New Drugs Require New Terms for HCV Virologic Response

From Medscape Medical News

Daniel M. Keller, PhD

May 8, 2012 (Barcelona, Spain) — The development of drugs to treat hepatitis C virus (HCV) is progressing rapidly, but the terminology to quantify virologic response is lagging. A consortium of interested organizations is creating nomenclature for virologic responses in trials of direct-acting antiviral drugs, which are small-molecule inhibitors of viral enzymes that hold the promise of interferon-free treatment regimens.

During a poster session here at the International Liver Congress 2012, Donald Jensen, MD, professor of medicine at the University of Chicago Medical Center in Illinois, presented the rationale for and principles of the nomenclature being developed by the Hepatitis C Virus Drug Development Advisory Group (HCV DrAG).

HCV DrAG is a project of the Forum for Collaborative HIV Research, which has a subgroup devoted to HCV research with experts from the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver (EASL), and the Infectious Diseases Society of America. The forum is a broad consensus panel that includes industry representatives, members of American and European drug regulatory agencies, academic investigators, and representatives of advocacy groups.

Direct-acting antiviral drugs have potent antiviral actions and appear to produce a more rapid virologic response, with or without interferon, than interferon-based regimens without the new drugs. More intuitive and flexible virologic measures are needed that can adapt to these advances in HCV treatment.

"We wanted to do this before all the new oral therapies hit the market," Dr. Jensen told Medscape Medical News.

He said current terminology can be confusing when describing virologic response to the new therapies. "We felt that there was a need to have this description of virologic responses more consistent across studies — something that could also be used in manuscripts and in clinical practice," he said. A panel of experts set out to develop a nomenclature "that was intuitive, that made sense, and that was descriptive of virologic responses during the course of therapy for hepatitis C."

Considerations for Nomenclature Development

Comparisons between drugs or regimens is difficult or impossible without a common nomenclature. The propsed nomenclature will assign a description of the time frame and the level of response to the measures, as opposed to a qualitative description such as "rapid virologic response."

The proposed terminology for key decision points in treatment trials takes into account the assay-specific lower limits of quantification of HCV RNA (as opposed to lower limits of detection), with responses defined as quantifiable or unquantifiable levels of HCV RNA.

Key components in expressing virologic response are the week of treatment, the quantifiable decline in viral load from initiation of treatment (expressed as log₁₀ decline), any lead-in treatment duration (days or weeks), and whether the target HCV RNA was detected or not. The panel explains that the lower limit of quantitation (LLOQ) of a virologic assay should be clearly specified. (One common problem in current trials is the use of different commercial assay systems.) The target may or may not be detected at levels below the LLOQ.

HCV viremia at levels less than the LLOQ in trials without a lead-in treatment period — what has been called a rapid virologic response — would now be W4U, meaning an unquantifiable HCV RNA level at week 4, whether detectable or undetectable. The old complete early virologic response will now be W12U, denoting a week 12 unquantifiable HCV RNA level.

For trials with a lead-in (LI) period at, for example, weeks 0 to 4, and unquantifiable levels at week 8 (the old rapid virologic response), the new nomenclature would specifically refer to it as LI_4w-W8U. Each term would be appended with TD or TND to denote whether target HCV RNA was detected or not detected.

One holdover from the current system is sustained virologic response (SVR).

"We decided to keep SVR...but it will be sustained virologic response with a bracket after it" to denote how long the response has been sustained, Dr. Jensen noted. "We're going to keep [it] because I think that's a concept that will be consistent with future therapies."

Having a uniform reporting system will allow the comparison of results across clinical trials. In addition, the system will be able to adapt as virologic response times become shorter. Beyond clinical trials, specific terminology will aid in the development of treatment guidelines for clinical practice.

The panel has submitted a manuscript for publication. Dr. Jensen hopes that industry will adopt the system for their clinical trials and that journals will require the system as the accepted nomenclature. The US Food and Drug Administration and the European Medicines Agency, as part of the HCV DrAG working group, have stated that they would like the nomenclature to be adopted.

Dr. Jensen predicts that in the future, if very effective drugs come along and therapy becomes standardized, many of the current or proposed measures of virologic response will go by the wayside, and patients will be treated with a fixed course of therapy with an expectation of cure, as is now common with antibiotics for many infections.

George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the EASL Governing Board Scientific Committee, told Medscape Medical News that he would like to see a consensus terminology adopted, but he does not expect that it will happen soon.

Nomenclature is not the only problem in defining a response, Dr. Papatheodoridis noted.

He referred to a presentation at the congress in which researchers found a discrepancy in the viral levels of 28% of the more than 1000 samples tested with a new polymerase chain reaction (PCR) assay and the original PCR assay. With the original assay, 75% of samples had undetectable HCV DNA; with the new assay, only about 50% did. Such a difference might be reflected in the "response-guided therapy we're using now with the telaprevir or boceprevir combination," he said.

With the drugs currently in development, the companies decide which assays to use to report their findings. "All the trials are controlled by the companies. They are not controlled by us," Dr. Papatheodoridis explained.

"Another problem, which is very relevant in clinical practice, is the timing of the HCV RNA determination," Dr. Papatheodoridis explained. We don't know if a difference of a few days is relevant. If you have some new excellent drug that achieves a 100% SVR 100%, you don't care, but these are not yet available.

Mark Thursz, MBBS, MD, professor of hepatology in the Department of Medicine at Imperial College London, United Kingdom and secretary general of EASL, agreed that measures of virologic response designed for interferon-based regimens are inadequate in an era of direct-acting antiviral drugs, "because the dynamics are much quicker now. A new set of specific targets are going to be really important when we assess how well the new drugs are working."

Dr. Jensen, Dr. Papatheodoridis, and Dr. Thursz have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 897. Presented April 20, 2012.

Source

Lab Values Predict Acute-on-Chronic Liver Failure Mortality

From Medscape Medical News

Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — High international normalized ratio (INR), serum creatinine, and serum bilirubin levels independently predict mortality in patients with acute-on-chronic liver failure (ACLF).

Although the causes of underlying liver disease and acute liver insults differ in Asia and Western countries, the mortality rates are similar, Hitendra Garg, MD, DM, assistant professor at the Institute of Liver and Biliary Sciences and member of the Department of Gastroenterology at the G.B. Pant Hospital in New Delhi, India, reported here at the International Liver Congress 2012.

ACLF, a condition with high mortality, results from an acute hepatic insult in a patient with diagnosed or undiagnosed chronic liver disease. It manifests as jaundice and coagulopathy followed by ascites and/or encephalopathy. Little is known about the natural history of ACLF and the predictors of survival.

Dr. Garg explained that chronic liver disease in the West is mainly of alcoholic (65%) and viral (17%) origin; in the East, the main causes are hepatitis B virus (HBV) infection (37%) and alcohol (34%).

For this prospective study involving 8 Asian and South Asian countries, the investigators enrolled 340 patients from October 2009 to October 2011 with an acute hepatic insult, bilirubin of at least 5 mg/dL, and INR greater than 1.5, complicated within 4 weeks by ascites and/or encephalopathy in patients with chronic liver disease. Patients were excluded if they had hepatocellular carcinoma, portal vein thrombosis, cardiovascular comorbidities, or sepsis.

Mean patient age was 42 ± 13 years, and there were 3 times as many men as women. They were evaluated and given standard medical treatment.

As expected, the most common causes of chronic liver disease were alcohol and HBV. The most common causes of acute liver insult were alcoholic hepatitis, hepatitis E virus infection, and reactivation of chronic HBV. Dr. Garg said that most of the patients with HBV were given the antiviral drug tenofovir.

At 3-month follow-up, 53% (176 of 340) of the cohort had died. At 1 month, the mortality was 40%. For the 126 evaluated patients who died, the cause was multiorgan failure in 75%, progressive liver failure in 10%, and upper gastrointestinal bleeding in 6%.

In a multivariate analysis, 3 baseline parameters emerged as significant predictors of mortality within 3 months: hepatic encephalopathy (odds ratio [OR], 2.5; 95% confidence interval [CI], 0.28 to 0.73; P = .001), serum bilirubin greater than 21.7 mg/dL (OR, 1.8; 95% CI, 1.02 to 1.10; P = .006), and INR greater than 2.2 (OR, 1.6; 95% CI, 1.1 to 1.7; P = .001).

There was no difference in mortality between patients with HBV reactivation, those with alcoholic hepatitis, and those with other causes, Dr. Garg said.

Session moderator Rajendar Reddy, MD, professor of medicine, director of hepatology, and medical director of liver transplantation at the University of Pennsylvania in Philadelphia, told Medscape Medical News that the definitions of ACLF are different in the East and the West; there is a lot of alcoholic hepatitis, reactivation of HBV, and superinfection with hepatitis A or E in the East.

