AASLD 2010 Summary Of Hepatitis C Oral Inhibitors

This entry of new investigational oral inhibitors is only a brief collection of data accumulated from following sites: HCV Advocate ,CCO, Medpage, AASLD, NATAP HIV and Hepatitis,Medscape, The Street.com. Biopharma report and TheMedGuru
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The links through out this summary provide the additional information needed to give a complete and accurate profile of these new agents.
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The AASLD has released "The Best of The Liver Meeting® State-of-the-Art-Lectures" . The presentation's are available in a multimedia format. As the remainder of these lectures are released they will be added to the blog.
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*A link to "The Best of the liver meeting" is on the sidebar
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This summary will be updated over the next few weeks with a link also on the sidebar with the current review date.
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*data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Telaprevir
Telaprevir is an investigational oral protease inhibitor used in combination with pegylated interferon plus ribavirin and is being developed by Vertex in collaboration with Johnson & Johnson.
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The two trials named "ADVANCE and ILLUMINATE" were for patients with genotype 1 who have not previously treated.

Response-guided therapy (Response guided therapy is intended to enable the physician to determine the duration of combination therapy based on a patient's viral response during treatment) was used in ADVANCE, whereby patients whose virus was undetectable at weeks 4 and 12 of treatment with telaprevir-based therapy were eligible to reduce their treatment from 48 weeks to 24 weeks.

The Phase 3 ILLUMINATE trial was designed to confirm both the use of *response-guided therapy and to evaluate whether there was any benefit to extending total treatment duration from 24 to 48 weeks."

In ADVANCE and ILLUMINATE, 58% and 65% of people, respectively, met these criteria for 24-week total treatment. In ILLUMINATE there was no benefit in extending therapy to 48 weeks.

Phase 3 REALIZE
Trial REALIZE was the second pivotal Phase 3 trial and was designed to evaluate telaprevir-based regimens in people who had received pegylated-interferon-based therapy but did not achieve a cure. REALIZE is the only Phase 3 clinical trial to date of an investigational direct-acting antiviral to include all major subgroups of difficult-to-treat patients including null responders, who were defined as people who had a less than a 2 log10 reduction in viral load by week 12 of a prior course of therapy.

The Results
.ADVANCE
Overall in ADVANCE, 75% of people treated with a telaprevir-based combination regimen for 12 weeks, followed by an additional 12 or 36 weeks of pegylated-interferon and ribavirin alone, achieved SVR, compared to 44% of people treated with 48 weeks of pegylated-interferon and ribavirin alone.

ILLUMINATE
In ILLUMINATE, 72% of people overall achieved SVR with telaprevir-based therapy. New data from this study showed that 60% of African Americans/Blacks and 63% of people with advanced liver fibrosis or cirrhosis achieved SVR with telaprevir-based therapy in the overall study analysis. Of African Americans/Blacks whose virus was undetectable at weeks 4 and 12, 88% of people achieved SVR in both the 24-week and 48-week randomized treatment arms. There was no control arm of pegylated-interferon and ribavirin alone in ILLUMINATE.

REALIZE
Results of the REALIZE trial showed that 65 percent of patients treated with telaprevir plus the standard of care were cured, or sustained viral response compared to 17 percent of patients in the control group who were re-treated with just the standard of care.

SVR In The Three Different Groups Were As Follows:
86 percent of re-lapsers were cured after telaprevir treatment compared to 24 percent in the control arm.
Among the second group, the cure rate for the telaprevir-treated patients was 57 percent compared to 15 percent for the control arm.

Control Arm = *SOC pegylated interferon plus ribavirin

Finally, in the last group which consisted of the most difficult to treat patients, telaprevir achieved a 31 percent cure rate compared to 5 percent for the control arm. Results across all three patients types were statistically significant in favor of telaprevir over standard of care, officials report.

Complete Information

Side Effects :In ADVANCE, discontinuation of telaprevir or placebo only due to adverse events during the telaprevir treatment phase occurred in 11% of people in the 12-week telaprevir arm, 7% of people in the 8-week telaprevir arm and 1% of people in the control arm. In ILLUMINATE, 12% of people overall discontinued telaprevir only due to adverse events during the telaprevir treatment phase.

Discontinuation of all drugs due to either rash or anemia was low in both studies (1% to 3%). Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. Ninety-two percent and 95% of rash was mild to moderate in ADVANCE and ILLUMINATE, respectively. Rash was managed with the use of topical corticosteroids and antihistamines, and anemia was primarily managed by reducing the dose of ribavirin. The use of erythropoiesis-stimulating agents (ESAs) were not allowed in any of the Phase 3 clinical studies.

