janssen R&D Ireland
Recruiting - verified October 2012
Viral Kinetics in HCV Clearance in Subjects With Hemophilia
Friday, October 05, 2012, 9:00:00 AM
Condition: Hepatitis C With Hemophilia
Interventions: Drug: Arm 1 - PegInterferon + Ribavirin (4 weeks); PegInterferon + Ribavirin + Telaprevir (12 weeks); PegInterferon + Ribavirin (8 weeks); Drug: Arm 2 - No 4-week lead in therapy; PegInterferon + Ribavirin + Telaprevir (12 weeks); PegInterferon+ Ribavirin (12 weeks)
Sponsors: University of Cincinnati; Kenneth Sherman; National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI)
Not yet recruiting - verified October 2012
Evaluation of Safety Tolerability and Antiviral Activity of ACH-0143102 Plus RBV Treatment Naive HCV GT1b Subjects
Tuesday, October 02, 2012, 9:00:00 AM
Condition: Chronic Hepatitis C Infection
Interventions: Drug: ACH-0143102; Drug: Ribavirin
Sponsors: Achillion Pharmaceuticals; Achillion Pharmaceuticals
Recruiting - verified October 2012
Safety and Efficacy of Sofosbuvir/GS-5885 Fixed-Dose Combination (FDC) +/-Ribavirin for the Treatment of HCV
Tuesday, October 02, 2012, 9:00:00 AM
Condition: Chronic Hepatitis C Virus
Interventions: Drug: Sofosbuvir/GS-5885 400/90 mg; Drug: Ribavirin
Sponsors: Gilead Sciences; Gilead Sciences
Recruiting - verified October 2012
Click here to view all updates.......
Liver transplant survival higher among patients with NASH, HBV; lower for HCV, HCC
October 30, 2012
LAS VEGAS — Patients who underwent liver transplantation to treat nonalcoholic steatohepatitis, HBV or alcoholic liver disease had higher survival rates than those treated for HCV or hepatocellular carcinoma, according to data presented at the 2012 American College of Gastroenterology Annual Scientific Meeting.
Researchers determined the graft and patient survival rates of patients who underwent liver transplant for alcoholic liver disease (ALD; n=8,940), primary biliary cirrhosis (PBC; n=3,052), cryptogenic cirrhosis (CC; n=5,856), primary sclerosing cholangitis (PSC; n=3,854), HCV (n=15,147) or HBV (n=1,816) infection, a combination of alcohol-related illness and HCV (n=6,066), nonalcoholic steatohepatitis (NASH; n=1,368) and hepatocellular carcinoma (HCC; n=8,588).
“Data are unclear on the impact of last-decade evolutions on liver graft and patient survival depending on the etiology of cirrhosis,” researcher Habeeb Salameh, MBBS, department of internal medicine at the University of Texas Medical Branch in Galveston, told Healio.com. “These evolutions include [the] introduction of MELD score for listing, HCC appeal criteria for MELD exception points, and the listing of NASH as a distinct etiology of cirrhosis.”
The number of performed liver transplants increased from 2,906 in 1994 to 5,357 in 2009, with more procedures performed to treat NASH, HCC and alcohol/HCV, fewer performed to treat PBC, PSC, CC and HBV or HCV infection, and a similar number for ALD. Investigators noted that simultaneous liver and kidney (SLK) transplants made up a larger amount of total procedures after the introduction of MELD score (2.5% of procedures in 2001 compared with 10.3% in 2009).
Salameh attributed the increase in transplants for NASH to the prevalence of obesity in the United States, and noted that the condition is projected to overtake HCV as a transplant indication by 2020. The decrease in transplants performed for HBV and PBC, he added, is likely the result of other potent treatments developed for both illnesses.
Survival rates at 5 years were between 75% and 80% for graft and 80% and 85% for patient survival among those receiving transplant for PBC, PSC, NASH or HBV infection, and between 70% and 75% (HR=1-1.5 compared with PBC) for graft and 75% and 80% (HR=1.5-2.0) for patient survival in ALD or CC. Survival rates were lowest among patients treated for HCC, HCV or combined alcohol consumption/HCV (65%-70%; HR=1.5-2.4 for graft and 70%-75%, HR=1.8-2.3 for patient survival), and were particularly low in patients with HCV-associated HCC.
“This study clearly shows excellent post-transplant outcomes of patients transplanted for ALD,” Salameh said. “With the emerging data on beneficial outcomes of liver transplant for patients with severe alcoholic hepatitis who do not respond to medical management, transplants are likely to be more widely accepted in the near future.”
For more information:
Salameh H. P234: Evolving Frequency with Graft and Patient Survival of Liver Transplantation Based on Etiology of Liver Disease. Presented at: the 2012 American College of Gastroenterology Annual Scientific Meeting; Oct. 19-24, Las Vegas.
Researchers Build on Diabetes-Liver Cancer Connection
October 30, 2012
Diabetes mellitus is associated with a higher risk of having advanced liver cancer at the time of diagnosis, suggesting that the presence of diabetes may promote more invasive tumor biology, a University of Rochester Medical Center study found.
A number of prior studies have shown various associations between diabetes and cancer in general. The connection makes sense, in part due to the liver’s regulation of sugars, and longtime observations that people prone to liver failure also are prone to diabetes. In addition several prior studies have shown that cancer patients with diabetes often have worse outcomes; the reason for this is not clear.
The recent URMC study adds an important new dimension because it links diabetes to distant metastasis in patients with hepatocellular cancer, a form of liver cancer usually found in people with liver cirrhosis, said corresponding author Gregory C. Connolly, M.D., senior instructor of Medicine at the James P. Wilmot Cancer Center at URMC.
The study was published this month by the journal Cancer Investigation.
“Although our research is preliminary and based on a retrospective dataset, the findings are very interesting and hypothesis-generating,” Connolly said. “The association we detected suggests that patients with liver cancer and diabetes may have changes in cancer cell signaling that promote tumor invasiveness. The more we understand about the mechanisms at work, the more successful we’ll be at treating patients with both diseases.”
Connolly and colleagues looked at disease trends among 265 primary liver cancer patients diagnosed between 1998 and 2008 at Strong Memorial Hospital at URMC. Of the total, they found that 34 percent had diabetes at the time of the cancer diagnosis. And among the diabetic group, 33 percent had liver cancer that had already spread to distant organs -- compared to 9.7 percent of patients with advanced liver cancer who did not also have diabetes.
Moreover, the diabetic patients who took insulin had the highest rates of advanced cancer, compared to diabetics who managed their blood sugars through diet restriction or oral medications.
In the United States the incidence of diabetes mellitus (high blood sugar) has roughly doubled in the past 20 years; at the same time the rates of hepatocellular carcinoma, the most common form of liver cancer, also rose steadily. Most primary liver cancer is attributed to hepatitis or chronic alcohol abuse, but the National Cancer Institute reported in 2010 that now diabetes is actually associated with a greater percentage of liver cancer cases than any other factor.
Survival rates for advanced liver cancer are dismal. In the URMC study, 85 percent (or 237 people) died during the median follow-up period of 6.5 months. But the patients without diabetes had a median survival time of 7.55 months versus 6.04 months for those who also had diabetes.
“Because the incidence of people with glucose intolerance and liver cirrhosis or primary liver cancer is so strong, it is imperative that we better understand the relationship so that these patients can be treated and managed in the best way possible,” said senior author Aram F. Hezel, M.D., assistant professor of Medicine in Hematology/Oncology at Wilmot.
Connolly is supported by a grant from the James P. Wilmot Research Foundation. Other co-authors are: Alok A. Khorona, M.D., Richard F. Dunne, M.D., and research assistant Afamefuna Nduaguba, of the Department of Medicine; Saman Safadjou, information analyst in the Division of Solid Organ Transplant and Hepatobilary Surgery; and Rui Chen, Ph.D., research assistant professor of Biostatistics.
Two Hep C Questions: What will happen to me? Should I go on treatment?: new booklet
Wednesday, 31 October 2012 13:41
This new booklet from Hepatitis NSW, ‘Two Hep C Questions: What will happen to me? Should I go on treatment?’ ("2Qs") aims to help people make good decisions about their health. It provides a guide to long term hep C health outcome and is intended for use by people affected by hep C and their GP, liver specialist or treatment CNC (Clinical Nurse Consultant).
People with hepatitis C mightn't feel ill and may not think the booklet relates to them but liver disease can occur, though, without major symptoms of illness. Hepatitis NSW recommends people to use this booklet, working with their healthcare providers in order to assess what condition their liver is in.
The booklet has been designed to appeal to all key priority populations and the wider general community. It is about a person's hep C journey: their illness outcome and treatment, and how to best care for their liver.
Click here to download booklet.
Click here to download order form for bulk copies.
To order single copies, contact the NSW Hepatitis Helpline, ph 1800 803 990.
Achillion Pharma Worthy of New Look
By Nathan Sadeghi-Nejad
NEW YORK (TheStreet) -- The midsummer implosion of Bristol-Myers Squibb's (BMS) BMS-094 (formerly INX-189) and subsequent FDA clinical hold for Idenix Pharmaceuticals' (IDIX) IDX-184 and IDX-19368 has winnowed the field of late-stage hepatitis C drug candidates. Given these shifting dynamics, the outlook for Achillion Pharmaceuticals' (ACHN) hepatitis C drug pipeline has improved and the stock is a solid long idea for investors seeking exposure to the hepatitis C market.
I haven't always been an Achillion fan. After attending the European Association for the Study of the Liver (EASL) meeting this spring, I gave Achillion a C-minus on my hepatitis C scorecard, largely due to indifference. I noted back then:
Achillion has two NS5A inhibitors, ACH-3102 and ACH-2928, which look okay in early studies, but I'm not sure what makes these drug candidates stand out. I feel similarly unexcited about ACH-1625, a protease inhibitor, which looked decent in a confusing study that combined it with interferon and ribavirin. I'm just not convinced these are valuable assets, so I'm going to wait on the sidelines.
I wasn't the only one confused by Achillion's Phase IIa study of ACH-1625, which is now known as sovaprevir. On the same day as my EASL review, the company issued a press release clarifying the results. Let's take another look.
