Oral CMV Therapeutic
Cytomegalovirus (CMV)
Human cytomegalovirus (CMV) is a member of the herpesvirus family of double stranded DNA (dsDNA) viruses that typically causes mild or subclinical disease, but can cause severe systemic or localized disease in immunocompromised individuals. Organ involvement manifestations of CMV disease include hepatitis, pneumonitis, pancreatitis, colitis, erosive gastrointestinal bleeding, meningoencephalitis, myocarditis, and chorioretinitis. In most developed countries, 40-80% of children are infected with CMV before puberty and exposure to virus increases with age in the general population. Like other members of the herpesvirus group, CMV rests in the host in a latent state following primary infection. The virus can emerge from latency when the immune system becomes compromised causing significant morbidity and mortality.
Historically, CMV induced disease has been most frequently observed in HIV/AIDS patients, immunosuppressed transplant recipients and cancer patients receiving chemotherapy. In the late 90’s, the most common CMV disease associated with AIDS, CMV retinitis, was reduced dramatically as a result of the successful implementation of highly active anti-retroviral therapy (HAART) for HIV infection. However, the emergence of multidrug resistant HIV-1 and the realization that the long term prognosis for people living with HIV may be better if they are treated early for CMV infection (before clinical signs or symptoms) has resulted in an increased need for CMV drugs with high efficacy and long term tolerability. The HIV infected population is large and growing. In the US more than one million people are HIV positive and there are approximately 45,000 new infections every year. More than 360,000 people currently receive anti-HIV treatment in the US with 50,000 starting each year. Many of these individuals are or will be candidates for CMV prophylaxis/treatment.
Currently the greatest use of CMV prophylaxis and treatment is in organ transplantation. Cytomegalovirus is present in more than two-thirds of donors and recipients prior to transplantation. In a study of transplant patients who did not receive induction therapy or CMV prophylaxis, the relative risk of overall mortality was 2.5 to 2.9 times higher than those without CMV for CMV disease and CMV infection, respectively. The burden of CMV disease in the transplant population has increased as the frequency of organ transplantation has increased. There are 70,000 transplant operations performed every year worldwide with 25,000 of these in the US. The number of operations is limited only by the number of organs available. Organ loss and other morbidities due to CMV remain a large and costly issue.
Therapy for CMV in transplant patients may be prophylactic, preemptive or treatment of disease. Despite prophylaxis, often continued for 100 days, disease prevalence at 6 months is estimated to be from 12 to 22 percent.
The in vitro activity of CMX001 against CMV has been assessed in MRC-5 cells (a human lung fibroblast-derived cell line) and human foreskin fibroblast (HFF) cells. Depending on cell type, virus strain, and method of assay (DNA or plaque reduction), EC50 values ranged from 2 x 10-6 µM to 2.5 x 10-2 µM. In all cases, CMX001 was from 2 to 5 logs more potent than CDV. This increased potency has been correlated with increased intracellular delivery of CDV.
CMX001 is expected to have a decided advantage over current treatments for prophylaxis of CMV infection in bone marrow transplant recipients and in cancer patients receiving myelosuppressive chemotherapy or radiation therapy based on its increased potency, favorable toxicity, broader spectrum antiviral activity and no cross resistance profile.
Phase I clinical development for smallpox and CMV
A blinded, randomized, parallel-group, placebo-controlled Phase I clinical study to evaluate the safety and pharmacokinetics of orally administered CMX001 in healthy volunteers is in progress.