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Development of CMX001 for the Treatment of Poxvirus Infections
Chimerix, Inc., 2505 Meridian Parkway, Suite 340, Durham, North Carolina, NC 27713, USA
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Received: 28 October 2010; in revised form: 17 November 2010 / Accepted: 22 November 2010 / Published: 17 December 2010
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.
Keywords: CMX001; smallpox; dsDNA virus; antiviral; cidofovir; variola
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Lanier, R.; Trost, L.; Tippin, T.; Lampert, B.; Robertson, A.; Foster, S.; Rose, M.; Painter, W.; O’Mahony, R.; Almond, M.; Painter, G. Development of CMX001 for the Treatment of Poxvirus Infections. Viruses 2010, 2, 2740-2762.
Lanier R, Trost L, Tippin T, Lampert B, Robertson A, Foster S, Rose M, Painter W, O’Mahony R, Almond M, Painter G. Development of CMX001 for the Treatment of Poxvirus Infections. Viruses. 2010; 2(12):2740-2762.
Lanier, Randall; Trost, Lawrence; Tippin, Tim; Lampert, Bernhard; Robertson, Alice; Foster, Scott; Rose, Michelle; Painter, Wendy; O’Mahony, Rose; Almond, Merrick; Painter, George. 2010. "Development of CMX001 for the Treatment of Poxvirus Infections." Viruses 2, no. 12: 2740-2762.