Wendy Painter

Safety and Efficacy of CMX001 as Salvage Therapy for Severe Adenovirus Infections in Immunocompromised Patients

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

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.

Eradication of disseminated adenovirus infection in a pediatric hematopoietic stem cell transplantation recipient using the novel antiviral agent CMX001.

Adenovirus infection is a serious and often fatal complication in hematopoietic stem cell transplant patients. There are currently no FDA-approved therapies for adenovirus infection, with only anecdotal, off-label uses described for a variety of anti-viral agents or immune therapies. We report the first case of successful eradication of disseminated adenovirus infection by the novel antiviral agent CMX001 in a severely immunocompromised pediatric stem cell transplant recipient following failure to respond to intravenous cidofovir. Complete clinical and virologic response was documented; virologic and pharmacokinetic data are reported. CMX001 is a promising new oral antiviral agent under development for the prophylaxis and treatment of severe infections caused by double-stranded DNA viruses including adenovirus in immunocompromised patients.

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.

Progressive vaccinia: case description and laboratory-guided therapy with vaccinia immune globulin, ST-246 and CMX001

Progressive vaccinia (PV) is a rare but potentially lethal complication that develops in smallpox vaccine recipients with severely impaired cellular immunity. We describe a patient with PV who required treatment with vaccinia immune globulin and who received 2 investigational agents, ST-246 and CMX001. We describe the various molecular, pharmacokinetic, and immunologic studies that provided guidance to escalate and then successfully discontinue therapy. Despite development of resistance to ST-246 during treatment, the patient had resolution of PV. This case demonstrates the need for continued development of novel anti-orthopoxvirus pharmaceuticals and the importance of both intensive and timely clinical and laboratory support in management of PV.

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.