Elsewhere on the site - Sofosbuvir OR Daclatasvir Based HCV Regimens
Daclatasvir/Asunaprevir and Beclabuvir ( BMS-791325)
(Oct 7- 2014-Bristol-Myers withdraws FDA NDA for asunaprevir)
Mar 2015 - Bristol-Myers Squibb Announces Acceptance of New Drug Application for Investigational Daclatasvir for FDA Review for the Treatment of Hepatitis C Genotype 3
Bristol-Myers Squibb is developing both oral inhibitors; Asunaprevir (BMS-650032) a NS3 protease inhibitors and Daclatasvir (BMS-790052) a NS5A complex inhibitor. Beclabuvir (BMS-791325) is a non-nucleoside NS5B polymerase inhibitor or (nuc), the three drug combination is currently in clinical trials.
Updates and News; Sofosbuvir OR Daclatasvir Based HCV Regimens
Hepatitis C: Asunaprevir/Daclatasvir National Patient Consultation Webinar
Nov 26 2014
Bristol-Myers: FDA Blocks Hepatitis C Drug for Now
U.S. regulators have declined to approve Bristol-Myers Squibb's daclatasvir as part of a combination hepatitis C treatment with another antiviral drug called asunaprevir.
Jensen discusses high SVR rates in HALLMARK-QUAD trial
PHILADELPHIA — Donald M. Jensen, MD, professor of medicine at the University of Chicago and director of the Center for Liver Diseases at the University of Chicago Hospitals, discusses results of the phase 3 HALLMARK-QUAD clinical trial.
According to Jensen, difficult-to-treat patients with hepatitis C virus genotype 1 and 4 were able to achieve a sustained virologic response after therapy with a regimen of daclatasvir and asunaprevir plus pegylated interferon and ribavirin.
“Ninety-three percent of the patients with HCV genotype 1 achieved an SVR with 24 weeks of therapy and 100% of genotype 4 patients achieved an SVR with 24 weeks of therapy,” Jensen told Healio.com/Hepatology. “The high response rates are noteworthy.”
View Video Here
Oct 7 2014
Bristol-Myers withdraws FDA NDA for asunaprevir
Bristol-Myers Squibb (BMY) has decided that it will not pursue U.S. Food and Drug Administration (FDA) approval of the dual regimen of daclatasvir and asunaprevir for the treatment of HCV genotype 1b patients in the United States and has therefore withdrawn its new drug application (NDA) for asunaprevir, an NS3/4A protease inhibitor.
Aug 8 2014
High HCV Response Rates With Daclatasvir/Asunaprevir: Phase III Data
In the HALLMARK-DUAL study, Dr. Mann and colleagues at 116 sites in 18 countries enrolled 307 treatment-naive patients, 205 patients who had not responded to IFN and ribavirin, and 235 patients who were either medically ineligible for IFN and ribavirin, could not tolerate the drug combination, or both. A third of patients had cirrhosis.
Treatment-naive patients were initially randomized to daclatasvir 60 mg once a day and asunaprevir 100 mg twice daily, or placebo, for 12 weeks. Afterward, the patients in the active-treatment group continued on the drug combination for 12 more weeks, while the placebo group patients were switched to a different daclatasvir plus asunaprevir study.
Everyone else - i.e., the non-responders and ineligible, intolerant, or ineligible/intolerant patients - received open-label daclatasvir plus asunaprevir for 24 weeks.
Ninety percent of patients in the treatment-naive group had a sustained virological response, as did 82% of the non-responders and 82% of the ineligible/intolerant group, the researchers found.....
HALLMARK, COSMOS: New HCV regimens show high cure rates
Archives April 2013-2010
BMS-650032 (Asunaprevir) / BMS-790052 (Daclatasvir)
Dr. Gregory T. Everson discusses his January 2014 manuscript "Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection."
To view abstract http://bit.ly/1astcIL.
In The News
Bristol-Myers Squibb’s Daklinza (daclatasvir), Approved By European Commission - for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic hepatitis C virus (HCV) infection in adults.
Daklinza, when used in combination with sofosbuvir, is an all-oral, once daily regimen that yields cure rates of up to 100%
Daklinza + sofosbuvir offers potential cure for a broad range of EU HCV patients, including those with advanced liver disease, genotype 3 and protease inhibitor failures
Japan Approves HCV Daklinza® (daclatasvir) and Sunvepra® (asunaprevir) Dual Regimen
EU smiles on a key cog in Bristol-Myers' hep C combo
A 4-week hep C cure? Bristol to test drugs with Gilead's Sovaldi
A 4-week hep C cure? Bristol to test drugs with Gilead's Sovaldi
Daclatasvir and Asunaprevir/Bristol-Myers toes the next hep C frontier: a four-week cure
Hepatitis C Genotype 4 - Triple Antiviral Therapy Achieves Near 100% Response
An all-oral, ribavirin-free, interferon-free combination of three direct-acting antiviral agents that had achieved sustained virologic response (SVR) in 92% of patients with chronic HCV genotype 1 infection has demonstrated even greater response in patients with genotype 4 infection.