Discontinuation (%) of all drugs during the telaprevir treatment phase

ADVANCE


12-week telaprevir arm ..................................7%
8-week telaprevir arm......................................8%
Control Arm.................................... 4%

ILLUMINATE*
Total .................................................7%*

There was no control arm in ILLUMINATE

Telaprevir may have * fewer side effects (like anemia) than boceprevir.

Vertex announced a new trial which will be called the "OPTIMIZE" and is for genotype 1 patients who have not previously treated.

AASLD/2010 Telaprevir 3 Studies Showed Superior SVR (Viral Cure)Regardless of Race/Stage Of Liver Disease

AASLD:Telaprevir SVR/Decreased Adverse Events Presented Nov 2

Telaprevir will be filing their FDA Application in the next few weeks
Telaprevir® Vertex To File FDA Application “Within Weeks”
The Cost : Telaprevir


Boceprevir
Boceprevir is also an investigational oral HCV protease inhibitor used in combination with pegylated interferon plus ribavirin and is being developed by Merck.

*Excerpt:
The two trials were the SPRINT-2 trial which enrolled genotype 1 patients who have never treated previously. The RESPOND-2 trial enrolled genotype 1 patients who previously treated but did not respond to or relapsed after treatment.

Merck released final results from two phase-3 studies of boceprevir, saying it produced “significantly higher” results compared with patients in the control group.

In the "RESPOND 2" trial at 24 weeks after conclusion of treatment, the patients treating in the *control arm with "no telaprevir" or with only *SOC achieved a SVR of 21 percent.

Adding Boceprevir to the treatment increased SVR to 59 percent for the second arm *(Second arm received 4 weeks of lead-in therapy of peginterferon alpha 2b and ribavirin followed by response-guided therapy of peginterferon alpha 2b and ribavirin combined with 800 mg of Boceprevir three times a day) and 67 percent for the third arm *(Third arm received 4 weeks of lead-in therapy of peginterferon alpha 2b and ribavirin followed by 44 weeks of peginterferon alpha 2b and ribavirin combined with 800 mg of Boceprevir).

It was noted that previous relapsers fared better than nonresponders in all arms. The therapy was well-tolerated, and the most common reason for discontinuing treatment was for patients who still had detectable HCV-RNA at week 12.

From HCV Advocate

SPRINT-2
The SPRINT-2 study included 1,097 HCV genotype 1
treatment-naïve patients (never been treated). The treatment
protocol consisted of a 4 week lead-in phase of
PegIntron plus ribavirin (without boceprevir), followed
by the triple combination of boceprevir, PegIntron
and ribavirin. Duration and continuation of treatment
was guided by the type of on-treatment response to the
medications.*
.The SVR or sustained virological response rates (HCVRNA negative 24 weeks after the last dose of medicine is taken) by different treatment arms are listed below:
.a. If HCV RNA (viral load) negative at week 8 through week 24,
triple therapy was continued for a total treatment duration of 28 weeks;
sustained virological response (SVR) = 63%
a. If HCV RNA positive at week 8 but undetectable at week 24, boceprevir was stopped at week 28 and PegIntron/ribavirin combination therapy (without boceprevir) was continued for a total treatment duration of 48 weeks;SVR = 66%
a. The control arm was standard of care – PegIntron plus ribavirin—with a treatment duration of 48weeks;SVR = 38%
.African Americans/Blacks—Treatment Response
There were also 159 African American/Black patients in the study—
African Americans/Blacks comprised 15% of the patient population in this trial.
The SVR rates by different treatment arms are listed below:
.a. If HCV RNA negative at week 8 through week 24,triple therapy was continued for a total treatment duration of 28 weeks: SVR = 42%
a.If HCV RNA positive at week 8 but undetectable at week 24, boceprevir was stopped at week 28 andPegIntron/ribavirin combo therapy without boceprevir) was continued for a total treatment duration of 48weeks; SVR = 53%
a. The control arm was standard of care – PegIntron plus ribavirin—with a treatment duration of 48weeks; SVR = 23%
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*If any patients were HCV RNA positive at week 24 all treatment was stopped.