Achillion's explanation for the uninspiring efficacy results in the EASL poster makes sense: Data included semi-compliant patients who were not consistently taking drug. In fact, viral loads for all 22 patients that completed treatment -- 12 weeks of sovaprevir combined with the immune boosters interferon and ribavirin, followed by 12 weeks of interferon and ribavirin alone -- reached undetectable levels. That's far more intriguing than the initially reported end-of-treatment response rates, which dipped as low as 69%. At a recent R&D day, management provided updated data from the same Phase IIa study: 78% (200 mg once-daily), 77% (400 mg), and 85% (800 mg) sovaprevir-treated patients achieved a sustained virologic response -- a reliable indicator of cure -- at 12 weeks (SVR12). Although that's somewhat less effective than other protease inhibitors in development, such as Abbott's ritonavir-boosted ABT-450 (88% SVR12) or Johnson & Johnson's TMC-435 (82% SVR12), it's good enough to make sovaprevir an attractive asset for combination therapy regimens. At the R&D day, Achillion also discussed sovaprevir's side effects in detail. At the highest dose tested (800 mg once-daily), one patient had significantly elevated liver enzymes and three patients (16%) had increased bilirubin levels. The combination of both elevated liver enzymes and bilirubin levels in patients raises concerns about Hy's Law, a reliable prognostic indicator for severe liver damage. This is the safety signal that worried me about sovaprevir at last spring's EASL meeting.
Continue reading... Page 2, Page 3
- Posted by HCV New Drugs
- File Under BCX5191
(Reuters) - BioCryst Pharmaceuticals Inc said it would withdraw an application to test its experimental hepatitis C drug in humans after the U.S. Food and Drug Administration expressed concern about its safety.
The FDA had concerns about the preclinical toxicity profile of the drug candidate, BCX5191, the company said.
The drug belongs to a new class of hepatitis C treatments, known as nucs, that is widely expected to be a game-changer in hepatitis C management but has been plagued by safety concerns.
In the past few months, the FDA has placed multiple nucs on clinical holds, citing safety issues, including Bristol-Myers Squibb Co's BMS-986094 and Idenix Pharmaceuticals Inc's IDX19368 and IDX184.
BioCryst said it would conduct additional preclinical studies to determine if low doses of the drug that were not associated with toxicity in animals exhibit meaningful viral load reductions in animals infected with the hepatitis C virus.
The company said it would then determine whether to continue development of the drug, based on the results of the studies.
(Reporting by Esha Dey in Bangalore; Editing by Maju Samuel)
Read more here: http://blogs.newsobserver.com/business/durhams-biocryst-forced-to-halt-hepatitis-treatment#storylink=cpy
Devon Nicholson begins treatment that could cure his Hep-C
THUNDER BAY – Healthbeat – Hepatitis C is a deadly “blood to blood” disease that attacks the liver causing liver cancer, liver failure and death. It now kills more people than AIDS, and is the number one reason for liver transplants in the US. The former National Champion amateur and retired professional wrestler Devon Nicholson began the first day Hep C treatment on October 15th 2012.
Nicholson brought two successful wrestling shows to Thunder Bay several years ago.
Nicholson is excited to be starting the 24 week “triple therapy” that will include the new Hep C miracle drug Incivek (Telaprivir).
“I’m very grateful to get the opportunity to take this medication” the former Canadian open winner in grappling told NetNewsLedger. “Although it has been highly successful at treating patients with Hep C genotype 1, I am genotype 2 and the medication is still in the experimental phase for my type.”
Nicholson was first told about Incivek’s possible effectiveness with genotype 2 patients by Dr. Hector Rodriguez, who studied at the world famous Mayo Clinic in Phoenix AZ. Rodriguez is the Hep C specialist who performed the liver transplant on legendary wrestling champion “Superstar” Billy Graham. Graham set up a meeting between Rodriguez and Nicholson who wasn’t having luck finding treatment in Canada.
“After failing my first Hep C treatment my Hep C liver specialist in Canada (Dr. Curtis Cooper) told me I would have to wait 4 years for a new medication. Knowing how deadly the disease is I wasn’t ready to accept that answer,” stated Nicholson.
Devon went to Phoenix to visit the specialist there, “Dr. Rodriguez seemed very positive that the Incivek treatment would work for me. He gave me requisitions to have more testing done in Canada including a liver biopsy and told me he would look into getting me into an experimental treatment program at the Mayo once he had the results.”
Prior to committing to be treated in the US Nicholson decided to get a second opinion from another Hep C specialist in Canada. “I saw Dr. Linda Scully and informed her of what the US specialist had told me. She said it could be possible to attempt the Incivek treatment in Canada despite my type 2 genotype.” Dr. Scully further researched the possibility at a Hep C summit in Prague before meeting with Nicholson again.
Nicholson’s official Hep C treatment website is www.dontbleedonme.com.
Good Luck Devon, and Happy Belated Birthday!
- Monday, October 29, 2012
- Posted by HCV New Drugs
- File Under gallstones
Misinformation on gallstones drew more views on YouTube than useful, medically accurate videos
October 29, 2012
LAS VEGAS — YouTube videos advocating ineffective or potentially dangerous natural therapies for gallstone disease attracted more viewers than those providing useful information, according to data presented at the 2012 American College of Gastroenterology Annual Scientific Meeting.
Researchers screened 300 YouTube videos after a search for “gallstones,” of which 228 videos were considered relevant. The sources of each video were identified as a health agency (n=20.3%), an independent source (n=70%) and a medical advertisement (n=9.6%), and data on total views, video duration, upload date and content were collected.
Among the 228 relevant videos, investigators considered 121 useful (containing accurate and beneficial information) and 66 were labeled as misleading, with an additional 41 videos excluded for being shorter than 1 minute or not being spoken in English.
Investigators wrote that the misleading videos frequently discussed natural therapies such as yoga, cryptomonadales or barley or flush therapies, many of which have been disproven as ineffective or potentially harmful. Per-day viewership was significantly higher for misleading videos than for useful videos (18.2 views/day compared with 14 views/day; P=.03). Three videos classified as useful provided information refuting the benefits of the natural therapies, explaining why they were not effective or potentially dangerous.
Researcher Aakash Aggarwal, MBBS, a resident at State University of New York Upstate Medical University, told Healio.com that many people who posted comments on the misleading videos indicated they were interested in alternative therapies because they did not want to undergo surgery for their conditions.
“Not only were they trying therapies that may be harmful, but they’re not going in for surgery, which can lead to other complications,” Aggarwal said. He suggested that health care agencies should consider developing official videos on medical topics to post to social media sites, in order to effectively disseminating useful and accurate information on medical conditions to the public. “Now that people are using those as sources of information, it’s very important for health care agencies to use these great resources to promote public awareness … and [develop] videos that are factually correct.”
For more information:
Aggarwal A. P677: YouTube as a Source of Information for Gallstone Disease. Presented at: the 2012 American College of Gastroenterology Annual Scientific Meeting; Oct. 19-24, Las Vegas.
Alisporivir (DEB025) - Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection
2012, 4, 2558-2577; doi:10.3390/v4112558
Download PDF Full-Text
[394 KB, uploaded 29 October 2012 09:36 CET]
Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection
1,* and Philippe Gallay 2,*
1 Autoimmune Technologies, LLC, 1010 Common Street, Suite 1705, New Orleans, LA 70112, USA
2 Department of Immunology and Microbial Science, IMM-9, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA *
Authors to whom correspondence should be addressed; E-Mails: S.Hopkins@autoimmune.com (S.M.); firstname.lastname@example.org (P.G.); Tel.: +1-504-529-9944 (S.M.); +1-858-784-8180 (P.G.); Fax: +1-858-784-8831 (P.G.).
Received: 3 September 2012; in revised form: 18 October 2012 / Accepted: 20 October 2012 / Published: 29 October 2012
The advent of the replicon system together with advances in cell culture have contributed significantly to our understanding of the function of virally-encoded structural and nonstructural proteins in the replication cycle of the hepatitis C virus. In addition, in vitro systems have been used to identify several host proteins whose expression is critical for supporting such diverse activities as viral entry, RNA replication, particle assembly, and the release of infectious virions. Among all known host proteins that participate in the HCV replication cycle, cyclophilins are unique because they constitute the only host target that has formed the basis of pharmaceutical drug discovery and drug development programs. The introduction of the nonimmunosuppressive cyclophilin inhibitors into clinical testing has confirmed the clinical utility of CsA-based inhibitors for the treatment of individuals with chronic hepatitis C infection and has yielded new insights into their mechanism(s) of action. This review describes the biochemical evidence for the potential roles played by cyclophilins in supporting HCV RNA replication and summarizes clinical trial results obtained with the first generation of nonimmunosuppressive cyclophilin inhibitors.
HCV; cyclophilins; cyclophilin inhibitors Viruses 2012, 4 2559
The advent of the replicon assay has unquestionably expanded our knowledge of the hepatitis C virus (HCV) replication cycle . In particular, the increased understanding of the function of virally-encoded, nonstructural proteins has led to the identification of multiple new classes of Direct Acting Anti-HCV Agents (DAAs) for the treatment of individuals with chronic HCV infection . These DAAs include the recently approved NS3/4A serine protease inhibitors Victrelis (boceprevir) and Incivek (telaprevir) and investigational agents including NS5A inhibitors as well as several diverse types of nucleoside/nucleotide and nonnucleoside inhibitors of NS5B, the RNA-dependent RNA polymerase. More recent advances in cell culture techniques including the use of soluble recombinant E2, HCV pseudo particles, and infectious cell culture-produced virions have enabled a better understanding of the function of virally-encoded nonstructural proteins and has led to the development of in vitro systems that support the complete HCV replication cycle . These same advances have also led to the identification of a subset of host-encoded cofactors whose expression is essential in order to support virtually all aspects of the viral replication cycle. In several instances approved drugs have been used as prototypical inhibitors in order to vet these host proteins as potential targets for pharmaceutical intervention strategies. Anti-cancer agents were most recently used to identify the receptor tyrosine kinase activity associated with epidermal growth factor receptor and ephrin receptor A2 as potential host targets . Inhibition of receptor tyrosine kinase activity by erlotinib or dasatinib prevented CD81 and claudin-1 co-receptor association and viral glycoprotein-dependent membrane fusion. At this time no receptor tyrosine kinase inhibitors have attained a clinical testing status. The importance of host lipid metabolizing enzymes was established by demonstrating the in vitro anti-HCV activity of lovastatin, a specific inhibitor of 3-hydroxy-3-methyl-glutaryl Coenzyme A reductase (HMG CoA reductase) and geranylgeranyl transferase I . Exposure of replicon cells to lovastatin promoted disassembly of the replication complex, which was reversible upon addition of geranylgeraniol to the culture medium. Various members of the statin family have been assessed for their in vitro anti-HCV activity; however, the clinical utility of statins in the treatment of chronic hepatitis C infection remains controversial. Cyclosporine A (CsA) is a well-characterized immunosuppressive agent that inhibits the peptidyl-prolyl isomerase activity associated with the broad family of cyclophilins (Cyps) at nanomolar concentrations . The complex formed between CsA and cyclophilin A (CypA) is a potent inhibitor of calcineurin. The formation of this ternary complex leads to inhibition of the intrinsic phosphatase activity of calcineurin, which abolishes the dephosphorylation-driven nuclear translocation of the nuclear factor of activated T cells (NFAT). This ultimately contributes to the failure of T cells to respond to antigenic stimuli. Early studies comparing the in vitro anti-HCV activities of CsA and NIM811 (a nonimmunosuppressive analog of CsA that binds to CypA, but lacks the ability to inhibit calcineurin phosphatase) established that antiviral effects were associated with binding to host CypA and were independent of inhibitory effects on calcineurin and were also independent of inhibitory activity towards the multi-drug resistance protein, P-glycoprotein (P-gp) . Further studies established that replication of HCV-specific RNA depends on the expression of CypA . CsA was therefore used as the starting material for medicinal chemical programs in order to generate analogs that retained their CypA binding properties, but lacked the dose-limiting calcineurin binding activity. SCY-635 and Alisporivir (DEB025) together with NIM811, Viruses 2012, 4 2560 which was isolated as a side product of CsA biosynthesis, now represent the most advanced of all host-targeted antiviral agents. Clinical proof of concept has been established for all three compounds either as monotherapy [9,10] or when given in combination with pegylated interferon .