EASL-Bristol-Myers hepatitis C treatment cures up to 90 pct -study
The Phase III trial of more than 700 patients called Hallmark-Dual tested a combination of Bristol's daclatasvir and asunaprevir over 24 weeks of therapy in patients with genotype 1b of the virus that causes progressive liver disease.
Bristol-Myers Squibb Submits Two NDAs for Hepatitis C Treatment
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that they have submitted new drug applications (NDAs) with the U.S. Food and Drug Administration (FDA) for the investigational products daclatasvir (DCV), an NS5A replication complex inhibitor, and asunaprevir (ASV), a NS3 protease inhibitor. The data submitted in the NDAs support the use of DCV+ASV in patients with genotype 1b hepatitis C (HCV). The DCV NDA also seeks approval for use of this compound in combination with other agents for multiple genotypes. The submissions are subject to FDA review for acceptance for filing.
“These FDA submissions represent a major step towards offering daclatasvir-based regimens to U.S. HCV patients, many of whom continue to have high unmet medical needs,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “We are excited to have achieved this milestone and, looking forward, will continue to innovate and invest in daclatasvir in a range of patient types and regimens.”
These submissions follow the recent announcement that the FDA granted the investigational DCV Dual Regimen (DCV+ASV) Breakthrough Therapy Designation. In 2013, the investigational all-oral 3DAA Regimen (daclatasvir/asunaprevir/BMS-791325) also received Breakthrough Therapy Designation, and the company anticipates submitting this regimen for FDA review in Q1 2015.
In January 2014, the European Medicines Agency (EMA) validated the company’s marketing authorization application for the use of DCV in combination with other agents for the treatment of adults with HCV with compensated liver disease, including genotypes 1, 2, 3, and 4, and this application is under accelerated review. In addition, NDAs for DCV and ASV are under priority review by Japan’s Pharmaceutical and Medical Devices Agency for patients with chronic HCV genotype 1b, classified as either interferon-ineligible naïve/intolerant or non-responders to interferon and ribavirin.
Read more @ BMS
March 5 2014
Triple-DAA Combo (a Possible 3-in-1 Pill) Yields SVRs Over 90% After 12 Weeks
Slides @ NATAP: All-Oral Combination of Daclatasvir, Asunaprevir, and BMS-791325 for HCV Genotype 1 Infection
Twelve weeks of a regimen containing three direct-acting antivirals (DAAs) that may become the first anti-HCV triple coformulation produced sustained virologic response rates above 90% through 12 weeks after treatment ended (SVR12) . The 166-person study had 11 virologic failures (6.6%), all in people with HCV genotype 1a.
The combination includes daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a nonnucleoside NS5B polymerase inhibitor). Because the three-drug regimen produced high SVR12s in HCV-infected people without cirrhosis, researchers extended that study to include patients with cirrhosis. Although daclatasvir can be dosed once daily, all three drugs were given twice daily in this trial, with an eye toward a developing a twice-daily fixed-dose triple combination. The primary endpoint was SVR12 with response determined by an assay that has a lower limit of 25 IU/mL.
The only difference between the two study arms was the dose of BMS-791325, 75 or 150 mg. Eighty people got randomized to 75 mg and 86 to 150 mg. All 166 study participants were treatment naive and had genotype 1 infection. Most participants were white (83%), men (67%), and had the GT1a genotype (82%) and an IL28B non-CC genotype (67%). Only 9% of participants had cirrhosis, 10% in the 75-mg arm and 8% in the 150-mg arm. Age averaged about 55.
At the end of treatment, 97.5% in the 75-mg arm and 94.2% in the 150-mg arm had an undetectable HCV load. Overall SVR12 (an undetectable load 12 weeks after treatment stopped) stood at 92.2% in the 75-mg group and 91.7% in the 150-mg group. The investigators counted 11 virologic failures, 6 in the 75-mg arm and 5 in the 150-mg arm. Failures included 2 on-treatment breakthroughs and 4 relapses before week 4 in the 75-mg group and 3 breakthroughs and 2 relapses in the 150-mg group.
Everyone with virologic failure had genotype 1a. But SVR12s were 91% for 1a-infected people in both treatment arms. SVR12s were 100% for genotype 1b patients taking the lower dose of BMS-791325 and 94% in those taking the higher dose. Among people with cirrhosis, SVR12s were 100% in the 75-mg arm and 71% in the 150-mg arm, but the study included few cirrhotics. SVR12 varied little by study arm in people with an IL28B CC genotype or a non-CC genotype.
While 2 people in the 75-mg group discontinued treatment, 6 in the 150-mg group discontinued. But only 1 person in each group discontinued because of adverse events. No one taking 75 mg of BMS-791325 stopped treatment for lack of efficacy, compared with 3 people taking 150 mg. Poor adherence explained 1 discontinuation in the 150-mg arm and none in the 75-mg arm.
