Abstract
CMX001 (phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester) is a lipid conjugate of the acyclic nucleotide phosphonate, cidofovir (CDV). CMX001 is currently in Phase II clinical trials for the prophylaxis of human cytomegalovirus infection and under development using the Animal Rule for smallpox infection. It has proven effective in reduction of morbidity and mortality in animal models of human smallpox, even after the onset of lesions and other clinical signs of disease. CMX001 and CDV are active against all five families of double-stranded DNA (dsDNA) viruses that cause human morbidity and mortality, including orthopoxviruses such as variola virus, the cause of human smallpox. However, the clinical utility of CDV is limited by the requirement for intravenous dosing and a high incidence of acute kidney toxicity. The risk of nephrotoxicity necessitates pre-hydration and probenecid administration in a health care facility, further complicating high volume CDV use in an emergency situation. Compared with CDV, CMX001 has a number of advantages for treatment of smallpox in an emergency including greater potency in vitro against all dsDNA viruses that cause human disease, a high genetic barrier to resistance, convenient oral administration as a tablet or liquid, and no evidence to date of nephrotoxicity in either animals or humans. The apparent lack of nephrotoxicity observed with CMX001 in vivo is because it is not a substrate for the human organic anion transporters that actively secrete CDV into kidney cells. The ability to test the safety and efficacy of CMX001 in patients with life-threatening dsDNA virus infections which share many basic traits with variola is a major advantage in the development of this antiviral for a smallpox indication.
Highlights
Variola virus, the etiologic agent of smallpox, is a CDC Category A pathogen
These doses did not reduce mortality, an explanation was provided by pharmacokinetic analysis which showed that systemic exposure of cynomolgus monkeys to CMX001 following oral administration was very low compared to that seen in other species including mice, rabbits, and humans, with humans having by far the best systemic exposure (AUC) after oral administration
This comparison will validate that drug exposures necessary to treat smallpox can be achieved in humans and that these doses are efficacious in humans as evidenced by activity against similar double-stranded DNA (dsDNA) virus infections
Summary
The etiologic agent of smallpox, is a CDC Category A pathogen. Smallpox is one of the most pestilent diseases feared by mankind since antiquity, and historically has been associated with the periodic occurrence of widespread, often devastating epidemics. In addition to the indication for the treatment of smallpox in the general population, the drug would be the first line of defense for the tens of millions of people who are at risk of life-threatening vaccinia infections if vaccinated with a live attenuated virus vaccine such as the currently stockpiled ACAM2000. These populations include pregnant women and many groups of patients whose immune systems are weakened (e.g., AIDS patients, organ transplant recipients and patients on cancer therapy). It is clear that the complete defense of the country against a terrorist attack using variola virus, whether modified or not, requires safe, administered antiviral drugs ready for use in the Strategic National Stockpile
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