"In the United States...we see acute infections that cause liver failure in a patient who has stable underlying liver disease, so fundamentally, there's a difference in the definitions," he said. Although Dr. Reddy struggles with whether these findings are clinically useful in the West, he said that ACLF in both regions is associated with increased morbidity and mortality, and that all the patients go on to multiorgan failure.

Dr. Reddy thinks the predictors of mortality should be valid regardless of the causes of ACLF, "although there's one other major difference.... In areas where liver transplantation is available, we potentially could rescue quite a few of those patients, so the mortality rate may not be similar." Dr. Reddy explained.

He called ACLF "an ominous phenomenon," and said strategies are needed to prevent it, including ways to prevent infections.

Dr. Reddy has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 69. Presented April 20, 2012.

Source

Two Oral Drugs Clear HCV Without Interferon

From Medscape Medical News

Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — Twelve weeks of treatment with a combination of 2 direct-acting antiviral drugs plus ribavirin achieved a sustained virologic response rate of more than 80% in patients chronically infected with genotype 1 hepatitis C virus (HCV), Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas, reported here at the International Liver Congress 2012.

In a pilot study of 11 treatment-naive noncirrhotic patients, 91% achieved a sustained virologic response at 12 weeks after the end of treatment (SVR12), and 82% had a sustained virologic response at 36 weeks (SVR36).

Currently, the only approved regimens for the treatment of patients with genotype 1 HCV contain interferon. For patients who cannot tolerate interferon, there are no other options.

The 2 direct-acting antiviral drugs are ABT-450, a potent inhibitor of the HCV NS3 protease, and ABT-072 (Abbott Labs), a nonnucleoside inhibitor of HCV NS5B RNA polymerase. Both drugs are dosed orally once daily. ABT-450 is boosted with ritonavir (ABT-450/r) to maintain high ABT-450 exposure and to allow once-daily dosing.

This trial is the first to evaluate the 2 drugs plus ribavirin in an interferon-free regimen for the treatment of HCV genotype 1.

The researchers enrolled only patients who were of the interleukin-28B CC genotype, which is the genotype most amenable to treatment with pegylated interferon and ribavirin, in case the trial regimen failed.

Patients were treated with ABT-450/r plus ABT-072 daily plus ribavirin for 12 weeks and then followed for 48 weeks after the end of treatment. To be eligible for the study, patients had to be 18 to 65 years of age; had to have HCV genotype 1 infection for at least 6 months, no evidence of cirrhosis or bridging fibrosis, and no coinfection with hepatitis B or HIV; and had to be eligible for treatment with pegylated interferon plus ribavirin.

Baseline characteristics were similar in the the 2 groups (mean age, 56.4 years; mean weight, 79.6 kg). Mean HCV RNA level was 6.93 ± 0.22 log₁₀ IU/mL, and all patients had HCV RNA levels above 800,000 IU/mL.

Rapid, Sustained Virologic Responses

All 11 patients achieved a rapid virologic response and an extended rapid virologic response. Sustained virologic responses at 12, 24, and 36 weeks occurred in 91%, 91%, and 82% of the cohort, respectively.

There were no virologic breakthroughs on therapy, but 2 patients relapsed after therapy ended — one at week 12 and the other at week 36.

All patients experienced adverse effects, but most were mild and included headache, nausea, fatigue, dry skin, and rash. One person had a fasting glucose level above 250 mg/dL, and 2 had indirect bilirubin elevations without concomitant transaminase elevations 1 week after treatment initiation, which resolved with continued dosing. The elevation was consistent with the known effect of ABT-450 on the OATP1B1 bilirubin transporter.

The were no study drug interruptions or discontinuations and no early trial discontinuations. There were also no deaths or serious adverse effects.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the European Association for the Study of the Liver Governing Board Scientific Committee, told Medscape Medical News that in light of the small sample size, the 1 late relapse at 36 weeks may or may not be important.

"If these very late relapsers are just 1% or 2%, then it will be of no clinical relevance.... If it's really 1 of 11 (so close to 10%), these late relapsers will be very important," he said. "Because these are new regimens, we don't know how the responders will behave in the long term, so I think the SVR12 should be the gold standard for reporting the results of the trials. [In addition], all trials should still have at least 1 HCV RNA follow-up...1 year after these SVR12 determinations."

Dr. Lawitz reports financial relationships with Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, sanofi-aventis, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and ZymoGenetics. Dr. Papatheodoridis has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 13. Presented April 19, 2012.

Source

Twelve Weeks of GS-7977 Eliminates HCV as Well as 24 Weeks

From Medscape Medical News

Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — Twelve weeks of GS-7977 (Gilead Sciences) plus pegylated interferon (pegIFN) and ribavirin was as effective as 24 weeks of treatment in eliminating hepatitis C virus (HCV) genotype 1.

In the phase 2 ATOMIC trial, the drug was found to be safe and well tolerated, according to Kris Kowdley, MD, director of the Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, and clinical professor of medicine at the University of Washington in Seattle, who reported the interim results here at the International Liver Congress 2012.

GS-7977 is a potent oral nucleotide analogue inhibitor of HCV NS5B RNA polymerase that has a high barrier to the development of viral resistance. In another trial (PROTON), 12 weeks of GS-7977 in combination with pegIFN/ribavirin followed by 12 weeks of pegIFN/ribavirin was associated with a sustained virologic response (SVR) rate of 91% at 12 (SVR12) and 24 weeks (SVR24) after the end of therapy in patients infected with HCV genotype 1. In light of those results, the aim of the ATOMIC trial was to see if only 12 weeks of therapy could achieve similar results.

In the ATOMIC trial, treatment-naive patients chronically infected with HCV genotype 1 were randomly assigned to 1 of 3 treatment groups: GS-7977 plus pegIFN/ribavirin for 12 weeks (n = 52), GS-7977 plus pegIFN/ribavirin for 24 weeks (n = 125), or GS-7977 plus pegIFN/ribavirin for 12 weeks followed by 12 weeks of GS-7977 alone (n = 75) or in combination with pegIFN/ribavirin (n = 75).

Participants were predominantly white, male, about 50 years of age, had HCV RNA levels of at least 50,000 IU/mL, and had adequate hematologic values. The treatment groups were generally well matched for baseline characteristics.

Drug Combination Yields Rapid and Sustained Virologic Response

In all treatment groups, there was rapid viral suppression over the first 2 weeks of therapy, regardless of interleukin-28B genotype. At the end of treatment, 98% to 99% of patients in each group had achieved HCV RNA levels below the limits of detection, and 92% to 94% achieved a sustained virologic response at 4 weeks (SVR4).

An SVR12 of 90% was achieved in all treatment groups. At the time of the presentation, SVR12 data were available for only some of the patients treated with GS-7977 plus pegIFN/ribavirin for 12 weeks, When only those patients were included, an SVR12 of 94% was achieved, "suggesting that this is a very effective and successful combination," Dr. Kowdley said.

"In fact, when we examined the reasons for failure to achieve an SVR, in most cases it was because of a lack of follow-up rather than because of virologic failure or relapse," he reported. Only 4 patients in the 3 groups experienced a relapse at the SVR4 time point. In the 4 patients who relapsed, no S282T resistance mutations have been detected in the viral NS5B RNA polymerase.

GS-7977 plus pegIFN/ribavirin was generally well tolerated. Less than 5% of patients discontinued the study because of adverse effects related to GS-7977. Most adverse effects were constitutional symptoms generally associated with pegIFN/ribavirin. Neutrophil and lymphocyte counts and hemoglobin and alanine aminotransferase levels quickly improved after pegIFN/ribavirin was discontinued.

Dr. Kowdley concluded that 12 weeks of GS-7977 in combination with pegIFN/ribavirin appears to be as effective as 24 weeks of the same therapy.

Session moderator Mark Thursz, MBBS, MD, professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, and secretary general of the European Association for the Study of the Liver, who was not involved in the ATOMIC trial, said during a news conference that SVR24, an absence of viremia for 6 months after the end of treatment, has been the standard definition of cure until recently. Now, "we've started to become used to SVR12 as an end point. I understand that the FDA [US Food and Drug Administration] is now interested in SVR12 if it can be subsequently established as meaning a cure," he said.

"Now the companies are coming to us with SVR4 data.... SVR4 certainly predicts the final outcome. It may not be quite the same as the cure rate, the SVR24 rate, but it's pretty close and gives us a very good indication," Dr. Thursz explained. The implication is that when abstracts are submitted to meetings, "SVR4 is something that we have to take seriously...whereas previously we would regard [the results] as merely interim data," he said.

He told Medscape Medical News that the program for the development of GS-7977 is "progressing very rapidly. I know that Gilead [the drug's manufacturer] is looking at what the best option is" to get the drug approved and available to patients as quickly as possible. He said that some reports suggest that Gilead could file for approval with the FDA in late 2013, with the potential for approval in 2014.

