December 6, 2011

Telaprevir for the treatment of chronic hepatitis C infection

Summary

Expert Review of Anti-infective Therapy
December 2011, Vol. 9, No. 12, Pages 1105-1114 , DOI 10.1586/eri.11.133
(doi:10.1586/eri.11.133)

Drug Profile

Andrew J Muir

Telaprevir is an NS3/4A protease inhibitor that has recently received US FDA approval for the treatment of chronic HCV infection. Telaprevir is given in combination with peg-IFN-α and ribavirin and is indicated for both treatment-naive and treatment-experienced patients with genotype 1 infection. Along with the other first generation NS3/4A protease inhibitor boceprevir, these combination regimens have immediately become the standard of care for genotype 1 patients. The adverse event profile for the combination regimen remains dominated by peg-IFN-α and ribavirin, but there is additional anemia and rash with telaprevir. Owing to telaprevir’s metabolism by the CYP3/4A pathway, drug–drug interactions could lead to toxicity from other medications or decreased efficacy of telaprevir. Viral resistance can develop during treatment with telaprevir, and patients will need to be educated on their role in adherence to minimize the risk of resistance and improve their chances of cure of HCV infection.

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New Data Reported on INX-189, HCV Nucleotide

top-line safety and antiviral data from its ongoing clinical trial designed to evaluate additional doses of INX-189, an oral nucleotide polymerase inhibitor being developed to treat chronic infections caused by hepatitis C virus (HCV), administered as monotherapy or in combination with ribavirin (RBV) for seven days.

Inhibitex Reports Recent Clinical and Corporate Developments

AASLD: Antiviral Activity and Safety of INX-08189, a Nucleotide Polymerase Inhibitor, Following 7-Days of Oral Therapy in Naïve Genotype-1 HCV Patients - (11/07/11)

Inhibitex Nucelotide INX-189 Higher Dosing Increases Viral Load Reduction - Inhibitex reports third quarter financial results and recent corporate developments - (11/07/11)

Inhibitex Commences Dosing of Phase 2 Clinical Trial of INX-189 in HCV Infected Genotype 2/3 Patients - (11/04/11)
Released: 11/29/11 07:00 AM EST

Inhibitex, Inc. (NASDAQ:INHX) (the "Company") today announced several recent clinical and corporate developments, including top-line safety and antiviral data from its ongoing clinical trial designed to evaluate additional doses of INX-189, an oral nucleotide polymerase inhibitor being developed to treat chronic infections caused by hepatitis C virus (HCV), administered as monotherapy or in combination with ribavirin (RBV) for seven days.

"We believe the significant increase in antiviral activity demonstrated with 100 mg INX-189 in combination with RBV, as compared to 100 mg INX-189 dosed as monotherapy, further confirms the antiviral synergy between INX-189 and RBV that we have consistently observed in preclinical and clinical results to-date," stated Dr. Joseph Patti, Senior Vice President and CSO of Inhibitex, Inc. "We look forward to further exploring this antiviral synergy with 200 mg of INX-189 and expanding the scope of our ongoing and planned Phase 2 clinical trials to include interferon-free combinations of INX-189 with other antiviral agents in HCV genotype 1, 2, and 3 patients in 2012."

Recent Corporate Developments

INX-189 for Chronic Hepatitis C - The Company today reported top-line safety and antiviral data from an ongoing Phase 1b extension trial of INX-189, which is designed to further evaluate the safety, tolerability, pharmacokinetics and antiviral activity of various doses of INX-189, administered as monotherapy or in combination with RBV, for seven days in treatment-naïve patients infected with chronic HCV genotype 1. In the ongoing trial, 100 mg INX-189, dosed once-daily for seven days in combination with RBV, continued to demonstrate potent and dose-dependent synergistic antiviral activity with a median HCV RNA reduction from baseline of -3.79 log10 IU/mL. Further, 100 mg INX-189 in combination with RBV was well tolerated and there were no serious adverse events. For comparison purposes, in a clinical trial completed earlier this year, 100 mg INX-189 dosed as monotherapy once-daily for seven days resulted in a median -2.53 log10 IU/mL reduction in HCV RNA levels. In this same clinical trial, the Company also reported antiviral data indicating that INX-189, when dosed once-daily at 9 and 25 mg in combination with RBV for seven days, demonstrated dose-dependent, synergistic antiviral activity.

The Company also reported today that, subject to regulatory review, it plans to further expand its ongoing Phase 1b extension trial to evaluate once-daily doses of 200 mg INX-189 in combination with RBV; 300 mg INX-189 as monotherapy; and 200 mg INX-005 (a single isomer of INX-189) as monotherapy, respectively, for seven days. The Company anticipates that the Phase 1b extension trial will be completed in the first quarter of 2012.

Additionally, the Company reported that it plans to submit a protocol amendment this quarter to its ongoing Phase 2 study in genotype 2 and 3 HCV-infected patients to include the evaluation of 100 mg and 200 mg of INX-189 dosed once-daily in combination with RBV for 12 weeks.

Financing Activity - The Company reported today that it had recently sold a total of 1,949,015 shares of common stock at an average price per share of $10.25 for total gross proceeds of $19,983,396 through its at-the-market (ATM) financing vehicle. The Company entered into a $20 million ATM financing arrangement with McNicoll, Lewis & Vlak LLC (MLV) in November 2010, which provides it the opportunity to sell registered shares into the open market through MLV from time-to-time under its effective shelf registration. After commissions, the Company received $19,383,274 in net proceeds. The intended use of the net proceeds is to support the expansion of the Company's planned Phase 2 program for INX-189 in 2012 and for general corporate purposes.