HCV RESPOND 2
The RESPOND 2 study included 403 HCV genotype 1
“treatment-failure” patients. The study included a 4
week lead-in phase of PegIntron plus ribavirin
(without boceprevir), followed by the triple combination
of boceprevir, PegIntron and ribavirin1 and treatment
duration was based on type of on-treatment response.
.The SVR rates and duration of treatment periods for all
patients are listed below.
a. If HCV RNA negative at week 8 and at week 12 the total
treatment duration was 36 weeks; SVR = 59%
a. IF HCV RNA positive at week 8, but undetectable at
week 12, boceprevir was stopped at week 36 and the
combination of PegIntron/ribavirin was continued for a
total treatment duration of 48 weeks; SVR = 66%
a. Control arm was standard of care – combination of
PegIntron plus ribavirin—for a total treatment duration
of 48 weeks; SVR = 21%
*If any patients were HCV RNA positive at week 12 all
treatment was stopped.
.It is important to know that the treatment duration in the
boceprevir containing arms were 28, 36 or 48 weeks
depending on the type of on-treatment response.

Side Effects: Treatment appeared to be associated with two side effects compared with placebo -- anemia and a distorted sense of taste, or disgeusia. Overall, patients on treatment had greater use of erythropoietin "Note (rescue drugs)" to treat anemia compared with controls (43% for short- and full-course, versus 24% of those on placebo). More boceprevir patients also had to reduce their treatment dose due to anemia (20% and 21% versus 13%). Other adverse events included nausea, headache, and fatigue, at similar rates across all three groups".

Merck began submission of a new drug application for boceprevir on a rolling basis and expects to complete that process by the end of the year.

AASLD Presented Nov 2/Final Results of Clinical Trial on Boceprevir
AASLD:Hepatitis C Drug Boceprevir Six Months of Novel Agent Works
Boceprevir Achieved Significantly Higher SVR Rates In Treatment-Failure And Treatment-Naïve Adult Patients With Chronic Hepatitis C Genotype 1 Compare

Telaprevir Over Boceprevir?
AASLD:Telaprevir/Boceprevir/Similar Cure Rates/Shorter Treatment Duration


TMC435
.TMC435 is a protease inhibitor used in combination with peg-interferon and ribavirin and is being developed by Medivir and Tibotec Pharmaceuticals .

Tibotec is a global pharmaceutical and research development company. The Company's main research and development facilities are in Beerse, Belgium with offices in Titusville, NJ and Cork, Ireland.
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*Excerpt :
In the PILLAR study genotype 1 treatment-naive patients were enrolled in a week-24 planned interim analysis of response-guided treatment.

The compound is given once a day -- an easier regimen than that of the two protease inhibitors closest to market, boceprevir and telaprevir, which are administered thrice daily.
As well, the new data reported for the Tibotec protease TMC435 shows potency with 95% achieving week 24 response rate.

The results showed that in the four TMC435 treatment groups between 79 and 86 percent of patients were able to stop all therapy at Week-24, according to the response criteria defined in the study protocol. There were no relevant differences for adverse events between TMC435 treatment groups and placebo

The PILLAR study [Protease Inhibitor TMC435 trial assessing the optimaL dose and duration as once daiLy Anti-viral Regimen] (TMC435-C205; NCT00882908) is an ongoing, five-arm, global phase 2b randomized, double-blind, placebo controlled study in 386 treatment-naive patients. TMC435 was administered in doses of 75mg or 150mg q.d. for either 12 weeks or 24 weeks in combination with 24 weeks of peg-interferon and ribavirin (PR).

Patients in the placebo arm receive 24 weeks of placebo plus peg-interferon and ribavirin followed by 24 additional weeks of peg-interferon and ribavirin treatment. The primary endpoint of the study is sustained virologic response at Week-72 (SVR24). The PILLAR study is being conducted in 13 countries in Europe, North America, and Australasia.

Patients receiving TMC435 were allowed to stop all treatment at week 24 when a) HCV RNA levels less then 25 IU/mL at week 4 and b) HCV RNA less then 25 IU/mL levels at weeks 12, 16 and 20. Patients who did not meet the above response-guided criteria continued with peg-interferon and ribavirin until Week-48.
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Majority Of Patients were undetectable at week 12
TMC435 demonstrated potent antiviral activity, at week 4 (rapid virologic response (RVR)) and at week 12 (complete early virologic response (cEVR)) HCV RNA was undetectable (less then 25IU/ml) for the majority of patients. The viral breakthrough rate was 4.9 percent in the TMC435 treatment groups.

