Pharmacokinetics and Safety of Letermovir and Midazolam Coadministration in Healthy Subjects.

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem-cell transplant recipients. In vitro studies have identified letermovir as a potential cytochrome P450 (CYP) 3A inhibitor. Thus, the effect of letermovir on the CYP3A isoenzyme-specific probe drug midazolam was investigated in a phase 1 trial. Healthy female subjects received single-dose intravenous (IV; 1 mg) and oral (2 mg) midazolam on days -4 and -2, respectively. Letermovir 240 mg once daily was administered on days 1 to 6, and further single doses of midazolam 1 mg IV and oral midazolam 2 mg were administered on days 4 and 6, respectively. Pharmacokinetics, tolerability, and safety were monitored throughout the trial. Following coadministration with letermovir, the least square means ratio for maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last measurable concentration was 172.4% and 225.3%, respectively, for oral midazolam, and 105.2% and 146.6%, respectively, for midazolam IV. The area under the plasma concentration-time curve from time 0 to the last measurable concentration ratio of midazolam to 1-hydroxymidazolam increased slightly in the presence of letermovir following IV (8.8-13.1; 49% increase) and oral (3.3-5.3; 59% increase) midazolam. Letermovir reached steady state, on average, by days 5 to 6. All treatments were generally well tolerated. Letermovir demonstrated moderate CYP3A inhibition.

The Effect of Oral Letermovir Administration on the Pharmacokinetics of a Single Oral Dose of P-Glycoprotein Substrate Digoxin in Healthy Volunteers.

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor approved in the United States, Canada, Japan, and the European Union for prophylaxis of CMV infection and disease in CMV-seropositive, allogeneic, hematopoietic stem-cell transplant recipients. In vitro, letermovir is a substrate and potential modulator of P-glycoprotein. The potential of letermovir to alter the pharmacokinetics of digoxin (a P-glycoprotein substrate) upon coadministration in healthy subjects was therefore investigated in a phase 1 trial (EudraCT: 2011-004516-39). Oral letermovir 240 mg was administered twice daily for 12 days with a single oral digoxin 0.5-mg dose on day 7; after a washout period, oral digoxin 0.5 mg was administered on day 35 (sequence 1). The period order was reversed after a 28-day washout for sequence 2. Pharmacokinetics and safety were evaluated. The presence of steady-state letermovir reduced digoxin area under the plasma concentration-time curve from administration until last quantifiable measurement by 12% and maximum plasma concentration by 22% compared with digoxin alone; digoxin half-life and elimination rate remained similar in both conditions. The between-subject variability of digoxin maximum plasma concentration was higher with letermovir than without (42% vs 31%) and similar for digoxin area under the plasma concentration-time curve in both periods. No specific safety or tolerability concerns were identified. Overall, letermovir had no clinically relevant effect on concomitant administration with digoxin.

The T cell-selective IL-2 mutant AIC284 mediates protection in a rat model of Multiple Sclerosis.

Targeting regulatory T cells (Treg cells) with interleukin-2 (IL-2) constitutes a novel therapeutic approach for autoimmunity. As anti-cancer therapy with IL-2 has revealed substantial toxicities a mutated human IL-2 molecule, termed AIC284 (formerly BAY 50-4798), has been developed to reduce these side effects. To assess whether AIC284 is efficacious in autoimmunity, we studied its therapeutic potential in an animal model for Multiple Sclerosis. Treatment of Lewis rats with AIC284 increased Treg cell numbers and protected the rats from Experimental Autoimmune Encephalomyelitis (EAE). AIC284 might, thus, also efficiently prevent progression of autoimmune diseases in humans.

Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance. METHODS: In this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection. RESULTS: The reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity. CONCLUSIONS: Letermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.).

Structures of ClpP in complex with acyldepsipeptide antibiotics reveal its activation mechanism.

Clp-family proteins are prototypes for studying the mechanism of ATP-dependent proteases because the proteolytic activity of the ClpP core is tightly regulated by activating Clp-ATPases. Nonetheless, the proteolytic activation mechanism has remained elusive because of the lack of a complex structure. Acyldepsipeptides (ADEPs), a recently discovered class of antibiotics, activate and disregulate ClpP. Here we have elucidated the structural changes underlying the ClpP activation process by ADEPs. We present the structures of Bacillus subtilis ClpP alone and in complex with ADEP1 and ADEP2. The structures show the closed-to-open-gate transition of the ClpP N-terminal segments upon activation as well as conformational changes restricted to the upper portion of ClpP. The direction of the conformational movement and the hydrophobic clustering that stabilizes the closed structure are markedly different from those of other ATP-dependent proteases, providing unprecedented insights into the activation of ClpP.