About Inhibitex

Inhibitex, Inc. is a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. The Company's clinical-stage pipeline includes two Phase 2 development programs for which it has retained all future rights: INX-189, a nucleotide polymerase inhibitor in development for the treatment of chronic HCV infections, and FV-100, a nucleoside analogue in development for the treatment of shingles-associated pain. The Company also has additional HCV nucleotide polymerase inhibitors in preclinical development and has licensed the use of its proprietary MSCRAMM¨ protein platform to Pfizer for the development of a staphylococcal vaccine, which is currently being evaluated in a Phase 1/2 clinical trial. For additional information about the Company, please visit www.inhibitex.com.

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INX-189 Continues to Shape Up as a Very Potent Nuke
"Y. Katherine Xu - William Blair & Company, L.L.C."

· Before the markets opened on Tuesday, Inhibitex reported data from an additional arm in the Phase Ib study of its lead nuke (nucleotide polymerase inhibitor) candidate INX-189 in combination with ribavirin (R). Viral load drop at 7 days from the INX-189 100 mg QD+R combo was 3.79 logs, versus 2.53 logs for monotherapy INX-189 at 100 mg QD, demonstrating again the synergy between the two compounds, as R usually could contribute 0.5 log drop on its own. Earlier data from the Phase Ib study demonstrated dose-dependent additive/synergistic antiviral activity with 9 mg and 25 mg QD doses of INX-189 in combination with R; at the current dose of 100 mg, the synergy appears to be stronger. We summarize the 7-day viral kinetic activity from the Phase Ib study to date in table 1. In addition, the combination was determined to be safe and well tolerated, with no serious adverse events (SAEs).

· Further expansion of Phase Ib study to climb up the dose on monotherapy as well as combo therapy with R, as expected. Inhibitex plans to amend the ongoing Phase Ib study to include three additional 7-day treatment cohorts 1) INX-189 200 mg QD+R; 2) monotherapy INX-189 300 mg QD; and 3) monotherapy INX-005 (single isomer of INX-189) 200 mg QD.

· The monotherapy potency and the synergy with R demonstrated to date are encouraging; looking to match up PSI-7977 of Pharmasset and Gilead. As summarized in table 1, so far INX-189 monotherapy at 200 mg QD monotherapy produced 4.25 log drop, and 100 mg QD+R produced 3.79 log. Going forward, the 300 mg QD monotherapy and the 200 mg QD+R combo could produce higher viral load drops, approaching the 4.7 log drop demonstrated by Pharmasset's PSI-7977. We note that a potent nuke in combination with R, as demonstrated by Pharmasset, could become a stand-alone therapy.

· Expansion of the ongoing Phase IIb study by adding interferon-free, INX-189+R arms, following Pharmasset's footstep. Initiated in September 2011, the ongoing 12-week Phase IIb study planned to enroll and randomize 90 treatment-naïve GT2/3 into four cohorts 1) INX-189 25 mg QD +P/R (PEG-interferon+ribavirin) (n=25); 2) INX-189 50 mg QD + P/R (n=25); 3) INX-189 100 mg QD + P/R (n=25); or 4) placebo+P/R (n=15). Inhibitex will submit a protocol amendment by year end to include two additional interferon-free cohorts to the study: 1) 100 mg QD +R and 2) 200 mg QD +R. Completion of enrollment of the first four cohorts is expected by year end, and preliminary rapid virologic response (RVR) and early virologic response (EVR) data are anticipated by first quarter 2012.

· With such potency demonstrated, safety is now the gating point for INX-189's commercial viability. Should INX-189 demonstrate satisfactory 12-week safety, the probability of INX-189 eventually becoming commercially viable will be dramatically increased, in our opinion. .....We expect 12-week safety data from the first four cohorts of the Phase IIb study in the beginning of second quarter 2012; however, we would not be fully convinced of the safety profile until we see the full 12-week safety data from the planned interferon-free 200 mg QD of INX-189+R cohort. Such data may be available during the second half of 2012.

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Inhibitex jumps as company expands drug testing

Shares of Inhibitex Inc. climbed Tuesday after the company said it plans to expand studies of its experimental hepatitis C drug.

THE SPARK: The Atlanta company said it will ask the Food and Drug Administration for authorization to expand a mid-stage trial of its drug INX-189. Inhibitex wants to test larger doses of the drug and also wants to test a combination of INX-189 and ribavirin, a standard hepatitis C treatment. The regimen would exclude pegylated interferon, also a standard drug used in hepatitis C treatment.

The patients in the trial have genotype 2 or 3 hepatitis C. They are currently getting as much as 100 milligrams of INX-189 per day in the 12-week study. If the new trial design is approved, some patients will get 100 milligrams and 200 milligrams per day.

The company said it sold $20 million in stock to fund expansion of the trial.

Inhibitex also said it will expand a shorter early-stage trial of the drug to include 200-milligram and 300-milligram doses of INX-189. It will test the drug by itself, in combination with ribavirin, and combined with a second drug it is developing.

THE BIG PICTURE: Inhibitex is a development-stage company. It has no products on the market and INX-189 is its most advanced product. The drug is given by mouth and it is considered a promising treatment for hepatitis C. The chronic form of the disease can cause severe liver damage and is the primary cause of liver transplants in the U.S. The disease is expected to become a larger public health problem as baby boomers age.

Several companies are studying hepatitis C treatment regimens that don't include pegylated interferon, a drug that is administered by injection and can cause severe side effects. Inhibitex's decision to test INX-189 without interferon suggests the company thinks INX-189 will also be just as effective without interferon, matching the convenience and lower side effects of other experimental hepatitis C drugs.

SHARE ACTION: Inhibitex stock rose $1.62, or 14.2 percent, to $13.02 in morning trading. Earlier the shares reached an all-time high of $13.94. The stock doubled in value on Nov. 4 after Inhibitex said a 200-milligram dose of INX-189 reduced virus levels in patients during an early clinical trial.