Dr. Kowdley reports being a consultant/advisor for Novartis, Vertex, Pharmasset, Merck, and Abbott; and receiving grants and research support from BMS, Intercept, Abbott, Pharmasset, Merck, Gilead, GSK, Mochida, Conatus, Boeringer Ingelheim, and Genentech. Dr. Thurzs has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 1. Presented April 19, 2012.

Source

New Antivirals Show Poor Safety in HCV With Cirrhosis

From Medscape Medical News

Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — Two relatively new direct-acting antiviral drugs have poor safety profiles in patients with hepatitis C virus (HCV) and cirrhosis, including a high rate of serious adverse events leading to study discontinuation. However, the efficacy of the drugs is good, as evidenced by high rates of on-treatment virologic responses, Christophe Hézode, MD, from Hôpital Henri Mondor in Créteil, France, reported here at the International Liver Congress 2012.

In phase 3 trials of the 2 drugs — telaprevir and boceprevir — rash, pruritus, and anemia were reported with telaprevir, and anemia and dysgeusia were reported with boceprevir. However, those trials included a relatively small number of patients with cirrhosis. A French compassionate-use program allowed the early use of these 2 protease inhibitors before they were approved for patients with cirrhosis, who were entered into a national multicenter registry to prospectively collect clinical data and biological specimens.

An interim analysis evaluated the safety and efficacy of the drugs in these patients who received at least 16 weeks of antiviral treatment (n = 455). The patients had compensated cirrhosis and had relapsed after previous treatment or were partial responders (defined as having had a decrease in HCV RNA of at least 2 log₁₀ IU/mL at week 12 of therapy).

Telaprevir patients (n = 296) received 12 weeks of telaprevir with pegylated interferon (pegIFN) plus ribavirin and then continued only the pegIFN/ribavirin out to week 48. Boceprevir patients (n = 159) received pgIFN/ribavirin for 48 weeks, during which they also received boceprevir for weeks 4 to 48. Both groups were followed for virologic response after week 48.

The telaprevir and boceprevir groups were similar at baseline; mean age was 57 years, HCV RNA level was 6.5 log₁₀ IU/mL, mean hemoglobin was 14.4 to 14.8 g/dL, mean neutrophil count was 3.2 to 3.3 × 10⁹/mm³, and mean platelet count was 150,000/mm³.

High Serious Adverse Event Rate

"The rate of serious adverse events was high, around 50%, with early discontinuation due to severe adverse events observed in 14% of the patients," Dr. Hézode said.

"The second message is that 6 patients died — 2% of the cohort. The main reasons for these deaths were sepsis and hepatic decompensation" that was probably related to interferon, not telaprevir.

A third safety signal was the "difficult management of anemia," requiring the use of recombinant erythropoietin or transfusions, he explained.

Dr. Hézode said that in the boceprevir group, "the serious adverse event rate was high, around 40%, and early discontinuation due to serious adverse events was observed in 7% of patients." Two patients died from sepsis. Hepatic decompensation occurred in 4.4% of patients. Significant anemia occurred in one third of patients, two thirds required recombinant erythropoietin, and 10.7% received transfusions.

Dr. Hézode presented efficacy data on boceprevir, which was fairly good; 37% achieved undetectable HCV RNA levels at week 8 in an intention-to-treat analysis, rising to 58% at week 12 and 61% at week 16.

He concluded that the safety profile of these 2 direct-acting antiviral drugs in compensated cirrhotic patients is poor, but virologic responses are good. The high rate of serious adverse events (38.4% to 48.6%) was much higher than in phase 3 trials (9% to 14%).

Dr. Hézode recommended that patients with cirrhosis be treated cautiously with telaprevir or boceprevir and that they be monitored carefully, especially in light of the high incidence of anemia and its poor response to erythropoietin administration.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the European Association for the Study of the Liver Governing Board Scientific Committee, told Medscape Medical News that "we were surprised by that high rate of so many serious adverse events, and even deaths, but I believe...they had included many patients with, in fact, contraindications to treatment."

He cited, for example, a low platelet count as a contraindication to interferon. "They went beyond the official indications, beyond the inclusion and exclusion criteria that were present in the phase 3 trials. I believe this is why they had such high rates of serious adverse events," Dr. Papatheodoridis said.

He noted that the number of platelets or neutrophils is a laboratory marker that reflects the severity of liver disease. "These were patients with very advanced liver disease who...should not have been treated with interferons," he said. "If you add the [protease inhibitor], which has more side effects, of course the safety profile will be worse."

Dr. Papatheodoridis said the investigators should do "the easy subanalysis" of patients with and without contraindications or who met or failed to meet prespecified criteria for entry into the trial, which Dr. Hézode said he plans to do.

Although there were no deaths in the telaprevir or boceprevir phase 3 trials, it is now obvious that it is very dangerous to use these drugs in such advanced patients.

"The usual indications are the indications for interferon — the inclusion criteria," Dr. Papatheodoridis said.

"For the new drugs, the only new contraindication might be other drugs that the patients take for other diseases because they might have drug–drug interactions."

Dr. Hézode and Dr. Papatheodoridis have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 8. Presented April 19, 2012.

Source

EASL 2012: New HCV Drug Induces Rapid, Durable Drops in Viral Load

From Medscape Medical News

Daniel M. Keller, PhD

April 30, 2012 (Barcelona, Spain) — In 3 phase 2 trials of GS-7977, there was a concordance between the sustained virologic response (SVR) 4 weeks after the end of therapy (SVR4) and SVRs at 12 and 24 weeks after therapy (SVR12 and SVR24) in treatment-naive patients infected with hepatitis C virus (HCV) genotypes 1, 2, or 3.

No patient relapsed after posttreatment week 12, and 99% of patients with SVR4 for whom posttreatment week 12 data were available achieved SVR12, Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas, reported here at the International Liver Congress 2012.

GS-7977 (formerly PSI-7977) is a specific nucleotide analogue inhibitor of HCV NS5B RNA polymerase and is taken orally once daily. Previous reports have shown that it has broad antiviral activity against HCV genotypes 1, 2, and 3, with or without interferon, in treatment-naive patients, and has a high barrier to the development of viral resistance.

The aim of the study was to evaluate concordance between SVR4 and SVR12 or SVR24 among treatment-naive patients taking GS-7977 400 mg daily in the PROTON (n = 144), ELECTRON (n = 120), and ATOMIC (n = 332) phase 2 clinical trials. The trial protocols differed somewhat, but in general were various combinations and durations of GS-7977, pegylated interferon (Peg-IFN), and ribavirin.

In the PROTON and ATOMIC trials, depending on viral genotype, patients received GS-7977 plus Peg-IFN/ribavirin for 12 weeks followed by Peg-IFN for 12 weeks, Peg-IFN/ribavirin alone for 48 weeks, GS-7977 plus Peg-IFN/ribavirin for 12 or 24 weeks, GS-7977 plus PegIFN/ribavirin for 12 weeks followed by 12 weeks of GS-7977 alone or by GS-7977 plus ribavirin.

In the ELECTRON trial, some patients with genotypes 2 or 3 virus received similar combinations but only out to 12 weeks. Other patients with genotypes 1, 2, or 3 received GS-7977 plus ribavirin for 12 weeks.

The analysis involved only patients treated with GS-7977 400 mg in combination with interferon, ribavirin, or both for at least 4 weeks who had SVR4 plus SVR12 or SVR4 plus SVR24 data available. Of the 596 patients in the 3 studies, 259 (43%) were eligible for analysis.

At baseline in all treatment groups, mean age ranged from 43 to 52 years, and most patients were white, male, had similar body mass indices (mean, 26 to 28 kg/m²), and had interleukin-28B genotype non-CC. Mean baseline HCV RNA levels were mainly in the range of 6.3 to 6.7 log₁₀ IU/mL.

Dr. Lawitz presented results for virologic response at the end of therapy and for SVR4, SVR12, and SVR24.

"If we look at all regimens and look at the concordance between SVR4 and SVR12, we can see that 249 of the 251 [patients] were concordant between SVR4 and SVR12 — a concordance rate of 99%," he said. "If we look at concordance between SVR4 and SVR24, we can see that although the numbers are smaller, there is complete concordance — all 107 patients who had an SVR4 achieved an SVR24.... The concordance held, irrespective of the presence or absence of interferon. However, the dataset is fairly small in the noninterferon arm, limiting conclusions."

Dr. Lawitz concluded that "much of the concordance is due to the high response rates observed across all treatment groups. To date, relapse after week 4 is infrequent and was only observed in patients who received a peg-interferon-containing regimen."

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital, in Athens, Greece, and a member of the European Association for the Study of the Liver Governing Board Scientific Committee, told Medscape Medical News that GS-7977 "is a very interesting, very promising molecule. It seems to be rather safe and very effective, even in combination with ribavirin." Dr. Papatheodoridis was not involved in any of the studies.

In terms of new drugs to treat HCV, he said, "some of the new molecules are very genotype-specific.... Most of the protease inhibitors are developed to work only for genotype 1; some of them work for genotype 2, but not 3 and 4. The nucleoside polymerase inhibitors seem to work better across almost all genotypes, so this is the only class [of drug] that is not that genotype-specific."

