Sunday Spotlight Hepatitis C Drug Danoprevir : (RG7227/ITMN-191) / Nov 28th

  • Sunday, November 28, 2010
  • Posted by HCV New Drugs
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From NATAP RG7128

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RG7128
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RG7128, being developed jointly by Roche and Pharmasset
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Background on non-nucleoside polymerase inhibitors "(non-nucs), and nucleoside polymerase inhibitors (nucs)".
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Excerpt*
Both Vertex and Merck intend on launching new HCV treatments in 2011 based on a new class of compounds known as NS3 protease inhibitors (PI). These drugs herald a new breed of targeted medicines- sometimes called direct acting antivirals (DAA). The advantage is a significantly higher cure rate and shorter duration of treatment. However, these drugs are susceptible to viral resistance and require concurrent use with both interferon and ribavirin. A second type of compound focuses on inhibition of the NS5B polymerase. Of these there are two classes, non-nucleoside polymerase inhibitors (non-nucs), and nucleoside polymerase inhibitors (nucs). Both have been shown to be effective in combination with interferon + ribavirin, but non-nucs, like protease inhibitors, are also prone to mutation driven resistance.
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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.
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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.
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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
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RG7128 had safety profile similar to standard of careRG7128 not associated with treatment-emergent viral breakthrough or resistance
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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
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INFORM-1 Trial
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
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From Doctors Guide:
INFORM-1 trial was designed to assess the safety, tolerability, and antiviral activity of an oral combination treatment with 2 experimental drugs, RG7128 (a polymerase inhibitor that blocks elongation of the new HCV RNA chain) and danoprevir (a protease inhibitor that blocks an enzyme the virus needs to replicate itself) in patients with chronic HCV.A total of 88 patients with HCV genotype 1 were recruited into 1 of 7 treatment groups and randomised to receive various doses and schedules of the combined treatment (n = 74) or placebo (n = 14) for up to 13 days. Some patients had never been treated before, while others had failed interferon-based standard therapy.
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Change in HCV RNA concentration was measured at the start of the study and at regular intervals during treatment up to day 14.
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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.
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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
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PROPEL: RG7128 Plus PegIFN alfa-2a/RBV Demonstrates High Rates of RVR and cEVR in Treatment-Naive Patients Infected With Genotype 1/4 HCV
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Also See :Hepatitis C Drugs: R7128 with the protease inhibitor R7227
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*Pharmasset Riding High on Nucs
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*See NATAP: New HCV Drugs: R7128 nucleoside, PSI7977 nucleotide, PSI938 nucleotide, ANA598 nnrti (rash), danoprevir protease, IMO-2125, a TLR agonist
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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.
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Slide Presentations:
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
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E. Lawitz et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MA
Oct 29-Nov 2, 2010
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High Rapid Virologic Response (RVR) with PSI-7977 daily dosing plus PEG-IFN/RBV in a 28-day Phase 2a trial
E. Lawitz et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010.....
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Danoprevir
Roche Acquired the rights to InterMune HCV Protease Inhibitor Danoprevir
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*Excerpt:
From Medscape:
The investigational protease inhibitor danoprevir, which targets the hepatitis C virus (HCV), combined with the standard of care for HCV infection — peg-interferon alpha-2a and ribavirin — produces rapid and profound reductions in HCV RNA..Entry criteria were noncirrhotic treatment-naïve adults (predominately genotype 1 virus) with serum HCV RNA levels of 50 000 IU/mL or more and without advanced fibrosis..All patients were administered a standard of care regimen of pegylated interferon alpha-2a plus weight-based ribavirin, and were randomized, for 12 weeks, to placebo or 1 of 3 danoprevir groups: 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours. When danoprevir was stopped, all patients continued on standard therapy for an additional 24 or 48 weeks, depending on whether or not they achieved a rapid virologic response.The second part of the study was a planned continuation of danoprevir to week 24, but that "never was undertaken" because of incidents of reversible grade 4 ALT elevations in 3 patients in the 900 mg group, the highest dose of the study, said Dr. Terrault. Patients already enrolled in the 900 mg group were rerandomized to 300 or 600 mg.
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The principle measure of efficacy was an undetectable HCV RNA level (less then 15 IU/mL); measurements were taken at baseline and at weeks 2, 4, and 12. Missing data points were considered to be nonresponders.
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Dr. Terrault reported that the interim analysis of those who completed 12 weeks of danoprevir therapy was based on 62 patients receiving 300 mg (93%), 61 receiving 600 mg (94%), and 8 receiving 900 mg (16%).
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.
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Side Effects
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.".

Hepatic encephalopathy increases falls in cirrhotic patients
Last Updated: 2010-11-26 9:00:47 -0400

(Reuters Health)

By David Douglas
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."
SOURCE: http://link.reuters.com/map66q
Am J Gastroenterol 2010.


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