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Slides Available @ NATAP- High Rate of Sustained Virologic Response With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients Chronically Infected With HCV GT 1, 2, or 3
WSJ - Hepatitis C Drug Derailed by Deal
Promising HCV Combo May Not See Light of Day
By Michael Smith, North American Correspondent, MedPage Today
Published: November 14, 2012
The study was supported by Vertex Pharmaceuticals. Sulkowski reported financial links with the company, as well as Novartis, BMS, Gilead, Janssen, Vertex, BIPI, Abbott, Merck, Roche/Genentech, BIPI, and Pfizer.
Pockros reported financial links with Novartis, Tibotec, GlobeImmune, Genentech, Merck, BMS, Gilead, Vertex, Three Rivers Pharmaceuticals, Debio, Pfizer, Conatus Pharmaceuticals, Abbott, and Mochida Pharmaceuticals.
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
BOSTON – In a trial described by one expert as a "home run," a combination of two investigational oral hepatitis C (HCV) medications delivered highly promising results.
But despite the excellent results, it's unlikely the combination of daclatasvir and sofosbuvir will go forward – the drugs are owned by different pharmaceutical companies.
Action Points
The combination appeared to yield similar results regardless of viral genotype or the presence of ribavirin, Sulkowski told a late-breaker session at the annual meeting here of the American Association for the Study of Liver Diseases.
"That's a home run," commented hepatologist Paul Pockros, MD, of Scripps Clinic in La Jolla, Calif., who was not involved in the study.
"The issue is they're not likely to go forward," he told MedPage Today.
Daclatasvir, an NS5A replication complex inhibitor, is owned by Bristol-Myers Squibb, while sofosbuvir, a nucleotide analog NS5B polymerase inhibitor, is being developed by Gilead Sciences.
Observers, including Pockros, don't think a phase III trial of the combination is likely, which means FDA approval could not be given. Sulkowski did not comment on the issue during his presentation.
On the other hand, Pockros said, the trial serves as proof of principle that a combination of drugs in those classes can have powerful effects. Both companies have their own versions of the other's medication, he noted, so that future combinations remain possible.
In addition, he said, both daclatasvir and sofosbuvir are likely to be approved soon, with an indication for therapy in combination with the standard HCV drugs, pegylated interferon and ribavirin.
There would then be nothing to stop doctors from using them together off-label, while avoiding the other two, which are associated with a host of adverse effects.
The trial, Sulkowski reported, was designed to test the combination in all three major genotypes of the virus, with or without ribavirin, for 12 or 24 weeks of therapy, and with or without a week-long run-in with sofosbuvir.
Key is the absence of interferon, which aside from its difficult-to-tolerate side effects, is injected; all drugs tested in this trial are given orally.
The primary endpoint was the so-called sustained virologic response 12 weeks after the end of treatment (SVR12), defined as a viral RNA level too low to quantify. Here, Sulkowski reported a slightly higher bar – unquantifiable and undetected HCV RNA.
A total of 44 patients with the relatively easy-to-treat viral genotypes 2 and 3 were enrolled in three arms – one with a seven-day sofosbuvir run-in followed by 23 weeks of the two together, one with the combination for 24 weeks, and one with the combination plus ribavirin for 24 weeks.
Sulkowski said 88% of patients in the first group reached an SVR12, compared with 100% in the second group, and 86% in the third group.
In genotype 1, regarded as more difficult to treat, the researchers had three arms, with a total of 44 patients, with the same regimens as in the genotype 2/3 patients.
They also tested the combination with and without ribavirin for 12 weeks in a total of 82 patients.
All patients getting the first three regimens achieved an SVR12 and, indeed, all but one remained aviremic at week 24 post treatment. Sulkowski said genetic analysis showed that patient had acquired a new infection, rather than relapsing.
Of the 82 patients in the 12-week arms, Sulkowski reported, 68 had reached 12 weeks post treatment and all had SVR12.
The virologic response did not vary according to viral subtype or patient genetics, Sulkowski said, and the combination was generally well tolerated with and without ribavirin. Hemoglobin declines were only seen in the arms with ribavirin, he added.
The study gave positive answers to two important questions, Pockros said: Is the combination effective without ribavirin, and is it effective with 12 weeks of treatment?
Using one drug from each class – even if they turn out not to be the ones used in this study – "looks like a compelling combination," he said.
But despite the excellent results, it's unlikely the combination of daclatasvir and sofosbuvir will go forward – the drugs are owned by different pharmaceutical companies.
Action Points
- 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.
- In a trial described by one expert as a "home run," a combination of two investigational oral hepatitis C (HCV) medications, daclatasvir plus sofosbuvir, delivered highly promising results.
- Note that the virologic response did not vary according to viral subtype or patient genetics, and the combination was generally well tolerated with and without ribavirin
The combination appeared to yield similar results regardless of viral genotype or the presence of ribavirin, Sulkowski told a late-breaker session at the annual meeting here of the American Association for the Study of Liver Diseases.
