Sofosbuvir (GS-7977) Updates-Sofosbuvir combination shows promise in non-cirrhotic, treatment-naive HCV



Sofosbuvir combination shows promise in non-cirrhotic, treatment-naive HCV
Lawitz E. Lancet Infect Dis. 2013;doi:10.1016/S1473-3099(13)70033-1.

March 27, 2013
Data from a phase 2 trial suggest that adding 12 weeks of sofosbuvir to peginterferon alfa-2a and ribavirin may be beneficial in non-cirrhotic, treatment-naive patients with genotypes 1, 2 and 3 hepatitis C virus infection.

In the two-cohort trial, patients with HCV genotype 1, 2 or 3 from 22 centers in the United States were recruited from Aug. 16 to Dec. 13, 2010. The 122 patients with HCV genotype 1 were allocated to cohort A. These patients were randomly assigned to 200 mg sofosbuvir (Gilead Sciences), 400 mg sofosbuvir or placebo for 12 weeks, with peginterferon and ribavirin. Depending on viral response, the patients continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks. The 25 patients with genotypes 2 or 3 comprised cohort B. These patients all received 400 mg sofosbuvir plus peginterferon and ribavirin for 12 weeks.

In cohort A, 43 patients who received 200 mg sofosbuvir and 43 patients who received 400 mg sofosbuvir had undetectable HCV RNA at week 12 post-treatment, as did 26 patients in the placebo group. In cohort B, 23 patients had undetectable HCV RNA at week 12 post-treatment. The most common adverse events were fatigue, headache, nausea and chills, which are consistent with adverse events associated with peginterferon and ribavirin.

“Our data suggest further testing of the 400 mg once-daily dose of sofosbuvir in interferon-containing and interferon-free regimens for a total duration of 12 weeks across HCV genotypes, and that these regimens should be testing in a broader population of patients, including those with cirrhosis,” the researchers wrote. “In the ongoing phase 3 study, we are assessing sofosbuvir in combination with peginterferon and ribavirin for 12 weeks in treatment-naïve patients with HCV genotype 1.”

Disclosure: See the study for a list of financial disclosures.
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Mar 15
The Lancet
Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial
The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV.
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Mar 27
Gilead-Medivir Hepatitis C Drug Clears Virus in Patients
An experimental drug combination from Gilead Sciences Inc. (GILD), Medivir AB (MVIRB) and Johnson & Johnson (JNJ) eradicated the virus that causes hepatitis C in patients with the liver disease in a study.

The trial’s 80 patients, who had tried and failed other medications, took a two-drug mixture of Medivir’s simeprevir and Gilead’s sofosbuvir, according to research presented at the Conference on Retroviruses and Opportunistic Infections today in Atlanta. The patients took the combination for 12 or 24 weeks, with and without the antiviral ribavirin, researchers said.
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Mar 12
Simeprevir & sofosbuvir demonstrates good early cure rate with or without ribavirin
Simeprevir & sofosbuvir demonstrates good early cure rate with or without ribavirin

Liz Highleyman 
An all-oral combination of simeprevir plus sofosbuvir, with or without ribavirin, led to an early cure for most hard-to-treat prior null responders with genotype 1 hepatitis C studied in the phase 2a COSMOS trial, according to a presentation last week at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.
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Mar 4
Medivir:Simeprevir (TMC435) and Sofosbuvir (GS-7977) interim results from a phase IIa study
Medivir AB (sto:MVIR-B) today announced first interim results from the cohort 1 of a Phase IIa study of the investigational protease inhibitor simeprevir (TMC435) administered once daily with Gilead's investigational nucleotide inhibitor sofosbuvir (GS-7977) with and without ribavirin for 12 and 24 weeks in genotype 1 prior null-responder hepatitis C patients with mild to moderate fibrosis (METAVIR F0-2). Simeprevir is jointly developed by Medivir AB and Janssen R&D Ireland, an affiliate of the Janssen Pharmaceutical Companies.
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Press Release