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Inhibitex Soars as Investors Chase Hepatitis Drug Developers
excerpted

http://www.minyanville.com, By Brett Chase Nov 29, 2011 1:20 pm

Gilead's $11 billion planned takeover of Pharmasset is generating investor excitement for rivals. Achillion and Idenix also rising.

The conventional wisdom after Gilead Sciences' (GILD) recently announced $11 billion takeover of hepatitis drug developer Pharmasset (VRUS) is that similar companies will be gobbled up for big prices.

The deal gave a boost to the already rising stocks of three smaller companies developing their own treatments for the liver-wasting virus hepatitis C: Inhibitex (INHX), Achillion Pharmaceuticals (ACHN) and Idenix Pharmaceuticals (IDIX).

But one only need look at the large players in various stages of developing their own hepatitis treatments to find potential suitors. Merck (MRK), for instance, beat Vertex to market with its new hepatitis treatment Victrelis by about a week but that product is being trounced by Incivek. (See Vertex Hepatitis Drug Beats Estimates.) Other big companies studying treatments include Vertex's development partner Johnson & Johnson (JNJ), Bristol-Myers Squibb (BMY), Abbott Laboratories (ABT), Novartis (NVS), Roche and Boehringer Ingelheim.

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Boceprevir Case Study

Download the PDF here

Hepatology december 2011
Haripriya Maddur and Paul Y. Kwo
From the Gastroenterology/Hepatology Division, Indiana University School of Medicine, Indianapolis, IN

Received October 24, 2011; accepted October 25, 2011.
Address reprint requests to: Paul Y. Kwo, M.D.,
Gastroenterology/Hepatology

Division, Indiana University School of Medicine, 975 West Walnut, IB 327,

Indianapolis, IN 46202-5121. E-mail: pkwo@iupui.edu; fax: 317-274-3106

Boc, boceprevir; HCV, hepatitis C virus; IL-28, interleukin-28; PCR, polymerase chain reaction; PR, pegylated interferon and ribavirin; SPRINT-2, Serine Protease Inhibitor Therapy 2; SVR, sustained virological response.

Case Scenario

A 52-year-old male executive who is asymptomatic is evaluated for abnormal liver biochemical tests. The aspartate aminotransferase level is 138 U/L, and the alanine aminotransferase level is 164 U/L; the bilirubin, alkaline phosphatase, and albumin levels and the complete blood counts are normal. The international normalized ratio is 1.1, and the serum creatinine level is 0.9 mg/dL. The hepatitis C virus (HCV) RNA level is 1,600,000 IU/mL, and the genotype is 1B. The patient has read about boceprevir and wants to know whether he is a candidate for treatment with this drug. He also wants to know whether he really requires liver biopsy before the initiation of treatment.

Will you use boceprevir in this patient? How will you determine whether he is responding to the drug, how long will you give him the medication, and how will you monitor him for side effects? How will you determine that treatment-related anemia is related to boceprevir and is not related to ribavirin? Which side effects of boceprevir will warrant the discontinuation of treatment? Will your approach vary with the genotype for the interleukin-28 (IL-28) polymorphism?

The Problem

Chronic HCV affects approximately 170 million people worldwide.1 HCV, the most common blood-borne infection in the United States, is a major cause of chronic liver disease, which can lead to death from liver failure or hepatocellular carcinoma.2-4 For the past decade, therapy for HCV infection has entailed the use of pegylated interferon and ribavirin (PR). Although the sustained virological response (SVR) rates with this treatment regimen have been as high as 80% for genotypes 2 and 3, the rates for genotype 1 have been less favorable (approximately 40%-50%).4-6 In May 2011, the Food and Drug Administration approved two direct-acting antiviral agents, telaprevir and boceprevir, for the treatment of HCV genotype 1 in both previously untreated patients and patients who failed to achieve SVR with PR.7 When they are added to the standard of care (PR), SVR rates for genotype 1 infections are markedly improved in patients who have not been treated; SVR rates of 63% to 75% have recently been reported.8, 9 Boceprevir is not currently recommended for HCV genotype 2 or 3 infections.

Boceprevir

The current treatment regimens with direct-acting antiviral agents incorporate nonstructural protein 3 protease inhibitors in conjunction with PR. Boceprevir is a linear peptidomimetic keto amide serine protease inhibitor that binds reversibly to the HCV nonstructural protein 3 active site.10 In the recently reported Serine Protease Inhibitor Therapy 2 (SPRINT-2) study,10 the addition of boceprevir to pegylated interferon alfa-2b and ribavirin significantly improved SVR rates in nonblack patients from 38% for patients with just PR to 67% for patients with 24 weeks of boceprevir in response-guided treatment arms (28 or 48 weeks of therapy according to viral clearance). Patients who received 48 weeks of treatment (i.e., 44 weeks of boceprevir with PR after a 4-week PR lead-in period) achieved an SVR rate of 68% (Supporting Fig. 1).

The side effects associated with the addition of boceprevir to PR include increased rates of dysgeusia, neutropenia, and anemia. Dysgeusia that is observed when boceprevir is added to the standard of care is usually mild and rarely, if ever, requires the discontinuation of therapy. Although neutropenia may lead to infections in those receiving PR, severe infections are infrequent, and treatment cessation is rarely warranted. Anemia associated with triple therapy (PR and boceprevir) is primarily driven by ribavirin-related hemolytic anemia, which begins during the 4-week PR lead-in period and is responsible for the majority of the hemoglobin decline.11 Anemia associated with boceprevir typically contributes an additional decline of 1 g/dL to the decline associated with ribavirin therapy. Anemia associated with boceprevir is thought to be due to the bone marrow-suppressive effect of the drug, whereas anemia associated with ribavirin is attributed to hemolysis. Similar to the development of anemia with PR therapy, the development of anemia with boceprevir-based treatment is associated with higher SVR rates.12 In the SPRINT-2 trial, dose modifications due to anemia were required almost twice as often for patients on boceprevir regimens versus the PR control groups (21% versus 13%). However, the rates of discontinuation due to adverse events were not significantly different for the patients on boceprevir-containing regimens (13%) and the PR controls (12%), and discontinuation due to anemia was rare as well (2% for the patients on boceprevir-containing regimens and 1% for the PR controls). It should be emphasized that erythropoietin supplementation was used in the trial.

