Chimerix

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Clinical Trials

Chimerix has established a pipeline of therapeutics addressing life-threatening viral diseases. Our lead compound, CMX001, is currently being developed to treat dsDNA viruses – potentially deadly diseases for immunocompromised patients. A second compound, CMX157, is being advanced to treat human immunodeficiency virus (HIV). In addition, we have identified highly active compounds against hepatitis C and influenza. We are also screening our proprietary Chimerix Chemical Library for compounds with activity against dengue virus, malaria and tuberculosis.

CMX001-201 Phase 2 Trial

CMX001 has completed a Phase 2 randomized, double-blind, placebo-controlled, dose-escalation study designed to assess the safety, tolerability and ability of CMX001 to prevent or control cytomegalovirus (CMV) infection in 230 hematopoietic cell transplant (HCT) recipients (Study 201). CMV, a member of the herpesvirus family of dsDNA viruses, is present in more than two-thirds of the population and typically causes manageable disease in individuals with responsive immune systems. However, in immunosuppressed and immunocompromised transplant recipients, CMV is a major cause of morbidity and mortality.

CMX001-202 Phase 2 Trial (AdV HALT Trial)

CMX001 is being studied in a randomized, placebo-controlled, Phase 2 trial evaluating the safety and efficacy of preemptive treatment with CMX001 versus placebo for the prevention of adenovirus (AdV) disease in 48 pediatric and adult hematopoietic cell transplant (HCT) recipients with asymptomatic AdV viremia (Study 202). Adenoviruses are responsible for respiratory diseases, including pneumonia and bronchitis, as well as other infections, including gastroenteritis and acute diarrheal diseases. In immunocompromised patients who have undergone HCT, AdV infections are recognized as a significant cause of morbidity and mortality. Immunocompromised pediatric HCT patients are particularly susceptible to serious and/or fatal AdV infections. The U.S. FDA has granted CMX001 Fast Track designation status for the AdV development program.

CMX157

CMX157 demonstrated a favorable safety, tolerability and drug distribution profile in a first-in-human clinical trial. The Phase 1 study was a randomized, blinded, single dose, dose-escalation trial to evaluate safety, tolerability and pharmacokinetics of CMX157 in healthy volunteers.

Research Programs

Our core scientific assets, the Lipid-Antiviral-Conjugate Technology and the Chimerix Chemical Library provide us with a rich source for new drug leads. 

In evaluating the compounds within the Chimerix Chemical Library, we have identified several unique classes of nucleoside analogues, including several extremely potent drug leads against hepatitis C virus (HCV).  We plan to select a candidate for preclinical development, as well as additional promising back-up compounds.  HCV is the primary cause of chronic liver disease in the U.S., accounting for up to 50 percent of cirrhosis, end-stage renal disease and liver cancer.  An estimated 4.1 million Americans are believed to be infected with HCV.

We are also screening compounds to address influenza A and B, as well as dengue virus, malaria and tuberculosis.

CMX157

HIV

HIV therapies have advanced substantially in recent years, yet HIV can develop resistance to all current agents and significant drug side effects remain an issue for many patients.  Tenofovir (marketed in a prodrug form by Gilead as Viread^®) is one of the most widely used antiretrovirals and is part of the Truvada^® and Atripla^® fixed-dose combinations.  Tenofovir has also been associated with renal toxicity and resistance can be conferred by a single mutation.  

CMX157, a nucleotide analog, is being developed as an antiviral therapy against HIV.  We believe CMX157 has the potential to be less nephrotoxic than tenofovir based on in vitro data showing CMX157 is not a substrate for the membrane pumps that secrete tenofovir into kidney cells.  Combined with high in vitro potency against all common NRTI-resistant HIV genotypes, this suggests CMX157 could be a best-in-class antiretroviral with the potential to address an estimated worldwide market of $1 billion. 

CMX001

Smallpox

In addition to the company's development of its lead candidate, CMX001, for transplant recipients, CMX001 is also being developed as a medical countermeasure in the event of a smallpox release, with the potential to provide an important therapeutic option for the 80 million people in the U.S. currently estimated to be immunocompromised, or a household contact of a contraindicated individual, and thus not candidates to receive a smallpox vaccine (for additional information click here). Chimerix has received federal funding for the development of CMX001 as a medical countermeasure against smallpox from the National Institute of Allergy and Infectious Diseases under Grant No. U01-A1057233 and from the Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under Contract No. HHSO100201100013C.

An acute, highly contagious disease caused by variola virus, a member of the orthopoxvirus family, smallpox is a disease of significant interest to government agencies because of concerns that the virus could be used for bioterrorism.