Serious adverse event rates were 1.3% with 75 mg of BMS-791325 and 2.3% with 150 mg. Respective discontinuations for adverse events were 1.3% and 1.2%. No one in the 75-mg arm and 1 in the 150-mg arm had a grade 3 or 4 adverse event. Headache was the most frequent adverse event, affecting about 25% of participants.
Two phase 3 trials of the triple fixed-dose combination, UNITY 1 and UNITY 2, are fully enrolled (clinicaltrials.gov identifiers NCT01979939 and NCT01973049). UNITY 1 excludes people with cirrhosis and UNITY 2 includes people with compensated cirrhosis who may be randomized to add ribavirin to the triple pill.
1. Everson GT, Thuluvath PJ, Lawitz E, et al. All-oral combination of daclatasvir, asunaprevir, and BMS-791325 for HCV genotype 1 infection. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 25.
All-Oral HCV Regimen Works in 9 Out of 10
BOSTON -- An all-oral, 12-week regimen appears to successfully treat hepatitis C virus (HCV) infection in about 90% of patients, researchers reported here.
Of the 166 treatment-naive patients in the study, 92% achieved a sustained virologic response at 12 weeks (SVR-12) on the combination of the investigative NS5A inhibitor daclatasvir, the protease inhibitor asunaprevir and the non-nucleoside BMS-791325, said Trevor Hawkins, MD, chief medical officer at Southwest CARE Center and professor of medicine at the University of New Mexico in Santa Fe.
"The observed analysis showed a 92% SVR12, and in the modified intent-to-treat analysis -- wherein data at week 12 is counted as failure if it is missing -- [it] was 89%," Hawkins told MedPage Today at the annual Conference on Retroviruses and Opportunistic Infections.
A cure in the context of HCV is a sustained virologic response (SVR) -- defined as undetectable viral RNA at some prespecified point after ending therapy, usually 12 or 24 weeks.
At the end of treatment in Hawkins' study, 97.5% of those in the low-dose BMS-971325 group showed a complete viral response compared with 94.2% of those taking the high dose; the SVR4 was 92.4% in the low-dose group and 91.7% in the high-dose-treated patients. The SVR12 was achieved by 92.2% in the low-dose treatment group and by 91.7% of those taking high-dose BMS-791325, the researchers reported.
In the trial, Hawkins said that 9% of the patients were diagnosed with cirrhosis. He said that there did not appear to be a difference in outcome among the cirrhotic patients compared with those who were not cirrhotic -- 13 of the 15 cirrhotic patients achieved an SVR12.
Hawkins said that the next trials -- called UNITY 1 and UNITY 2 -- will separate cirrhotic and noncirrhotic patients to examine if there are differences in outcomes depending on the extent of liver disease. These trials will use the 75-mg dose of BMS-791325.
The trial he reported here showed that patients were able to tolerate the regimen. "There were two discontinuations due to adverse events in the entire 166-patient cohort," he said at a press conference.
The patients diagnosed with HCV genotype 1 were randomly assigned to receive a twice-daily regimen of daclatasvir 30 mg, asunaprevir 200 mg and BMS-791325 at 75 mg or 150 mg for 12 weeks. Hawkins said outcomes were similar for the 80 patients on BMS-791325 given 75 mg twice daily and the 86 patients given BMS-791325 at a dose of 150 mg twice daily.
"There were 11 virologic failures and we attempted to find out if there were any predictors of failure," he said. "The only thing that appeared to predict failure was being of genotype 1a. We tried to determine if there were any polymorphisms at baseline that would predict virologic failure, but we were unable to do that. There really was no obvious correlation."
In pilot studies, the 24-week SVR was 94% and the 12-week SVR was 94% with use of the 75-mg dose of BMS-791325; with the 150-mg dose, the 24-week SVR was 94% and the 12- week SVR was 89%.
The patients were about 54 years old, 67% were men, 83% were white, 82% were genotype 1a, and 15 patients in the study -- 9% -- were diagnosed with cirrhosis.
"This looks good," press conference moderator Jean-Michel Pawlotsky, MD, of the Hôpital Henri Mondor Creteil/University of Paris-Est, told MedPage Today. "There are several potential combinations that are going to work in patients with HCV. This combination with three drugs has good potency and a high barrier to resistance. This is promising."
Hepatitis C combo Daclatasvir and Asunaprevir gets breakthrough designation
The U.S. Food and Drug Administration (FDA) has granted its investigational DCV Dual Regimen (daclatasvir and asunaprevir) Breakthrough Therapy Designation for use as a combination therapy in the treatment of genotype 1b chronic hepatitis C infection (HCV). The designation is based on data from the company’s ongoing Phase III clinical trial program evaluating the all-oral combination regimen of DCV, an investigational NS5A replication complex inhibitor, and ASV, an investigational NS3 protease inhibitor, without ribavirin...
A Next Step for Genotype 1 HCV Regimens: Eliminating Ribavirin
Atif Zaman, MD, MPH reviewing Everson GT et al.
Gastroenterology 2014 Feb.