This review will focus on describing the discovery of Cyps as essential host co-factors that support HCV RNA replication, biochemical studies that identify the potential mechanism(s) of action for nonimmunosuppressive Cyp inhibitors, and clinical trial results obtained to date with all members of this emerging class of host-targeted antiviral agents
2. Results and Discussion
2.1. Host Cell Expression of Cyclophilins Is Essential in Order to Support HCV RNA Replication for All Genotypes
The Shimotohno laboratory was the first to demonstrate that the immunosuppressive drug CsA efficiently suppresses HCV replication in cultured hepatoma cells . This prime discovery was corroborated by subsequent studies, which showed that not only CsA, but non-immunosuppressive CsA derivates such as NIM811, Alisporivir and SCY-635 also block HCV replication [7,13–17]. Moreover, studies showed that sanglifehrins as well as polyketide sanglifehrin derivates also inhibit HCV replication [14,18–20]. Sanglifehrins are natural products that also bind Cyps, but are structurally distinct from CsA . Since Cyps represent the main intracellular targets for CsA and sanglifehrins, the above findings strongly suggest a direct relationship between Cyps and HCV. Corroborating this hypothesis, transient knockdown studies indicated that multiple Cyps assist HCV [21,22]; then stable knockdown studies suggested that CypA is the main Cyp member, which governs HCV replication [8,22,23]. Further supporting that CypA is vital for HCV, the reintroduction of CypA into CypA-knockdown cells restores HCV replication [8,22,23]. CypA was found to be associated with HCV replication complexes [24,25], suggesting that the host protein is expressed in the relevant biological compartment to support HCV. Altogether these data strongly suggest that HCV highly relies on host CypA to replicate in cells.
CypA was originally discovered as a cellular ligand for CsA . CypA is an abundant cytosolic protein that is expressed in all eukaryotic cells . CypA is a peptidyl-prolyl cis-trans isomerase , which accelerates the cis to trans interconversion of proline-containing peptides or proteins . CypA possesses a hydrophobic pocket that contains both the enzymatic and ligand binding sites of the protein . CsA, sanglifehrins and their derivates, by binding within this hydrophobic pocket, neutralize both the enzymatic and ligand binding activities of CypA [19,20]. Although CypA has been shown to act as a peptidyl-prolyl cis-trans isomerase in vitro, its true cellular function remains to be demonstrated. Importantly, CypA-knockout mice and T cell lines are perfectly viable [30,31], suggesting that CypA represents an appropriate target for Cyp inhibitors (nonimmunosuppresive CsA and sanglifehrin derivates) in HCV patients.
2.2. Biochemical Studies Describing the Potential Mechanism(s) of Action of Cyclophilin Inhibitors
The antiviral mechanisms of action of Cyp inhibitors are not fully understood. However, several key findings provide putative mechanisms of action for these potent anti-HCV agents. The first key finding is that the isomerase pocket of CypA is critical for HCV replication [8,24]. Specifically, in contrast to wild-type CypA, isomerase-deficient CypA mutants, which harbor mutations in their hydrophobic pocket, are unable to support HCV replication [8,24,32]. This is in accordance with the fact that Cyp inhibitors neutralize the enzymatic activity of CypA by binding to its hydrophobic pocket [33,34]. The second key finding is that CypA binds directly to the HCV nonstructural 5A (NS5A) protein. Early studies nicely showed that HCV variants, which arose under Cyp inhibitor selection, developed mutations in the NS5A gene [14,18,35–42]. This led researchers to postulate that NS5A serves as a viral ligand for CypA. Several independent laboratories using various technologies (i.e., NMR, recombinant and cellular pulldowns) convincingly demonstrated that indeed CypA and NS5A form complexes [20,35,37,39,42–46]. CypA-NS5A interactions are conserved among all HCV genotypes [37,42]. The third key finding is that Cyp inhibitors prevent and disrupt CypA-NS5A complexes. Several studies showed that all classes of Cyp inhibitors—CsA, nonimmunosuppressive CsA derivates (e.g., Alisporivir and SCY-635), sanglifehrins and sanglifehrin derivates—block CypA-NS5A interactions in a dose-dependent manner [20,35,37,39,42,44–46]. The Cyp inhibitor-mediated block was observed for all NS5A genotypes [37,42]. These data strongly suggest that CypA-NS5A interactions are critical for HCV replication. Altogether these findings provide the first and so far the most tangible initial mechanism of action of Cyp inhibitors that is the prevention of CypA-NS5A contacts.
If this hypothesis is correct, we need to understand how CypA-NS5A interactions govern HCV replication. Key clues came from the Lippens laboratory, which showed that several NS5A prolines, but not all, serve as substrates for cis-trans isomerization by CypA [45,47]. Interestingly, the Harris laboratory demonstrated that CypA, via its isomerase pocket, enhances the NS5A RNA-binding capacities . One thus can envision that CypA, by catalyzing the cis-trans isomerization of specific proline bonds within NS5A, promotes NS5A binding to viral RNA and facilitates HCV RNA replication. Another possibility is that CypA modulates the contact between NS5A and NS5B, the virally-encoded RNA-dependent RNA polymerase. Previous work showed that NS5A binds directly to NS5B . Moreover, NS5A possesses the capacity to affect the polymerase activity of NS5B [49–51]. One thus can envision that CypA, by isomerizing proline bonds in NS5A, influences the ability of NS5A to promote the NS5B polymerase activity. Several studies also suggested that NS5A attenuates the innate immune response towards infection in order to facilitate HCV replication . One cannot exclude the possibility that the cis-trans isomerization of NS5A by CypA represents a necessary event for the ability of NS5A to impact the innate response. Therefore, Cyp inhibitors could exert anti-HCV activity through direct (inhibition of recruitment of CypA by virally-expressed proteins impacting the efficiency of viral RNA replication) as well as indirect mechanisms (modulating the innate immune response).
2.3. The Clinical Status of Cyclophilin Inhibitors
The clinical utility of CsA-based inhibitors in the treatment of chronic hepatitis C infection has been demonstrated by the introduction of nonimmunosuppressive Cyp inhibitors including NIM811, SCY-635 and Alisporivir (DEB025) (Figure 1). All three compounds retain the undecapeptide core structure of CsA, but differ from the parent molecule at the 3-sarcosine and 4-N-methyl leucine positions. All three compounds are nanomolar inhibitors of the PPIase catalytic activity and form binary complexes with CypA; however, when compared with CsA the binary complexes exhibit greatly diminished affinity for calcineurin. Clinical trials with NIM811 and SCY-635 have been limited to exploratory phase I and II trials enrolling small, relatively well-defined patient populations; therefore, the complete clinical safety profile for these compounds has yet to be determined. In contrast, the safety profile for Alisporivir (DEB025) has been derived from a total patient population consisting of approximately 1,800 patients, which supported the initiation of phase III pivotal clinical testing.
Structural formulas for Cyclosporin A together with three non-immunosuppressive derivatives including NIM811, Alisporivir, and SCY-635.
The safety, pharmacokinetics, and antiviral activity of monotherapy with NIM811 following single- and multiple-dose administration to treatment-experienced and treatment-naïve adults with chronic genotype 1 hepatitis C infection (n = 72) have been reported . NIM811 was administered orally at total daily doses ranging from 25 mg to 1,200 mg. In general, NIM811 was well-tolerated across all dose groups. Clinically insignificant increases in bilirubin and triglycerides were observed throughout the 14-day treatment period. Thrombocytopenia was observed at total daily doses equal to or greater than 200 mg. No dose reductions were required; however, the authors indicated that the need for dose reduction was mitigated by the relatively short duration of the dosing period. The pharmacokinetics of NIM811 were reported as parameters derived from whole blood concentration versus time data; no plasma concentration versus time data were reported. Whole blood exposure to NIM811 increased with increasing doses of NIM811. Dose-related, subproportional increases in Cmax and AUC were reported. Suppression of plasma viremia was not observed at any dose level tested as monotherapy including the maximum daily dose of 1,200 mg. Interestingly, rapid normalization of transaminases was observed in the majority of patients who received total daily doses equal to or greater than 100 mg. One additional cohort of patients was added at the completion of the monotherapy phase in order to assess the antiviral activity of NIM811 when administrated in combination with pegylated interferon. Twenty-one patients, all with evidence of relapse following prior treatment with pegylated interferon and ribavirin, were randomly assigned to receive either placebo (n = 10) or NIM811 (n = 11) at a dose of 600 mg given twice daily. Patients in both arms received pegylated interferon (given once weekly on study days 1 and 8 according to the manufacturer’s instructions). Adverse events typically associated with the administration of pegylated interferon (malaise, fever and headache) were reported in the majority of all patients in both arms. Thrombocytopenia (also observed in the monotherapy phase) was more pronounced in patients who received active combination therapy. Whole blood pharmacokinetic parameters in patients who received combination therapy were similar to values reported for patients who received NIM811 monotherapy. At day 14 significant reductions from baseline in viral load were reported for patients who received active combination therapy (2.85 ± 1.02 log10 IU/mL; p = 0.0001) when compared to patients who received pegylated interferon plus placebo (0.65 ± 0.77 log10 IU/mL). The authors speculate that the absence of an antiviral effect with monotherapy may be explained on the basis of the sharp in vitro dose response of NIM811 in replicon cells coupled with suboptimal clinical dosing; increasing the total daily dose to 1,600 mg (800 mg bid) may be required in order to elicit an antiviral effect as monotherapy. The authors state that the observation of clinical antiviral activity in combination with pegylated interferon was expected on the basis of in vitro studies showing potent synergistic effects between NIM811 and interferon in replicon cells. Novartis has discontinued further NIM811 development for Hepatitis C as its antiviral effect was weaker than Alisporivir.
