Efficacy of CMX001 against Herpes Simplex Virus Infections in Mice and Correlations with Drug Distribution Studies

Abstract

CMX001, an orally active lipid conjugate of cidofovir (CDV), is 50 times more active in vitro against herpes simplex virus (HSV) replication than acyclovir (ACV) or CDV. These studies compared the efficacy of CMX001 to ACV in BALB/c mice inoculated intranasally with HSV types 1 or 2. CMX001 was effective in reducing mortality using doses of 5 to 1.25 mg/kg administered orally once daily even when treatments were delayed 48-72 h post viral inoculation. Organ samples from mice treated with CMX001 had titers three to five log10 pfu/gram of tissue lower than samples from ACV treated mice, including five different regions of the brain. Detectable concentrations of drug-related radioactivity were documented in the central nervous system of mice following oral administration of 14C-CMX001. These studies indicated that CMX001 penetrates the blood brain barrier, is a potent inhibitor of HSV replication in disseminated and CNS infections and is superior to ACV.

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

“…Its principal side effect was significant diarrhea in over 50% of the patients treated with 100 mg twice weekly which became dose-limiting at 200 mg twice weekly. This toxicity was likely determined by an excessive concentration of CDF in enterocytes as reported in animal models [83]. The SUPPRESS trial, a phase III randomized multicenter, placebo-controlled (ratio 2:1), on 450 CMV seropositive allogeneic HSCT recipients treated with BDF at a dose of 100 mg twice weekly has recently stopped recruiting patients.…”

Backs against the Wall: Novel and Existing Strategies Used during the 2014-2015 Ebola Virus Outbreak

“…The proofreading 3=-to-5= exonuclease activity is also inhibited (40). Brincidofovir was shown to possess antiviral activity against cytomegalovirus (CMV) (41), adenovirus (Ad) (42), herpes simplex virus (43), and poxvirus (44) in animal models and is currently in phase III clinical trials against CMV and Ad infections (45,46).…”

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“…Phase I studies reported that this compound is well tolerated with significantly reduced kidney accumulation. CMX001 avoided the nephrotoxicity associated with CDV [109,111].…”