WUPPERTAL, GERMANY and Whitehouse Station, N.J., May 8, 2014
AiCuris and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the publication of results from a Phase 2 clinical trial evaluating the safety and efficacy of letermovir, an investigational, oral antiviral agent for the prevention of human cytomegalovirus (CMV) infection in patients receiving bone marrow transplant. The results published in the latest issue of the New England Journal of Medicine (NEJM) show that letermovir in CMV-seropositive allogeneic human blood precursor cell recipients (bone marrow transplant patients) met the study’s two primary efficacy endpoints. Merck plans to conduct a Phase 3 trial of letermovir, also known as AIC246 or MK-8228, starting in the first half of 2014.
"We are very pleased to see the encouraging data regarding the efficacy and tolerability of our innovative drug for treatment of CMV infection among transplant recipients published in this prestigious journal," notes Prof. Helga Rübsamen-Schaeff, CEO of AiCuris. "We are looking forward to the start of Phase 3 clinical testing."
The paper describes the findings of a Phase 2 double-blind, randomized, placebo-controlled trial, evaluating the effect of letermovir on the incidence and time-to-onset of CMV prophylaxis failure in CMV seropositive matched bone marrow transplant recipients during 12 weeks of treatment. Patients (n=131) received one of three oral doses of letermovir (60, 120, 240 mg/day) or placebo starting after engraftment. The primary endpoint was all-cause prophylaxis failure defined as discontinuation of study drug due to CMV antigen or CMV DNA detection, end-organ disease, or any other causes unrelated to CMV. The primary efficacy analysis population was a modified intention-to-treat (mITT), which included all patients who received at least one dose of the study drug and had at least one measurement of the CMV viral load during the study.
"Based on the data from this study, and Merck’s own evaluations, we are pleased to be moving forward with plans to initiate a Phase 3 trial of letermovir in the first half of this year," said Dr. Eliav Barr, Vice President, Infectious Diseases, Merck Research Laboratories.
In the Phase 2 study (sponsored by AiCuris), the incidence of all-cause prophylaxis failure in the mITT population was significantly lower in the groups that received letermovir at doses of 120 mg/day or 240 mg/day, compared with the placebo group (32% and 29% vs. 64%; p = 0.01 and p = 0.007, respectively). The incidence of virololgic failure was also markedly lower in the 240 mg group (6%) than in the 120 mg group (19%), the 60-mg group (21%), or the placebo group (36%). Virologic failure was defined as either detectable CMV antigen or DNA in blood at two consecutive time points (with at least one instance confirmed by the central laboratory), leading to discontinuation of the study drug and administration of rescue medication, or the development of CMV end-organ disease. No virologic failures were observed in patients receiving the 240 mg dose of letermovir who were CMV negative at baseline.
The other primary end point, the time to the onset of prophylaxis failure, was significantly shorter in the 240 mg group (range, 1 to 8 days) than in the placebo group (range, 1 to 21 days) (P-0.002), but comparisons with the placebo group were not significant for the 60-mg group (range, 1 to 42 days; P=0.15) or the 120-mg group (range, 1 to 15 days; P=0.13). A separation of the Kaplan-Meier curves was evident between the 240 mg group and the placebo group after 8 days. The median time to prophylaxis failure could not be calculated because of the low incidence. These results were consistent with those in the per-protocol population.
The most common recorded adverse events during treatment were gastrointestinal disorders (diarrhea, nausea, and vomiting) in 66 percent of patients in the letermovir groups versus 61 percent in the placebo group. The majority of these events were of mild or moderate intensity; 24 percent of letermovir treated patients versus 30 percent of placebo patients experienced severe adverse events during treatment.
Under an agreement signed in 2012, Merck (through a subsidiary) purchased worldwide rights to develop and commercialize letermovir from AiCuris.
Letermovir is an investigational oral, once-daily candidate for the prevention and treatment of HCMV infection. It is derived from a novel chemical class (quinazolines) and is designed to inhibit the HCMV viral terminase. Letermovir has been granted Orphan Product Designation by the EMA and FDA for the prevention of CMV viremia and disease in at risk populations, and has also been granted Fast Track Status in the United States.
The Human Cytomegalovirus (HCMV) is widely spread in the human population and can cause severe, life-threatening infections in cases of immune incompetency or immune deficiency, such as, for example, cases in transplant recipients, newborn babies and HIV/AIDS patients. HCMV infection is characterized by fever, leucopenia (very low white blood cell count) and thrombocytopenia (very low platelet numbers) with or without specific organ dysfunction. Two main strategies to prevent HCMV infection have been adopted: anti-HCMV drug prophylaxis or pre-emptive treatment of transplant recipients who are at risk and have evidence of HCMV infection upon screening.
AiCuris GmbH & Co KG (name derived from Anti-Infective Cures) was founded in 2006 and is focused exclusively on the discovery, research and development of novel, resistance breaking antiviral and antibacterial agents for the treatment of severe and potentially life-threatening infectious diseases. Majority investors are Drs. Strüngmann, founders and former owners of the pharmaceutical company Hexal. Besides the HCMV program, AiCuris is pursuing several other candidates in various stages of clinical development including a Gram-negative, resistance-breaking antibiotic for hospital use, an immune modulator for Hepatitis B and fibrosis, an HIV compound and several research projects in Hepatitis B and bacteriology. A novel antiHerpes Simplex compound completed phase II clinical testing. For more information, please visit www.aicuris.com.
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To view the article: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1309533