Dr. Papatheodoridis wondered about the use of SVR4 as a standard efficacy measure. "I don't think that SVR4 will and should be the standard for SVR," he told Medscape Medical News. "Of course, we know that the FDA and most of the physicians have now accepted SVR12. So probably...SVR12 is going to be the standard for reporting trials in the near future. Still, with all these combinations, patients should have at least 1 examination, maybe 6 months or 12 months after SVR12, so we can be sure that this SVR remains over time. I think that SVR12 is going to be the standard from now on, but the patients treated with the new regimens should be followed for a bit longer."

He admitted that SVR4 looks predictive of later sustained responses. "You expect most of the patients to relapse soon after stopping treatment [if they are going relapse]. Of course, SVR4 is reasonable; we know and we expect that it is going to be associated with SVR12 and SVR24. There is no rush to decide the SVR just 4 weeks after treatment.... We should be sure that we eradicated the virus," he cautioned.

Dr. Lawitz reports financial relationships with Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, sanofi-aventis, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and ZymoGenetics. Dr. Papatheodoridis has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 7. Presented April 19, 2012.

Source

Non-Interferon-Based Combination Therapy Offers High Response Rates for Hepatitis C Patients

By Chris Berrie

BARCELONA, Spain -- April 25, 2012 -- Combining ABT-450 with ritonavir
(ABT-450/r) plus ABT-333 plus ribavirin (RBV) is well tolerated, provides high
sustained virological response (SVR) in treatment-naïve patients infected with
hepatitis C virus (HCV) genotype 1, and shows relatively high SVR in previous
interferon-based nonresponders, researchers said here at the 47th Annual
Meeting of the European Association for the Study of the Liver (EASL).

At present, there are no treatment options for HCV-infected patients who are
ineligible or intolerant to the interferons.

“This is the first study combining ABT-450 with ABT-333 with ribavirin without
interferon in genotype 1 patients who were either treatment-naïve or previous
treatment failures,” stated Fred Poordad, MD, Chief of Hepatology and Liver
Transplantation at the Comprehensive Transplant Center of Cedars-Sinai Medical
Center, Los Angeles, California, presenting this open-label study here on April
21.

The study design included 3 arms, the first 2 of which treated naïve patients
with chronic HCV genotype 1 infection using ABT-333 400 mg twice daily plus RBV
1,000-1,200 mg once daily plus ABT-450/r either 250/100 mg once daily (arm 1; n
= 19) or 150/100 mg once daily (arm 2; n = 14). The third treatment arm was
similar to arm 2, but treated prior partial or null responders to previous
pegylated interferon plus RBV treatments (arm 3; n = 17).

The treatments were for 12 weeks, with 48 weeks follow-up.

These patients were mainly male, with a mean age of just over 50 years, and
were largely HCV genotype 1a. For IL28B genotype, 52.6% were CC in arm A and
35.7% in arm B, with no IL28B CC in arm 3.

The primary endpoint was extended rapid virological response (eRVR) based on
HCV RNA lower than the limit of detection from treatment weeks 4 to 12. As the
intent-to-treat analysis, these reached 90%, 79% and 59% in arms 1, 2, and 3,
respectively.

Similarly, for SVRs at weeks 4 (SVR4) and 12 (SVR12), high levels of response
were achieved for arms 1 (95%, 93%, respectively) and 2 (95%, 93%). These SVR4
and SVR12 responses were also relatively high for the previous nonresponding
patients in arm 3 (47%, 47%).

Comparisons across IL28B CT versus TT showed no differences in SVR12 either for
treatment-naïve patients, as arms 1 plus 2 (100% vs 100%) or for previous
nonresponders (50% vs 40%).

Based on clonal sequencing, Dr. Poordad highlighted the resistant variants at
baseline and at virologic failure in the previous nonresponders of arm 3. “It
is important to note that patients who had virologic failure developed
resistance variants to both the protease inhibitor as well as the polymerase
inhibitor,” he noted.

In the safety analysis, there were no deaths or serious adverse events
throughout, with only 1 adverse event leading to premature discontinuation, in
arm 1. Four patients showed adverse events assessed as severe, without
requiring study-drug interruption or discontinuation: hyperbilirubinaemia,
fatigue, pain, and vomiting.

The treatment-emergent adverse events and the laboratory abnormalities noted
were largely the same type and levels across the 3 treatment arms. Dr. Poordad
also noted that the transient asymptomatic elevation of indirect bilirubin that
was seen is consistent with the known effect of ABT-450 on the bilirubin
transporter OATO1B1.

“It does appear that ABT-450 with ritonavir, ABT-333 plus ribavirin for 12
weeks has the potential to achieve very high SVR in a high proportion of
patients without interferon,” he concluded.

Funding for this study was provided by Abbott.

[Presentation title: A 12-Week Interferon-Free Regimen of ABT-450/r +
ABT-333 + Ribavirin Achieved SVR12 in More Than 90% of Treatment-Naïve HCV
Genotype-1 Infected Subjects and 47% of Previous Non-responders. Abstract 1399]

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EASL 2012: Interferon Lambda Beats Alfa in Clearing HCV Genotype 2 or 3

From Medscape Medical News

Daniel M. Keller, PhD

April 27, 2012 (Barcelona, Spain) — In a phase 2b study of treatment-naive adults with chronic hepatitis C virus (HCV) infection, pegylated interferon-lambda was more effective and safer than interferon-alfa in eliminating the virus in patients infected with HCV genotypes 2 or 3. The study is the first report of sustained virologic response with lambda.

Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, who presented the results here at the International Liver Congress 2012, showed data demonstrating that 180 μg of lambda, compared with alfa, produced a more rapid virologic response and a greater sustained virologic response at 24 weeks (SVR24), and was associated with fewer adverse events and less need for a dose reduction of lambda and of the accompanying ribavirin.

Treatment of chronic HCV with alfa interferons and ribavirin is limited by hematologic toxicity and other adverse effects. Lambda has marked activity against HCV and a restricted distribution of receptors in the body, which could make organ systems outside the liver less susceptible to its effects.

Dr. Zeuzem and colleagues performed a blinded randomized study of 526 noncirrhotic treatment-naive HCV-infected adults, 18 to 70 years of age, 118 of whom were chronically infected with genotype 2 or 3 and had HCV RNA levels of at least 100,000 IU/mL. The genotype 2/3 patients received daily ribavirin and weekly doses of lambda 120 μg (n = 29), 180 μg (n = 29), or 240 μg (n = 30) for 24 weeks. Other patients (n = 30) received daily ribavirin plus alfa 180 μg weekly for 24 weeks.

At baseline, the 4 groups were similar in age (range, 48.1 to 50.6 years), sex (range, 52% to 70% male), body mass index (range, 27.8 to 29.0 kg/m²), and viral load (range, 6.42 to 6.66 log₁₀ IU/mL). Most participants were white (range, 76.7% to 89.7%). The proportion of genotype 2 patients was 41.4% in the 120 μg group, 58.6% in the 180 μg group, 53.3% in the 240 μg group, and 50% in the alfa group. A large majority of patients in each group had low liver fibrosis scores.

Lambda Effective With Fewer Adverse Events

Lambda/ribavirin treatment was associated with an early and rapid drop in HCV RNA in a dose-dependent manner. After 2 weeks of treatment, the greatest reductions were seen with the 180 μg and 240 μg doses. All 3 doses of lambda produced more rapid decreases in virus level than alfa/ribavirin. The 180 μg dose will be used going forward in phase 3 trials.

HCV RNA was undetectable at week 4 in 75.9% of patients in the 180 μg group and in 30.0% in the alfa group (P < .05). Complete early virologic response (meaning HVC RNA was detectable at week 4 but not at week 12) and SVR24 were somewhat better with lambda than with alfa, but the difference was not statistically significance. In the lambda groups, 96.6% of patients achieved a complete early virologic response and 75.9% achieved SVR24.

With lambda 180 μg, 70.6% of genotype 2 patients achieved SVR24, as did 83.3% of genotype 3 patients.

Relapse rates, defined as an HCV RNA level of 25 IU/mL or greater during the follow-up period, were low, at about 21% in the lambda 180 μg group and about 25% in the alfa group.

Although all groups experienced a high level of adverse events (in the range of about 95%), some long associated with alfa therapy — "in particular, flu-like symptoms...such as myalgia, arthralgia, pyrexia, and chills" — were significantly lower in the lambda groups (7% to 17% in the 180 μg group) than in the alfa group (20% to 33%). Flu-like symptoms were definitely lower in all 3 lambda groups (20.7% for 180 μg) than in the alfa group (40%), Dr. Zeuzem said, as were musculoskeletal symptoms (20.7% vs 63.3%).

However, the prevalence of psychiatric adverse events (e.g., depression, irritability, or insomnia) was greater in the lambda groups than in the alfa group (41.4% vs 33.3%).

