Merck to Initiate Proof-of-Concept Study of Posaconazole for Chronic Chagas Disease, Recognized by WHO as One of the World’s Neglected Tropical Diseases
Whitehouse Station, N.J. - Merck today announced plans to initiate a Phase II investigational proof-of-concept clinical study to evaluate its oral antifungal agent posaconazole for the treatment of chronic Chagas disease. Chagas disease results from infection with the parasite Trypanosoma cruzi that is spread by biting insects. The disease is estimated to affect approximately eight million people in Latin America, of whom approximately 30-40 percent will develop serious cardiac disease, digestive disease, or both as a result of this infection. Recognized by the World Health Organization (WHO) as a neglected tropical disease, Chagas disease also is becoming an emerging health problem in non-endemic areas through migration of infected populations from endemic areas. Currently, only two drugs are approved for treatment: benznidazole and nifurtimox.
“While significant progress has been made in recent years in the prevention of the transmission of this potentially life-threatening disease, no new drugs have been approved for the treatment of chronic Chagas disease in over three decades,” said Roger J. Pomerantz, M.D., F.A.C.P., global franchise head for infectious diseases and senior vice president, Merck Research Laboratories.
In planning the study to evaluate posaconazole, Merck has consulted with international agencies and research organizations to identify the current medical needs and reach consensus on a study design for posaconazole in asymptomatic chronic Chagas disease. The proposed study is a randomized, placebo-controlled Phase II study of posaconazole oral suspension (400 mg twice daily) given for 60 days, either as monotherapy or concomitantly with benznidazole. Benznidazole monotherapy will serve as an active control. The study is planned to enroll 160 adult patients with chronic Chagas disease at several sites in South America and follow them for a total of 360 days. The study will utilize polymerase chain reaction (PCR) to evaluate the levels of Trypanosoma cruzi in blood samples as the primary endpoint for response to treatment. Safety will be monitored by an external independent Data and Safety Monitoring Board (DSMB) on an ongoing basis and the DSMB will make recommendations as appropriate. Results from the study are expected in 2012. If successful, Phase III clinical studies with posaconazole would follow. Merck looks forward to working with interested partners to facilitate access if posaconazole is shown to be beneficial in the treatment of chronic Chagas disease.
About Chagas Disease
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and was discovered in 1909 by the Brazilian physician Carlos Chagas (1879-1934). It continues to represent a serious social and economic problem in many Latin American countries, with approximately 20,000 deaths each year attributed to Chagas disease. Chagas disease is transmitted to humans mainly by insect bites, but also can be transmitted via blood transfusion, transplantation and vertically from mother to infant. Rarely, it can be contracted by ingestion of contaminated food or liquid. The initial phase of acute infection lasts for four-to-eight weeks and the chronic phase persists for the person’s lifespan. In most individuals, irrespective of the mode of transmission, acute Chagas infection is usually asymptomatic. The clinical outcome of the chronic phase of Chagas disease ranges from the absence of signs and symptoms of disease to severe illness and premature death. Typical clinical manifestations of the chronic phase are related to the pathological involvement of the heart, esophagus, colon, or a combination, and are grouped into three major forms: cardiac, digestive, and cardiodigestive. It may take more than 20 years from the time of the original infection to develop serious heart or digestive disease. Benznidazole and nifurtimox are the only drugs with proven efficacy against Chagas disease. Benznidazole is usually used for first-line treatment.
Merck’s Ongoing Commitment to Improving Global Health
Merck has a long history of engaging in public-private partnerships and research initiatives to develop and foster access to its medicines and vaccines worldwide. These efforts include:
* Working with the Drugs for Neglected Diseases initiative (DNDi), Medicines for Malaria Venture (MMV) and other partners to advance the discovery and development of novel treatments for malaria, Chagas disease and other Neglected Tropical Diseases;
* Fighting onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) through the MECTIZAN Donation Program, a diverse global partnership;
* Partnering with the Government of Botswana and the Bill and Melinda Gates Foundation to support Botswana’s comprehensive national response to HIV and AIDS through the African Comprehensive HIV/AIDS Partnerships;
* Collaborating with the Government of Nicaragua to demonstrate the feasibility and impact of rotavirus vaccine introduction in a GAVI-eligible country; and,
* Developing new and improved vaccines to address unmet medical needs in low-income countries by establishing, through a novel joint venture with the Wellcome Trust, the MSD Wellcome Trust Hilleman Laboratories.
Posaconazole is approved and marketed in the United States, European Union and several other countries as NOXAFIL® (posaconazole) oral suspension. In the U.S., NOXAFIL is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy. NOXAFIL also is indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory to itraconazole and/or fluconazole.
Selected Safety Information for NOXAFIL (posaconazole) Oral Suspension
Use in patients with hypersensitivity to the active substance or to any of the excipients is contraindicated. Coadministration with sirolimus or ergot alkaloids is contraindicated. Coadministration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine, is also contraindicated since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes.
NOXAFIL has been shown to interact with several medications, including drugs that suppress the immune system, and these reactions may be serious. The product label should be consulted when other drugs are prescribed with NOXAFIL.
Serious and rare fatal toxicity from cyclosporine has occurred when taken in combination with NOXAFIL and therefore reduction of the dose of drugs like cyclosporine or tacrolimus and frequent monitoring of drug levels of these medications are necessary when taking them in combination with NOXAFIL.
In clinical trials, there were infrequent cases of hepatic reactions (e.g., mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis). Rarely, more severe hepatic reactions including cholestasis or hepatic failure including fatalities were reported in patients with serious underlying medical conditions (e.g., hematologic malignancies) during treatment with posaconazole. Liver function tests should be monitored at the start of and during the course of therapy. Discontinuation of NOXAFIL must be considered in patients who experience symptoms consistent with liver disease that may be attributable to NOXAFIL.
The safety and effectiveness of NOXAFIL in patients below the age of 13 years old have not been established.
The most common treatment-related serious adverse events (1% each) in the combined prophylaxis studies were bilirubinemia, increased hepatic enzymes, hepatocellular damage, nausea, and vomiting.
In the pooled prophylaxis safety analysis, fever, headache, anemia, diarrhea, nausea, vomiting, abdominal pain, hypokalemia, and thrombocytopenia were frequently reported treatment-emergent adverse events.
In clinical studies of OPC and refractory OPC, adverse events were reported more frequently in the pool of patients with refractory OPC. The most commonly reported serious adverse events in refractory OPC patients included fever (13%) and neutropenia (10%).
U.S. prescribing information for NOXAFIL is attached and also is available at http://www.spfiles.com/pinoxafil.pdf.
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