"That's a home run," commented hepatologist Paul Pockros, MD, of Scripps Clinic in La Jolla, Calif., who was not involved in the study.
"The issue is they're not likely to go forward," he told MedPage Today.
Daclatasvir, an NS5A replication complex inhibitor, is owned by Bristol-Myers Squibb, while sofosbuvir, a nucleotide analog NS5B polymerase inhibitor, is being developed by Gilead Sciences.
Observers, including Pockros, don't think a phase III trial of the combination is likely, which means FDA approval could not be given. Sulkowski did not comment on the issue during his presentation.
On the other hand, Pockros said, the trial serves as proof of principle that a combination of drugs in those classes can have powerful effects. Both companies have their own versions of the other's medication, he noted, so that future combinations remain possible.
In addition, he said, both daclatasvir and sofosbuvir are likely to be approved soon, with an indication for therapy in combination with the standard HCV drugs, pegylated interferon and ribavirin.
There would then be nothing to stop doctors from using them together off-label, while avoiding the other two, which are associated with a host of adverse effects.
The trial, Sulkowski reported, was designed to test the combination in all three major genotypes of the virus, with or without ribavirin, for 12 or 24 weeks of therapy, and with or without a week-long run-in with sofosbuvir.
Key is the absence of interferon, which aside from its difficult-to-tolerate side effects, is injected; all drugs tested in this trial are given orally.
The primary endpoint was the so-called sustained virologic response 12 weeks after the end of treatment (SVR12), defined as a viral RNA level too low to quantify. Here, Sulkowski reported a slightly higher bar – unquantifiable and undetected HCV RNA.
A total of 44 patients with the relatively easy-to-treat viral genotypes 2 and 3 were enrolled in three arms – one with a seven-day sofosbuvir run-in followed by 23 weeks of the two together, one with the combination for 24 weeks, and one with the combination plus ribavirin for 24 weeks.
Sulkowski said 88% of patients in the first group reached an SVR12, compared with 100% in the second group, and 86% in the third group.
In genotype 1, regarded as more difficult to treat, the researchers had three arms, with a total of 44 patients, with the same regimens as in the genotype 2/3 patients.
They also tested the combination with and without ribavirin for 12 weeks in a total of 82 patients.
All patients getting the first three regimens achieved an SVR12 and, indeed, all but one remained aviremic at week 24 post treatment. Sulkowski said genetic analysis showed that patient had acquired a new infection, rather than relapsing.
Of the 82 patients in the 12-week arms, Sulkowski reported, 68 had reached 12 weeks post treatment and all had SVR12.
The virologic response did not vary according to viral subtype or patient genetics, Sulkowski said, and the combination was generally well tolerated with and without ribavirin. Hemoglobin declines were only seen in the arms with ribavirin, he added.
The study gave positive answers to two important questions, Pockros said: Is the combination effective without ribavirin, and is it effective with 12 weeks of treatment?
Using one drug from each class – even if they turn out not to be the ones used in this study – "looks like a compelling combination," he said.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Sulkowksi MS, et al "High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5a inhibitor) plus sofosbuvir (nucleotide NS5b inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCV GT 1, 2, or 3" AASLD 2012; Abstract LB-2.
AASLD Coverage @ MedPage Today
11/14/2012
BOSTON - A simplified hepatitis C regimen with just two oral drugs had promising results in a difficult-to-treat population, a researcher reported here. more
Fatty Liver Ups Risk for Liver Cancer
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HCV Drug Combo Promising All on Its Own
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Some Kids with CF Face Early Liver Disease
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HBV Drugs Cut Risk of Cancer Recurrence
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Antiviral Drug Cuts Cancer Risk in Hepatitis B
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11/13/2012
BOSTON -- Non-alcoholic fatty liver disease is an independent risk factor for hepatocellular carcinoma, even in the absence of cirrhosis, a researcher reported. more
HCV Drug Combo Promising All on Its Own
11/13/2012
BOSTON -- A three-drug regimen that eliminated both standard hepatitis C drugs has yielded positive early results in hard-to-treat patients, a researcher reported. more
Some Kids with CF Face Early Liver Disease
11/12/2012
BOSTON -- The development of cirrhosis in children with cystic fibrosis might occur sooner than expected, a researcher reported. more
HBV Drugs Cut Risk of Cancer Recurrence
11/12/2012
BOSTON -- Antiviral therapy after surgery appears to reduce the risk of recurrence of hepatocellular carcinoma related to hepatitis B, a researcher reported here. more
Antiviral Drug Cuts Cancer Risk in Hepatitis B
11/12/2012
BOSTON -- For patients with chronic hepatitis B, long-term treatment with entecavir (Baraclude) significantly cut the risk of liver cancer, researchers reported. more
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