- Atif Zaman, MD, MPH
- Atif Zaman, MD, MPH
The purpose of the current phase IIA, open-label study was to examine the efficacy and safety of an interferon- and ribavirin-free regimen for treatment of genotype 1 HCV infection. Sixty-six treatment-naive patients without cirrhosis were randomly assigned to receive either a 12-week or 24-week regimen comprising daclatasvir (an NS5A replication complex inhibitor; 60 mg daily), asunaprevir (an NS3 protease inhibitor; 200 mg twice daily), and BMS-791325 (a non-nucleoside NS5B inhibitor; 75 mg or 150 mg twice daily). The primary endpoint was sustained virologic response at 12 weeks after treatment (SVR12).
Sixty-one of 66 patients (92%) achieved SVR12. Similar response rates were achieved in genotypes 1a and 1b (94% and 88%), in IL28B host genotypes CC and non-CC (100% and 89%), with 75-mg and 150-mg doses of BMS-791325 (94% and 91%), and with durations of 12 and 24 weeks (94% and 91%). During treatment, two patients experienced virologic breakthrough, and one patient relapsed. There were no adverse events leading to discontinuation.
Comment This small study suggests that we will soon have effective regimens for hepatitis C virus infection that are not only interferon-free, but also ribavirin-free, using the next generation of direct antiviral agents. This regimen is now moving into the next phase of clinical studies with a larger sample size that will include patients with cirrhosis as well as treatment-experienced patients.
Editor Disclosures at Time of Publication
- Disclosures for Atif Zaman, MD, MPH at time of publication Speaker’s bureau Bristol-Myers Squibb; Genentech; Gilead; Kadmon; Merck; Salix; Vertex
- Everson GT et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology 2014 Feb; 146:420. (http://dx.doi.org/10.1053/j.gastro.2013.10.057)
PubMed abstract (Free)
Jan 9 2014
Triple-antiviral therapy achieves 94% response without interferon, ribavirin
By: MICHELE G. SULLIVAN, Internal Medicine News Digital Network
Both a 12-week and a 24-week regimen of three oral antiviral drugs achieved sustained viral remissions at 12 weeks in up to 94% of treatment-naive patients with genotype 1 hepatitis C virus infections.
The three oral antivirals included daclatasvir, an NS5A replication complex inhibitor; asunaprevir, an NS3 protease inhibitor; and BMS-791325, an investigational selective non-nucleoside polymerase inhibitor. A key point of the study is its proof that short-duration treatment – even without interferon or ribavirin – can result in sustained remission, Dr. Gregory T. Everson and his colleagues wrote in the February issue of Gastroenterology (doi.org/10.1053/j.gastro.2013.10.057).
"Shorter treatment durations are preferable because they may improve patient compliance. In this study, treatment periods of both 12 and 24 weeks yielded high SVR (sustained viral remission) rates, suggesting no advantage for extending treatment duration to 24 weeks."
Further, the triple-antiviral combination apparently controlled viral replication without using interferon or ribavirin, thus avoiding their side effects. The current regimen for treatment-naive patients with genotype 1 hepatitis C virus infections calls for a 48-week treatment with peginterferon and ribavirin with telaprevir or boceprevir.
"Ribavirin contributes to anemia and it is teratogenic; thus, effective treatments without ribavirin are desirable," wrote Dr. Everson of the University of Colorado, Denver, and his coauthors. "This interferon- and ribavirin-free regimen did not alter hemoglobin levels in a clinically meaningfully manner, as evidenced by no grade 1 or higher hemoglobin reductions and no adverse events of anemia."
Dr. Everson and his colleagues gave the regimen for periods of 12 and 24 weeks and with two different doses of BMS-791325, resulting in a four-way randomized study. Groups 1 and 2 were treated for 12 weeks with the combination of daclatasvir 60 mg once daily, asunaprevir 200 mg twice daily, and BMS-791325 (twice daily 75 mg or 150 mg). Groups 3 and 4 had exactly the same two-treatment regimen, but took the drugs for 24 weeks. After treatment, there was a 48-week follow-up period.
Among the 66 patients in the study, the average age was about 50 years old, and the mean HCV-RNA level was 6 log10 IU/mL. Most (75%) had HCV genotype 1a; the rest had 1b. All were treatment naive. Four patients withdrew before the study’s end; none of the withdrawals were for adverse events.
In groups 1 and 2 (75 mg BMS-791325, twice daily for 12 and 24 weeks), the viral load decreased rapidly. By week 4, all of these patients achieved a HCV-RNA level of less than 25 IU/mL; 97% maintained that level through the end of treatment. In a modified intent-to-treat analysis, 94% achieved a sustained viral response by week 12.
In groups 3 and 4 (150 mg BMS-791325, twice daily for 12 or 24 weeks), HCV-RNA levels also fell rapidly in the first month, By week 4, all of those in the 12-week group and all but one in the 24-week group had levels of less than 25 IU/mL, which were sustained through the end of treatment. In the intent-to-treat analysis, 91% overall had an HCV-RNA load of less than 25 IU/mL by the end of treatment.
Overall, there were three treatment failures: one each in groups 3 and 4 had viral breakthrough, and one in group 4 experienced a relapse at week 4.