(TMC435 is also being studied in HCV genotype-1 treatment-experienced patients who have failed treatment with peg-interferon and ribavirin. The ASPIRE study (Antiviral STAT-C Protease Inhibitor Regimen in Experienced patients; TMC435-C206; NCT00980330) is an ongoing global phase 2b randomized, double-blind, placebo controlled study in 463 patients)

Side Effects: The most common adverse events were headache and fatigue, 46 percent and 42 percent in the TMC435 groups and 51 percent and 47 percent in the placebo group respectively. There were no clinically significant differences in frequency of rash, anemia or gastrointestinal events between the TMC435 groups and placebo. Most AEs were mild to moderate in severity. AEs leading to treatment discontinuation were reported in 7.1 percent of patients in TMC435 arms and 7.8 percent in placebo arm. In laboratory parameters, significant decreases in transaminases (ALT and AST) were observed in all treatment groups. Small and transient bilirubin elevations (direct and indirect) were seen in the TMC435 150mg dose groups.

AASLD: TMC435 Rapid Response for Once-Daily Protease Inhibitor
AASLD:TMC435 PILLAR study in treatment-naive patients/ genotype 1


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
*From biopharma report: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
.RG7128 had safety profile similar to standard of care
RG7128 not associated with treatment-emergent viral breakthrough or resistance
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INFORM-1 Trial
Roche is conducting a combination trial of R7128 with the protease inhibitor R7227=( also known as Danoprevir/ITMN-191) 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 (also known as R-7227/ITMN-191) (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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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:
JG. McHutchinson et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010
Clinical synergy of an anti-HCV nucleotide analog with SOC: Viral kinetics of PSI-7977 with SOCE. Lawitz et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010
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
Danoprevir= (RG7227 formerly R7227 also known as ITMN-191) is a investigational protease inhibitor, which targets the hepatitis C virus, used in combination with the standard of care for HCV infection; peg-interferon alpha-2a and ribavirin. It has demonstrated rapid and profound reductions in HCV RNA.

Roche Acquired the rights to InterMune HCV Protease Inhibitor Danoprevir
.*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.
.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.
.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.
.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."
.AASLD:HCV Protease Inhibitor Danoprevir is Positive

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BMS-790052 and BMS-650032
BARACLUDE, BMS-790052, and BMS-650032 were discovered by Bristol-Myers Squibb Research and Development. PEG-Interferon lambda was discovered by ZymoGenetics, Inc. Bristol-Myers Squibb and ZymoGenetics announced a global collaboration for PEG-Interferon lambda and its related development program in 2009. In September 2010, Bristol-Myers Squibb announced its intent to acquire ZymoGenetics.

*Excerpt: Combination therapy with BMS-790052 and BMS-650032 alone or with pegylated interferon and ribavirin (pegIFNα/RBV) results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders.
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Study Objective:
To assess the safety and antiviral activity of BMS-790052 and BMS-650032 alone or combined with pegIFNα/RBV in patients with HCV genotype 1 who have not responded to prior standard of care treatment (null responders)
Materials and Methods
Patients in Group A were treated with BMS-790052 and BMS-650032. Patients in Group B were treated with BMS-790052, BMS-650032 and pegIFNα/RBV. The response rates for both treatment groups are as follows
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One patient in Group B did not meet cEVR; however, on retesting the patient’s viral load was undetectable.** Viral breakthrough was defined as a) any increase in HCV RNA more then 1 log10 from nadir, or b) any detectable HCV RNA more then 25 IU/mL on or after week 4, or c) any detectable HCV RNA less then 25 IU/mL on or after week 4 confirmed by retesting.
Study Conclusion:
Seven out of 11 patients receiving BMS-790052 and BMS-650032 without pegIFNα/RBV achieved rapid virologic response, defined as undetectable viral load by week 4. However, viral breakthrough occurred in six of the 11 patients in this treatment group. Nine out of 10 patients receiving the combination of BMS-790052, BMS-650032 and pegIFNα/RBV achieved complete early virologic response (cEVR), defined as undetectable viral load by week 12.
Side Effects:
Two patients experienced a severe (Grade 3 or 4) adverse event – one patient in Group A experienced fatigue and one patient in Group B experienced low white blood cell count (neutropenia). There was no discontinuation of BMS study drugs due to adverse events (AEs).
AEs were mainly mild to moderate in severity. The most common AEs (more than three occurrences) across both study groups were:

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Lambda Pegylated Interferon
PEG-IFN-lambda is one of several molecules Bristol-Myers Squibb is studying for the potential treatment of hepatitis C..
The EMERGE study is a two-part, randomized, controlled, multicenter phase II, phase II study of PEG-IFN lambda in treatment-naïve patients with chronic hepatitis C genotype 1, 2, 3 or 4. ...
To assess the safety and antiviral activity of four fixed doses of PEG-IFN-lambda in treatment-naïve patients with HCV genotypes 1, 2, 3, and 4
.These data are from the first part of the EMERGE study. In this ongoing, open-label Phase IIa study, 55 patients were randomized to receive PEG-IFN-lambda at one of four dose levels (80, 120, 180 or 240 mg) or PEG-IFN-alpha at 180 μg.
Patients received PEG-IFN lambda and PEG-IFN alpha administered subcutaneously on a weekly basis, as well as ribavirin on a daily basis, dosed according to HCV genotype and body weight. Patients with HCV genotype 2 or 3 were studied for up to 24 weeks; patients with genotype 1 or 4 were studied for up to 48 weeks.
.Study Conclusion:
At PEG-IFN-lambda’s three highest dosing levels (120 mcg, 180 mcg, 240 mcg), virologic response at 4 and 12 weeks was similar to or greater than that observed and reported with standard interferons (PEG-IFN-alpha).
Adverse events were mild to moderate in severity and led to few treatment discontinuations.
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.Genotypes 1 or 4

