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Next-Generation Protease Inhibitor Effective for HCV Infection.

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Patients who received vaniprevir achieved higher rapid virologic response rates than those who received placebo.

Adding telaprevir and boceprevir to standard peginterferon and ribavirin therapy has been shown to significantly improve virologic response rates for patients with genotype 1 hepatitis C virus (HCV) infection (JW Gastroenterol Jul 1 2011 and JW Gastroenterol Mar 30 2011). However, these first-generation HCV nonstructured protein (NS)3/4A protease inhibitors require a complex administration schedule and are associated with additional adverse effects.

To evaluate the efficacy and safety of vaniprevir (MK-7009) — a macrocyclic next-generation HCV NS3/4A protease inhibitor that is administered once or twice daily — investigators conducted an industry-funded, phase II, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study involving 94 treatment-naive adults with chronic HCV genotype 1 infection. Patients were assigned to vaniprevir (300 mg twice daily, 600 mg twice daily, 600 mg daily, or 800 mg daily) or matched placebo in combination with peginterferon (180 μg weekly) and ribavirin (1000–1200 mg daily) for 4 weeks. Thereafter, all patients continued peginterferon and ribavirin for 44 weeks. The primary endpoint was rapid virologic response (RVR); exploratory endpoints included sustained virologic response (SVR).

All 94 patients completed the 4-week triple-dosing regimen. Of these, 78 completed 48 weeks of peginterferon and ribavirin treatment, and 84 completed a 6-month post-therapy follow-up. The rate of viral decline by week 4 was at least 3log10 IU/mL greater in the vaniprevir groups versus the placebo group. Rates of RVR were significantly higher in all vaniprevir groups versus the placebo group (68.8%–83.3% vs. 5.6%; P<0.001). SVR rates were nonsignificantly higher in the vaniprevir groups than the placebo group (61.1%–84.2% and 63.2%, respectively), likely due to the small sample size. Safety profiles were similar between the vaniprevir and placebo groups, except vomiting occurred more often in the vaniprevir groups. HCV resistance variants were noted in three patients receiving vaniprevir.

Comment: This phase II study of vaniprevir shows early promise for a next-generation protease inhibitor–based triple therapy that is easy to administer in a daily or twice-daily dosing schedule. Subsequent vaniprevir studies are needed to identify the optimal dose and duration of therapy to maximize SVR and maintain an excellent safety profile.

Source: Journal Watch Gastroenterolog

 

c-Met inhibition to radiosensitize NSCLC tumors.

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Despite advances in diagnosis and treatment over the past several years, unresectable lung cancer remains a highly lethal disease, with a 5-year survival rate of only about 14% to 15% among patients selected for combined-modality treatment in clinical trials. However, a larger percentage of patients…

Abstract

Introduction The radiation doses used to treat unresectable lung cancer are often limited by the proximity of normal tissues. Overexpression of c-Met, a receptor tyrosine kinase, occurs in about half of non–small-cell lung cancers (NSCLCs) and has been associated with resistance to radiation therapy and poor patient survival. We hypothesized that inhibiting c-Met would increase the sensitivity of NSCLC cells to radiation, enhancing the therapeutic ratio, which may potentially translate into improved local control.
Methods We tested the radiosensitivity of two high-c-Met–expressing NSCLC lines, EBC-1 and H1993, and two low-c-Met–expressing lines, A549 and H460, with and without the small-molecule c-Met inhibitor MK-8033. Proliferation and protein expression were measured with clonogenic survival assays and Western blotting, respectively. [gamma]-H2AX levels were evaluated by immunofluorescence staining.
Results MK-8033 radiosensitized the high-c-Met–expressing EBC-1 and H1993 cells but not the low-c-Met–expressing cell lines A549 and H460. However, irradiation of A549 and H460 cells increased the expression of c-Met protein at 30 minutes after the irradiation. Subsequent targeting of this up-regulated c-Met by using MK-8033 followed by a second radiation dose reduced the clonogenic survival of both A549 and H460 cells. MK-8033 reduced the levels of radiation-induced phosphorylated (activated) c-Met in A549 cells.
Conclusions These results suggest that inhibition of c-Met could be an effective strategy to radiosensitize NSCLC tumors with high basal c-Met expression or tumors that acquired resistance to radiation because of up-regulation of c-Met.

Bhardwaj, Vikas Phd*; Zhan, Yanai MS†; Cortez, Maria Angelica Phd*; Ang, Kie Kian Md, Phd*; Molkentine, David BS‡; Munshi, Anupama Phd§; Raju, Uma Phd‡; Komaki, Ritsuko MD*; Heymach, John V.Md, Phd[forms Double Vertical]; Welsh, James Phd*

Departments of *Radiation Oncology, †Investigational Cancer Therapeutics, ‡Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; §Department of Radiation Oncology, College of Medicine, The University of Okhlahoma, Okhlahoma City, OK; and [forms double vertical]Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: James Welsh, MD, Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: jwelsh@mdanderson.org

Source: www. getinsidehealth.com