RG7128, being developed jointly by Roche and Pharmasset
Background on non-nucleoside polymerase inhibitors "(non-nucs), and nucleoside polymerase inhibitors (nucs)".
On the other hand, nucleoside polymerase inhibitors have a high barrier to resistance. In studies shown by Roche, no resistance was observed in cultures treated with R7128, its nucleoside polymerase inhibitor licensed from Pharmasset, for two weeks as monotherapy. Cultures treated with non-nucs or protease inhibitors all developed resistance. R7128 was also shown to reduce the formation of resistant colonies when added to either a non-nuc or PI. These studies show the flexibility of nucs in combination treatment.
Pharmasset’s lead compound is currently in multiple Phase II trials. Results from the 12 week R7128 treatment portion of a 48 week triple combo PROPEL trial with interferon + ribavirin trial have been released showing high rapid virologic responses and a low rate of adverse events. Full SVR data will be available in 2011. A longer trial involving 24 weeks of dosing called JUMP-C is now dosing. Phase III studies are expected to begin in 2011 as well, with an NDA filing anticipated in 2013.
PROPEL trialRG7128 plus peginterferon (pegIFN) alfa-2a with ribavirin (RBV) demonstrated high rapid virologic response (RVR) and complete early virologic response (cEVR) rates in treatment-naive patients with genotype 1 or 4 HCV infection
See Slides @ NATAP High rates of early viral response, promising safety profile and lack of resistance-related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12 interim analysis from the PROPEL study
Roche is conducting a combination trial of R7128 with the protease inhibitor R7227 from Intermune. Results from a 14 day INFORM-1 trial showed the drugs were safe when administered together and resulted in a sustained viral load reduction. Continuing studies will add the drug Ritonavir to boost R7227 without increasing side effects
From Doctors Guide:
Change in HCV RNA concentration was measured at the start of the study and at regular intervals during treatment up to day 14.
Patients who had never been treated before who received the highest doses of the 2 drugs (1000 mg RG7128 and 900 mg danoprevir BID) had a median HCV RNA reduction after 14 days of 5.1 log10 IU/ml, compared with a reduction of 4.9 log10 IU/ml in patients who had shown no response to previous standard treatment, and an increase of 0.079 log10 IU/ml in patients taking placebo.The combined treatment of RG7128 and danoprevir was generally well tolerated with no treatment-related severe side-effects, and no safety-related treatment discontinuations.In addition, there was no evidence of treatment resistance, unlike the rapid development of resistance shown by some classes of direct-acting antiviral drugs when given as monotherapy.
The balance of Pharmasset’s HCV pipeline consists of PSI-7977, which is enrolling patients in Phase IIb and PSI-938, which has completed Phase 1b. The company is planning studies combining these two nucs; initial data should be available Q1 next year. Phase II combo studies are expected to begin around the second or third quarter of 2011
PROPEL: RG7128 Plus PegIFN alfa-2a/RBV Demonstrates High Rates of RVR and cEVR in Treatment-Naive Patients Infected With Genotype 1/4 HCV
Also See :Hepatitis C Drugs: R7128 with the protease inhibitor R7227
*Pharmasset Riding High on Nucs
*See NATAP: New HCV Drugs: R7128 nucleoside, PSI7977 nucleotide, PSI938 nucleotide, ANA598 nnrti (rash), danoprevir protease, IMO-2125, a TLR agonist
Pharmassets candidates nearing preparation for clinical development:RG7128, a pro-drug of PSI-6130 for the treatment of HCV, is entering a phase 2b clinical trial through a collaboration with Roche;PSI-7977, an isomer of PSI-7851 is a nucleotide analog for the treatment of HCV, and is currently in a phase 2b trial;PSI-352938 (PSI-938), a purine nucleotide analog for the treatment of HCV, recently completed a phase 1 trial.
IL28B SNP geographical distribution and antiviral responses in a 28-day phase 2a trial of PSI-7977 daily dosing plus PEG-IFN/RBV
JG. McHutchinson et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010
E. Lawitz et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010.....
At week 2, levels of HCV RNA were undetectable in 52% of the 300 mg group, 57% of the 600 mg group, 62% of the 900 mg group, and 0% of the placebo group.
At week 4, that progressed to 73%, 86%, 86%, and 7%, respectively; and at week 12, to 88%, 89%, 92%, and 43%..Viral resistance to danoprevir emerged in the low-dose (300 mg) group in 2 patients at week 2 and in 5 patients at weeks 4 and 12. In the 600 mg group, patients fared better, with 3 developing treatment-emergent resistance by week 12. No patients developed resistance in the highest-dose (900 mg) group, but the cumulative exposure was significantly less because of the emerging toxicity and discontinuation of that dosing regimen. All of the resistance was seen in patients with HCV genotype 1a.
Rates of most common adverse events in the danoprevir groups were at least twice as high as those seen with standard care alone. Often, there was little difference in the incidence of adverse effects with an increase in the dose of danoprevir.Although the serious adverse event of grade 4 ALT elevation was most likely to occur at the highest dose of the drug (3 incidents) and led to the discontinuation of that dosing, there also was 1 incident among the 60 patients in the 600 mg group. Dr. Terrault said that "modeling the available pharmacokinetics data showed a relationship between danoprevir exposure, specifically AUC and the likelihood of having ALT elevation.".
Last Updated: 2010-11-26 9:00:47 -0400
NEW YORK (Reuters Health) - Minimal hepatic encephalopathy (MHE) increases the risk of falls in patients with cirrhosis, Spanish researchers report in an October 26th online paper in the American Journal of Gastroenterology.
"MHE causes a decline in cognitive function and impairs the ability to perform daily activities in patients with cirrhosis," Dr. Germ�n Soriano, senior author on the study, told Reuters Health by email. "In the present study involving 130 cirrhotic patients and 43 controls, previous falls were more frequent in patients with MHE than in those without MHE and controls."
Dr. Soriano of Hospital de la Santa Creu i Sant Pau, Barcelona, and colleagues note that MHE can only be detected by psychometric or neurophysiological testing and is present in a variable proportion of patients depending on the populations studied and the criteria used for diagnosis.
In the current study, of the 130 patients, 34.6% exhibited MHE and of this group, 40% reported falls in the previous 12 months. This was true of only 12.9% of those without MHE and 11.6% of controls. In the MHE group, falls led to a greater need for primary health care services (8.8% versus none).
In the subset of 21 patients on psychoactive drugs, 75% with MHE reported falls compared to only 15.3% of those without the condition.
Independent risk factors associated with previous falls were MHE (odds ratio, 2.91), previous encephalopathy (odds ratio, 2.87) and antidepressant therapy (odds ratio, 3.91).
The researchers concede that the study was retrospective, but observe that in light of these findings future prospective studies are warranted. In particular, Dr. Soriano added, "Falls represented a significant cause for healthcare and hospitalization requirements in these patients."
Am J Gastroenterol 2010.
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