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Genotypes 2 or 3




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Side Effects
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BI-201335/BI 207127
The Boehringer Ingelheim group who is developing BI-201335, BI 207127 is located in Ingelheim, Germany.
*They are now in Phase Ib deemed "SOUND-C1". Planning is currently underway to begin Phase II trials of BI 207127 with BI 201335 in interferon-sparing regimens both with and without ribavirin.
BI 201335 is an investigational oral HCV NS3/4A protease inhibitor, discovered from Boehringer Ingelheim’s own research and development, which has completed clinical trials through Phase IIb (SILEN-C studies). This Phase II program supports the investigation of BI 201335 in Phase III trials. BI 207127 is an NS5B RNA-dependent polymerase inhibitor that has completed Phase I clinical trials.
Boehringer Ingelheim Oral Hepatitis C Protease Inhibitor and Polymerase Inhibitor Combination Shows Rapid Viral Response without Use of Pegylated Interferon
*Excerpt:
The Phase Ib study, SOUND-C1, showed the combination of two oral hepatitis C virus (HCV) compounds, the protease inhibitor BI 201335 and the polymerase inhibitor BI 207127, with ribavirin reduced viral load to the lower limit of quantifiable levels in HCV treatment-naïve patients. The regimen did not include interferon through the first 28 days of treatment
New protease-polymerase inhibitor combination resulted in 73-100% rapid virological responses without pegylated interferon. In this randomised open-label trial, 32 treatment-naïve genotype-1 HCV patients received a combination of BI 207127 in either 400mg or 600mg doses three times a day (TID) with BI 201335 120mg once daily (QD) together with ribavirin (RBV) (1000/1200mg daily in two doses) for 28 days.
All patients had a rapid and sharp decline in HCV viral load during the first two days, followed by a slower second phase decline. In the lower and higher dose groups, 73 and 100% of patients achieved a rapid virological response (i.e. had a HCV RNA below thelower limit of quantification after 4 weeks of treatment).
One patient experienced a viral breakthrough (increase by more then 1 LOG10 from nadir during treatment) and one other experienced a 0.7 LOG10 increase in viral load. Both patients were in the lower dose group of BI 207127 and were patients with a high baseline viral load. On day 29, all patients were switched to treatment with BI 201335 and PegIFN/RBV for an additional 44 weeks per the defined study protocol, and will be followed to evaluate sustained virological response.
“These early data suggest that there is the potential for the combination of oral anti-HCV therapies to reduce the viral load in a more tolerable, interferon-sparing regimen.
Side Effects:The PegIFN sparing treatment was well tolerated. Investigators reported that the most common adverse events observed in the study were mild gastro-intestinal effects (diarrhea, nausea, vomiting), rash or photosensitivity. Laboratory parameters did not indicate any relevant changes from baseline, except for a continuous drop in amino alanine transferase (ALT) in all patients, a decrease of hemoglobin (median -1.7 and -2.6 g/dL) and an increase of unconjugated bilirubin (median +9.8 and +11.5 umol/L) similar to reported results from earlier BI 201335 trials. There were no serious or severe adverse events and no discontinuations due to adverse events reported in the study during treatment with BI 207127 and BI 201335. A phase IIb trial testing different dose regimens of this combination with longer durations is planned to evaluate sustained virological response rates
Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127, and ribavirin, in patients with chronic hepatitis C:
The SOUND-C1 trial
The drugmaker Abbott and its investigational drug ABT-450 is used along with NORVIR® (ritonavir) for the treatment of HCV . "NORVIR is in a class of medicines called the HIV protease (PRO-tee-ase) inhibitors. NORVIR is used in combination with other anti-HIV medicines to treat people with human immunodeficiency virus (HIV) infection. NORVIR is for adults and for children age greater than 1 month and older."
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*Excerpt :
Abbott and Enanta Pharmaceuticals had positive results from a Phase 2 study of ABT-450/r, an investigational, oral protease inhibitor being developed for the treatment of hepatitis C (HCV) infection. Initial 3-day and 4-week results suggest that ABT-450/r (ABT-450 with 100mg of ritonavir to support once-daily dosing) demonstrates potent antiviral activity in genotype 1 treatment-naïve adults.
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Results show that more than 90 percent of patients (21 of 23) on study drug achieved HCV-RNA levels less then 25 IU/mL at four weeks. Results were presented at the AASLD.
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Key findings:-- After three days, treatment with ABT-450/r alone resulted in statistically significant, 4-log mean reductions of HCV RNA, across the three dose ranges of ABT-450 (50mg, 100mg, 200mg, once-daily dosing) compared to placebo--
