Alice Robertson

CMX001 to Prevent Cytomegalovirus Disease in Hematopoietic-Cell Transplantation

BACKGROUND The use of available antiviral agents for the prevention of cytomegalovirus (CMV) disease is limited by frequent toxic effects and the emergence of resistance. CMX001 has potent in vitro activity against CMV and other double-stranded DNA viruses. We evaluated the safety and anti-CMV activity of CMX001 in patients who had undergone allogeneic hematopoietic-cell transplantation. METHODS From December 2009 through June 2011, a total of 230 patients with data that could be evaluated were enrolled in the study. We randomly assigned these adult CMV-seropositive transplant recipients from 27 centers to oral administration of CMX001 or placebo. Patients were assigned in a 3:1 ratio to five sequential study cohorts according to a dose-escalating, double-blind design. Randomization was stratified according to the presence or absence of acute graft-versus-host disease and CMV DNA in plasma. Patients received the study drug after engraftment for 9 to 11 weeks, until week 13 after transplantation. Polymerase-chain-reaction analysis of CMV DNA in plasma was performed weekly. Patients in whom CMV DNA was detected at a level that required treatment discontinued the study drug and received preemptive treatment against CMV infection. The primary end point was a CMV event, defined as CMV disease or a plasma CMV DNA level greater than 200 copies per milliliter when the study drug was discontinued. The analysis was conducted in the intention-to-treat population. RESULTS The incidence of CMV events was significantly lower among patients who received CMX001 at a dose of 100 mg twice weekly than among patients who received placebo (10% vs. 37%; risk difference, -27 percentage points; 95% confidence interval, -42 to -12; P=0.002). Diarrhea was the most common adverse event in patients receiving CMX001 at doses of 200 mg weekly or higher and was dose-limiting at 200 mg twice weekly. Myelosuppression and nephrotoxicity were not observed. CONCLUSIONS Treatment with oral CMX001 at a dose of 100 mg twice weekly significantly reduced the incidence of CMV events in recipients of hematopoietic-cell transplants. Diarrhea was dose-limiting in this population at a dose of 200 mg twice weekly. (Funded by Chimerix; CMX001-201 ClinicalTrials.gov number, NCT00942305.).

First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses.

ABSTRACT CMX001 is a novel, broad-spectrum lipid antiviral conjugate (LAC) that produces high intracellular levels of the active antiviral agent cidofovir diphosphate (CDV-PP). Study CMX001-102 was a randomized, double-blind, placebo-controlled, parallel group, dose-escalating study in healthy volunteers. The objectives of the study were to evaluate the safety and pharmacokinetic parameters of CMX001 after single and multiple doses. Single doses ranging from 0.25 to 2.0 mg/kg of body weight and multiple doses ranging from 0.1 to 1.0 mg/kg (3 total doses, administered every 6 days) were given orally. Safety was assessed using comprehensive clinical and laboratory evaluations, including enhanced monitoring for potential gastrointestinal (GI) effects using wireless capsule endoscopy (WCE). Serial plasma and pooled urine samples were collected to estimate pharmacokinetic parameters for both CMX001 and cidofovir (CDV). No adverse events occurred that prevented dose escalation. No clinically significant drug-related changes in blood chemistry, hematology, renal function, or intraocular pressure were observed. No CMX001-related gastrointestinal mucosal changes were observed by WCE. CMX001 was absorbed rapidly, with maximum plasma concentrations observed 2 to 3 h postdose. Maximum plasma drug concentration and systemic exposure of CMX001 increased approximately in proportion to dose following single and multiple doses; no significant accumulation of CMX001 or CDV was observed following multiple doses. We conclude that CMX001 is orally bioavailable and well tolerated in healthy volunteers at doses up to 2 mg/kg, approximately 140 mg in a typical adult. This is the first demonstration of the use of phospholipid conjugation technology to achieve plasma drug exposures that are expected to result in activity against multiple double-stranded DNA viruses.

Synergistic efficacy of the combination of ST-246 with CMX001 against orthopoxviruses.

ABSTRACT The combination of ST-246 and hexadecyloxypropyl-cidofovir or CMX001 was evaluated for synergistic activity in vitro against vaccinia virus and cowpox virus (CV) and in vivo against CV. In cell culture the combination was highly synergistic against both viruses, and the results suggested that combined treatment with these agents might offer superior efficacy in vivo. For animal models, ST-246 was administered orally with or without CMX001 to mice lethally infected with CV. Treatments began 1, 3, or 6 days postinfection using lower dosages than previously used for single-drug treatment. ST-246 was given at 10, 3, or 1 mg/kg of body weight with or without CMX001 at 3, 1, or 0.3 mg/kg to evaluate potential synergistic interactions. Treatment beginning 6 days post-viral inoculation with ST-246 alone only increased the mean day to death at 10 or 3 mg/kg but had no effect on survival. CMX001 alone also had no effect on survival. When the combination of the two drugs was begun 6 days after viral infection using various dosages of the two, a synergistic reduction in mortality was observed. No evidence of increased toxicity was noted with the combination either in vitro or in vivo. These results indicate that combinations of ST-246 and CMX001 are synergistic both in vitro and in vivo and suggest that combination therapy using ST-246 and CMX001 for treatment of orthopoxvirus disease in humans or animals may provide an additional benefit over the use of the two drugs by themselves.

