R7128 is Safe, Effective in Short-Term for Patients With Hepatitis C Virus Genotype 1: Presented at EASL

By Emma Hitt, PhD

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MILAN, Italy -- April 29, 2008 -- R7128, a potent inhibitor of hepatitis C virus (HCV) polymerase, appears effective and well tolerated at week 4 after initiation of treatment in combination with pegylated interferon alfa-2a (PEG-INF)/ribavirin, according to interim findings of a randomised trial of patients with genotype 1 HCV, researchers reported here at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL).

John McHutchison, MD, Associate Director, Duke Clinical Research Institute, Durham, North Carolina, described how the study sought to evaluate the efficacy and safety of R7128 at a dose of 500 mg BID (n = 20) and 1500 mg BID (n = 20), compared with placebo (n = 10) at 4 weeks; each arm also received PEG-INF/ribavirin. Patient characteristics were similar among study arms.

R7128 demonstrated a dose-dependent effect on efficacy parameters. Patients in the placebo group had a 2 log10 reduction in HCV RNA, compared with a 3 log10 reduction of in the 500-mg BID arm and a 5 log10 reduction in the 1500-mg BID arm. Rapid viral response was achieved in 10%, 30%, and 95% of patients in the placebo arm, the 500-mg BID, and the 1500-mg BID R7128 arms, respectively. alanine aminotransferase normalisation was achieved in 60%, 80%, and 70% of the 3 arms, respectively.

R7128 was generally well tolerated, with no apparent serious adverse events associated with R7128. The most common mild adverse events with the 1500-mg BID dose included fatigue (40% vs 20% in placebo), chills (35% vs 20% in placebo), and headache (65% vs 40% in placebo). No evidence of additional haematologic adverse events with R7128 was noted. In addition, amylase, bilirubin, blood urea nitrogen, and creatinine measurements were comparable at week 4 among treatment arms, with no evidence of renal toxicity.

Dose reductions and discontinuations were similar among treatment arms. One patient receiving R7128 1500 mg BID discontinued all treatment due to anorexia, diarrhea, and weight loss on study day 24.

"We observed a significant antiviral effect of R7128 in combination with PEG-INF [plus ribavirin] at week 4," Dr. McHutchison concluded. "Approximately 85% of patients receiving R7128 achieved undetectable HCV RNA by week 4."

According to Dr. McHutchison, two additional cohorts will be enrolled in the current 4-week triple combination study: a 1000-mg BID arm in treatment-naive patients with genotype 1 HCV and a 1500-mg BID arm in treatment-experienced patients with genotype 2 or 3 HCV. Both arms will also receive PEG-INF/ribavirin. An international phase 2b study is also underway to evaluate R7128 in triple combination for up to 12 weeks.

Funding for this study was provided by Roche.

[Presentation title: Potent Antiviral Activity of the HCV Nucleoside Polymerase Inhibitor R7128 With PEG-IFN and Ribavirin: Interim Results of R7128 500mg BID for 28 Days. Abstract 66]

Nitazoxanide Demonstrates Activity in Treatment-Naive Patients With Hepatitis C Virus Genotype 4: Presented at EASL

By Emma Hitt, PhD

www.docguide.com

MILAN, Italy -- April 29, 2008 -- Nitazoxanide significantly improves response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic hepatitis C virus genotype 4 (HCV-4), according to new research findings presented here at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL).

Jean-Francois Rossignol, MD, Research Scientist, and Cofounder, Romark Institute For Medical Research, Tampa, Florida, reported the results of a randomised trial of nitazoxanide, an oral agent that targets host-cell interactions with HCV. Dr. Rossignol and colleagues sought to evaluate the antiviral activity and safety of nitazoxanide in combination with PEG-IFN alfa-2a, with or without ribavirin.

A total of 120 patients with chronic HCV-4 were sequentially randomised to 1 of 3 treatment arms. The first arm was a standard-of-care arm: PEG-IFN alfa-2a plus ribavirin (RBV) for 48 weeks. The second arm was nitazoxanide for 12 weeks followed by nitazoxanide plus PEG-IFN alfa-2a for 36 weeks. The third arm was a triple therapy consisting of nitazoxanide for 12 weeks followed by nitazoxanide combined with PEG-IFN alfa-2a plus RBV for 36 weeks.

PEG-IFN alfa-2a was injected by clinical investigators at 180 mcg/kg/week while ribavirin was dosed at 1000 to 1200 mg/day. Nitazoxanide was administered at 500 mg twice daily with food.

Patients were previously untreated, with the exception of 12 interferon-experienced patients included in each of the nitazoxanide-containing arms.

During the monotherapy lead-in phase with nitazoxanide, a modest (0.25 log10) but statistically significant decrease in HCV ribonucleic acid (RNA) from baseline to week 12 was observed (P = .0032). Out of 76 patients, 5 had a drop in HCV RNA of greater than 1 log10 from baseline to week 12; and 1 patient had undetectable HCV RNA, with a 5.4 log10 decline in HCV RNA and normalised alanine aminotransferase (ALT) test results at week 12. There was no significant change in overall ALT measurements during the lead-in period.

