AiCuris, Merck announce publication of Phase II study results for Letermovir in New England Journal of Medicine

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 III trial of letermovir, also known as AIC246 or MK-8228, starting in the first half of 2014.

The paper describes the findings of a Phase II 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, 240mg/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.

Merck Research Laboratories Infectious Diseases vice president Dr Eliav Barr said: "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."

In the Phase II 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 120mg/day or 240mg/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 240mg group (6%) than in the 120mg group (19%), the 60mg 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 240mg 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 240mg group and the placebo group after eight 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% of patients in the letermovir groups versus 61% in the placebo group. The majority of these events were of mild or moderate intensity; 24% of letermovir treated patients versus 30% 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.