The proof of concept for SCY-635 was established in a phase I clinical trial in adults with chronic hepatitis C infection.  Twenty patients with genotype 1 infection received multiple ascending oral doses of SCY-635 or a matching placebo. Total daily doses of SCY-635 equaling 300, 600, or 900 mg/day were administered on a divided schedule three times daily for 15 consecutive days. No evidence of dose-limiting clinical or laboratory toxicity was identified at any dose level. Plasma exposure parameters (Cmax and AUC) increased in a greater than proportional manner as the total daily dose of SCY-635 was increased. Significant distribution of SCY-635 into the plasma compartment was observed in patients receiving the 900 mg daily dose. C8hr plasma concentrations for this cohort remained at or slightly below the replicon-derived EC90 value (463 ng/mL) from Study Day 3 (when the highest plasma concentrations of SCY-635 were achieved) through the completion of treatment on Study Day 15. Treatment with SCY-635 at total daily doses of 300 or 600 mg was associated with minimal, clinically insignificant changes in viral load. In contrast, all 6 subjects who received 900 mg/day exhibited clinically relevant declines in viral load. On Study Day 15 (the final day of treatment) the median viral load reduction for all subjects who received the 900 mg total daily dose was 1.90 log10 IU/mL below baseline; the group mean (± SD) viral load reduction was 2.24 (± 1.74) log10 IU/mL below baseline. Within this dose group, individual maximal declines in viral load ranged from 0.84 to 5.47 log10 IU/mL below baseline. Among subjects receiving 900 mg/day Cmax plasma concentrations and AUC0-8 values exhibited a 2.6- and a 2.9-fold range, respectively, whereas the maximum virological responses differed by approximately 42,000-fold. A post hoc analysis across all dosing groups indicated that subjects with the CC IL28B genotype exhibited the greatest responses to SCY-635 monotherapy. This trend was especially apparent among subjects who received the 900 mg total daily dose. In all subjects who received the 900 mg/day dose there was a concordance between the absorption and disposition of SCY-635 in the plasma compartment and transiently increases from baseline in the plasma protein concentrations of interferon α, interferon λ1 and λ3, as well as the interferon-stimulated gene product, 2'5' oligoadenylate synthetase 1 (2'5' OAS-1). Pearson correlation coefficients were calculated for the pair-wise comparison of the plasma concentration of SCY-635 together with the plasma concentrations of interferon α, interferons λ1 and λ3, and 2'5' OAS-1. All comparisons yielded values ranging between +0.5 to +1.0 indicating a strong positive correlation for all covariates. Interestingly, the plasma concentration of interferon β, a potent antiviral cytokine, was decreased during dosing with SCY-635; however, the decrease of interferon β did not preclude SCY-635 from exerting antiviral activity at the 900 mg total daily dose especially in patients with the CT and CC IL28B genotypes. The magnitude and the kinetics of the decline in viral load together with the correlation of the antiviral response with host IL28B genotype and the direct demonstration of transient (8 h) increases in the plasma protein concentrations of interferons α, λ1 and λ3, and the interferon-stimulated gene product 2'5' OAS-1 suggest that the SCY-635-mediated viral replication block (plasma viral load decrease) restores, at least transiently, the innate response. It is important to note that the administration of SCY-635 does not influence interferon and 2'5' OAS-1 plasma levels in non-infected individuals. It is likely that the block of HCV replication in patients treated with SCY-635 allows the innate response to be transiently restored. Indeed, the disappearance of viral proteins, which normally counteract the innate response, should permit its reactivation. Further studies are required to determine whether several weeks of SCY-635 treatment, which should eliminate the virus from the blood, would allow complete reactivation of the innate response.
2.3.3. Alisporivir (DEB025)
Alisporivir (DEB025) represents the most advanced of the host-targeted Cyp inhibitors now in clinical development. Proof-of-concept was established for Alisporivir when administered as monotherapy to patients who were co-infected with HIV-1 and HCV . Subsequent phase II studies demonstrated the benefit of combination therapy with Alisporivir and pegylated interferon in patients who were naïve to any form of antiviral treatment  and combination therapy with Alisporivir together with pegylated interferon and ribavirin in patients with prior evidence of null response . The results of three large randomized phase II studies have been reported. The ESSENTIAL study evaluated the effect of adding Alisporivir to background therapy comprised of pegylated interferon and ribavirin in patients with chronic genotype 1 infection who were naïve to any form of prior treatment . The VITAL-1 study evaluated the effect of Alisporivir administered either as monotherapy, as a 2-drug combination with ribavirin, or with the delayed addition of pegylated interferon and ribavirin to patients with chronic genotype 2 or 3 infection who were naïve to any form of prior treatment . The FUNDAMENTAL study evaluated the effect of adding
Alisporivir to background therapy comprised of pegylated interferon and ribavirin in patients with genotype 1 infection and documented evidence of prior nonresponse to interferon-based therapy . Additional phase II and III clinical studies were recently initiated. Unfortunately, a small number of cases reported as acute pancreatitis, including one fatal case in phase 2 and 3 trials in patients treated with Alisporivir in combination with pegylated interferon and ribavirin has placed these clinical studies on partial hold by the FDA. Novartis is currently working with the FDA to resolve their questions. At the time of this writing, there is relatively little publically available information, which can be analyzed in order to evaluate the relationship between the administration of Alisporivir and the development of acute, potentially life-threatening pancreatitis. Unresolved questions concern the possibility that treatment with Alisporivir contributed to pancreatitis by exacerbating underlying conditions associated with individual patient characteristics such as their history of alcohol use, cigarette smoking, or evidence of progressive metabolic disease.
Observations of hyperbilirubinemia in previous clinical studies have been explained on the basis of in vitro observations demonstrating that Alisporivir is a potent, dose-related inhibitor of the mrp2-mediated transport of conjugated bilirubin. However, the possibility exists that elevations in bilirubin and the observations of pancreatitis in the phase III program, may have been caused by complications due to other pre-existing undiagnosed conditions such as gall stone disease and are, therefore, unrelated to the administration of Alisporivir. Because these issues remain unresolved the following sections will concentrate only on summarizing published results obtained through the completion of the phase II program.
2.3.4. Exploratory Phase I and II Investigations
Clinical proof-of-concept was established for Alisporivir in patients, who were co-infected with HIV-1 and HCV . Twenty-three adults were randomized to receive either Alisporivir (1,200 mg bid) or a matching placebo for 15 days. The mean maximal reduction from baseline in HCV RNA (expressed as log10 copies/mL) for all individuals, who received Alisporivir was 3.63 compared to 0.73 for individuals, who received placebo. Patients with genotype 3 infection exhibited a mean maximal reduction from baseline in viral load of 4.46 while patients with either genotype 1 or 4 infection exhibited a mean maximal reduction from baseline in viral load of 3.19. These data clearly support the hypothesis that targeting a host factor or inhibiting the recruitment of host factors by virally-expressed proteins confers significant antiviral activity irrespective of the viral genotype. Alisporivir was well absorbed and exhibited a mean plasma Cmax value at steady state of 4,250 ng/mL. Accumulation ratios of 4.9 and 10.1 were calculated for Cmax and AUC0-12, respectively. The most commonly reported adverse events were abdominal pain, feeling hot, vomiting, fatigue, and pyrexia; however, none of these were considered dose-limiting. Fifteen individuals in the Alisporivir group exhibited elevated total bilirubin with 10 individuals becoming icteric, 4 of whom prematurely discontinued treatment. All instances of hyperbilirubinemia were reversible following the cessation of treatment with Alisporivir.
Lower doses of Alisporivir were tested in combination with pegylated interferon in a phase II, 29-day clinical trial in 90 treatment-naive patients with chronic hepatitis C infection . Patients were randomly assigned to one of five cohorts. In the first four cohorts patients received either placebo or one of three escalating doses of Alisporivir (200, 600, or 1,000 mg) in combination with pegylated
interferon. In the fifth cohort patients received Alisporivir monotherapy at a dose of 1,000 mg. In an attempt to evaluate a loading dose strategy, patients received their assigned dose of Alisporivir on a twice daily basis for the first week of treatment. In weeks 2, 3, and 4 patients received their assigned dose of Alisporivir once daily. On day 29 the mean reduction from baseline in viral load was 3.56 log10 IU/mL for patients who received pegylated interferon plus placebo; 3.30 log10 IU/mL for patients, who received 200 mg Alisporivir plus pegylated interferon; and 2.87 log10 IU/mL for patients, who received 1,000 mg Alisporivir monotherapy. Larger declines in viral load were observed in patients who received 600 mg Alisporivir plus pegylated interferon (5.07 log10 IU/mL) and 1,000 mg Alisporivir plus pegylated interferon (5.09 log10 IU/mL). In all treatment groups the declines in viral load were more rapid during the first week of treatment when Alisporivir was administered twice daily. Reductions in viral load among patients, who received Alisporivir monotherapy were more pronounced in patients with genotype 2 or 3 infection when compared with patients with genotype 1 or 4 infection. Headache, nausea, fatigue, and hyperbilirubinemia were the most frequently reported adverse events in patients, who received the 1,000 mg dose of Alisporivir either as monotherapy or in combination with pegylated interferon. The frequency of nausea, fatigue, and hyperbilirubinemia were decreased in patients, who received the two lower doses of Alisporivir.
Alisporivir was assessed in combination with pegylated interferon and ribavirin in genotype 1 null responders . Fifty patients were randomly assigned to one of five treatment arms for a 29-day course of treatment. In treatment arm 1 patients received pegylated interferon plus ribavirin with Alisporivir at a dose of 400 mg given once daily; in treatment arm 2 patients received monotherapy with Alisporivir at a dose of 400 mg given once daily; in treatment arm 3 patients received pegylated interferon with Alisporivir at a dose of 400 mg given once daily; in treatment arm 4 patients received pegylated interferon and ribavirin with Alisporivir at a dose of 800 mg given once daily; and in treatment arm 5 patients received pegylated interferon and ribavirin with Alisporivir given at a dose of 400 mg twice daily for 7 days followed by 400 mg given once daily for the following 22 days. No suppression of viral replication was observed in patients, who received monotherapy with Alisporivir. Alisporivir at a total daily dose of 800 mg when administered in combination with pegylated interferon and ribavirin produced significant suppression of plasma viremia. At day 29 the antiviral activity of Alisporivir was comparable among patients who received Alisporivir when administered as 800 mg qd (2.38 log10 IU/mL decline from baseline) and patients, who received Alisporivir when administered as 400 mg bid (1.96 log10 IU/mL decline from baseline) suggesting that the addition of Alisporivir to pegylated interferon and ribavirin is a viable treatment strategy for patients who exhibit prior null response to interferon-based therapy.
2.3.5. Large Randomized Phase II Investigations
Table 1 contains a brief summary of the study objectives and major findings for the principal clinical trials that comprise the phase II development program for Alisporivir.
