gw-257406x and HIV-Infections

Maribavir is a novel benzimidazole riboside compound that is currently in clinical development with ViroPharma for the prevention of cytomegalovirus (CMV) infections in transplant patients. Maribavir is thought to inhibit viral DNA assembly and inhibit egress of viral capsids from infected cell nuclei. This mechanism is different to other available CMV treatments that inhibit CMV DNA polymerase. Maribavir, originally developed by GlaxoSmithKline, was licensed to ViroPharma in August 2003. Glaxo was conducting phase I/II clinical studies in the EU and the US in 2001, but discontinued development because the company felt that there was no longer a significant clinical need for maribavir as advances in the treatment of HIV have lead to improved immune systems in patients, resulting in a reduction in the incidence of CMV and CMV retinitis. In August 2003, ViroPharma acquired exclusive worldwide rights (excluding Japan) to develop and commercialise maribavir for the prevention and treatment of CMV infections related to transplant and congenital transmission and in patients with HIV infection. ViroPharma paid GlaxoSmithKline a $US3.5 million upfront licensing fee and will pay additional milestones based on defined clinical development and regulatory events. The company will also pay royalties on product sales in the US and the rest of the world, excluding Japan.A phase III study with maribavir as a prophylactic agent in patients undergoing allogeneic stem cell transplant who are CMV seropositive has been initiated and another phase III trial in solid organ transplant patients is planned. The stem cell transplant trial will take approximately 18 months to complete enrolment and the solid organ transplant trial, which won't be as large as the stem cell transplant trial, will be completed within this time-frame also. ViroPharma hopes to file an NDA for maribavir in 2009. Maribavir was granted fast-track status by the US FDA in February 2006 for the prevention of CMV infection in allogeneic bone marrow and solid organ transplant patients. Maribavir has received orphan drug status in the US for the prevention of CMV viraemia and disease in at-risk populations. ViroPharma has conducted a dose-ranging phase II clinical study designed to evaluate the antiviral activity, safety and pharmacokinetic profile of maribavir for the prevention of CMV infection in patients who have undergone allogeneic stem cell transplantation. The randomised, double-blind, placebo-controlled,

Topics: Animals; Antiviral Agents; Benzimidazoles; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; HIV Infections; Humans; Ribonucleosides

1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1, beta-L-ribofuranosyl-1-H-benzimidazole], a novel benzimidazole compound, has been demonstrated to potently and selectively inhibit human cytomegalovirus replication in vitro and to have favorable safety profiles in animal species. Two phase I trials evaluated the safety and pharmacokinetics of escalating single doses of 1263W94 in 13 healthy subjects (dose, 50 to 1,600 mg) and 17 human immunodeficiency virus (HIV)-infected subjects (dose, 100 to 1,600 mg). No severe safety concerns were observed in the evaluation of adverse events, vital signs, electrocardiograms, and clinical laboratory tests following administration of a single dose of 1263W94. The most frequently reported adverse events in both populations were taste disturbance (80%) and headache (53%). 1263W94 was rapidly absorbed following oral administration, with peak concentrations in plasma (C(max)) occurring 1 to 3 h after dosing. The increases in the C(max) of 1263W94 and the area under the concentration-time curve from time zero to infinity (AUC(0- infinity )) for 1263W94 were dose dependent; C(max) increased slightly less than proportionally to the dose, and AUC(0- infinity ) increased slightly more than proportionally to the dose. 1263W94 was rapidly eliminated, with a mean half-life in plasma of 3 to 5 h; the half-life was independent of the dose level. Less than 2% of the 1263W94 dose administered was eliminated unchanged in urine. The principal metabolite of 1263W94 was 4469W94 (which is derived by N-dealkylation of 1263W94 via CYP3A4), which accounted for 30 to 40% of the dose in urine. Greater than 98% of the 1263W94 in plasma is bound to proteins, and the extent of binding appears to be constant over the dose range of 200 to 1,600 mg. In the trial with HIV-infected subjects, consumption of a high-fat meal decreased the 1263W94 AUC(0- infinity ) and C(max) in plasma by approximately 30%.

Topics: Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Double-Blind Method; HIV Infections; Humans; Male; Ribonucleosides

1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1,beta-L-ribofuranosyl-1-H-benzimidazole] is a novel benzimidazole compound for treatment of human cytomegalovirus (HCMV) infection and disease, with potent in vitro activity against HCMV and good oral bioavailability. A phase I study was conducted to determine the pharmacokinetics (PK), anti-HCMV activity, and safety of 1263W94 administered as multiple oral doses to human immunodeficiency virus type 1-infected adult male subjects with asymptomatic HCMV shedding. Subjects received one of six dosage regimens (100, 200, or 400 mg three times a day, or 600, 900, or 1,200 mg twice a day) or a placebo for 28 days. 1263W94 demonstrated linear PK, with steady-state plasma 1263W94 profiles predictable based on single-dose data. 1263W94 was rapidly absorbed following oral dosing, and values for the maximum concentration of the drug in plasma and the area under the concentration-time curve increased in proportion to the dose. 1263W94 demonstrated in vivo anti-HCMV activity in semen at all of the dosage regimens tested, with mean reductions in semen HCMV titers of 2.9 to 3.7 log(10) PFU/ml among the four regimens evaluated for anti-HCMV activity. 1263W94 was generally well tolerated; taste disturbance was the most frequently reported adverse event over the 28-day dosing period.

Topics: Adult; Area Under Curve; Benzimidazoles; Cells, Cultured; Culture Media; Cytomegalovirus Infections; DNA, Viral; Dose-Response Relationship, Drug; HIV Infections; Humans; Male; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleosides; Semen; Urine; Viral Plaque Assay; Virus Shedding

Topics: Animals; Anti-HIV Agents; Benzimidazoles; Biological Availability; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Microbial; Drugs, Investigational; Haplorhini; HIV Infections; Humans; Rats; Ribonucleosides