Both breakthrough patients were given peginterferon-alfa/ribavirin in addition to the direct-acting antivirals. After 16 weeks, one discontinued treatment because of interferon-related cerebral vasoconstriction. That patient had an undetectable HCV-RNA level at the end of treatment, but relapsed by post treatment week 4. The other patient had a sustained viral response.
The study was sponsored by Bristol-Myers Squibb. Dr. Everson listed financial and research relationships with numerous pharmaceutical companies, including Bristol-Myers. His coauthors also declared relationships with numerous drug manufacturers, including Bristol-Myers.
Daclatasvir: Present and Future DAA Combinations
Interferon/ribavirin-free triple therapy highly effective for chronic HCV genotype 1
WASHINGTON — Patients with chronic hepatitis C genotype 1, including those with cirrhosis, experienced high rates of sustained virologic response at 12 weeks post-treatment with a safe, well-tolerated, interferon- and ribavirin-free regimen of three direct-acting antivirals in a study presented at The Liver Meeting.
In a phase 2b, open-label study, researchers randomly assigned 166 patients to triple therapy with NS5A inhibitor daclatasvir, NS3 inhibitor asunaprevir and 75 mg (n=80) or 150 mg (n=86) non-nucleoside NS5B inhibitor BMS-791325 for 12 weeks. All patients were treatment naive, had HCV genotype 1, and 9% of the cohort had biopsy-confirmed cirrhosis. Eighty-two percent of patients had genotype 1a, 67% had a non-CC IL28B genotype and 38% had a METAVIR fibrosis stage of F3 or F4. SVR at 12 weeks post-treatment was the primary endpoint.
End-of-treatment response occurred in 97.5% of the 75-mg group and 94.2% of the 150-mg group. SVR at 12 weeks was approximately 92% across the cohort, with no significant impact observed as a result of BMS-791325 dosage. Among cirrhotic patients, overall rates of SVR12 were more than 90%, regardless of genotype 1 subtype or IL28B status.
Virologic breakthrough occurred in two patients in the 75-mg group and three in the 150-mg group. Relapse occurred in four 75-mg patients and in two 150-mg recipients, all within 4 weeks of treatment initiation. All patients who experienced virologic failure had genotype 1a; no other characteristics at baseline were associated with breakthrough.
Treatment was well tolerated in both groups. No patients discontinued treatment because of treatment-related serious adverse events, and symptoms while on treatment were mild or moderate in all but one patient who developed an AST elevation of grade 3-4 that later normalized, and one cirrhotic patient who experienced an elevation in bilirubin.
“This looks like a fairly good regimen: It’s a 12-week course of therapy, interferon-free, ribavirin-free, all-oral, three DAAs, and achieves an SVR12 in over 90% of treated patients,” presenter Gregory T. Everson, MD, University of Colorado, Denver, said. “And, in this study, this was achieved despite a high prevalence of genotype 1a subtype, advanced fibrosis, cirrhosis and a predominance of non-CC IL28B genotype. … These results support phase 3 trials with a twice-daily, fixed-dose combination of this regimen at the 75-mg dose of [BMS-791325].”
Disclosure: The researchers report numerous financial disclosures.
For more information:
Everson GT. LB-1: Late-Breaking Abstract Session: Phase 2b Study of the Interferon-free and Ribavirin-free Combination of Daclatasvir, Asunaprevir, and BMS-791325 for 12 Weeks in Treatment-Naive Patients with Chronic HCV Genotype 1 Infection. Presented at: The Liver Meeting 2013; Nov. 1-5, Washington.
Bristol seeks Japan approval of all-oral hepatitis C treatment
By Bill Berkrot
(Reuters) - Bristol-Myers Squibb Co has filed with Japanese health regulators seeking approval of its experimental all-oral combination of hepatitis C treatments, the U.S. drugmaker said on Saturday.
The submission with Japan's Pharmaceutical and Medical Devices Agency marks the first time that any drugmaker has filed for approval of a hepatitis C treatment regimen that does not include either of the standard older treatments - the injected, difficult-to-tolerate interferon, or ribavirin, a pill.
Gilead Sciences Inc, widely seen as the leader in a crowded race to develop highly effective, interferon-free treatments for the serious liver disease, has sought U.S. approval of its highly regarded anti-viral drug sofosbuvir in combination with ribavirin. A Food and Drug Administration advisory panel last week voted unanimously to recommend its approval.
The Bristol-Myers filing was based on data from a Phase III study of Japanese patients who either could not tolerate interferon, which causes miserable flu-like symptoms, or those who had previously failed to be helped by treatment with the older drugs - a particularly tough-to-treat patient population.
Patients in the trial were given a combination of daclatasvir, from a promising new class of drugs called NS5A inhibitors, and the protease inhibitor asunaprevir for 24 weeks. Those who had no detectable levels of the virus in their blood 24 weeks after completing the therapy were deemed to be cured, a measure known as SVR24, for sustained virologic response.
The overall cure rate in the 222-patient study was 84.7 percent, according to the data to be presented next week at the American Association for the Study of Liver Diseases (AASLD) meeting in Washington.