There were no discontinuations because of adverse events in the 180 μg group, but 6.7% dropped out of the alfa group. In the lambda groups, there were dose reductions in lambda or ribavirin at a rate of 6.9% for each; in the alfa group, there were dose reductions at rates of 26.7% for alfa and 43.3% for ribavirin.

Serious adverse events affected less than 4% of patients in the 180 μg and alfa groups. There were no serious adverse events directly related to treatment in the lambda groups.

It has been reported that lambda causes elevations in serum bilirubin, but in this trial at the 180 μg dose, there was only 1 patient (3.4%) with bilirubin elevation (in the range of 1.6 to 2.5 times the upper limit of normal).

There were no reductions in neutrophil or platelet counts associated with any dose of lambda. There were drops in both in the alfa group as long as therapy continued. Low hemoglobin (below 10 g/dL, or a drop of at least 3.4 g/dL), often associated with alfa/ribavirin, occurred in 44.8% of the alfa group and necessitated a ribavirin dose reduction in 23.3% of patients. Hemoglobin levels did not drop as much in the 180 μg group; only 6.9% were classified as having low hemoglobin, and none required a ribavirin dose reduction.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University and Hippokration General Hospital in Greece, and a member of the Governing Board Scientific Committee of the European Association for the Study of the Liver (EASL), summarized the findings for Medscape Medical News.

"It seems that the efficacy of interferon lambda might be slightly higher [than alfa], but definitely we can say that the safety profile is better.... The only side effect that was higher, and we cannot explain that, is the psychiatric side effects," he said.

In light of a robust pipeline of oral drugs now in development, Dr. Papatheodoridis said the use of interferons could be fairly limited in the treatment of HCV in the future. "I don't know what role interferon lambda may find when and if it gets licensed. After 2 or 3 years, it is possible that most of the patients will be treated with interferon-free regimens," he explained.

Mark Thursz, MD, professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, and secretary general of the EASL, alluded to this point during a news conference, drawing attention to the safety profile of lambda. Patients receiving ribavirin typically show a drop in hemoglobin, "but there's a smaller drop...in the lambda- than in the alfa-treated patients," he said. "More important are these data on neutrophils and platelets.... You can see no drop in patients who were treated with the lambda interferon.... For patients who still need an interferon and in whom problems with cell counts are going to be an issue, this is a solution."

Dr. Papatheodoridis noted that the bilirubin increase seen with lambda probably does not indicate any damage to the liver, but is perhaps the effect of "this interferon on the enzymes that are involved in the metabolism of bilirubin, which is not very dangerous; it's a lab finding without major clinical significance."

Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Papatheodoridis and Dr. Thursz have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 10. Presented April 19, 2012.

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EASL 2012: Nonalcoholic Fatty Liver Disease Raises Liver Cancer Risk

From Medscape Medical News

 

Daniel M. Keller, PhD

April 25, 2012 (Barcelona, Spain) — A study with a large multicenter cohort has shown that nonalcoholic fatty liver disease (NAFLD) is a predisposing factor for hepatocellular carcinoma (HCC) in the absence of other liver diseases, and frequently without cirrhosis.

Here at the International Liver Congress 2012, Helen Reeves, BMedSci, BM, PhD, senior lecturer and honorary consultant gastroenterologist at Newcastle Hospitals in the United Kingdom, presented evidence that obesity is a worldwide problem and, as a result, the prevalence of NAFLD is rising.

Dr. Reeves spoke on behalf of the Fatty Liver Inhibition of Progression consortium, which was formed in January 2010 to address the problem. A central goal of the consortium is to create an "observatory" of HCC, NAFLD, and metabolic syndrome to characterize the diseases with high-quality data and sample collection.

The consortium has been collecting data for 3 years on patients with HCC and no other liver disease and who imbibe less than 50 g/day of alcohol. Unless the features of metabolic syndrome or NAFLD were present on liver histology or ultrasound, cases were considered cryptogenic.

A Minority of Cases Are Cryptogenic

"The fact is that only very few of these patients develop their hepatocellular cancer in the absence of metabolic syndrome, so just 20 of 221, which is 9%, had no metabolic risk factor," Dr. Reeves reported. Of the 201 remaining cases, 187 had metabolic syndrome risk factors, 66 had fatty liver diagnosed on ultrasonography, and 37 had fatty liver diagnosed on liver biopsy.

Alcohol consumption appeared to play a minor role at most. Fifty-five percent of participants rarely or never drank alcohol, 33% drank moderately in the past but no longer drink, and only 12% consume alcohol now but not more than 50 g/day.

Mean age at HCC diagnosis was 69 years, almost 4 times as many men as women were diagnosed, and fatty liver was previously diagnosed in 50% of the cohort. HCC was detected with scheduled monitoring in 48%; for most of the rest, it was detected with ultrasound for other reasons or from symptoms.

A single liver nodule was detected in 58% of the cohort, and 75% had preserved liver function (Child-Pugh grade A). Dr. Reeves said that despite the high prevalence of preserved liver function, 55% of the participants were graded as Barcelona Clinic Liver Cancer stage C or D, indicating symptomatic disease at the time of presentation.

"Forty-three percent developed their cancer in the absence of cirrhosis," Dr. Reeves told the delegates. The ratio of men to women was similar in those with and without cirrhosis, as was body mass index and the prevalence of diabetes. Still under analysis are the alcohol and smoking history of the cohort.

"What was significantly different was the size of the largest nodule.... [It] was significantly greater in those who did not have cirrhosis," she explained (30 vs 48 mm; P < .001). Patients with cirrhosis were more likely to have encephalopathy at the time of diagnosis than patients without cirrhosis (12% vs 3%; P = .04), and trended toward more ascites (33% vs 18%, P = .062).

Only about 10% of the patients received no definitive treatment for their liver cancer and were referred for best supportive palliative care. For the rest, only a few received liver transplants, but many received radiofrequency ablation, transarterial chemoembolization, medical therapy with sorafenib, or other treatment.

Dr. Reeves concluded that NAFLD is a predisposing condition for HCC in the absence of other liver diseases, and that NAFLD-associated HCC often occurs in the absence of cirrhosis. She said many of the patients were eligible for potentially curative therapies, and the consortium will continue to follow this cohort to observe outcomes.

Mark Thursz, MBBS, MD, secretary general of the European Association for the Study of the Liver and professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, told Medscape Medical News that, ironically, there is good news for patients with hepatitis C, in that several new drugs are coming along. "You can see cures just around the corner for high proportions of patients. Nonalcoholic fatty liver is much more difficult to deal with. It's quite difficult to change people's lifestyles."

He noted that NAFLD is now the leading cause of liver disease in North America, and will be in Europe before too long. "The fact that people are developing cancer before they develop cirrhosis — that's a concern because our current guidelines tell us we should be instituting surveillance programs for cancer in cirrhotic patients," Dr. Thursz said. "Extending that into precirrhotic patients is going to be quite challenging to resources, and the selection of patients is then going to be really critical."

He said the risk factors for NAFLD are well known and include abdominal fat, diabetes (or at least insulin resistance), low high-density-lipoprotein cholesterol, and high low-density-lipoprotein cholesterol.

"We can't predict with any accuracy which individual patient has progressive disease, as opposed to pure fat in the liver," he said.

There is no noninvasive way to tell if a patient has pure steatosis, has fat and inflammation, or has fat, inflammation, and fibrosis. "It's the latter group that is at risk" for HCC, he warned.

Dr. Thursz and Dr. Reeves have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 5. Presented April 19, 2012.

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More EASL 2012 Conference Coverage from Barcelona

Provided By Clinical Care Options (All links open into new windows)

Highlights From EASL 2012

Source: CCO Independent Conference Coverage of the 2012 Annual Meeting of the European Association for the Study of the Liver*

*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.