Among the interferon-naive patients (n = 96), the patients receiving the triple regimen (nitazoxanide plus PEG-IFN plus RBV) achieved a higher sustained viral response (SVR) than the patients receiving the standard of care (79% vs 50%; P = .023). In the nitazoxanide arm without RBV, the SVR was 61%. The rapid viral response (RVR) was also higher in patients receiving the triple therapy compared with those receiving the standard of care (64% vs 38%; P = .048).

In the interferon-experienced patients (n = 24), no efficacy differences were observed between the 2 nitazoxanide-containing arms (not compared with standard of care).

"Adverse events in the overall population were characteristic of those typically observed with pegylated interferon and ribavirin, with no additional effects resulting from nitazoxanide," Dr. Rossignol noted here on April 25. "Additional clinical trials of nitazoxanide in interferon-naive patients and nonresponders to pegylated interferon plus ribavirin have been initiated in patients with HCV genotype 1 in the United States and Europe."

Nitazoxanide was initially developed as an antiprotozoal, antiviral, and antibacterial agent, and is approved for the treatment of diarrhoea caused by Cryptosporidium and Giardia in children. Nitazoxanide has since shown activity against HCV and hepatitis B virus.

[Presentation title: Randomized Controlled Trial of Nitazoxanide-Peginterferon-Ribavirin, Nitazoxanide-Peginterferon and Peginterferon-Ribavirin in the Treatment of Patients With Chronic Hepatitis C Genotype 4. Abstract 68]

December 30, 2008

Reprinted from SPECIALTY PHARMACY NEWS, a monthly newsletter designed to help health plans, PBMs, providers and employers manage costs more aggressively and deliver biotechs and injectables more effectively.

By Angela Maas, Managing Editor, (amaas@aispub.com)

With hepatitis C patients, the length of treatment depends upon which of the six hepatitis C genotypes the person has. According to Beckie Fenrick, Pharm.D., director of clinical pharmacy at Blue Cross and Blue Shield of Florida, the treatment regimen for genotypes 2 and 3 is generally 24 weeks, while the regimen for 1, 4, 5 and 6 is 48 weeks. The most common genotypes in the U.S. are 1, 2 and 3.

Many health plans require physicians to provide the organization with the genotype information so they can be sure the patient is receiving the appropriate length of therapy. According to Enoch Strollo, vice president of sales and marketing for BioPlus Specialty Pharmacy, genotype testing costs typically between $450 and $600, and health plans typically cover this expense.

Some plans that spoke to SPN say they require genotype testing either before therapy begins or shortly thereafter.

According to Beverly Franklin-Thompson, Northeast regional pharmacy director for BlueCross BlueShield of Tennessee, BCBST allows patients to immediately begin treatment but then requires the physician to follow up with the patient's genotype. "This minimizes impediments to treatment initiation, allowing a patient to immediately fill the prescriptions for the hepatitis C medications," she says. After a physician notifies BCBST of the patient's genotype, "an approval for a specific duration of treatment is granted," she explains. "A nurse contacts the prescriber to assure that certain tests are being performed and to obtain the results of those tests so that the duration of treatment can be determined and authorization loaded. No prior authorization is required to begin therapy; however, to continue treatment beyond the first few months, clinical parameters such as genotyping must be obtained."

The Florida Blues plan requires physicians to determine patients' genotype so it can make sure patients undergo the appropriate length of therapy. The plan also has practitioners notify it of patients' viral loads at the 12-week mark. If there has been "an appropriate reduction, the approval for additional weeks occurs," Fenrick explains. CIGNA HealthCare also requires a follow-up lab test after the first 12 weeks of therapy, says Todd Cooperman, Pharm.D., director of specialty pharmacy clinical program development.

Mark Leeper, vice president of marketing and clinical program development for PrecisionRx Specialty Solutions, WellPoint, Inc.'s specialty pharmacy, says that when a plan does not require genotype testing, "we do highly encourage it." He explains that "a member's hepatitis C genotype will drive treatment and monitoring. Type 1 genotype is more difficult to treat and requires members to stay on the therapy longer. Also, changes in viral load are influenced by genotype. We conduct baseline information on viral load, and then repeat testing for all genotypes at four, 12 and 24 weeks. For Type 1, we continue testing at 36 weeks and 48 weeks. This schedule is important to allow physicians to adjust dosing to respond to the patient's viral load."

He says if those patients with genotype 1 "don't respond by week 12, they are unlikely to respond, and continuing with therapy is not productive."

Sara Deno, Pharm.D., a manager of clinical services for BioScrip, Inc., who also oversees the adherence and therapy optimization program BioScripCare for hepatitis C, says that plans can structure prior authorizations so that patient response is checked at various intervals.

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