Efficacy of CMX001 as a Prophylactic and Presymptomatic Antiviral Agent in New Zealand White Rabbits Infected with Rabbitpox Virus, a Model for Orthopoxvirus Infections of Humans

Abstract

CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination.

Efficacy of CMX001 as a Post Exposure Antiviral in New Zealand White Rabbits Infected with Rabbitpox Virus, a Model for Orthopoxvirus Infections of Humans

“…Therefore, it was hypothesized that a single treatment with CMX001 might be sufficient to prevent lethal RPV disease as described in the accompanying paper [19]. We tested the efficacy of CMX001 in intradermally infected rabbits when dosed one, two, or three times over the course of five days starting on 3 or 4 dpi (ear lesions typically occur beginning on 4 dpi).…”

Protective Properties of Vaccinia Virus-Based Vaccines: Skin Scarification Promotes a Nonspecific Immune Response That Protects against Orthopoxvirus Disease

“…Body temperature has been observed to be an excellent indicator of both disease and the host response to infection (9,17,18,20). Therefore, the timing of the change in body temperature, as well as the maximum, is important in gauging the level of response to an infection.…”

“…Criteria for euthanizing the rabbits included openmouth breathing, severe difficulty in breathing, or a loss of body weight greater than 20% from the beginning initial weight. These criteria are the established euthanasia criteria for the rabbit model previously published and correspond to mortality; however, no animals were permitted to succumb to disease (9,17,18). In all animals noted in this publication, euthanasia was dictated by severe respiratory failure, defined as less than 40 breaths per minute and/or open-mouth breathing upon stimulation.…”

Poxvirus DNA Replication

“…Cidofovir and oral derivatives are acyclic nucleoside analogs that are incorporated into the growing DNA strand and inhibit the 5 0 -to-3 0 chain extension and 3 0 -to-5 0 exonuclease activities of poxvirus DNA polymerase (Andrei and Snoeck 2010; Rice et al 2011).…”