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At week four, 91.3 percent (21 of 23) of patients receiving ABT-450/r in combination with standard of care (SOC) pegylated alpha interferon and ribavirin (pegIFN/RBV) achieved HCV-RNA less then 25 IU/ml--
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Safety appears consistent to that expected with SOC
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"ABT-450 was discovered as part of an alliance between Abbott and Enanta and is being developed with low-dose ritonavir, which enhances the pharmacokinetic properties of ABT-450, allowing for once-daily dosing. This Phase 2 study also evaluated ABT-333 and ABT-072, two of Abbott's internally discovered compounds that are part of the company's ongoing non-nucleoside polymerase inhibitor development program. The study findings for these two compounds have been submitted for presentation at a future scientific meeting."
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*See Slides @ NATAP Initial Antiviral Activity of the HCV NS3 Protease Inhibitor ABT-450 When Given with Low-dose Ritonavir as 3-Day Monotherapy: Preliminary Results of Study M11-602 in Genotype 1 (GT1) HCV-infected Treatment-naïve Subjects
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ANA598
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Anadys investigational polymerase inhibitor ANA598 was studied in treatment-naive patients with genotype-1, used in combination with standard HCV therapy.
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*Excerpt:
From Medpage: Adding the investigational polymerase inhibitor ANA598 to standard care speeded up the clearance of hepatitis C, compared with standard care alone, a researcher reported here.
.An ongoing double-blind, placebo-controlled phase II trial among more than 100 patients, found that after 12 weeks of therapy with one of two doses of ANA598, 73% and 75% of patients had undetectable levels of hep C virus, depending on dose, according to Eric Lawitz, MD, of Alamo Medical Research in San Antonio, Texas.
.In contrast, 63% of those getting only standard care with pegylated interferon alpha-2a and ribavirin had undetectable hep C levels, Lawitz said at the annual meeting of the American Association for the Study of Liver Diseases.
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To examine the efficacy and safety of the compound, he and colleagues enrolled 105 treatment-naive patients with genotype-1 virus and randomly assigned them to either 200 or 400 mg of ANA598 twice a day, or to placebo. Those getting active drug also had a loading dose of 800 mg on the first day of therapy.
.All of the trial patients also got standard treatment with pegylated interferon alpha-2a and ribavirin.
.Patients with undetectable hep C virus at weeks four and 12 weeks, Lawitz explained, were re-randomized to continue standard care for another 12 or 32 weeks.
.There was little difference between the two arms in terms of the speed at which the drug cleared the virus, Lawitz said, but viral clearance was always faster than the standard care alone.
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Side Effects :The main difference between the two arms was in the adverse events. In the high-dose group "400 mg" 62% of the patients reported rash, including 17 with grade 1, one with grade 2, and three patients with grade 3 rash.
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PPI-461
Presidio's drug PPI-461 is a NS5A inhibitor PPI-461 exhibits activity against 1-7 HCV genotypes in laboratory assays.
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*Excerpt:
The pharmacokinetic results indicated that all subjects rapidly achieved substantial blood levels of PPI-461, which far exceeded the concentrations of PPI-461 needed to inhibit HCV (genotypes 1-7) in the laboratory. For PPI-461 doses of 50 mg or more, all subjects achieved blood levels of PPI-461 that would be expected to inhibit HCV replication for 24 hours or longer. This profile suggests that PPI-461 may be effective when administered to hepatitis C patients at relatively low oral doses on a once-daily dosing schedule, which would facilitate its convenient use in future co-formulated combination therapies
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First Study of PPI-461 in Hepatitis C Patients UnderwayBased on the encouraging Phase 1a results, Presidio has initiated a Phase 1b proof-of-concept clinical trial of PPI-461 in hepatitis C patients. This dose-ranging trial will evaluate the safety, pharmacokinetics and antiviral efficacy of PPI-461 in previously-untreated patients with HCV genotype-1 infection.
From NATAP : The new Merck also once-daily HCV protease MK5172 also looks very good: "Safety and Antiviral Activity of MK-5172, a Novel HCV NS3/4a Protease Inhibitor with Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients".
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The protease has activity against genotype 1 and 3. Multiple oral doses of 400 mg MK-5172 qd for 7 days were generally well tolerated in HCV-infected patients. Mean maximum reductions from baseline of HCV viral RNA (Ses) were 5.4 (0.21) and 3.98 (0.22) log10 IU/mL for GT 1 and 3, respectively.