Capsule Summaries

• ATOMIC: GS-7977 Plus PegIFN/RBV for 12 or 24 Weeks of Therapy Achieves Rapid, Sustained Viral Suppression in Treatment-Naive Patients With Genotype 1 HCV
• ASPIRE: TMC435 Plus PegIFN/RBV Significantly Improves SVR24 Rates Over PegIFN/RBV Alone in Patients With Genotype 1 HCV Who Failed Previous PegIFN/RBV Therapy
• In Interim Analysis of Early Access Cohort, Telaprevir- and Boceprevir-Based Regimens Associated With Poor Safety but High On-Treatment Efficacy in Treatment-Experienced Genotype 1 Patients With Compensated Cirrhosis
• EMERGE: PegIFN lambda-1a Associated With Comparable SVR Rates, Less Dose Modification vs PegIFN alfa-2a in Treatment-Naive Patients With Genotype 2/3 HCV
• PROVIDE Interim Results: Substantial Proportion of Genotype 1 HCV Previous PegIFN/RBV Null Responders Achieved SVR Upon Retreatment With Boceprevir Plus PegIFN/RBV
• Quadruple Therapy With Tegobuvir and GS-9256 Plus PegIFN/RBV Shows Potent Viral Suppression With Shortened Therapy in Genotype 1 HCV, but Safety Concerns Preclude Further Development of the Combination
• Pilot Study: Interferon-Free Regimen of ABT-450/Ritonavir, ABT-072, ABT-450, and Ribavirin Achieved SVR12 in 91% of Noncirrhotic Treatment-Naive Genotype 1 HCV Patients With IL28B CC Genotype
• Dual Oral Therapy With Daclatasvir and Asunaprevir Achieves 77% SVR in Genotype 1b HCV–Infected Patients With Previous Null Response, Medical Ineligibility, or Intolerance to Peginterferon/Ribavirin
• Boceprevir or Telaprevir in Combination With PegIFN/RBV Improved On-Treatment Virologic Response Rates in Patients With Severe Genotype 1 Hepatitis C Recurrence Following Liver Transplantation vs Historical Treatment With PegIFN/RBV
• Boceprevir Plus PegIFN/RBV Appears Safe, Effective in Genotype 1 HCV Therapy-Naive, HIV-Coinfected Patients on Stable Antiretroviral Therapy
• Retrospective Analysis of Viral Kinetics During Treatment With Telaprevir Plus PegIFN/RBV Underscores Validity of Futility Rules
• Miravirsen Safe, Well Tolerated With Durable Antiviral Activity in Phase IIa Trial in Treatment-Naive Patients With Chronic Genotype 1 HCV
• SOUND-C2 Interim Results: High Efficacy, Good Safety Profile of IFN-Free BI 201335, BI 207127, and RBV Combination Therapy in Treatment-Naive Patients With Genotype 1 HCV
• BRISK-PS: Brivanib Fails to Improve OS in Patients With Advanced HCC Who Failed Sorafenib
• Co-Pilot Study: IFN-Free Regimen of ABT-450/Ritonavir, ABT-333, and Ribavirin Achieved 12-Week SVR Rates > 90% in Genotype 1 HCV
• VITAL-1: Interim Results Indicate Alisporivir Plus Ribavirin Achieved High SVR Rates With or Without Addition of PegIFN in Treatment-Naive Patients With Genotype 2/3 HCV Infection
• INFORM-SVR: Safety and Efficacy of Interferon-Free Combination of Mericitabine, Ritonavir-Boosted Danoprevir, and Ribavirin in Treatment-Naive Patients With Genotype 1b HCV
• SVR Rates Similar in Boceprevir-Treated Patients Randomized to RBV Dose Reduction or Erythropoietin for Anemia Management in Prospective Trial
• High SVR Rates and Acceptable Safety Profile With Interferon-Free, All-Oral, Quad Regimen of GS-5885, GS-9451, Tegobuvir, and Ribavirin in Treatment-Naive Patients With Genotype 1 HCV Infection
• Interferon-Free Combination of Daclatasvir (NS5A Inhibitor) Plus GS-7977 (NS5B Inhibitor) Demonstrates High Rates of SVR4 in Treatment-Naive Patients With Chronic Genotype 1, 2, or 3 HCV Infection

Disclaimer: The materials published on the Clinical Care Options Sites reflect the views of the reviewers or authors of the CCO material, not those of Clinical Care Options, LLC, the accredited provider, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials

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Interferon-Free Regimens at EASL 2012

Provided by NATAP (All links open into new windows)

from Jules: There are about 8 interferon-free regimens below and/or presented at EASL, again bear in mind this is a work in process, this is the first step in designing the best interferon-free terapies, but the SVR rates are very good here, although admittedly in small studies this shows and proves what we are capable of seeing here, with better & more potent regimens coming in the future. All the companies & researchers are working towards 2-4 drug all oral regimens for naives with SVR rates approaching & achieving for some 100%. For null-responders we will likely need improved regimens, at this meeting Abbott reported 94% SVR rates with 12 weeks therapy with a 3-drug all oral regimen of their protease+NNRTI+RBV & 47% in null responders, but this was not their best regimen, 24 weeks needs more exploration, and if we need 3 potent orals or even 4 potent orals not including RBV this will be studied and if perhaps some interferon for these patients are needed we will see that studied as well, as the hardest to treat are the cirrhotic, non-CC null responders. We have potent protease inhibitors, potent NS5A inhibitors, potent nucleotides and useful potent NNRTIs so there is a lot to work with.

EASL 47th Annual Meeting
Barcelona, Spain
April 18th - 22nd 2012

EASL: Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)

EASL: A 12-Week Interferon-Free Regimen of ABT-450/r + ABT-333 + Ribavirin Achieved SVR12 in More Than 90% of Treatment-Naïve HCV Genotype-1-Infected Subjects and 47% of Previous Non-Responders - (04/23/12)

EASL: A 12-Week Interferon-Free Regimen of ABT-450/r, ABT-072, and Ribavirin was Well Tolerated and Achieved Sustained Virologic Response in 91% Treatment-Naïve HCV IL28B-CC Genotype-1-Infected Subjects - (04/19/12)

EASL: Once Daily GS-7977 Plus Ribavirin in HCV Genotypes 1-3: The ELECTRON Trial - (04/21/12)

EASL: Gilead Announces Early Sustained Virologic Response Rates for GS-7977 Plus Ribavirin in Genotype 1 Treatment-Naïve Hepatitis C Patients - press release - (04/19/12)

EASL: Gilead Announces Sustained Virologic Response Data for 12-Week Regimen of GS-7977 Plus Pegylated Interferon and Ribavirin in Genotype 1 Hepatitis C Patients - press release - (04/19/12)

EASL: Dual Oral Therapy with NS5A Inhibitor Daclatasvir (BMS-790052) and NS3 Protease Inhibitor Asunaprevir (BMS-650032) in HCV Genotype 1b-Infected Null Responders or Patients Ineligible/Intolerant to Peginterferon/Ribavirin - (04/19/12)

EASL: SVR4 and SVR12 with an interferon-free regimen of BI 201335 AND BI 207127, +/- ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: Interim results of SOUND-C2 - (04/22/12)

EASL: The efficacy and safety of the interferon-free combination of BI 201335 and BI 207127 in genotype 1 HCV patients with cirrhosis: Interim analysis from SOUND-C2 - (04/20/12)

EASL: Gilead: Interim Sustained Virologic Response Rates in Treatment-Naïve HCV Genotype 1a and 1b Patients Treated for 12 or 24 Weeks with an Interferon-Free All-Oral Quad Regimen - (04/21/12)

EASL: 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 - (04/22/12)
-----------------------------
relevant studies

EASL: RAPID AND SUSTAINED ACHIEVEMENT OF UNDETECTABLE HCV RNA DURING TREATMENT WITH RITONAVIR-BOOSTED DANOPREVIR/PEG-IFNα-2A/RBV IN HCV GENOTYPE 1 OR 4 PATIENTS: DAUPHINE WEEK 36 INTERIM ANALYSIS - (04/22/12)

EASL: GS-7977 + PEG/RBV in HCV Genotype 1: The ATOMIC Trial An End To Response-Guided Therapy - (04/20/12)

EASL: TMC435 with peginterferon and ribavirin in treatment-experienced HCV genotype 1 patients: the ASPIRE study, a randomised Phase IIb trial - (04/19/12)

EASL: TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon / ribavirin treatment: Virologic analyses of the ASPIRE trial - (04/19/12)

EASL: 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 - (04/22/12)

New Protease Inhibitor TMC435 Cures Most HCV Patients

From Medscape Medical News

Daniel M. Keller, PhD

April 24, 2012 (Barcelona, Spain) — In patients infected with hepatitis C virus (HCV) genotype 1 for whom previous treatment with pegylated interferon plus ribavirin (PR) failed to eliminate the virus, treatment with TMC435 plus PR was significantly more effective than PR plus placebo. TMC435 is a once-daily oral therapy that inhibits HCV NS3/4A protease.

Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, presented the results of the international, double-blind, placebo-controlled phase 2b ASPIRE clinical trial here at The International Liver Congress 2012.

The 462 patients in this trial were assigned to 48 weeks of active therapy with 1 of 4 treatment regimens: TMC435 + PR for 12 weeks, followed by PR + placebo weeks for 36 weeks; TMC435 + PR for 24 weeks, followed by PR + placebo for 24 weeks; TMC435 + PR for 48 weeks; or PR + placebo for 48 weeks (control group).

In patients receiving TMC435, the dose was 100 or 150 mg daily. All patients were followed for 24 weeks after the 48-week treatment period.

Eligible men and women were 18 to 70 years of age, had a body weight of 40 to 125 kg, were chronically infected with HCV genotype 1 HCV, and had plasma HCV RNA greater than 10,000 IU/mL. They had to have received at least 1 previous course of PR for at least 12 consecutive weeks.