Drug interactions are significant with boceprevir and are discussed in the next section.

Monitoring for Drug-Related Side Effects

Boceprevir is primarily metabolized by two pathways: the aldo-keto reductase pathway and the cytochrome P450 3A4 pathway. Importantly, it is a reversible inhibitor of cytochrome P450 3A4. All individuals who are candidates for boceprevir therapy require an assessment of drug-drug interactions (Supporting Table 1).

Before therapy is started, thyroid-stimulating hormone levels must be determined, and pregnancy testing is required for women of child-bearing potential. Additionally, complete blood count monitoring should be performed before treatment initiation, at weeks 2, 4, 6, 8, and 12, and monthly thereafter.

The management of anemia involves ribavirin dose reductions (200 mg/day) when hemoglobin levels decline to <10 g/dL in patients without underlying cardiovascular disease or when there is a >2 g/dL drop in hemoglobin levels over any 4-week interval during the treatment course (including the 4-week lead-in period). If the hemoglobin concentration declines to <8.5 g/dL, ribavirin should be discontinued. The boceprevir dose should never be reduced during ribavirin or interferon dose modifications. Additionally, if the discontinuation of either interferon or ribavirin is required, all three treatments should be discontinued to prevent potential boceprevir resistance.

Areas of Uncertainty

Need for Liver Biopsy Before Treatment.

A liver biopsy sample provides important information about the prognosis and the urgency of treatment and excludes other forms of liver disease.13 The degree of fibrosis has also been shown to be an independent predictor of the response to therapy. In patients with HCV genotype 1 infections, the need for liver biopsy is less compelling because of the higher SVR rates observed with the addition of boceprevir to the standard of care. However, information about advanced fibrosis from a pretreatment liver biopsy sample may be used to predict the response to therapy, even with the advent of newer direct-acting antiviral agents. Indeed, in the SPRINT-2 study, the SVR rates of patients with F3/F4 fibrosis in the boceprevir arms were only 41% to 52%. If a patient's liver biopsy sample reveals mild fibrosis (F0-F2), there is a higher chance of SVR (67% in the SPRINT-2 study) with boceprevir-based treatment. A finding of minimal fibrosis may reduce the urgency of therapy, and the patient could await possible newer therapies. On the other hand, if the liver biopsy sample demonstrates cirrhosis, 48 weeks of treatment is recommended.

Testing for IL-28 Polymorphisms.

The SVR rates for PR-treated HCV genotype 1 patients with the IL-28 CC genotype were more than 2-fold greater than the rates for patients with the CT or TT genotype.14-15 Data regarding the use of IL-28B with the addition of direct-acting antiviral agents to PR are emerging, and as the discovery of IL-28B occurred after the large phase 3 trials with telaprevir and boceprevir had been initiated, we will need to wait for more complete data sets in naive patients. In the SPRINT-2 trial, IL-28 data were available for 62% of the patients (653/1048). The addition of boceprevir was associated with higher SVR rates for the patients with the IL-28 CT and TT genotypes (Supporting Fig. 1).16 Those with the IL-28 CC genotype had SVR rates comparable to those of the controls, but 88% of these individuals cleared the virus by week 8 and were eligible for short-term (28-week) therapy.

Testing for IL-28 polymorphisms could be used for counseling patients. If a patient has the IL-28 CC genotype, he may require only 28 weeks of therapy instead of 48 weeks. If he has the IL-28 CT or TT genotype, the addition of boceprevir will substantially improve his chances of SVR in comparison with just PR therapy. However, we could also use a week 4 viral decline after the PR lead-in period as a marker because an HCV decline at 4 weeks appears to be a stronger predictor of SVR than the IL-28 status.

Use of Erythropoiesis-Stimulating Agents.

In the SPRINT-2 study, 43% of the patients receiving boceprevir-based therapy received erythropoiesis-stimulating agents, whereas only 24% of the PR-receiving controls did. Thromboembolic events have been associated with the use of erythropoiesis-stimulating agents in patients with peginterferon-alfa-treated HCV, and these agents are not approved for the treatment of ribavirin-related anemia. In the SPRINT-2 study, similar SVR rates were observed regardless of the anemia management strategies, which included ribavirin dose reductions, erythropoiesis-stimulating agents, both ribavirin dose reductions and erythropoiesis-stimulating agents, and no dose modifications.12 These findings call into question the precise role of erythropoiesis-stimulating agents when antiviral agents are used for the treatment of HCV. A large, prospective, randomized trial evaluating the use of an erythropoiesis-stimulating agent versus ribavirin dose reduction in patients receiving boceprevir with PR is fully enrolled (ClinicalTrials.gov identifier: NCT01023035) and should address this important question.