AASLD: Safety and Antiviral Activity of MK-5172, a Novel HCV NS3/4a Protease Inhibitor with Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients

M11-602From NATAP Preliminary Results of Study M11-602 in Genotype 1 (GT1) HCV-infected Treatment-naïve Subjects" Abbott also reported 4 weeks data in a poster here in combination with peg/rbv. Subjects were randomized to one of 3 doses of ABT-450/r (50/100 mg, 100/100 mg or 200/100 mg) or placebo once daily for 3 days, followed by ABT-450/r or placebo in combination with standard of care (SOC) consisting of pegylated interferon alfa-2a 180 µg/week + weight-based ribavirin 1000-1200 mg/day through week 1.
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.Merck Vaniprevir MK-7009 protease inhibitor
Idera Pharmaceuticals data on IMO-2125 phase 1 trial.
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IMO-2125 is currently in a Phase 1 clinical trial in null-responder patients, defined as those who did not achieve a 2 log10 reduction with prior standard of care treatment, as monotherapy for 4 weeks. IMO-2125 is also being evaluated in a Phase 1 clinical trial in treatment-naive patients in combination with ribavirin for 4 weeks.
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From The Street : This Phase 1 clinical trial evaluated 51 null-responder HCV patients; 41 patients received IMO-2125 monotherapy at five dose levels and 10 patients received placebo once per week for four weeks. Most of these patients were infected with HCV genotype 1 and had the CT or TT IL28B gene alleles.
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IMO-2125 was well tolerated at all dose levels. IMO-2125 induced a broad immune response with dose-dependent increases in serum concentrations of antiviral proteins and activation of cellular immune responses.
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Across the three highest dose levels, 75% of patients achieved a 1 log10 or greater decrease in viral load at least once during the treatment period. Consistent with the proposed mechanism of IMO-2125, induction of higher serum concentrations of interferon-alpha correlated with greater decreases in HCV viral load. Additional patients are being enrolled in this Phase 1 trial to evaluate twice-weekly dosing of IMO-2125.
Inhibitex has initiated a Phase 1b, multiple ascending dose (MAD) clinical trial of INX-189, its nucleotide polymerase inhibitor in development for the treatment of chronic infections caused by hepatitis C virus (HCV).
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*Excerpt:
The trial, which is being conducted under an IND in the United States, is a double-blind, placebo-controlled, dose escalation study designed to evaluate the safety, tolerability, pharmacokinetics and anti-viral activity of INX-189 administered orally once daily for seven days in treatment naïve patients with HCV genotype 1.
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Each treatment cohort will include 10 patients, eight of which will receive INX-189 and two of which will receive placebo. The first cohort in the Phase 1b study will receive 9 mg of INX-189 once daily. In addition to evaluating INX-189 as monotherapy, the Company plans to evaluate two dose levels of INX-189 administered once daily for seven days in combination with ribavirin, which is one of the drugs currently approved for the treatment of HCV. The dose levels of INX-189 to be evaluated in combination with ribavirin will be determined based upon the results of the monotherapy cohorts.
Gilead's Investigational Hepatitis C Compounds GS 9190 and GS 9256 in treatment Naïve, genotype 1 HCV Subjects. Used in Combination with Standard of Care Therapies Achieve Substantial Viral Suppression in Phase II Study **See Links For Complete Information
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Excerpt: Gilead's three-arm Phase IIa trial (Study 196-0112) evaluated the safety and efficacy of GS 9190, an oral polymerase inhibitor, in combination with GS 9256, an oral protease inhibitor, when used as:
1) a dual antiviral therapy alone
2) a three-drug regimen with RBV
3) a four-drug regimen with RBV and Peg-IFN.
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The study found that the all-oral regimen of GS 9190, GS 9256 and RBV produced substantial viral suppression, with a median maximal decline from baseline in HCV RNA of 5.1 log10 IU/mL during 28 days of treatment.
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Among patients given the four-drug regimen of GS 9190, GS 9256, RBV and Peg-IFN, 100 percent (14/14 patients) achieved Rapid Virologic Response (RVR) (HCV RNA less then 25 IU/mL) at day 28, with 93 percent (13/14 patients) achieving undetectable viral levels (HCV RNA less then 10 IU/mL). No virologic breakthroughs were observed in this arm
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Gilead HCV Pipeline Research In addition to Study 196-0112, data from seven additional studies will be presented at The Liver Meeting highlighting the clinical profile of the company's other HCV pipeline candidates, including another protease inhibitor, GS 9451, and a novel NS5A inhibitor, GS 5885. Gilead's HCV pipeline now includes seven unique molecules spanning six therapeutic classes with different mechanisms of action. Five of these compounds are currently in clinical trials, and two are slated to enter human clinical studies early next year.
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Side Effects: The majority of adverse events were Grade 1 or 2 in severity and resolved with continued treatment. The most common adverse events observed in each of the three arms were headache, diarrhea and nausea. Some patients taking the three-drug combination also experienced fatigue and insomnia, and some patients taking the four-drug combination experienced influenza-like illness, fatigue, myalgia and cough. There were two serious adverse events including one case of bursitis and a hospitalization for vasovagal collapse (fainting), which was attributed to gastroenteritis and occurred in a patient who continued therapy and achieved RVR. Elevations in bilirubin were observed across all three study arms, the majority of which were Grade 1 or 2 in severity and none of which resulted in study drug discontinuation.
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GI-5005
GlobeImmune Expands GI-5005-02 Phase 2b Trial to Include Additional Treatment Naive IL28B T/T Subjects With Chronic Genotype 1 HCV
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Phase 2b Study Demonstrates GlobeImmune's GI-5005 HCV Therapeutic Vaccine Increases Sustained Virologic Response by 12 Percent in Patients Who Previously Failed Therapy With Standard of Care
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Results in both subgroups were similar to the overall outcome but did not reach statistical significance compared with standard care, Pockros told a late-breaker session at the annual meeting of the American Association for the Study of Liver Diseases. But the findings, based on just 133 patients, are enough to justify continued development of the vaccine, Pockros said, including tests to see if it can be effective without the standard hepatitis C treatment regimen, which has difficult side effects.
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Excerpt:
On an intent-to-treat basis (subjects who received at least one dose of combination therapy), prior non-responders receiving GI-5005 plus SOC as a triple therapy had an SVR rate of 17%, compared to an SVR rate of only 5% in patients receiving SOC alone. Prior non-responders in this study were defined as patients who did not clear virus after a minimum of 12 weeks of SOC, including null responders, poor responders, and partial responders. Relapsers and on-treatment breakthroughs were not enrolled in the study. The most common adverse events associated with GI-5005 were injection site reactions that were generally mild and transient in nature. Discontinuation rates due to adverse events in the GI-5005 triple therapy arm were comparable to the discontinuation rates in the SOC alone arm.
."Only 4-7% of patients with genotype 1 HCV who were null, poor or partial responders to their first course of pegylated interferon-based therapy would be expected to achieve a sustained virologic response with a second course of treatment," said Dr. Pockros. "In this study, GI-5005 conferred a three-fold improvement in SVR, an important treatment effect in this challenging patient population."
.Additional immunology data from the study will be presented in a poster on Tuesday, November 2, 2010 by John M. Vierling, M.D., of Baylor College of Medicine. These data show that GI-5005 improved HCV-specific T cell responses 10-fold over SOC alone in patients with the IL28B T/T genotype (~20% of chronically infected patients), the subgroup most likely to fail treatment with SOC alone.
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Additional AASLD News
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