Of those who were either ineligible for or intolerant of treatment with interferon, the cure rate was 87.4 percent, while 80.5 percent of past nonresponders to the older drugs were deemed cured.
"The Phase III study results of daclatasvir plus asunaprevir are exciting to see, especially in this difficult-to-treat patient population," Kazuaki Chayama, the study's lead investigator from Hiroshima University, said in a statement.
Twenty-eight patients dropped out of the study - a 12.6 percent discontinuation rate - and about 6 percent, or 13 patients, reported serious side effects, primarily elevated liver enzymes, an indication of inflammation.
Bristol-Myers has made Japan a particular focus of its all-oral efforts at tackling the hepatitis C virus, which if left untreated can cause cirrhosis, liver cancer or the need for a transplant.
About 1.2 million people in Japan suffer from hepatitis C. The patients tend to be older than those in other developed countries and about 70 percent have Genotype 1b, a form of the virus with very low response rates to the older treatments.
Several other companies are also developing all-oral hepatitis C treatments, including AbbVie Inc, Merck & Co and Johnson & Johnson, and expect to be able to shorten treatment duration to 12 weeks from the current 24- or 48-week regimens.
Bristol early next year plans to begin Phase III testing of an all-oral, three-drug combination that adds BMS791325 - a non-nucleoside polymerase inhibitor - to the two drugs tested in the Japanese study. The company envisions that its three-drug therapy will involve one combination pill taken twice a day for a 12-week course of treatment.
About 170 million people worldwide are infected with the hepatitis C virus. Some analysts believe the market for all-oral hepatitis C treatments could reach $20 billion as many more people get tested for the virus, given new testing recommendations, very high cure rates, shorter treatment durations and tolerable side effects seen with the newer drugs in clinical trials.
It is believed that tens of thousands of hepatitis C patients have delayed treatment while awaiting the new drugs expected to start reaching the market next year in order to avoid the unpleasant side effects of interferon. Physicians would also like to see regimens that do not require ribavirin, which can cause anemia, rash and other side effects.
(Editing by Matthew Lewis)
Three-Drug Combo Knocks Out HCV
Published: Oct 8, 2013
By Michael Smith, North American Correspondent, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
SAN FRANCISCO -- A triple-drug regimen for hepatitis C (HCV) led to a cure in about 90% of patients without using elements of the standard therapy for the disease, a researcher said.
In a randomized phase II trial, the combination of so-called "direct-acting agents" completely knocked out the virus in between 89% and 94% of patients 12 weeks after the end of therapy, according to Maribel Rodriguez-Torres, MD, of the Fundación de
Investigación in San Juan, Puerto Rico.
The combination of investigational drugs was "generally well tolerated" in patients with the difficult-to-treat genotype 1 of the virus, Rodriguez-Torres reported at the IDWeek meeting here.
For years, standard HCV therapy has included pegylated interferon alfa and ribavirin, drugs that are both difficult to take and in some cases dangerous.
And that therapy leads to sustained virologic responses in no more than half of patients with genotype 1, although adding either of the approved direct-acting agents – telaprevir (Incivek) and boceprevir (Victrelis) – improves those outcomes
So researchers are seeking regimens that both target the virus directly -- interferon and ribavirin do not -- and have better
In this case, they are testing once-daily daclatasvir, an NS5A replication complex inhibitor; twice daily asunaprevir, an NS3 protease inhibitor; and the as-yet-unnamed non-nucleoside NS5B polymerase inhibitor, BMS-791325, given twice a day.
The study is encouraging for those hoping that interferon- and ribavirin-free regimens will soon be approved, according to
Arthur Kim, MD, of Massachusetts General Hospital in Boston, who was not involved in the study but who moderated the session at which it was presented.
"Once you are able to attack multiple viral targets," he told MedPage Today, "it seems that even if there is baseline resistance or some poor prognostic indicators, the multiple targeting works to eradicate the virus and overcome the barriers."
As the new regimens work their way through the clinical trials process, he said, he and other doctors are trying to delay treatment "unless it is absolutely necessary."
But he cautioned that so far the "novel paradigms" are still being tested. "We're still waiting for the phase III trials and larger numbers," Kim said.
The study so far includes 66 patients in four treatment arms differing by the length of therapy and the dose of BMS-791325, Rodriguez-Torres reported.
The primary endpoint is the so-called SVR12 – viral levels too low to be quantified 12 weeks after the end of treatment.
Outcomes appeared similar regardless of the doses and length of treatment, Rodriguez-Torres reported -- in three arms, 94% of patients (or 15 out of 16) reached the primary endpoint.
In the fourth arm
-- with 12 weeks of treatment and a higher dose of BMS-791325 -- 16 of 18 patients (89%) reached SVR12. One patient had viral breakthrough while on therapy and another relapsed during follow-up, she said.
Investigators saw only one serious adverse event -- a case of renal calculus that was judged not to be related to the study drugs, she reported.
There were no adverse events that led to patients stopping treatment and only one clinical adverse event that reached grade 3 or 4 -- a headache that resolved as treatment continued.