Click To Enlarge
1 All patients received 7 days of Alisporivir 600 mg bid; on Day 8 patients initiated their randomized dose of Alisporivir. 2 Patients exhibiting RVR (<25 IU/mL) received their originally randomized regimen throughout the remainder of the 24-week treatment period. 3 Patients with viral load ≥25 IU/mL at Week 4 switched treatment at Week 6 to triple therapy containing Alisporivir 600 mg qd plus Peg IFN/ Ribavirin for the remaining 18 weeks. 4 Patients in Arms 1 and 2 received 7 days of loading dose treatment with Alisporivir 600 mg bid. On Day 8 patients initiated treatment with their randomized dose of Alisporivir.
Final results for the ESSENTIAL study have been reported . The objectives of the study were to evaluate the safety and efficacy of Alisporivir when added to a background regimen comprised of pegylated interferon and ribavirin when administered to treatment-naïve patients, who were chronically infected with genotype 1 virus. The primary endpoint was to compare the proportion of patients in each arm who achieved SVR24 using 10 IU/mL at the limit of detection for the plasma concentration of HCV-specific RNA. Two hundred and eighty-eight patients were randomly assigned to participate in 1 of 4 treatment arms. Patients in all arms received background therapy with pegylated interferon and ribavirin. In treatment arm 1 patients received placebo once daily (n = 73) for a total duration of 48 weeks. In arms 2, 3, and 4 patients received active treatment with Alisporivir once daily at a dose of 600 mg; however, during week 1 all patients in arms 2, 3, and 4 received Alisporivir administered twice daily at a dose of 600 mg (i.e., 1,200 mg total daily dose) as part of a loading dose strategy. Beginning on day 8 all patients received a reduced dose of Alisporivir. Study drug was administered once daily at a dose of 600 mg. This treatment schedule was maintained through the end of the dosing period. In treatment arm 2 patients received Alisporivir in combination with background therapy (n = 72) for 48 weeks; in treatment arm 3 Response Guided Therapy was used to determine the duration of treatment with Alisporivir in combination with background therapy (n = 71). Within arm 3, patients who demonstrated a rapid virological response were eligible to receive 24 weeks of treatment. Patients, who did not demonstrate a rapid virological response would continue treatment for 48 weeks; in treatment arm 4 patients received Alisporivir in combination with background therapy (n = 72) for 24 weeks. A planned follow up evaluation occurred 24 weeks after the end of treatment in all arms regardless of the length of the treatment period.
Alisporivir was well-tolerated in all arms through the 24- and 48-week treatment periods. There were no deaths and the frequencies of serious adverse events and discontinuations were similar across all arms. In all arms where Alisporivir was administered, there was an increased frequency of some laboratory abnormalities including total bilirubin. In the control arm the frequency of hyperbillirubinemia was 1.4%; whereas, the frequency of hyperbillirubinemia was 32.9, 25.4, and 41.7% in arms 2, 3, and 4, respectively. Hyperbilirubinemia was predominantly associated with the first week of therapy during which time patients received Alisporivir at a total daily dose of 1,200 mg. Total bilirubin values decreased beginning in week 2 when the total daily dose of Alisporivir was decreased to 600 mg; however, total bilirubin values remained elevated through the end of the treatment period. Total bilirubin returned to pretreatment values at the 12-week follow-up evaluation. The frequency of grade 3 and 4 neutropenia was 29.2% in the control arm. Although not reaching statistical significance, the frequency of neutropenia was greater than control in all arms containing Alisporivir. Values were 43.1, 38.0, and 33.3% for arms 2, 3, and 4, respectively. The frequency of thrombocytopenia was somewhat increased in patients in arm 3 who received 24 weeks of response-guided therapy with Alisporivir (7.0%) in comparison to patients in arm 1 who received control therapy (1.4%).
The addition of Alisporivir improved SVR24 in all arms relative to control therapy. SVR24 for the control arm was 55%. SVR24 for arm 2 (48 weeks of Alisporivir), arm 3 (24 or 48 weeks of Alisporivir RGT), and arm 4 (24 weeks of Alisporivir) was 76, 69, and 53%, respectively, with only arm 2 reaching statistical significance (p = 0.008) when compared to control. This result was achieved despite the observation that the frequency of the CC IL28B allele was 33% in the control arm and 19% in arm 2. Among patients with the CC IL28B allele, end-of-treatment responses were high (100% of patients exhibited undetectable HCV plasma RNA) and were maintained at the 24-week follow-up (100% SVR24) for the subgroups of patients who received either a planned treatment duration of 48 weeks or 24 weeks of RGT with Alisporivir. End-of-treatment responses declined at the 24-week evaluation for CC patients who received control treatment or a planned 24-week treatment with Alisporivir. The benefit of adding Alisporivir to background therapy was apparent among patients with the TT IL28B genotype. SVR 24 for patients with the TT IL28B genotype who received control therapy was 17%. SVR24 increased to 33% in patients who received 24 weeks of treatment with Alisporivir, 62% in patients who received 48 weeks of treatment with Alisporivir, and 73% in patients who received Alisporivir RGT. RVR was improved in all Alisporivir treatment groups relative to control.
The frequency of viral breakthrough was low (approximately 2.8%) in patients receiving Alisporivir. Viral breakthrough was observed only in patients with the CT or TT IL28B genotype and was associated either with reduction in dose or cessation of treatment with ribavirin or pegylated interferon or with suboptimal plasma concentrations of Alisporivir (reflecting either low individual oral bioavailability or poor compliance with the prescribed treatment). Near full-length HCV genomic RNA was sequenced at Baseline and at the time of breakthrough from 6 patients. The D320E mutation, which is located in the C-terminal portion of domain II in the NS5A protein, was detected in 3 of the 6 patients. D320E was detected in only one patient at the time of breakthrough whereas it emerged in the remaining two patients approximately 6 weeks and 18 weeks after the initial breakthrough was observed. Phenotypic analysis of drug sensitivity using replicons constructed with patient-derived NS5A sequences indicates that the D320E substitution is associated with causing a relatively modest (approximately 3-fold) increase in the EC50 value against Alisporivir. These results suggest that other mutations in concert with D320E may account for viral breakthrough during treatment with Alisporivir. The authors concluded that the addition of 48 weeks of Alisporivir at a total daily dose of 600 mg to pegylated interferon and ribavirin improves SVR24 in treatment-naïve patients infected with genotype 1 virus.
The initial results (representing 12 weeks of follow-up after the completion of treatment for the majority of all enrolled patients) of the VITAL-1 study were recently reported and are summarized here . The objectives of the study were to evaluate the safety and efficacy of Alisporivir when administered either as monotherapy, as part of a 2-drug combination with ribavirin, or as part of a 3-drug regimen with the delayed addition of pegylated interferon and ribavirin for the treatment of patients who were chronically infected with genotype 2 or 3 virus and were naïve to prior therapy with pegylated interferon and ribavirin. Three hundred and eighty-five patients were randomly assigned to participate in 1 of 5 treatment arms. In treatment arm 1 patients received Alisporivir once daily as monotherapy at a dose of 1,000 mg (n = 83); in treatment arm 2 patients received Alisporivir once daily at a dose of 600 mg in combination with ribavirin (n = 84); in treatment arm 3 patients received Alisporivir once daily at a dose of 800 mg in combination with ribavirin (n = 94); in treatment arm 4 patients received Alisporivir once daily at a dose of 600 mg in combination with pegylated interferon (n = 84); in arm 5 patients received control therapy comprised of pegylated interferon and ribavirin (n = 40). All patients in all arms received 7 days of loading dose treatment with Alisporivir at a dose of 600 mg given twice daily (i.e., 1,200 mg/day for the first 7 days of treatment) after which patients initiated treatment with their randomized dose of Alisporivir. The total duration of treatment for all arms was 24 weeks with planned follow-up evaluations at weeks 36 (to assess SVR12) and 48 (to assess SVR24). Viral load was assessed at week 4 for the determination of rapid virological response rates for all treatment arms and to determine if a modification of the originally randomized treatment was necessary. If a patient demonstrated a rapid virological response with viral load <25 IU/mL then the patient would remain on their originally assigned treatment; however, if a patient exhibited viral load at week 4 which was in excess of 25 IU/mL, then they would switch at the beginning of week 6 to treatment with Alisporivir administered once daily at a dose of 600 mg given in combination with pegylated interferon and ribavirin and maintain that regimen for the following 18 weeks through the end of treatment at week 24.
Alisporivir was well-tolerated in all arms through the 24-week treatment period. More serious adverse events and more discontinuations were reported in the arms containing Alisporivir; however, the majority of these events appeared to be unrelated to Alisporivir. As anticipated, the interferon-free arms were associated with a decreased frequency of adverse events such as psychiatric disorders, fatigue, nausea, influenza-like illness etc., when compared to arms containing pegylated interferon. There was also a decreased frequency of laboratory abnormalities including anemia, neutropenia, and thrombocytopenia in the interferon-free arms. The majority of patients, who received Alisporivir experienced hyperbilirubinemia, which was detected at the week 1 evaluation and was maintained through the end of treatment at week 24. The majority of patients exhibited values that exceed their pretreatment baseline values, but remained below 3× ULN; however, some patients exhibited values that exceeded 5× ULN. Patients exhibited mixed hyperbilirubinemia. Mechanistically this was attributed to in vitro observations, which indicate that Alisporivir inhibits the uptake transporters OATP1B1 and 1B3 (leading to elevated indirect bilirubin) and the efflux transporter mrp 2 (leading to elevated direct bilirubin).
SVR12 was higher among the four treatment arms that included Alisporivir in comparison to the control arm containing pegylated interferon and ribavirin when calculated both on an Intent-to-Treat basis and on an Efficacy-Evaluable basis. For the Intent-to-Treat population SVR12 values were 81, 83, 81, 77, and 58% for arms 1, 2, 3, 4, and 5, respectively. For the Efficacy-Evaluable population SVR12 values were 91, 91, 94, 86, and 74% for arms 1, 2, 3, 4, and 5, respectively. The proportion of patients, who achieved RVR was 29, 37, and 42% for arms 1, 2, and 3, respectively. Among patients, who demonstrated RVR 82, 93, and 91% of patients in arms 1, 2, and 3 achieved SVR12 indicating that Alisporivir administered either as monotherapy or in combination with ribavirin is a viable all-oral treatment strategy for treatment-naïve patients with chronic genotype 2 or 3 infection who demonstrate empiric evidence of a robust virological response after 4 weeks of treatment; however, the majority of all patients in arms 1 through 4 did not achieve RVR and therefore met the predetermined criterion for switching at week 6 to a regimen comprised of Alisporivir (600 mg qd) plus pegylated interferon and ribavirin. After switching, patients remained on this regimen for 18 weeks until the end of treatment. SVR12 values among patients who switched to triple therapy because they did not achieve RVR were 94, 92, and 96% for arms 1, 2, and 3, respectively, indicating that the delayed addition of pegylated interferon and ribavirin by 6 weeks to a background regimen containing Alispsorivir improves viral clearance in patients with chronic genotype 2 or 3 infection who do not achieve RVR.