Recommendations

This patient is clearly a candidate for therapy with boceprevir and PR and has a high possibility of achieving SVR. Liver biopsy, although it is not required, may help with prognostication. IL-28 testing may be helpful, especially if the patient is interested in truncating therapy with no compromise in the chance of achieving SVR. The treatment will entail a 4-week lead-in period with PR alone and then the addition of boceprevir (800 mg every 7-9 hours) with a light meal or snack, and his viral load response during the treatment will determine the treatment duration. The viral load can be reduced during the lead-in period before the addition of boceprevir, and this period can be used to assess the responsiveness to interferon/ribavirin and to predict the likelihood of SVR resistance. Indeed, if the viral decline is >1 log10 at the end of week 4, this patient has a >80% chance of achieving SVR with a response-guided treatment paradigm (Supporting Table 1). However, if the viral decline during the lead is <1 log10, then he is poorly responsive to interferon and will require PR and boceprevir for 44 weeks. HCV RNA levels should be determined at weeks 4, 8, 12, and 24 of therapy and at the end of the treatment course. When HCV RNA is undetectable by polymerase chain reaction (PCR) at weeks 8 and 24 of treatment with assay with lower limit of detection (LLOD) of 10-15 IU/ml (weeks 4 and 20 of boceprevir therapy), the treatment can be completed after 28 weeks (Fig. 1). If, however, HCV RNA is detectable by PCR at week 8 but is undetectable at week 24 (with PCR test with LOD <10-15 IU/ml), treatment with boceprevir should be continued until week 36 and should be followed by PR alone until week 48. The continuation of therapy despite these parameters will lead to a marked increase in the risk of resistance-associated variants.

Leaed.gif

Careful management of anemia will be required, but the preliminary data suggest that the anemia management strategy will not affect SVR rates. Finally, the measurement of viral levels at weeks 4, 8, 12, and 24 and adherence to futility rules will maximize SVR rates and minimize the emergence of resistance-associated variants.
Boceprevir is marketed in the United States as Victrelis by Merck. It is supplied as oral capsules at a strength of 200 mg. The cost for 24 weeks of boceprevir is approximately $25,000, and the cost for 44 weeks of therapy is approximately $46,000. The total cost of 28 weeks of triple therapy (including boceprevir) is $55,000, and the total cost of 48 weeks of therapy is approximately $101,000.

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Drug-resistant Hepatitis C

29/11/2011 00:53:00

Research into range of mutations provides clues to improve treatment
 
A team of international researchers, led by Matthias Götte from McGill’s Department of Microbiology and Immunology, believes it has found a key factor in understanding why certain drug-resistant strains of the hepatitis C virus are seen so frequently, while others are rarely detected.
 
It has been estimated that 170 million people around the world are infected with the hepatitis C virus (HCV). Close to 300,000 of them live in Canada. Chronic infection with the virus is associated with severe liver disease, including cirrhosis and cancer. Unlike hepatitis A and B, there is currently no vaccine to prevent people from catching the disease. Although new medications show great promise in curing HCV infection, the virus is able to develop resistance to each class of antiviral drugs. And as a result, treatment may fail.
 
It was already known that humans are not infected by a single species of virus, but rather by billions of different, mutant viruses that sometimes differ from one another only by a single nucleotide, i.e. the basic building blocks of viral RNA. The researchers have now demonstrated that the viral polymerase, the enzyme responsible for copying sequences from RNA, is inaccurate in the way it replicates these sequences and as a result generates mutations when connecting one nucleotide after the other. “The surprising finding we had is that some mutations are much more easily made than others,” says Götte.
 
They next submitted HCV RNA samples taken from infected patients to sequence analyses and were able to distinguish between rare and common types of mutations. Together, the data suggest that the bar for the development of drug resistance is much higher if rare mutations are involved. This study has therefore important implications for the development of potent drug combinations that are less likely to result in the emergence of resistance.
 
The research was funded by: Cancer Research Society, Canadian Institutes of Health Research
 
Career awards and stipends were provided by: Fonds de Recherche en santé du Québec, Canadian Institutes of Health Research, and the National Canadian Research Training Program in Hepatitis C.
 
The paper describing the research was published by the Proceedings of the National Academy of Sciences (PNAS).
 
To read an abstract of the paper: http://www.pnas.org

Source

Gastroenterology
Volume 141, Issue 6 , Pages 2047-2055, December 2011

Stefan Zeuzem, Tarik Asselah, Peter Angus, Jean–Pierre Zarski, Dominique Larrey, Beat Müllhaupt, Ed Gane, Marcus Schuchmann, Ansgar Lohse, Stanislas Pol, Jean–Pierre Bronowicki, Stuart Roberts, Keikawus Arasteh, Fabien Zoulim, Markus Heim, Jerry O. Stern, George Kukolj, Gerhard Nehmiz, Carla Haefner, Wulf Otto Boecher

Received 3 June 2011; accepted 30 August 2011. published online 16 September 2011.

Abstract

Background & Aims

Therapeutic regimens are being developed for patients with hepatitis C virus (HCV) infection that do not include the combination of peginterferon alfa and ribavirin. We investigated the antiviral effect and safety of BI 201335 (an inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B non-nucleoside polymerase) with ribavirin.

Methods

Thirty-two treatment-naïve patients with chronic HCV genotype 1 infection were randomly assigned to groups that were given 400 mg or 600 mg BI 207127 3 times daily plus 120 mg BI 201335 once daily and 1000 to 1200 mg/day ribavirin for 4 weeks. The primary efficacy end point was virologic response (HCV RNA level <25 IU/mL at week 4). Thirty-two patients received treatment; 31 completed all 4 weeks of assigned combination therapy.

Results

In the group given BI 207127 400 mg 3 times daily, the rates of virologic response were 47%, 67%, and 73% at days 15, 22, and 29; a higher rate of response was observed in patients with genotype-1b compared with genotype-1a infections. In the group given BI 207127 600 mg 3 times daily, the rates of virologic response were 82%, 100%, and 100%, respectively, and did not differ among genotypes. One patient in the group given 400 mg 3 times daily had virologic breakthrough (≥1 log10 rebound in HCV RNA) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity. There were no severe or serious adverse events; no patients discontinued therapy prematurely.

Conclusions

The combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127, and ribavirin has rapid and strong activity against HCV genotype-1 and did not cause serious or severe adverse events.

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Spotlight On Hepatitis-C Market

By Zacks Investment Research on December 6, 2011

Is the hepatitis-C market the next Mecca for the pharma/biotech sector? It seems so if we go by the flurry of activity and heightened interest in this market in the past few quarters. The hepatitis-C virus (HCV) market seems to have caught the eye of several pharma/biotech companies – as evident by the deals being signed for the development of drugs for the treatment of HCV.