Investigators did not see any grade 3 or 4 laboratory abnormalities, Rodriguez-Torres said.
Follow-up is continuing and the study is being expanded to include other patient populations, Rodriguez-Torres said,
adding: "We call it the study that never ends."
The study was supported by Bristol-Myers Squibb. Rodriguez-Torres reported financial links with the company and several authors are employees of BMS.
AASLD 2013 - Daclatasvir and asunaprevir Phase III trial in Japanese patients
AASLD 2013: Daclatasvir + Asunaprevir Cures 85% of Genotype 1b Hepatitis C Patients in Japanese Study
Published on Monday, 11 November 2013
Written by Liz Highleyman
An interferon- and ribavirin-free oral regimen of daclatasvir plus asunaprevir taken for 24 weeks led to sustained virological response in 85% of Japanese patients with hepatitis C virus subtype 1b, according to findings presented at the 64th AASLD Liver Meeting last week in Washington, DC.
The development of direct-acting antivirals has brought about a revolution in the treatment of chronic hepatitis C virus (HCV) infection. While the first of these new agents were initially approved as add-ons to interferon-based therapy, people with hepatitis C and their providers are eagerly awaiting all-oral regimens that avoid the difficult side effects of interferon.
Kazuaki Chayama from Hiroshima University presented results from a Phase 3 trial (AI447-017) testing an interferon-free regimen of Bristol-Meyers Squibb's HCV NS5A replication complex inhibitor daclatasvir (formerly BMS-790052) plus the NS3 protease inhibitor asunaprevir (formerly BMS-650032) for patients who were either non-responders to prior interferon-based therapy or ineligible for or intolerant of interferon.
The study enrolled 222 chronic hepatitis C patients with HCV subtype 1b, the predominant type in Japan. In contrast with most U.S. and European studies, two-thirds of participants were women and the average age was a bit older at 63 years; 40% were over age 65. Half had the favorable IL28B CC gene variant associated with interferon responsiveness and 10% had liver cirrhosis.
The population included 22% prior null responders (<2 log reduction in HCV RNA), 16% prior partial responders, 45% deemed ineligible to take interferon (for reasons such as pre-existing depression, anemia, other comorbidities, or advanced age), and 16% who were interferon intolerant (previously discontinued interferon before 12 weeks due to toxicities).
All participants in this open-label study received 60 mg once-daily daclatasvir plus 100 mg twice-daily asunaprevir for 24 weeks. They were followed for an additional 24 weeks after finishing treatment to determine sustained virological response (SVR24), or continued undetectable HCV RNA, which is considered a cure.
- The overall SVR24 rate was 85% in a modified intent-to-treat analysis, broken down to 87% for interferon ineligible or intolerant patients and 81% for prior non-responders.
- HCV viral load declined rapidly after starting therapy, with 84% of ineligible/intolerant patients and 61% of prior non-responders showing rapid virological response at week 4; 96% and 87%, respectively, had undetectable HCV RNA at the end of therapy.
- However, 11 ineligible/intolerant patients and six prior non-responders (8%) relapsed during post-treatment follow-up.
- High sustained response rates were obtained regardless of IL28B status (85% for favorable CC, 85% for intermediate CT, and 83% for least favorable TT).
- Other baseline factors did not significantly affect response rates.
- Interestingly, people with cirrhosis did at least as well as non-cirrhotics (91% and 84%, respectively) and patients age 65 and older fared slightly better than younger participants (90% vs 81%).
- Daclatasvir plus asunaprevirwas generally safe and well-tolerated.
- Overall, 6% of participants experienced serious adverse events, 7% developed grade 3-4 laboratory abnormalities, and 5% discontinued due to adverse events, with all these outcomes being a bit more common among ineligible/intolerant patients compared to prior non-responders.
- The most common adverse events were upper respiratory infections (30%), elevated ALT or AST liver enzyme levels (16% and 13%), headache (16%), fever (12%), and diarrhea (10%); anemia was rare (3%).
- All but 1 of the 11 patients who discontinued early due to side effects did so for elevated ALT or AST, which returned to normal after stopping treatment.
Based on these findings, Bristol-Myers Squibb announced during the conference that it has submitted this first interferon- and ribavirin-free regimen for regulatory approval in Japan, where an estimated 1.2 million people are living with hepatitis C.
While these are good results for people with HCV 1b, studies have shown that the dual regimen of daclatasvir/asunaprevir is not as effective against subtype 1a. (Asunaprevir is also not active against HCV genotypes 2 or 3.)
However, as also reported at the Liver Meeting, adding a third agent -- the non-nucleoside NS5B polymerase inhibitor BMS-791325 -- raised sustained response rates to 91% for people with HCV 1a and 100% for 1b. Bristol-Myers Squibb is working on a fixed-dose combination pill containing these 3 drugs.
K Chayama, Y Suzuki, K Ikeda, et al. All-oral Combination of Daclatasvir Plus Asunaprevir in Interferon Ineligible Naive/Intolerant and Nonresponder Japanese Patients Chronically Infected with HCV Genotype 1b: Results from a Phase 3 Trial. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract211.