The initial results (representing a planned interim analysis for data collected after 12 weeks of treatment) of the FUNDAMENTAL Study were recently reported and are summarized here . The objectives of the study were to evaluate the safety and efficacy of Alisporivir when administered in combination with pegylated interferon and ribavirin for the treatment of patients with chronic infection with genotype 1 virus with a documented history of relapse or nonresponse to prior treatment with pegylated interferon and ribavirin. Four hundred and sixty-one patients were randomly assigned to participate in 1 of 4 treatment arms. In treatment arm 1 patients received Alisporivir once daily at a dose of 600 mg (n = 121); in treatment arm 2 patients received Alisporivir once daily at a dose of 800 mg (n = 117); in treatment arm 3 patients received Alisporivir at a total daily dose of 800 mg administered as 400 mg bid (n = 109); in treatment arm 4 patients received placebo once or twice daily (n = 114). All patients in all groups received background treatment with pegylated interferon (180 μg/week) and ribavirin (1,000 or 1,200 mg/day based on BMI). All patients in arms 1 and 2 received 7 days of loading dose treatment with Alisporivir at a dose of 600 mg given twice daily (i.e., 1,200 mg/day for the first 7 days of treatment) after which patients initiated treatment with their randomized dose of Alisporivir. The total duration of treatment for all arms was 48 weeks with planned follow-up evaluations at weeks 60 (to assess SVR12) and 72 (to assess SVR24). The primary endpoint for the planned interim analysis at week 12 of treatment was a comparison of the proportion of patients in each treatment arm who achieved cEVR (defined as undetectable serum HCV RNA below the limit of quantitation of 25 IU/mL). cEVR rates were also evaluated based on the extent of prior response and based on IL28B genotype (CC versus CT/TT). Viral load was assessed at week 4 for the determination of rapid virological response rates for all treatment arms
Alisporivir was well-tolerated at all dose levels throughout the first 12 weeks of treatment. The frequency of serious adverse events and discontinuations due to adverse events were similar across the experimental and control arms. The most frequently reported adverse events were nausea, neutropenia, and insomnia. In all experimental arms the proportion of patients experiencing neutropenia was approximately 2-fold greater than control (32, 28, 35, and 16% for arms 1, 2, 3, and 4, respectively).
The addition of Alisporivir increased the proportion of patients, who achieved cEVR with 46.4, 61.1, 71.3, and 32.7% of all patients in arms 1, 2, 3, and 4 meeting the primary endpoint, respectively. Although the total daily nominal doses were identical in arms 2 and 3 (800 mg/day), Alisporivir administered as 400 mg bid (arm 3) yielded a higher proportion of patients who achieved cEVR in comparison to 800 mg qd (arm 2). Arm 3 also demonstrated consistently greater decreases in HCV-specific RNA over time in comparison to Arms 1 and 2 and in comparison to control. For relapsers, all doses of Alisporivir yielded higher proportions of patients achieving cEVR with values of 62.5, 77.6, 72.9, and 51.9 for arms 1 through 4, respectively. The same trends were apparent for nonresponders with arms 2 and 3 showing highly statistically significant differences in comparison to control (arm 2, 47.5% cEVR, p < 0.0001 versus control 14.3% cEVR; arm 3, 70% cEVR, p < 0.00001 versus control). The 400 mg bid dose (arm 3) was particularly effective among null nonresponders and partial nonresponders and yielded similar results (69.7 and 68.0%, respectively) between these two subgroups. The 400 mg bid dose was most effective in the null nonresponder subgroup and increased the proportion of patients achieving cEVR in comparison to placebo (69.7 versus 11.1%). Viral breakthrough was low across all groups and was 3.6, 3.7, 1.8, and 2.7% for groups 1 through 4, respectively, further reflecting the superior efficacy of the 400 mg bid dose. The authors concluded that the addition of Alisporivir to a background regimen comprised of pegylated interferon and ribavirin could represent a new option for difficult-to-treat patients, especially those with genotype 1 infection with demonstrated prior nonresponse to interferon-based regimens. This study is currently in progress and further interim analyses are planned for the week 24 time point.
A growing body of evidence now confirms that Cyps, and in particular CypA, are essential host cofactors whose expression is necessary in order to support HCV-specific RNA replication. By extension, nonimmunosuppressive Cyp inhibitors including NIM811, SCY-635, and Alisporivir have come under intense scrutiny in order to vet host CypA as a target for antiviral chemotherapy and for their use as chemical probes to understand the basic biology of HCV infection and to evaluate their use as potential therapeutic agents.
Cyp inhibitors may act through multiple mechanisms and exert antiviral activity through direct as well as indirect pathways. Direct effects of Cyp inhibitors include their potent inhibition of peptidyl-prolyl isomerase catalytic activity associated with the broad family of Cyps and their ability to promote the dissociation of multi-protein complexes formed between CypA and viral nonstructural proteins, in particular, NS5A. Dissociation of the CypA/NS5A complex may, in turn, decrease the affinity of NS5A for viral RNA leading to decreased efficiency of viral replication. Regarding possible indirect effects, recent evidence from clinical studies with SCY-635 monotherapy indicate that effective treatment was associated with a transient increased expression of multiple antiviral cytokines including interferons α, λ1 and λ3 and the interferon-stimulated gene product 2'5' OAS-1. This transient increase of components of the interferon response may facilitate the clearance of the virus. Further work is required to determine whether or not the transient reactivation of the innate response by Cyp inhibitor administration is simply due to a block in viral replication or to an unknown mechanism. It is unlikely that Cyp inhibitors alone trigger the activation of the innate response since no Cyp inhibitors effect was observed in non-infected individuals .
Clinical studies conducted to date, and especially those conducted with Alisporivir, have established that the addition of a potent Cyp inhibitor to a background regimen comprised of pegylated interferon and ribavirin improves SVR in multiple patient groups including treatment-naïve patients with genotype 1 infection, nonresponders/relapsers with genotype 1 infection, and treatment-naïve patients with genotype 2 or 3 infection. With the doses of ALV and RBV used in the VITAL-1 study, the proportion of patients that that achieved early HCV clearance (RVR—week 4) was about 40%, which is relatively low, however of those cases that had RVR and continued with ALV+RBV—92% achieved SVR24. These data substantiate the concept that Cyp inhibitors are effective components of all-oral treatment strategies and emphasize the point that future directions for clinical evaluation
should focus on determining the optimal all-oral treatment strategy for regimens that include Cyp inhibitors. Basic clinical studies would include determining drug interaction profiles between Cyp inhibitors and approved protease inhibitors as well as emerging investigational agents such as nucleoside-based polymerase inhibitors. Other approaches should include building on existing data in order to determine biochemical correlates of antiviral response (such as changes in basal levels of endogenous antiviral cytokines and interferon-stimulated genes) that may be used to identify patient populations that will derive the greatest benefit from treatment regimens that include Cyp inhibitors.
We acknowledge financial support from the U.S. Public Health Service grants no. AI087470 (P.A.G.). This is publication no. 21879 from the Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
Conflict of Interests
The authors declare no conflict of interest.
References and Notes
1. Lohmann, V.; Korner, J.; Koch, U.; Herian, L.; Theilmann, L.; Bartenschlager, R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999, 285, 110–113.
2. Fusco, D.N.; Chung, R.T. Novel therapies for hepatitis C: Insights from the structure of the virus. Ann. Rev. Med. 2012, 63, 373–387.
3. Wakita, T.; Pietschmann, T.; Kato, T.; Miyamoto, M.; Zhao, Z.; Murthy, K.; Habermann, A.; Krausslich, H.G.; Mizokami, M.; Bartenschlager, R.; et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat. Med. 2005, 11, 791–796.
4. Lupberger, J.; Zeisel, M.B.; Xiao, F.; Thumann, C.; Fofana, I.; Zona, L.; Mee, C.J.; Turek, M.; Gorke, S.; Royer, C.; et al. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat. Med. 2011, 17, 589–595.
5. Ye, J.; Wang, C.; Sumpter, R.; Brown, M.S.; Goldstein, J.L.; Gale, M. Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 15865–15870.
6. Lin, J.O. Calmodulin-dependent phosphatases, kinases, and transcriptional corepressors involved in T-cell activation. Immunol. Rev. 2009, 228, 184–198.
7. Ma, S.; Boerner, J.E.; TiongYip, C.; Weidmann, B.; Ryder, N.S.; Cooreman, M.P.; Lin, K. NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob. Agents Chemother. 2006, 50, 2976–2982.
8. Chatterji, U.; Bobardt, M.; Selvarajah, S.; Yang, F.; Tang, H.; Sakamoto, N.; Vuvagniaux, G.; Parkinson, T.; Gallay, P. The isomerase active site of cyclophilin A is critical for hepatitis C virus replication. J. Biol. Chem. 2009, 284, 16998–17005.
9. Hopkins, S.; DiMassimo, E.; Rusnak, P.; Heuman, D.; Lalezari, J.; Sluder, A.; Scorneaux, B.; Mosier, S.; Kowalczyk., Ribeill, Y.; et al. The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 HCV infection. J. Hepatol. 2012, 57, 47–54.
10. Flisiak, R.; Horban, A.; Gallay, P.; Bobardt, M.; Selvarajah, S.; Wiercinska-Drapalo, A.; Siwak, E.; Cielniak, I.; Higersberger, J.; Kierkus, J.; et al. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 2008, 47, 817–826.
11. Lawitz, E.; Godofsky, E.; Rouzier, R.; Marbury, T.; Nguyen, T.; Ke, J.; Huang, M.; Praestgaard, J.; Serra, D.; Evans, T.G. Safety, pharmacokinetics, and antiviral activity of the cyclophilin inhibitor NIM811 alone or in combination with pegylated interferon in HCV-infected patients receiving 14 days of therapy. Antivir. Res. 2011. 89, 238–245.
12. Watashi, K.; Hijikata, M.; Hosaka, M.; Yamaji, M.; Shimotohno, K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003, 38, 1282–1288.
13. Nakagawa, M.; Sakamoto, N.; Enomoto, N.; Tanabe, Y.; Kanazawa, N.; Koyama, T.; Kurosaki, M.; Maekawa, S.; Yamashiro, T.; Chen, C.H.; et al. Specific inhibition of hepatitis C virus replication by cyclosporin A. Biochem. Biophys. Res. Commun. 2004, 313, 42–47.