Mar 26
Update on Phase 3 Study of Oral Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients
Gilead Announces Update on Phase 3 Study of Oral Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients
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Mar 8
Interferon-free regimen cures 100% of hard-to-treat hepatitis C
By: PATRICE WENDLING Internal Medicine News Digital Network

ATLANTA – Adding ledipasvir to sofosbuvir and ribavirin produced sustained virological responses 12 weeks after therapy in 100% of treatment-naive and prior nonresponder patients with chronic hepatitis C genotype 1 in the ELECTRON trial.

"Certainly adding a second direct-acting antiviral agent, ledipasvir, increases the efficacy of sofosbuvir plus ribavirin," Dr. Edward Gane said at the Conference on Retroviruses and Opportunistic Infections.
 
Three-quarters of the roughly 170 million people infected with hepatitis C virus (HCV) worldwide have genotype 1, the most difficult strain to treat.
 
Current treatment includes triple therapy with a protease inhibitor plus peginterferon and ribavirin for 24-48 weeks, but PI-based therapy is limited by complex dosing regimens, the potential for resistance, and lower responses in prior nonresponders, explained Dr. Gane of Auckland Clinical Studies in New Zealand.
 
The investigators hypothesized that combining two direct-acting antivirals with a different mechanism would enhance response.
 
At last year’s CROI meeting, Dr. Gane reported that treatment with the nucleotide NS5B inhibitor sofosbuvir (formerly known as GS-7977) and ribavirin alone led to early viral load suppression, but relapses within 4 weeks of stopping treatment resulted in 12-week posttreatment sustained virological response (SVR12) rates of 84% among treatment-naive patients and only 10% among previous interferon-based therapy null responders.
 
In the current arm of the trial, the NS5A inhibitor ledipasvir (formerly known as GS-5885) was added to sofosbuvir and weight-based ribavirin, all for 12 weeks, in 25 noncirrhotic treatment-naive and 9 null responders, defined by less than a 2-log reduction in HCV RNA after 12 weeks of peginterferon and ribavirin.
 
The majority of treatment-naive and null responders were genotype 1a (80% and 89%) and had high baseline HCV RNA loads (mean 5.9 log10 IU/mL and 6.9 log10 IU/mL). The more favorable IL28B genotype CC genotype was present in 36% of treatment-naive patients, but in no null responders. The patients median age was 48; 94% were white.
 
Early on–treatment viral suppression was very rapid, with all treatment-naive patients and all but one prior null responder having an undetectable viral load at week 4, Dr. Gane said. This patient’s load was on the threshold at week 4 and became undetectable by week 5, resulting in SVR12 rates of 100% in both groups.
 
No viral breakthroughs were observed, and all patients achieved an end-of-treatment response.
Unlike the earlier arm of the trial, however, both groups maintained undetectable HCV viral loads at 4 and 12 weeks after therapy, he said.
 
The triple combination was well tolerated and safe. Three serious adverse events occurred, but none were treatment related. One patient had to stop therapy at week 8 due to the event, but subsequently achieved SVR24. The most common adverse events were anemia (20%), depression (8%), and headache (4%), and all were in treatment-naive patients.
 
Grade 3 laboratory abnormalities occurred in 52% of the treatment-naive and 22% of null responders. No grade 4 abnormalities were seen, Dr. Gane said.
 
Ledipasvir and sofosbuvir have been combined into a single fixed-dose tablet and is being evaluated in phase III studies in patients with cirrhosis and to determine whether there is a need for ribavirin, he said. Additional studies are also underway to explore shorter durations of therapy.
ELECTRON was sponsored by Gilead Sciences. Dr. Gane reported ties with Gilead, Janssen-Cilag, Novartis, Pharmasset, Roche and Vertex.
 
Also view - 2013-Interferon Free Combinations
Additional updates @ NATAP‏

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