In vivo, the antiviral activity of CMX001 has been characterized in mice infected with ectromelia, vaccinia, and cowpox viruses and in rabbits infected with rabbitpox. In each model, a dose of CMX001 was identified that provided protection against challenge with a lethal viral inoculum. Higher oxidative metabolism of CMX001 in monkeys necessitates efficacy trials in this species with cidofovir and extrapolation of human doses for CMX001 through the active antiviral cidofovir diphosphate. Since cidofovir and CMX001 produce the same active antiviral species in vivo (cidofovir diphosphate), it can be used as a product surrogate for CMX001 to test activity in monkeys. Cidofovir has provided protection in lethal models of monkeypox and variola (smallpox) infection in non-human primates. Chimerix is actively pursuing development of CMX001 for the prevention and treatment of smallpox under the "Animal Efficacy Rule," which allows the U.S. Food and Drug Administration to rely on efficacy data from animal models of human disease in the development and approval of a compound.

CMX001

dsDNA viruses

CMX001 is in development for the treatment of double stranded DNA (dsDNA) viruses in transplant recipients, representing an estimated market in excess of $1 billion. The compound has the potential to become a standard of care for "universal prophylaxis" for dsDNA viruses in immunocompromised patients due to its broad-spectrum antiviral activity.

Human cytomegalovirus (CMV) is a member of the herpesvirus family of dsDNA viruses that typically causes mild or subclinical disease, but can cause severe systemic or localized disease in immunocompromised individuals. CMV is a common virus that infects most people worldwide. In most developed countries, 40-80 percent of children are infected with CMV before puberty and exposure to the 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. Organ involvement manifestations of CMV disease include hepatitis, pneumonitis, pancreatitis, colitis, erosive gastrointestinal bleeding, meningoencephalitis, myocarditis, and chorioretinitis.

Historically, CMV-induced disease has been most frequently observed in HIV/AIDS patients, immunosuppressed transplant recipients and cancer patients receiving chemotherapy. We are initially developing CMX001 for use in transplant patients where there is a significant unmet medical need. 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. Each year more than 60,000 transplants are performed in the U.S. and Europe. Over 75 percent of these transplant recipients are at moderate-to-high risk of CMV a dsDNA viral infection adn a sizable proportion are co-infected with multiple dsDNA viruses. 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 with existing drugs, often continued for 100 days, disease prevalence at six 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 2 to 5 logs more potent than cidofovir.

CMX001 is expected to have a decided advantage over current treatments for prophylaxis of CMV infection in solid organ and bone marrow transplant recipients and in cancer patients receiving myelosuppressive chemotherapy or radiation therapy based on its potential for increased potency, decreased toxicity, broader spectrum antiviral activity and favorable cross resistance profile.

Like CMV, BK virus is widespread but rarely causes disease, except in immunosuppressed or immunocompromised patients. A member of the polyomavirus family, BK virus remains latent in the kidney and urinary tract where it persists throughout a patient's lifetime. In renal transplant patients, because of treatment with immunosuppressive agents, BK viruria is a serious complication that is growing in prevalence. BK viruria may eventually lead to loss of the kidney graft, or to uncontrolled bleeding in the bladder.

Pipeline

Chimerix has established a pipeline of therapeutics addressing life-threatening viral diseases.  Our lead compound, CMX001, is currently being developed to treat dsDNA viruses – potentially deadly diseases for immunocompromised patients.  As a potential broad-spectrum antiviral agent with enhanced in vitro potency, CMX001 is also being studied as a promising biodefense countermeasure for use in the event of a smallpox outbreak.  A second compound, CMX157, is being advanced to treat human immunodeficiency virus (HIV).  In addition, we have identified highly active compounds against hepatitis C and influenza and are screening our proprietary Chimerix Chemical Library for compounds with activity against dengue virus, malaria and tuberculosis.

CMX157

Chimerix's second clinical-stage antiviral compound, CMX157, a potent nucleoside analogue with in vitro activity against HIV and hepatitis B, has the potential to directly address several limitations of current HIV therapies. Chimerix is developing CMX157 for the treatment of HIV and HBV infections, including those caused by multi-drug resistant viruses. A Phase 1 clinical study has been completed demonstrating that the compound is well tolerated and that the active antiviral, TFV-PP, was measurable in peripheral blood mononuclear cells (PBMCs) after a single dose and remained detectable for six days, indicating that it may be suitable for once-weekly dosing.

CMX001

CMX001 combines Chimerix’s Lipid-Antiviral-Conjugate Technology with cidofovir, an approved antiviral agent, with the aim of creating a well-tolerated and highly potent new chemical entity with broad-spectrum antiviral activity.  We believe that if we can successfully develop a product with increased efficacy and reduced toxicities we can provide a powerful new option for patients and their physicians that may dramatically change antiviral treatment, particularly among immunocompromised patients.  In clinical testing to date, CMX001 has shown oral bioavailability in humans and has demonstrated a positive safety profile.

We are currently conducting clinical trials of CMX001 for the treatment of dsDNA viruses in immunocompromised transplant patients. 

CMX001 is a mimic of a naturally occurring lipid, lysolecithin, formed by linking a lipid, 3-hexadecyloxy-1-propanol, to the phosphonate group of cidofovir. CMX001 is designed to readily cross the intestinal wall and penetrate target cells before being cleaved to free the antiviral, cidofovir.  Cidofovir is phosphorylated by host cell nucleoside kinases to form the active antiviral agent cidofovir diphosphate.