14. Goto, K.; Watashi, K.; Murata, T.; Hishiki, T.; Hijikata, M.; Shimotohno, K. Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. Biochem. Biophys. Res. Commun. 2006, 343, 879–884.
15. Ishii, N.; Watashi, K.; Hishiki, T.; Goto, K.; Inoue, D.; Hijikata, M.; Wakita, T.; Kato, N.; Shimotohno, K. Diverse effects of cyclosporine on hepatitis C virus strain replication. J. Virol. 2006, 80, 4510–4520.
16. Paeshuyse, J.; Kaul, A; De Clercq, E.; Rosenwirth, B.; Dumont, J.M.; Scalfaro, P.; Bartenschlager, R.; Neyts, J. The non-immunosuppressive cyclosporin DEBIO 025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 2006, 43, 761–770.
17. Houck, D.R.; Hopkins, S. Preclinical evaluation of SCY-635, a cyclophilin inhibitor with potent anti-HCV activity. Hepatology 2006, 44, Abstract 934.
18. Puyang, X.; Poulin, D.L.; Mathy, J.E.; Anderson, L.J.; Ma, S.; Fang, Z.; Zhu, S.; Lin, K.; Fujimoto, R.; Compton, T.; et al. Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors. Antimicrob. Agents Chemother. 2010, 54, 1981–1987.
19. Gregory, M.A.; Moss, S.J.; Coates, N.; Foster, T.; Bobardt, M.; Chatterji, U.; Gallay, P.A.; Leyssen, P.; Neyts, J.; Nur-E-Alam, M.; et al. Preclinical characterization of naturally occurring polyketide cyclophilin inhibitors from the Sanglifehrin family. Antimicrob. Agents Chemother. 2011, 55, 1975–1981.
20. Moss, S.J.; Bobardt, M.; Leyssen, P.; Coates, N.; Chatterji, U.; Dejian, X.; Foster, T.; Liu, J.; Nur-e-Alam, M.; Suthar, D.; et al. Sangamides, a new class of cyclophilin inhibiting host targeted antivirals for treatment of HCV infection. Med. Chem. Commun. 2011, doi:10.1039/C1MD00227A.
21. Nakagawa, M.; Sakamoto, N.; Tanabe, Y.; Koyama, T.; Itsui, Y.; Takeda, Y.; Chen, C.H.; Kakinuma, S.; Oooka, S.; Maekawa, S.; et al. Suppression of hepatitis C virus replication by cyclosporin a is mediated by blockade of cyclophilins. Gastroenterology 2005, 129, 1031–1041.
22. Gaither, L.A.; Borawski, J.; Anderson, L.J.; Balabanis, K.A.; Devay, P.; Joberty, G.; Rau, C.; Schirle, M.; Bouwmeester, T.; Mickanin, C.; et al. Multiple cyclophilins involved in different cellular pathways mediate HCV replication. Virology 2010, 397, 43–55.
23. Yang, F.; Robotham, J.M.; Nelson, H.B.; Irsigler, A.; Kenworthy, R.; Tang, H. Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J. Virol. 2008, 82, 5269–5278.
24. Liu, Z.; Yang, F.; Robotham, J.M.; Tang, H. Critical role of cyclophilin A and its prolyl-peptidyl isomerase activity in the structure and function of the hepatitis C virus replication complex. J. Virol. 2009, 83, 6554–6565.
25. Chatterji, U.; Bobardt, M.D.; Lim, P.; Gallay, P.A. Cyclophilin A-independent recruitment of NS5A and NS5B into hepatitis C virus replication complexes. J. Gen. Virol. 2010, 91, 1189–1193.
26. Handschumacher, R.E.; Harding, M.W.; Rice, J.; Drugge, R.J.; Speicher, D.W. Cyclophilin: A specific cytosolic binding protein for cyclosporin A. Science 1984, 226, 544–547.
27. Lang, K.; Schmid, F.X.; Fischer, G. Catalysis of protein folding by prolyl isomerase. Nature 1987, 329, 268–270.
28. Fischer, G.; Bang, H.; Berger, E.; Schellenberger, A. Conformational specificity of chymotrypsin toward proline-containing substrates. Biochim. Biophys. Acta 1984, 791, 87–97.
29. Fischer, G.; Wittmann-Liebold, B.; Lang, K.; Kiefhaber, T.; Schmid, F.X. Cyclophilin and Peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 1989, 337, 476–478.
30. Colgan, J.; Asmal, M.; Yu, B.; Luban, J. Cyclophilin A-deficient mice are resistant to immunosuppression by cyclosporine. J. Immunol. 2005, 174, 6030–6038.
31. Braaten, D.; Luban, J. Cyclophilin A regulates HIV-1 Infectivity, as demonstrated by gene targeting in human T cells. EMBO J. 2001, 20, 1300–1309.
32. Kaul, A.; Stauffer, S.; Berger, C.; Pertel, T.; Schmitt, J.; Kallis, S.; Zayas, M.; Lohmann, V.; Luban, J.; Bartenschlager, R. Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics. PLoS Pathog. 2009, 5, e1000546.
33. Ke, H.M.; Zydowsky, L.D.; Liu, J.; Walsh, C.T. Crystal structure of recombinant human T-cell cyclophilin A at 2.5 A resolution. Proc. Natl. Acad. Sci. U. S. A. 1991, 88, 9483–9487.
34. Zydowsky, L.D.; Etzkorn, F.A.; Chang, H.Y.; Ferguson, S.B.; Stolz, L.A.; Ho, S.I.; Walsh, C.T. Active site mutants of human cyclophilin a separate peptidyl-prolyl isomerase activity from cyclosporin A bindinga and calcineurin inhibition. Protein Sci. 1992, 1, 1092–1099.
35. Fernandes, F.; Ansari, I.U.; Striker, R. Cyclosporine inhibits A direct interaction between cyclophilins and hepatitis c ns5a. PLoS One 2010, 5, e9815.
36. Fernandes, F.; Poole, D.S.; Hoover, S.; Middleton, R.; Andrei, A.C.; Gerstner, J.; Striker, R. Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B. Hepatology 2007, 46, 1026–1033.
37. Chatterji, U.; Lim, P.; Bobardt, M.D.; Wieland, S.; Cordek, D.G.; Vuagniaux, G.; Chisari, F.; Cameron, C.E.; Targett-Adams, P.; Parkinson, T.; et al. HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A-cyclophilin A interaction to cyclophilin inhibitors. J. Hepatol. 2010, 53, 50–56.
38. Yang, F.; Robotham, J.M.; Grise, H.; Frausto, S.; Madan, V.; Zayas, M.; Bartenschlager, R.; Robinson, M.; Greenstein, A.E.; Nag, A.; et al. A major determinant of cyclophilin dependence and cyclosporine susceptibility of hepatitis C virus identified by a genetic approach. PLoS Pathog. 2010, 6, e1001118.
39. Coelmont, L.; Hanoulle, X.; Chatterji, U.; Berger, C.; Snoeck, J.; Bobardt, M.; Lim, P.; Vliegen, I.; Paeshuyse, J.; Vuagniaux, G.; et al. DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A. PLoS One 2010, 5, e13687.
40. Robida, J.M.; Nelson, H.B.; Liu, Z.; Tang, H. Characterization of hepatitis C virus subgenomic replicon resistance to cyclosporine in vitro. J. Virol. 2007, 81, 5829–5840.
41. Hopkins, S.; Scorneaux, B.; Mosier, S.; Huang, Z.; Murray, M.G.; Harris, R.R. The genetic and biochemical basis for resistance to SCY-635. In Proceedings of the 59th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, NC, USA, 31 October–1 November 2008; Abstract 1814.
42. Hopkins, S.; Huang, Z.; Mosier, S.; Chatterji, U.; Gallay, P. The non-immunosuppressive cyclophilin inhibitor SCY-635 inhibits the association of NS5A and cyclophilin A. In Proceedings of the American Association for Study of the Liver Congress, Boston, MA, USA, 29 October–2 November 2010; Abstract 367.
43. Garcia-Rivera, J.A.; Lin, K.; Hopkins, S.; Gregory, M.A.; Wilkinson, B.; Gallay, P.A. Development of a live cell FACS assay for the screening of inhibitors of HCV replication. Open Virol. J. 2012, in press.
44. Garcia-Rivera, J.A.; Bobardt, M.D.; Chatterji, U.; Hopkins, S.; Gregory, M.A.; Wilkinson, B.; Lin, K.; Gallay, P.A. Multiple mutations in HCV NS5A domain II are required to confer significant level of resistance to alisporivir. Antimicrob. Agents Chemother. 2012, in press.
45. Hanoulle, X.; Badillo, A.; Wieruszeski, J.M.; Verdegem, D.; Landrieu, I.; Bartenschlager, R.; Penin, F.; Lippens, G. Hepatitis C virus NS5A protein is a substrate for the peptidyl-prolyl cis/trans isomerase activity of cyclophilins A and B. J. Biol. Chem. 2009, 284, 13589–13601.
46. Waller, H.; Chatterji, U.; Gallay, P.; Parkinson, T.; Targett-Adams, P.J. The use of alphalisa technology to detect interaction between hepatitis C virus-encoded ns5a and cyclophilin A. Virol. Methods 2010, 165, 202–210.
47. Badillo, A.; Receveur-Brechot, V.; Miron, S.; Hanoulle, X.; Molle, J.; Montserret, R.; Bartenschlager, R.; Lippens, G.; Ricard-Blum, S.; Penin, F. Overall structural model of non-structural protein 5A from hepatitis C virus and modulation by cyclophilin A. In Proceedings of the 18th International Symposium on Hepatitis C Virus & Related Viruses, Seattle, WA, USA, 8–12 September 2011; Abstract 09.14.
48. Foster, T.L.; Gallay, P.; Stonehouse, N.J.; Harris, M. Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner. J. Virol. 2011, 85, 7460–7464.
49. Shirota, Y.; Luo, H.; Qin, W.; Kaneko, S.; Yamashita, T.; Kobayashi, K.; Murakami, S. Hepatitis C Virus (HCV) NS5A binds RNA-dependent RNA polymerase (Rdrp) NS5B and modulates RNA-dependent RNA polymerase activity. J. Biol. Chem. 2002, 277, 11149–11155.
50. Ranjith-Kumar, C.T.; Wen, Y.; Baxter, N.; Bhardwaj, K.; Cheng, K.C. A cell-based assay for RNA synthesis by the HCV polymerase reveals new insights on mechanism of polymerase inhibitors and modulation by NS5A. PLoS One 2011, 6, e22575.
51. Quezada, E.M.; Kane, C.M. The hepatitis C virus NS5A stimulates NS5B during in vitro RNA synthesis in a template specific manner. Open Biochem. J. 2009, 3, 39–48.