Patients were ineligible for the trial if they had decompensated liver disease or liver disease from any cause other than HCV; if they had hepatocellular carcinoma; if they were infected with HIV, hepatitis B virus, or any HCV that was not genotype 1; or if they had any laboratory or hematologic abnormalities.

At baseline, about two thirds of the patients were men, median age was about 50 years, body weight ranged from 80.0 to 84.8 kg, and 83% to 89% had HCV RNA greater than 800,000 IU/mL. Previously in each group, about 40% had relapsed, 35% had partially responded, and 25% had not responded.

In the 3 TMC435 groups (both the 100 and 150 mg doses), 53% to 68% of patients achieved rapid viral responses, compared with 2% in the control group (P < .001 for all groups vs control group). Rapid viral response meant there was undetectable virus in the blood at week 4.

The sustained viral response rates at 24 weeks (SVR24) ranged from 61% to 80% for the TMC435 groups, compared with 23% in the control group.

In the TMC435 groups, compared with the control group, previous responders had the highest SVR24 rates (85% vs 37%), followed by previous partial responders (57% to 75% vs 9%), followed by previous nonresponders (46% to 51% vs 19%).

No patients with advanced liver fibrosis achieved a virologic cure in the control group, whereas with TMC435, "there was a substantial chance for the patients to achieve sustained virologic response rates," Dr. Zeuzem reported.

TMC435 Well Tolerated

Discontinuation of treatment because of viral breakthrough was 9% to 17% in the TMC435 groups and 53% in the control group. Viral relapse occurred in 6% to 18% of the TMC435 group and 44% of the control group.

The incidence and severity of adverse events were similar in the TMC435 and control groups. Serious adverse events affected 6% to 10% of patients in the TMC435 groups and 6% in the control group. Grade 3/4 adverse events occurred in 28% to 36% of the TMC435 groups and in 26% of the control group. The most frequently reported adverse events in patients receiving TMC435 were headache, fatigue, and influenza-like illness, but these events were present at equivalent levels in the control group.

However, pruritus was more common in the TMC435 groups than in the control group (35% VS17%). Similarly, more rash of any type occurred in the TMC435 groups than in the control group (23% to 30% vs 18%). However, less than 1% of patients receiving TMC435 experienced rash of grade 3 or lower.

The incidence of adverse events leading to treatment discontinuation and serious adverse events was similar in all groups. Decreases in and recovery of hemoglobin values and neutrophil counts were equivalent in all groups. However, the TMC435 groups showed mild and reversible increases in bilirubin not accompanied by changes in any other liver parameters.

For patients receiving 150 mg of TMC435, 85% of previous relapsers achieved SVR24, 75% of previous partial responders achieved SVR24, 51% of previous nonresponders achieved SVR24, and 31% to 82% of patients with cirrhosis achieved SVR24.

Dr. Zeuzem and colleagues conclude that in patients with HCV genotype 1 who failed previous PR therapy, once-daily TMC435 plus PR was significantly more effective in producing a sustained viral response than PR plus placebo.

In comparing the different durations of administration of TMC435, Dr. Zeuzem explained that "TMC435 for 12 weeks in combination with pegylated interferon and ribavirin for 48 weeks achieves optimal biologic response rates." Longer treatment with TMC435 did not produce any better virologic responses.

The drug is now entering phase 3 trials for both treatment-naive and treatment-experienced patients.

Session moderator Mark Thursz, MBBS, MD, secretary general of the European Association for the Study of the Liver and professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, asked Dr. Zeuzem if hepatologists need to continue to use SVR24 as the end point of a trial or if the follow-up period can be shortened by using sustained viral response at 12 weeks (SVR12) as the end point.

Dr. Zeuzem explained that current trials "typically use an SVR at week 12 of the follow-up period, and the concordance rates are extremely high [with SVR24]; therefore, SVR12 is the new standard."

He does not think there is a major difference between SVR12 and SVR24 for treatment-naive patients, nonresponders, or relapsers with an interferon-containing protocol such as this one. "I'm a little bit more conservative in trials using completely new drugs, [such as]...interferon-free regimens and all-oral regimens," Dr. Zeuzem said. He would like to see trials demonstrating the equivalence of SVR12 and SVR24 in those cases before adopting SVR12 for those drug regimens.

Dr. Thursz told Medscape Medical News that he, too, believes that SVR12 will be the new end point and will replace SVR24 as new drugs enter trials. "The only proviso is for people who've previously been treated and have been classified as null responders — that's a group of people with hepatitis C [in whom] the virus has not dropped by 2 logs [after 12 weeks of treatment]," he said. "These people are going to be really difficult to treat and very resistant to pretty much any kind of medication. I have some reservation about that group; otherwise, SVR12 is undoubtedly going to be, as it were, the standard."

Another group of particular concern is patients with advanced fibrosis or cirrhosis. "We know, certainly with interferon-based therapies, that response rates are much lower in that group. Then there is some concern in cirrhotics, particularly cirrhotics who've decompensated, that the metabolism of the drugs is going to be slightly different and may cause some problems," Dr. Thursz cautioned.

Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Thursz has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 2. Presented April 19, 2012.

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EASL 2012: TRANSGENE : Reports Positive Follow Up Phase 2 Data on Its HCV Therapeutic Vaccine TG4040

04/23/2012 | 02:05am

• Primary endpoint (efficacy at week-12) met
• Both faster effect on viral load decrease and significant improvement of viral response over time (week-24) in TG4040 pre-vaccination arm
• Late-breaker oral presentation at EASL in Barcelona

Regulatory News:

Transgene S.A. (Paris:TNG) (Euronext Paris : FR0005175080) announces today the presentation, during the EASL (European Association for the Study of Liver) congress in Barcelona, Spain, of follow up interim data showing both a more rapid response as well as an improved long term effect on viral load decrease in a combination of TG4040 with PEG-IFN? (pegylated interferon alpha) and ribavirin (the current standard of care) in patients chronically infected with genotype 1 hepatitis C virus.

These data were observed in a randomized phase 2 trial that has enrolled 153 patients (the "HCVac" study). HCVac had three treatment arms: one control arm (Arm A) with the current standard of care alone and two arms (B and C) with a combination of this standard of care and TG4040 delivered in two different administration schedules, including one schedule (Arm C) with pre-vaccination by TG4040 (i.e. TG4040 injected prior to the introduction of PEG-IFN? and ribavirin).

As reported in November 2011 at the AASLD meeting in San Francisco, the primary endpoint of the HCVac study was met in the pre-vaccination arm C with 64% (34/53) evaluable patients having achieved a complete early viral response¹ ("cEVR") at week-12 after initiation of treatment with the standard of care compared to 30% (9/30) in the control arm A (p=0.003).

The positive effect of TG4040 pre-vaccination was observed as early as one week after initiation of treatment with the standard of care: the slope of mean viral load decrease was significantly steeper in Arm C (1.4 log10 IU/ml) compared to Arms A and B (respectively 0.9 and 1.0 log10 IU/ml) (p=0.04), meaning a faster viral response in Arm C than in other arms.

When following the viral response at week-24 after the initiation of treatment with the standard of care in the patients evaluable for cEVR (week-12), the responses continue to improve as expected in all arms: 70% in the control Arm A, 67% in the Arm B (initiation of treatment with the standard of care before introduction of TG4040) and 79% (vs. 64% at week-12) in the Arm C.

Preliminary End-of-Treatment Response measurement ("ETR", or viral response measured at the end of 48 weeks of standard of care), is respectively 64% and 56% in Arm A and B. In arm C, 19 out of 19 patients analysed so far are undetectable.

"These data are important for TG4040 as they confirm the efficacy profile of our therapeutic vaccine. As far as we know, they are unheard of for an immunotherapy in HCV and this is one of the reasons why we were invited for a late breaker oral presentation in such a prestigious event" said Philippe Archinard, Chairman and CEO of Transgene. He added: "The benefit seen at week-12 in the pre-vaccination arm is further confirmed at week-24 and the preliminary data of ETR in this arm are also very encouraging".

Data were presented on Saturday April, 21, at the annual meeting of the European Association for the Study of Liver (EASL) in Barcelona, by Pr. Heiner Wedemeyer, MD, of the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School (Germany) and principal investigator of the HCVac study.

Pr. Wedemeyer said: "The data accumulated so far in the HCVac study illustrate the importance of immunity in the treatment of chronic hepatitis C". He added: "The assessment of TG4040 in a combination with directly acting agents (DAA) should be the next development step".

About TG4040:

Transgene's TG4040 vaccine candidate is a recombinant vector based on the MVA virus carrying and expressing three of the major non-structural proteins (NS3, NS4 and NS5B) of the hepatitis C virus ("HCV"). The MVA vector is a highly attenuated strain of vaccinia virus, which has been tested extensively in humans as a vaccine against smallpox and is known to strongly stimulate innate and adaptive immune responses to antigens.

