Date: 2014-05-08
Type of information:
phase: 2
Announcement: publication of results in the New England Journal of Medicine
Company: Aicuris (Germany) Merck&Co (USA)
Product: Letermovir (AIC246)
Action
mechanism: Letermovir (AIC246) is an innovative, highly active and specific inhibitor of HCMV. It stems from a novel chemical class (quinazolines) and addresses a novel target (the viral terminase). Based on this new mode of action, it retains full activity also against viruses which are resistant to marketed drugs (invariably inhibitors of the viral polymerase).
Letermovir has received Orphan Drug Status in the US and EU and Fast Track Designation in the US.
Disease: prevention of HCMV (human cytomegalovirus) disease
Therapeutic area: Infectious diseases
Country:
Trial details:
Latest
news: * On May 8, 2014, AiCuris and Merck&Co announced the publication of results from a Phase 2 clinical trial evaluating the safety and efficacy of letermovir 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&Co plans to conduct a Phase 3 trial of letermovir, starting in the first half of 2014. 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. 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 for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation. Roy F. Chemaly, M.D., Andrew J. Ullmann, M.D., Susanne Stoelben, M.D., Marie Paule Richard, M.D., Martin Bornhäuser, M.D., Christoph Groth, M.D., Hermann Einsele, M.D., Margarida Silverman, M.D., Kathleen M. Mullane, M.D., Janice Brown, M.D., Horst Nowak, Ph.D., Katrin Kölling, M.Sc., Hans P. Stobernack, D.V.M., Peter Lischka, Ph.D., Holger Zimmermann, Ph.D., Helga Rübsamen-Schaeff, Ph.D., Richard E. Champlin, M.D., and Gerhard Ehninger, M.D. for the AIC246 Study Team. N Engl J Med 2014; 370:1781-1789 -May 8, 2014DOI: 10.1056/NEJMoa1309533du-produit/?id_dnp=6) * On February 14, 2012, AiCuris has announced positive results from its placebo-controlled and dose-ranging trial with Letermovir (AIC246). 133 HCMV-seropositive allogeneic human blood precursor cell (HBPC) recipients were included in the trial. Given orally for 84 days, the two dosages of Letermovir, 120 mg and 240 mg once daily, meet both primary efficacy endpoints with high statistical significance vs. placebo. The efficacy endpoints are defined as incidence and time to onset of “HCMV prophylaxis failure”. Under Letermovir treatment such failure, defined as development of systemic detectable HCMV replication (viral load above assay cut-off of 42 DNA copies/ml) or HCMV End-Organ Disease, is suppressed.
In the primary Full Analysis Population, the incidence of failure due to efficacy failure of prophylaxis or due to discontinuation of treatment for any other reason prior to Day 84, is significantly lower in the Letermovir 240 mg/day (29.4%; p=0.007) and 120 mg/day (32.3%; p=0.014) groups compared to placebo (63.6%). The incidence of HCMV prophylaxis failure amongst patients receiving treatment for at least seven days prior to HCMV replication was none for Letermovir 240 mg (p=0.004 vs. placebo) and only 2 patients for Letermovir 120 mg (p=0.109 vs. placebo). Similarly, the time to onset of prophylaxis failure among patients receiving 240 mg/day of Letermovir was significantly different (p=0.02) compared to patients receiving placebo.
Letermovir, whatever the daily dosage, is safe and well tolerated. In addition, the analysis of safety demonstrates that - in all Letermovir groups combined - the percentage of patients with at least one treatment emergent adverse event (TEAE) either considered related to the treatment by the investigator, or leading to discontinuation of treatment (17.3% and 25.5%, respectively) is lower than in the placebo group (33.3% and 57.6%, respectively). On the basis of these results with Letermovir in transplant recipients, Aicuris is now preparing phase III development.