52. He, Y.; Staschke, K.A.; Tan, S.L. HCV NS5A: A multifunctional regulator of cellular pathways and virus replication. In Hepatitis C Viruses: Genomes and Molecular Biology; Tan, S.L., Ed.; Horizon Bioscience: Norfolk, UK, 2006; Chapter 9.
53. Flisiak, R.; Feinman, S.V.; Jablkowski, M.; Horban, A.; Kryczka, W.; Pawlowska, M.; Heathcote, J.E.; Mazella, G.; Vandelli, C.; Nicolas-Metral, V.; et al. The cyclophilin inhibitor debio 025 combined with Peg-Ifna2a significantly reduces viral load in treatment naïve hepatitis C patients. Hepatology 2009, 49, 1460–1468.
54. Nelson, D.R.; Ghalib, R.H.; Sulkowski, M.; Schiff, E.; Rustgi, V.; Pockros, P.J.; Wang, C.; Kerhuel, G.D.; Grosgurin, P.; Porchet, H.; et al. Efficacy and safety of the cyclophilin inhibitor debio 025 in combination with pegylated interferon alpha-2A and ribavirin in previously null responder genotype 1 HCV patients. J. Hepatol. 2009, 50, Abstract 95.
55. Flisiak, R.; Pawlotsky, J.M.; Crabbe, R.; Calistru, P.; Kryczka, W.; Haussinger, D.; Mazella, G.; Romero, M.; Purcea, D.; Vuagniaux, G.; et al. Once daily alisporivir (DEB025) plus peg-IFN-Alfa-2A/Ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment-naïve patients—The ESSENTIAL study. J. Hepatol. 2011, 55, Abstract 190.
56. Pawlotsky, J.M.; Sarin, S.K.; Foster, G.R.; Peng, C.Y.; Rasenack, J.; Flisiak, R.; Piratvisuth, T.; Wedemeyer, H.; Chuang, W.L.; Zhang, W.M.; et al. Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-G2 or G3 patients: SVR12 results from VITAL-1 phase 2b study. J. Hepatol. 2012, 56, Abstract 1405.
57. Alberti, M.; Chuang, W.L.; Flisiak, R.; Mazella, G.; Horban, A.; Goeser, T.; Calistru, P.; Buti, M.; Davis, G.; Gong, Y.; et al. Alisporivir (ALV) plus peg-interferon/ribavirin (PR) in HCV G1 treatment-experienced patients achieves primary endpoint with superior efficacy at treatment week 12 compared to retreatment with PR. J. Hepatol. 2012, 56, Abstract 1406.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Download PDF Full-Text [394 KB, uploaded 29 October 2012 09:36 CET]
Dates: May 18 - June 1, 2015
MedPage Today invited specialists from leading medical institutions to weigh in on the latest advancements in hepatitis C with one question each day for 10 days.
Digestive Disease Week 2015
Begins May 16 - 19
Topics with include hepatitis C treatments, HCV treatment in special populations, developments in gastrointestinal endoscopy, gastrointestinal bleeding in cirrhosis, surgical risk in patients with liver disease to name a few.
Hepatitis C News Of The Day
Where Can I Find A Specialist?
Find a Specialist In Your Area
Testing, Diagnosis and Treatment
Do You Have A Question About HCV?
HepCBC presents the March release of Peppermint Patti's Hepatitis C FAQs - version 10.
FDA Approved Drugs
FDA approved hepatitis C treatments
Drugs Under Development
– Detailed Reference Guide
Hepatitis C Links
These links will take you to the premier Hepatitis C sites and keep you informed with breaking news, clinical studies, new drugs, podcasts, newsletters, support, personal experiences and more.
CareLine will provide help to patients across the country to resolve healthcare access and insurance issues, at no charge to the patient.
Lucinda K. Porter, RN, the author of "Free from Hepatitis C" has graced the HCV community with a second book "Hepatitis C Treatment One Step at a Time" available now on Amazon.
- ► 2014 (614)
- ► 2013 (957)
- Mice with 'humanized' livers improve early drug te...
- Just For Fun - Could zombies exist?
- AASLD President's Press Conference for The Liver M...
- High prevalence of antibiotic-resistant bacterial ...
- Gilead's Once-Daily Novel Prodrug for the Treatmen...
- Black cohosh liver warning
- Hepatitis c clinical trials for October 2012-Clini...
- Liver transplant survival higher among patients wi...
- Researchers Build on Diabetes-Liver Cancer Connect...
- Two Hep C Questions: What will happen to me? Shoul...
- Hepatitis C-Achillion Pharma Worthy of New Look
- BioCryst drops hep C drug on safety issues
- Incivek (Telaprevir)-Hepatitis C Geno 2 Patient Tr...
- Misinformation on gallstones drew more views on Yo...
- Alisporivir (DEB025) - Cyclophilin Inhibitors: An ...
- Checkmate to liver biopsy in chronic hepatitis C?
- New developments in liver disease
- Rates of Transmitted HIV Drug Resistance Rising in...
- Health Canada pulls distribution of Novartis flu v...
- Black patients received less clinical trial inform...
- Watch - Management of Hepatitis C Virus in the New...
- Federal Judge Grants permanent injunction against ...
- Telaprevir, boceprevir offer similar efficacy for ...
- Few HCV/HBV infections identified in adults with a...
- Hepatitis—Do you “C” it?
- AASLD 2012-Galectin Therapeutics to Present New Da...
- MicroRNAs, Hepatitis C Virus, and HCV/HIV-1 Co-Inf...
- Diabetes in the Elderly Addressed in Consensus Rep...
- Antivirals Bust Risk of Cancer in HCV
- Telaprevir therapy required tacrolimus dose reduct...
- Hepatitis C - Finally a conference examines issue ...
- Medicine rarely a slam dunk, despite splashy studi...
- Will Dropping Interferon Be the Magic Bullet for R...
- Less Liver Cancer in HCV Patients Given Antiviral ...
- Hepatitis C virus: a critical appraisal of new app...
- The anti-viral effect of sorafenib in hepatitis C-...
- Hepatitis C–What Are Your Treatment Choices: New W...
- Encephalopathy - Unmanaged Condition Exacts a Heav...
- Naturally occurring mutations to HCV protease inhi...
- Patients with HCV, diabetes at greater risk for li...
- Learning From the Patient Experience: Optimizing T...
- Gilead Raises Sales Guidance, Talks Up Strong HIV ...
- TMC435 (Simeprevir)-Promising New Oral Therapy for...
- Is it a Liver Tumor…or Spilled Gallstones?
- EMA Probes Roche For Reporting Failures
- Bristol-Myers brought Insight Public Affairs- Prep...
- Setbacks in HCV Drug Development Highlight Uncerta...
- HCV Admissions Rise While HIV Ones Fall
- Hepatitis C-Expected Launch of GS-7977 in 2015 wil...
- Hepatitis C - Antiviral drugs cut liver cancer ris...
- Egypt launches world’s largest Hepatitis C patient...
- 'Bath Salts' Ingredient More Powerful, Dangerous T...
- Telaprevir had greater relative efficacy than boce...
- Hepatitis C-What if I need Financial Assistance to...
- Autoimmune thyroiditis in patients with chronic he...
- Differences in HCV Infection, and Effects of Treat...
- VX-135 (ALS-2200) Vertex Draws Collaboration Inter...
- Players In Hepatitis C Treatment Market Officially...
- Debilitating muscle cramps common among patients w...
- Common Medical Screen Predicts Liver Cancer Risk i...
- Simeprevir (TMC435) Data In Hepatitis C To Be Pres...
- Hepatitis C-BioCryst Pharmaceuticals and Presidio ...
- UPDATE: Abbott Hepatitis C Regimen Suppresses Viru...
- Hepatitis C Point-of-Care Tests Are Highly Accurat...
- AASLD-Bristol-Myers Squibb to Present New Data
- Interferon-free ABT-450 - Enanta enters phase 3 cl...
- A New And Interesting Addition To The Hep C Clinic...
- Low D status associated with impaired hepatitis C ...
- Are You Ready for Flu Season?
- Triple Therapy for Chronic HCV Infection Is Cost-E...
- Alternative-medicine doctor reprimanded, fined in ...
- Severity of depression in hepatitis B and hepatiti...
- High Incidence of Parkinsonism in Patients With Li...
- Hepatitis C and Human Immunodeficiency Virus Type ...
- Percutaneous RFA for HCC leads to frequent recurre...
- Prior Alcohol Consumption Does Not Impair HCV Trea...
- 2012 AASLD- What To Expect From Jules Levin
- Mental health in hepatitis C: A European expert co...
- Triple therapy with first generation HCV protease ...
- Hepatitis C-Update on Diagnosis and Treatment
- Living With Restless Legs Syndrome
- Podcast: Survival Model in Patients with HCC
- Cirrhotic patients coinfected with HIV, HCV less r...
- Etanercept Recommended for RA Complicated by Hepat...
- Strategies for Overcoming Practice-Based Barriers ...
- Part 2- 8 Renowned Hepatology Experts Answer 32 Qu...
- The Hepatitis-Fibromyalgia Connection
- October Hepatitis C Clinical Trial Updates From Cl...
- CLD Special Issue: Non-alcoholic Fatty Liver Disea...
- Patients With Diabetes,Chronic Hepatitis C Risk Fo...
- Insulin Resistance and Hepatic Fibrosis in HIV/Hep...
- A novel oncogenic network specific to liver cancer...
- Hepatitis C - The Risk And Free Home Confidential ...
- Liver Cancer - A Supplement Fairy Tale
- Missing Data Said to Threaten Trial Integrity
- Vaniprevir (MK-7009) Next-Generation Protease Inhi...
- Missing Data May Skew Clinical Trials
- Bone alterations in hepatitis C virus infected pat...
- The Top Phase III Disasters of 2012 - BMS-094 - Br...
- Many HBV, HCV infections remain unidentified in US...
- Bermudians may have been exposed to Hepatitis C vi...
- Hyperion Therapeutics to Report Results of HALT-HE...
- Coffee and Liver – Long Way To Go
- Webcast - HCV triple therapy adherence and importa...
- NATAP - Vertex Nuke Program ALS-2200
- Prognosis still poor for esophageal variceal bleed...
- Video- Hepatitis C Victims File Suit Against UPMC
- Achillion Pharmaceuticals moves up as a contender ...
- Medivir-Simeprevir (TMC435) Data Will Be Presented...
- New Hepatitis C Data from Boehringer Ingelheim to ...
- Merck to Present New Data for VICTRELIS®(boceprevi...
- Vertex Announces Presentation of New Data from Hep...
- New HCV drugs in development - Highlights Of The ...
- Hepatitis C - Response to Interferon-α/Ribavirin D...
- ▼ October (114)
- ► 2011 (1576)