Development of CMX001 for the Treatment of Poxvirus Infections

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.

Effects of Postchallenge Administration of ST-246 on Dissemination of IHD-J-Luc Vaccinia Virus in Normal Mice and in Immune-Deficient Mice Reconstituted with T Cells

“…8). On day 67 postinfection, all mice were rechallenged with 10 4 PFU of IHD-J-Luc and subjected to bioimaging for the following 10 days. No weight loss was noted in mice after rechallenge with IHD-J-Luc (data not shown).…”

“…Several limitations of CDV, such as the requirement for intravenous dosing and high incidence of acute kidney toxicity, promoted the development of CMX001, a lipid conjugate of CDV, which is orally bioavailable and does not induce nephrotoxicity. CMX001 is being evaluated in animal models according to the U.S. Food and Drug Administration (FDA) Animal Rule for licensure of new smallpox treatments (10).…”

Mutations Conferring Resistance to Viral DNA Polymerase Inhibitors in Camelpox Virus Give Different Drug-Susceptibility Profiles in Vaccinia Virus

“…The search for orally available ANPs led to the discovery of CMX001, a lipid conjugate of (S)-HPMPC. This molecule, compared to its parent counterpart (S)-HPMPC, exhibits a greater potency in vitro against various dsDNA viruses and no signs of nephrotoxicity, although gastrointestinal toxicity has been ob-served (45,52). CMX001 is currently under development for the treatment of poxvirus infections following the "Animal Efficacy Rule" promulgated by the FDA (40).…”

In Vitro Efficacy of Brincidofovir against Variola Virus

“…BCV has completed two phase 2 clinical trials for the prevention of clinically significant cytomegalovirus infection in hematopoietic stem cell transplant patients and is currently in phase 3 trials. Simultaneously, BCV has been in development for the treatment of smallpox under the Animal Rule, which states that when developing medical countermeasures for threat agents where human challenge studies are not ethical or feasible (e.g., VARV), FDA may grant approval based on animal model studies which demonstrate that the drug is reasonably likely to have clinical benefit in humans (http: //www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM078923.pdf) (3,4).…”