Bristol-Myers Squibb. BMS Submits First All-Oral, Interferon-Free and Ribavirin-Free Treatment Regimen for Regulatory Review in Japan for Patients with Chronic Hepatitis C Infection. Press release. November 2, 2013.
November 8 2013
Slides/Abstracts @ NATAP
AASLD: All-Oral Combination of Daclatasvir Plus Asunaprevir in Interferon-Ineligible Naïve/Intolerant and Nonresponder Japanese Patients Chronically Infected With HCV Genotype 1b: Results From a Phase 3 Trial -
HCV Regimen: No Interferon, No Ribavirin, No Problem
By Ed Susman , Contributing Writer, MedPage TodayReviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania
WASHINGTON -- Patients who failed to respond to standard treatment for hepatitis C virus (HCV) infection achieved greater than 80% sustained virologic response at 24 weeks with an all-oral regimen that eschewed both interferon and ribavirin, researchers reported here.
Among 135 patients who were either ineligible for interferon therapy or who were intolerant of the treatment, 87.4% achieved a sustained virologic response -- basically a treatment cure, reported Kazuaki Chayama, MD, PhD, professor of medicine and director of Hiroshima University Hospital.
In his plenary session report at the annual meeting of the American Association for the Study of Liver Diseases, Chayama also reported that 80.5% of 87 previous non-responders or partial responders achieved a sustained virologic response at 24 weeks.
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- Note that in this uncontrolled trial of patients with HCV, the combination of daclatasvir plus asunaprevir was very effective in inducing virologic response rates.
- Be aware that the trial only enrolled patients who had failed or were ineligible for interferon therapy.
He said that the response at 12 weeks was virtually the same as at 24 weeks: 88.1% of those ineligible or intolerant of interferon-based therapy reached the milestone compared with 80.5% of the non-responders or partial responders achieving a sustained virologic response at 12 weeks.
"Overall, 84.7% of these patients with limited therapeutic options and those patients typically associated with poor responses to other therapies were able to achieve a sustained virologic response," he said.
The 135 patients in the study received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily. The researchers also enrolled 87 non-responders to previous therapy who received the same treatment regimen.
"Current treatment for chronic hepatitis C virus infection consists of pegylated interferon/ribavirin combined with a direct-acting antiviral," he explained. "In Japan, many patients are excluded from therapy due to the combined effect of an aging Japanese population with chronic hepatitis C virus and the poor tolerability profile with peginterferon/ribavirin-based therapy in this population."
He noted that although telaprevir/peginterferon/ribavirin therapy was approved for both treatment-naïve and treatment-experienced patients, the efficacy in nonresponder patients with hepatitis C virus genotype-1 was insufficient -- about one-third of patients responded.
The two investigative agents attack the virus in different ways. Daclatasvir is a potent NS5A replication complex inhibitor with pan-genotypic antiviral activity. Asunaprevir is a potent NS3 protease inhibitor with antiviral activity against genotypes 1, 4, 5, and 6. Chayama said the phase III study he described follows successful phase II studies showing a strong impact on patients with genotype 1b.
The median age of the 222 participants in the trial was 62.5, about 35% were men, and about 10% were diagnosed with cirrhosis. Baseline factors, including male gender, advanced age, high baseline hepatitis C virus RNA, and cirrhosis, did not appear to have an impact on response rates, Chayama said.
Overall 12.6% of the patients in the study discontinued therapy -- 6.8% due to lack of efficacy and 5% due to adverse events. Chayama said 5.6% of patients experienced serious adverse events. There were no deaths in the study.
Although the study was conducted among a Japanese population, Michael Fried, MD, professor of medicine and director of the University of North Carolina Liver Center in Chapel Hill, told MedPage Today, "These results can be extrapolated to an American or European hepatitis C virus population that had genotype 1 infection."
"It will work in this population but it will be tested in this population as well. These drugs will have to be more broadly studied. As you have seen if we get the right combination of drugs we can get successful results," Fried said.
The Japanese population mainly had genotype 1b infections, he said. Yet the success rate in achieving sustained virologic response was greater than 80%. "When I first started treating hepatitis C virus infection in the 1990s we were getting sustained virologic response rate in the 7% area, and to be getting response in the 80% to 90% levels we are seeing today is phenomenal."
He acknowledged that historically genotype 1 hepatitis C infection has been considered a more difficult disease to treat than genotypes 2 or 3, but in studies presented at The Liver Meeting 2013, "What has emerged is that genotype 3 is the new genotype 1. With these new drugs I think there has been a surprise that we get suboptimal results with genotype 3."
Primary source: American Association for the Study of Liver Diseases
Source reference: Chayama M, et al "All-oral combination of daclatasvir plus asunaprevir in interferon ineligible naive/intolerant and nonresponder Japanese patients chronically infected with HCV genotype 1b: Results from a phase 3 trial" AASLD 2013.
This report is part of a 12-month Clinical Context series.
View All AASLD Meeting Coverage @ MedPage Today