We are talking about the recent announcements made by big players like Johnson & Johnson (NYSE:JNJ), Bristol-Myers Squibb (NYSE:BMY) and Gilead Sciences, Inc. (NASDAQ:GILD). All three companies have made it clear they want a piece of the HCV market pie.

Johnson & Johnson’s Tibotec Pharmaceuticals and Bristol-Myers Squibb recently announced that they have decided to join forces for the development of Bristol-Myers’ daclatasvir (BMS-790052) in combination with Tibotec’s TMC435, for the treatment of chronic HCV. What the partners are aiming to do is create an oral once-daily interferon-free cocktail treatment for HCV patients.

Bristol-Myers and Johnson & Johnson’s announcement comes on the heels of Gilead’s announcement regarding its intention to buy Pharmasset, Inc. (NASDAQ:VRUS), a company focused on developing HCV treatments. We think the main attraction for Gilead in this $11 billion deal is Pharmasset’s HCV pipeline. Lead candidate PSI-7977 is currently in two phase III studies, with a third phase III study scheduled to commence in the first half of 2012. Successful development could lead to US approval in 2014 thereby making Gilead a front-runner in the oral once-daily interferon-free cocktail treatment HCV market.

We note that both TMC435 and daclatasvir are being evaluated separately in combination with Pharmasset’s PSI-7977.

The Allure of the HCV Market

HCV is a hot development area which has come into the limelight with the launch of two new treatments – Vertex Pharmaceuticals’ (NASDAQ:VRTX) Incivek and Merck’s (NYSE:MRK) Victrelis. Both drugs gained approval in the US earlier this year. Incivek, which was launched in May 2011, posted a whopping $419.6 million in sales in the first full quarter of its launch.

So, with two new recently launched products in the market, why is the HCV market considered so attractive? Firstly, it is estimated that about 170 million people suffer from HCV infection across the world. However, the treated population is much lower. In major markets like the US, EU, Japan, Australia, Turkey, Canada, etc. only 200,000 HCV patients out of a total of more than 12 million are estimated to receive treatment each year. This means a huge number of HCV patients go untreated, leaving the field open for new treatments.

Secondly, the current standard of care comes with several side effects which make it difficult for patients to remain on treatment. A 48-week course of both peg-interferon (peg-INF – weekly injections) and ribavirin (RBV – oral drug), are the standard treatment for genotype 1 HCV infection. However, this treatment regimen is associated with significant side-effects like fatigue, flu-like symptoms, rash, depression and anemia.

With a large number of HCV patients failing to achieve a sustained viral response (SVR) on the current standard of care, there are several patients who would be open to treatment with new and potentially more effective therapies.

These factors have made the HCV market an attractive commercial opportunity for pharma and biotech companies. Victrelis and Incivek are examples of the changing treatment regimen in the HCV market. Both are protease inhibitors which when added to the standard of care reduce the treatment period and also improve the treatment outcome. However, both need to be administered with peg-IFN and RBV – this leaves the path open for the introduction of treatments with fewer side effects.

Cocktail Therapy – The Next Big Thing in HCV

Companies like Johnson & Johnson and Gilead are trying to develop the next crop of drugs, which are expected to change the treatment paradigm for HCV patients by providing them with all-oral treatment regimens. The aim is to develop a treatment which does not require the administration of interferon, thereby doing away with a whole range of side effects. The treatment duration will also be shorter.

Treatments being developed include HCV polymerase inhibitors and HCV NS5A inhibitors. The future HCV market will most likely consist of cocktail treatment regimens developed by combining different oral treatments.

Vertex Pharma has also recognized the need to continually evolve the HCV treatment pattern and is developing an all-oral combination of VX-222 (a polymerase inhibitor) and Incivek without peg-IFN.

Who Will Win the Rat Race?

With several companies pursuing cocktail therapies for HCV, it will be interesting to see which of these companies will be the first to hit the market with a new treatment option. Currently, it looks like Gilead might be the front-runner assuming the Pharmasset acquisition goes through.

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In an candid Opinion Editorial entitled "Are You Serious??", the FAIR Foundation has issued an open letter to President Obama chastizing him for his World AIDS Day pledge of another $50 million for HIV/AIDS.

Palm Desert, California (PRWEB) December 06, 2011

In an candid Opinion Editorial entitled "Are You Serious??", the FAIR Foundation has issued an open letter to President Obama chastising him for his World AIDS Day pledge of another $50 million for HIV/AIDS.

The FAIR Foundation opinion editorial questions if Obama has forgotten that his 2012 HIV/AIDS budget request of taxpayer dollars is already $28.3 billion and asks if the President has been told by his administration that over one-third of a trillion dollars has been spent on HIV disease since its inception.

FAIR also asks the President if he is aware that his National Institutes of Health (NIH) is spending less than $200 per patient in research on virtually every disease, including over 6,000 rare illnesses that receive pennies, while the NIH is spending over $3,000 research dollars on behalf of every patient with HIV/AIDS?

FAIR's letter points out that President Obama has been crisscrossing the country calling for fairness in taxes paid by all Americans and FAIR inquires of the President if he thinks the numbers above are “fair” to non-HIV patients.

A member of the FAIR Foundation’s Board of Directors, Ray Hill, also addresses the President. The letter points out that Hill was one of the most strident HIV/AIDS patient advocates who, for decades, fought for increased HIV funding. He was arrested for his advocacy and he eventually won his legal case in the United States Supreme Court (U.S. Supreme Court—Houston v. Hill, 482 U.S. 451) when Supreme Court Justice William Brennan labeled Mr. Hill a "Citizen Provocateur." The American Civil Liberties Union (ACLU) awarded Ray its Lifetime Achievement Award for advancing the rights of gay, lesbian and transgender citizens, and he has been voted "gay hero" seven years in a row by the gay community of Houston, Texas.