About TG4040 clinical development program:

Phase 1

Phase 1 clinical results in 39 treatment naïve genotype 1 HCV patients showed that the product is safe and well tolerated at all dose levels tested. Immunological analyses on 15 treatment naïve patients were encouraging and supported the expected mechanism of action of TG4040 which aims at inducing an effective HCV-specific T cell based immune response, able to control viral replication. Phase 1 data were published in the journal Gastroenterology and reported in Nature Reviews in 2011.

Phase 2

153 patients in the HCVac study were recruited in five countries in Europe, in the United States and in Israel, and were randomized in one control arm (Arm A) or one of the two experimental arms (Arms B and C). In the Arm B, the TG4040 dosage was administered 6 times and the standard of care was given 4 weeks prior to the initiation of TG4040. In the Arm C, the TG4040 dosage was administered 13 times and the standard of care was introduced 12 weeks after the initiation of treatment with TG4040. The HCVac study is investigating the efficacy and safety of two different schedules of administration of TG4040 administered in subcutaneous injections at the dose of 10⁷ pfu in combination with Peg-IFN and RBV.

About SAEs:

The three cases of severe haematological adverse events, one aplastic anemia and two cases of thrombocytopenia, reported in October 2011, all recovered within 1 to 4 months. A fourth case corresponding to a thrombocytopenia was recorded recently. Of interest, the three cases of thrombocytopenia share all a same class 2 Human Leukocyte Antigen ("HLA") allele. This association is statistically significant and, as these HLA types could be excluded a priori in a new clinical trial, this will be taken into account in future developments of the therapeutic vaccine, should it be combined with standard of care including PEG-IFN?. These adverse events should also have no impact in future developments without PEG-IFN?.

About chronic hepatitis C:

Hepatitis C currently represents a major public health concern. The population chronically infected with HCV in the world is estimated at 170 to 200 million and hepatitis-C-related deaths at approximately 470,000 annually. Peak of prevalence of HCV-related diseases is expected to occur in 2025-2030 in developed countries.

HCV infection leads to liver diseases such as fibrosis, cirrhosis and liver carcinoma, which are the prime indications for liver transplants. The commonly used treatment regimen for patients infected with the HCV genotype 1 (a combination of Pegylated Interferon ? and Ribavirin) is lengthy, often poorly tolerated and effective in only approximately 50% of patients completing therapy. In addition, a substantial number of patients never receive therapy. Therefore, there is a strong medical need for new alternative approaches, including combination therapies.

About Transgene:

Transgene, a member of the Institut Mérieux Group, is a publicly traded French biopharmaceutical company dedicated to the development of therapeutic vaccines and immunotherapeutic products in oncology and infectious diseases and has four compounds in phase 2 clinical development: TG4010 and JX594/TG6006 having already completed initial phase 2 trials, TG4001 and TG4040. Transgene has concluded strategic agreements for the development of two of its immunotherapy products: an option agreement with Novartis for the development of TG4010 to treat various cancers and an in-licensing agreement with US-based Jennerex, Inc. to develop and market JX594/TG6006, an oncolytic virus. Transgene has bio-manufacturing capacities for viral-based products. Additional information about Transgene is available at transgene.fr.

Disclaimer:

This press release contains certain forward-looking statements. Although the company believes its expectations are based on reasonable assumptions, these forward-looking statements are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those anticipated. In particular, the Company's ability to commercialize its first product depends on the continuing success of clinical studies, ongoing financing for further product developments and marketing launch, a positive response from the medical community regarding the product's costs and effectiveness. For a discussion of risks and uncertainties which could cause the company's actual results, financial condition, performance or achievements to differ from those contained in the forward-looking statements, please refer to the Risk Factors ("Facteurs de Risque") section of the Document de Reference prospectus, which is available on the AMF website (http://www.amf-france.org) or on Transgene's website (www.transgene.fr). This press release and the information contained herein do not constitute an offer to sell or a solicitation of an offer to buy or subscribe to shares in Transgene in any country.

¹ Limit of detection for the HCV RNA quantification test: 10IU/ml.

Transgene
Philippe Archinard, CEO
Phone: +33 (0)3 88 27 91 22
Stéphane Boissel, Executive Vice President & CFO
Phone: +33 (0)3 88 27 91 02
Elisabetta Castelli, Director IR
Phone: +33 (0)1 44 08 55 05
or
MC Services
Raimund Gabriel
Phone: +49 89 210 228 30
Shaun Brown
Phone: +44 207 148 5998

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EASL 2012: Achillion Clarifies End of Treatment Data From Phase 2a Trial With ACH-1625 Based Regimen in Hepatitis C

April 23, 2012

NEW HAVEN, Conn., April 23, 2012 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today provided clarification with respect to end of treatment (EOT) data from segment 2 of its Phase 2a trial of ACH-1625 that was presented during the 47^th Annual Meeting of the European Association for the Study of the Liver (EASL) International Liver Congress 2012 in Barcelona, Spain on April 21, 2012.

In this study, 58 patients were randomized to receive ACH-1625 at a once daily dose of 200 mg, 400 mg, or 800 mg in combination with pegylated interferon and ribavirin (P/R) for twelve weeks. At of the time of the poster presentation, a total of 22 patients had completed 12 weeks of ACH-1625 plus P/R followed by 12 weeks of P/R as per response guided treatment (RGT.) All (22/22, or 100%) patients had undetectable levels of HCV RNA at the end of the 24 weeks of treatment.

EOT was defined in the EASL poster presentation as any patient who returned for an EOT visit, which also included those patients who withdrew from the study prior to week 12. The additional EOT data is defined as patients who achieved extended rapid virological response (eRVR) and received a total of 24 weeks of therapy consisting of 12 week of ACH-1625 plus P/R followed by 12 weeks of P/R alone.

The rapid virological response (RVR) at week 4, cEVR at week 12 and EOT results for all patients returning for an EOT visit (30 patients) presented in the poster, as well as detailed results for patients who received a total of 24 weeks of therapy consisting of 12 weeks of ACH-1625 plus P/R followed by 12 weeks of P/R alone, are provided in the table below.

 

ACH-1625
Segment 2: 12-week treatment duration assessments	200 mg n=19	400 mg n=20	800 mg n=19
RVR (HCV RNA < 25 IU/mL week 4), % (n)	79% (15/19)	89% (16/18) **	90% (17/19)
cEVR (undetectable week 12), % (n)	100% (18/18) *	94% (15/16) **	100% (19/19)
EOT Visit (including patients who withdrew) (undetectable) *** % (n)	86% (6/7)	69% (9/13)	100% (10/10)
Reasons for discontinuation include: *200 mg 1 patient withdrew for unrelated AEs at Week 5. **400 mg 1 patient withdrew consent at Week 9, 1 patient moved at Week 2, each were undetectable at the time of withdrawal; 2 patients withdrew for unrelated AEs, one before Week 4 and one before Week 12. ***EOT denominator includes only patients who returned for their end of treatment visit.
Patients who achieved eRVR and received 12 weeks of ACH-1625 and P/R followed by 12 weeks of P/R	200 mg	400 mg	800 mg
Undetectable, % (n)	100% (5/5)	100% (7/7) †	100% (10/10) †
† Two patients in both the 400 mg and 800 mg dose groups had week 4 RVR (HCV RNA < 25) with remaining patients below lower limit of detection.

Michael Kishbauch, President and Chief Executive Officer, commented, "We are providing these results as we recognized that some of the data was not clear at our poster session at EASL. We remain both happy and encouraged with the continued potency of ACH-1625, including the 100% response for all patients who completed a full 24 week regimen, and we hope that this clarification provides additional transparency with respect to the ACH-1625 data."

About ACH-1625

ACH-1625 is a Phase 2 pan-genotypic HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. ACH-1625 has demonstrated rapid and extensive partitioning to the liver, as well as high liver/plasma ratios. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC₅₀ of approximately 1nM. ACH-1625 has shown clinical antiviral activity against genotypes 1 and 3. Fast Track status was granted to ACH-1625 in 2012 for the treatment of chronic HCV.

About HCV

The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide including nearly 4 million people in the United States, more than twice as widespread as HIV. Three-fourths of the HCV patient population is undiagnosed; it is a silent epidemic and a major global health threat. Chronic hepatitis, if left untreated, can lead to permanent liver damage that can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000

Forward-Looking Statements

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 important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to the potency, safety, tolerability, effectiveness and other characteristics of ACH-1625. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: replicate in later clinical trials positive results found in earlier stage clinical trials of ACH-1625 and its other product candidates; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates, and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2011 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

CONTACT:

Company Contact: Glenn Schulman Achillion Pharmaceuticals, Inc. Tel. (203) 752-5510 gschulman@achillion.com

Investors: Mary Kay Fenton Achillion Pharmaceuticals, Inc. Tel. (203) 624-7000 mfenton@achillion.com

Media: Christin Culotta Miller Ogilvy PR

Tel. (212) 880-5264 christin.miller@ogilvy.com

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