Development of CMX001 for the Treatment of Poxvirus Infections.

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.

Mousepox in the C57BL/6 strain provides an improved model for evaluating anti-poxvirus therapies

The intranasal lethal mousepox model employing the A/Ncr mouse strain is used to evaluate anti-orthopoxvirus therapies. These infections mimic large droplet transmission and result in 100% mortality within 7-10 days with as little as 1 PFU of ectromelia virus. Unlike the A/Ncr model, humans are less susceptible to lethal respiratory infections with variola virus and monkeypox virus as demonstrated by their lower mortality rates. In this study we show that a low dose intranasal infection of C57BL/6 mice results in 60-80% mortality and better models smallpox. Comparing CMX001 (HDP-cidofovir) efficacy in the A/Ncr strain and the C57BL/6 strain revealed that delayed treatment with CMX001 is more efficacious at preventing severe disease in the C57BL/6 strain. The increased efficacy of CMX001 in C57BL/6 over A/Ncr following an intranasal infection with ectromelia appears to be mediated by a stronger Th1 cell mediated response. Following footpad infection we show that the C57BL/6 strain has earlier and more robust transcriptional activity, Th1 cytokine secretions, antigen presenting activity and IFNgamma splenic CD8+ T cell responses as compared to the A/Ncr strain. As a result of the enhanced immune response in the C57BL/6 strain, non-lethal intradermal ectromelia infections can therapeutically protect up to 3 days following a homologous, lethal intranasal infection - much like how smallpox vaccination can protect humans for up to 4 days following intranasal variola infection.

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

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. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Previously, we demonstrated the efficacy of CMX001 in protecting New Zealand White rabbits from mortality following intradermal infection with rabbitpox virus as a model for smallpox, monkeypox and for treatment of adverse reactions to smallpox vaccination. Here we extend these studies by exploring different dosing regimens and performing randomized, blinded, placebo-controlled studies. In addition, because rabbitpox virus can be transmitted via naturally generated aerosols (animal to animal transmission), we report on studies to test the efficacy of CMX001 in protecting rabbits from lethal rabbitpox virus disease when infection occurs by animal to animal transmission. In all cases, CMX001 treatment was initiated at the onset of observable lesions in the ears to model the use of CMX001 as a treatment for symptomatic smallpox. The results demonstrate that CMX001 is an effective treatment for symptomatic rabbitpox virus infection. The rabbitpox model has key similarities to human smallpox including an incubation period, generalized systemic disease, the occurrence of lesions which may be used as a trigger for initiating therapy, and natural animal to animal spread, making it an appropriate model.

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

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.

The challenges of developing an antiviral agent for the treatment of smallpox using the animal efficacy rule

Smallpox, eradicated in the late 1970s, is considered a serious worldwide threat because of its potential use as a biological weapon. Attempts to develop an antiviral drug for the prophylaxis and treatment of the disease are complicated by the need to demonstrate effective antiviral activity and propose human dosing paradigms based on data generated in animals infected with related orthopoxviruses. This perspective article reviews the difficulties associated with developing an antiviral agent using animal models and the ‘animal efficacy rule’: a FDA regulation designed for situations where human clinical trials are not an option.

Results of a phase Ib study of Q-122 treatment of vasomotor symptoms in breast cancer patients.

99 Background: Breast cancer patients taking tamoxifen (TAM) or an aromatase inhibitor (AI) often develop severe vasomotor symptoms (VMS) yet the only FDA approved non-hormonal treatment for VMS, 7.5 mg paroxetine, has a warning against concomitant use with TAM. Q-122, an orally-available small molecule, is being developed to address this unmet medical need. Results from the Phase 1b study, Q-1001, are presented. METHODS Q-1001 was a Phase 1 open-label, two-dose, dose-escalation study of the safety and preliminary effectiveness of Q-122 in females with breast cancer currently taking TAM or an AI and experiencing an average of at least 7-8 moderate to severe hot flashes per day. Key exclusion criteria included significant renal or hepatic disease, untreated hyperthyroidism and clinically significant abnormal laboratory findings. The study period included a 2 week drug-free screening phase, 28 day treatment phase, and 2 week drug-free follow-up period. Subjects were initially enrolled into Group 1 (100 mg Q-122) followed by Group 2 (200 mg Q-122). Safety was assessed by review of adverse events (AEs), physical findings and laboratory values. The primary efficacy endpoints were mean changes in frequency and severity (hot flash severity score, HFSS) of moderate and severe hot flashes from baseline to Week 4. Menopausal symptoms were assessed using the Greene Climacteric Scale (GCS). RESULTS 10 and 11 subjects received 100 and 200 mg Q-122 respectively; 8 subjects in each group completed the study. At the end of treatment for groups 1 and 2 respectively, the daily average frequency of hot flashes was reduced from 9.9 to 4.1 and from 8.6 to 3.2, and the mean HFSS was reduced by 62% and 68% from baseline values. Menopausal symptoms assessed using the GCS were significantly reduced from baseline (psychological: -82%; somatic: -65%; vasomotor: -65%). All AEs (n = 29) were either mild (79%) or moderate (21%) in severity and only 3 (all in one subject) were considered possibly related to study drug. CONCLUSIONS Treatment with Q-122 resulted in significant reduction in the frequency and severity of VMS and improvement in menopausal symptoms as assessed by the GCS. No safety issues associated with the use of Q-122 were identified in this study.