Hill speaks to the President: “The funding for HIV has become a jobs program with billions of wasted dollars going to administrators in the USA and abroad. It is time for HIV funding to be reduced and redirected to other illnesses that have not had such exorbitant funding.”

FAIR’s letter states that FAIR supports efforts to provide the excellent HIV medicine to patients in poor countries; however FAIR is disgusted at the glee expressed by rock singer Bono at the President’s announcement ceremony when Bono celebrated this increased spending by “every taxpayer in this country.”

In FAIR’s letter to Obama, FAIR points out that in addition to the billions he is forcing taxpayers to spend on HIV/AIDS, billions more are spent annually on behalf of HIV/AIDS by others, including the 50 states, pharmaceutical companies and non-profit organizations such as the Bill and Melinda Gates Foundation.

FAIR then suggests that since Mr. Gates and Mr. Warren Buffet wish to pay more of their combined $90 billion dollars to our country’s treasury, Obama should give them a call and ask them for this extra $50 million he has just pledged.

FAIR's letter continues, “We realize it is an election year and, as the LA Times article states, you are trying to “renew the devotion of the liberal base” that helped elect you but we submit that such blatant pandering is an insult to all HIV/AIDS activists, including our Ray Hill.”

FAIR asks one last question: “Did you not see the results of the 2010 mid-term elections? Please allow us to remind you: American citizens assessed the trillion dollars spent by the Bush administration and the Congress at that time, the four trillion dollars you and your Congress have spent, and then these fed up citizens shouted within their voting booths and booted a majority of the big spenders out of Congress.”

FAIR's letter to the President reminds him that these voters are returning in 11 months and of their message to him and to Congress: STOP SPENDING TAXPAYER DOLLARS.

You may read the FAIR Foundation's rebuke of President Obama below or by clicking here.

The FAIR Foundation is a national non-profit organization with thousands of members and millions of supporters in all fifty states and the District of Columbia. FAIR's Board of Directors consists of twenty-seven transplant surgeons, medical directors and patient advocates.

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Telaprevir Effective in Hard-to-Treat Cirrhotic HCV

Neil Canavan

December 6, 2011 (San Francisco, California) — Adding the recently approved protease inhibitor telaprevir to pegylated interferon (peginterferon) plus ribavirin therapy achieved a 47% sustained viral response (SVR) in hard-to-treat patients with hepatitis C virus (HCV) infection and cirrhosis who had previously failed the standard 2-drug regimen. This finding comes from a subset analysis of the phase 3 REALIZE trial, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.

The REALIZE investigators originally looked at telaprevir in combination with peginterferon plus ribavirin in patients with HCV genotype 1 who had had a previous null or partial response, or who had relapsed after treatment with the 2-drug regimen. REALIZE had 3 treatment groups — 2 with different schedules of triple therapy and a third with placebo plus the 2-drug regimen.

Stanislas Pol, MD, PhD, from the Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, and Assistance Publique-Hôpitaux de Paris, Cochin Hospital, France, and colleagues performed the subanalysis of the REALIZE trial to gauge the effect of triple therapy on a subset of patients with Child class A cirrhosis who had responded poorly to the 2-drug regimen. "For this analysis, we pooled the 2 telaprevir arms since there was no difference in safety and efficacy" between the 2, he explained.

The REALIZE study population consisted of 169 patients with cirrhosis (stage F4) and 493 patients without cirrhosis (stages F0 to F3). For the entire cohort, median age was 52 years, 93% was white, 88% had an HCV RNA level of at least 800,000 IU/mL, and median body mass index was 28 kg/m². Just more than half of the patients were infected with HCV genotype 1a.

There were more null responders in the group with cirrhosis (36% vs 25%), but fewer relapsers (43% vs 57%).

Results showed that in patients with no, minimal, or portal fibrosis (F0 to F2), SVR was achieved in 75% of patients receiving telaprevir and in 22% of those receiving placebo.

"If we consider SVR according to fibrosis stage and prior response, we see no clear impact of fibrosis stage on the overall SVR rate of around 85%. For prior partial responders, there was a significant impact by fibrosis stage, with a decrease in SVR rate from 77% to 56% in patients with mild fibrosis, declining to 34% in those patients with cirrhosis," Dr. Pol told Medscape Medical News.

In previous null responders, the SVR rate after triple therapy was 41% in the patients without cirrhosis, 42% in those with mild fibrosis, and 14% in those with cirrhosis.

More than half (53%) of these previously treated patients with cirrhosis did not achieve an SVR with the addition of telaprevir, compared with 27% of patients without cirrhosis.

Regarding safety, the prevalence of rash was higher in patients with than without cirrhosis (67% vs 53%), but other rates for common adverse events were similar. For hematologic events, anemia was more frequent in patients with cirrhosis (42% vs 34%). In addition, neutropenia was higher (25% vs 17%) and, "as might be expected, platelet counts were lower in the cirrhotic subset," Dr. Pol noted.

Can Early Responders Stop Treatment?

The relatively high response rate in patients with cirrhosis and HCV who had failed previous treatment with peginterferon and ribavirin raises the question of whether treatment can be stopped early with triple therapy.

Michael Bernstein, MD, director of the hepatitis clinic at the Coney Island Hospital, Brooklyn, New York, asked: "If they had an extended RVR [rapid virologic response], if they were negative for virus at week 4 and again at week 12, for which there was evidence in REALIZE, then perhaps they could get just 24 weeks of treatment. That's called response-guided therapy."

Dr. Bernstein's reasoning is that in patients without cirrhosis, an extended RVR is indicative of a greater than 90% SVR rate.

"The current recommendation is to treat these patients for 48 weeks, whether they have an extended RVR or not. In this study, this is a special subgroup of patients — even a sub-subgroup — because it is not just cirrhotics, but cirrhotics who have not responded previously to treatment.... It may be feasible to stop [treatment] at 24 weeks if they have this very favorable RVR," he told Medscape Medical News. As phase 4 data accrue, evidence might support doing so.

Dr. Pol reports being a consultant for Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec, Novartis, and Gilead; and receiving grants for research from Bristol-Meyers Squibb, Gilead, Roche, and Schering-Plough/Merck. Dr. Bernstein has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 31. Presented November 6, 2011.

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Telaprevir Not Cost Effective in All Patients With HCV

Neil Canavan

December 6, 2011 (San Francisco, California) — The recently approved and highly effective hepatitis C virus (HCV) protease inhibitor telaprevir was shown not to be cost effective for the treatment of patients with HCV genotype 1 and the (CC) interleukin (IL)-28B polymorphism, a genetic variant that predicts a favorable response to treatment with the standard dual regimen of pegylated interferon (peginterferon) and ribavirin.

This cost analysis was reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.

"IL-28B is the strongest pretreatment predictor of sustained virologic response in genotype 1 patients," said study presenter Ziad Gellad, MD, MPH, from the Department of Medicine–Gastroenterology, Duke University Medical Center, Durham, North Carolina. "In genotype 1 patients with the favorable (CC) IL-28B polymorphism, dual therapy with peginterferon and ribavirin is effective in the majority of patients."

That said, telaprevir in combination with peginterferon plus ribavirin has demonstrated significantly increased sustained viral response rates, compared with peginterferon plus ribavirin alone in phase 3 studies of treatment-naive and treatment-experienced genotype 1 patients with HCV.

Dr. Gellad asked: Is the addition of telaprevir cost effective in the subpopulation of patients with IL-28B (CC)? The answer, he said, is no.

"One of the potential benefits of tailoring therapy is decreasing cost," Dr. Gellad said. The current wholesale cost of the 2-drug regimen is $18,336 at 24 weeks and $36,672 at 48 weeks; for the 3-drug regimen, the cost is $67,536 at 12 weeks and $85,872 at 36 weeks.

Because the addition of telaprevir more than doubles the cost of treatment, Dr. Gellad designed a cost-effectiveness model to determine whether the added expense is really worth it for a patient with the favorable genotype 1 (CC) IL-28B profile.

The model is based on a number of assumptions: that societal perspective is limited, that no patients would have a coinfection with other viruses that accelerate liver-related death or prevent treatment, "and importantly, that nonresponders or relapsers after dual therapy are retreated with a 48-week course of telaprevir."

The researchers developed a decision model that evaluated 3 treatment strategies:

  • peginterferon plus ribavirin for 48 weeks, with a 12-week stopping rule for nonresponse; patients who did not respond or who relapsed would be treated with telaprevir
  • a response-guided treatment approach with peginterferon plus ribavirin, in which those who achieved a rapid viral response (undetectable at week 4) would receive 24 weeks of dual therapy alone, and those with still-detectable viral loads at week 4 were treated for 48 weeks; nonresponsive or relapsed patients received telaprevir.
  • 12 weeks of telaprevir in combination with 24 or 48 weeks of peginterferon plus ribavirin based on the extended rapid virologic response.

Treatment outcomes generated by the model were based on outcomes data derived from the IDEAL, REALIZE, and ADVANCE clinical trials.

A theoretical cohort of patients with 10,000 iterations was performed. The end point assumed 1 of 2 health states: sustained virologic response (cure) or fibrosis progression. Dr. Gellad's team assessed the cost of each. "As patients progressed through the model, they accumulated costs, which were expressed in [quality-adjusted life-years]," Dr. Gellad explained.

"The key point is that the efficacy of all 3 strategies is similar, but when you consider point estimates, telaprevir is dominated by the interferon/ribavirin strategies, and this preference is driven by the cost of therapy," Dr. Gellad told Medscape Medical News.

Costs generated by the model were $46,785 for peginterferon plus ribavirin given as response-guided therapy, $54,931 for peginterferon plus ribavirin (not response-guided), and $68,788 for telaprevir plus peginterferon plus ribavirin.

"We then investigated the impact of the cost of telaprevir on the probability of cost effectiveness, and assumed a weekly cost of $3321 [the current cost of the drug].... If the cost dropped below $1433, a triplet with telaprevir became the preferred strategy," he reported.

Dr. Gellad concluded that in treatment-naïve patients with HCV genotype 1 and the (CC) IL-28B polymorphism, initial therapy with a telaprevir-based regimen is unlikely to be cost effective under current cost and efficacy conditions.

Comparison Shopping

"What this group from Duke did is very important because, with resources dwindling, we need to figure out whether a particular treatment is more cost effective than another," said AASLD president T. Jake Liang, MD, tenured senior investigator and chief of the Liver Diseases Branch at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. "This is somewhat related to so-called personalized medicine because it uses a genetic marker to identify patients who will respond well to a certain treatment."

Major genetic studies conducted over the past several years have indicated that (CC) IL-28B is a genetic marker highly associated with treatment response to interferon-based therapy. "This is a great marker — probably the best genetic marker we have so far — to gauge how a person will respond to treatment," Dr. Liang said.

The analysis by Dr. Gellad's team "suggests that this could be a way to save some money for patients with the favorable IL-28B genotype," he noted. Certainly, there is excitement about the recent availability of direct-acting antivirals, such as telaprevir, which greatly enhance treatment response, "but then again, maybe not one size fits all. In the spirit of personalized medicine, this may be one way we can reduce costs and, at the same time, retain the same success rate treating patients with HCV."

Dr. Gellad reports consulting for Merck & Co and receiving grants or research support from Merck & Co and PENTAX Medical. Dr. Liang has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 118. Presented November 7, 2011.

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