Luzelena Caro (United States of America)
Merck & Co., Inc ResearchAuthor Of 1 Presentation
PHARMACOKINETICS AND SERUM NEUTRALIZING ACTIVITY FROM A PHASE 1B/2A STUDY IN INFANTS SUPPORT MODEL-BASED EFFICACY PREDICTIONS FOR MK-1654, AN RSV NEUTRALIZING MONOCLONAL ANTIBODY
Abstract
Backgrounds:
MK-1654 is an investigational RSV-neutralizing monoclonal antibody in development for the prevention of medically-attended lower respiratory tract infection (MALRI) in infants. This work summarizes interim pharmacokinetic (PK) and serum neutralizing antibody (SNA) results in infants. The efficacy of MK-1654 is also predicted using a published model.
Methods
This phase 1b/2a double-blind, randomized, placebo-controlled, study evaluated the safety, tolerability, PK, and SNA of MK-1654 in pre-term (born 29-35 weeks gestational age) and full-term infants. Participants (n=180) 2 weeks to 8 months of age were randomized in a 4:1 ratio within five separate panels (pre-term: 20, 50, 75 or 100-mg, full-term: 100mg) to receive a single intramuscular dose of MK-1654 or placebo. Blood samples were collected to quantify MK-1654 serum concentrations and SNA titers. A preliminary population PK (popPK) model was developed to describe PK of MK-1654 in infants. The efficacy of MK-1654 was predicted using clinical trial simulations which were based on the popPK model and a published model-based meta-analysis.
Results:
Concentration data from 111 pre-term infants and 32 full-term infants through at least 150 days post-administration were available. The pharmacokinetics of MK-1654 were best characterized by a linear two-compartment popPK model with first-order absorption and elimination. Clearance and volume of distribution (Vd) were scaled allometrically using time-varying body weight. Age was also a covariate on Vd. The half-life of MK-1654 was approximately 42 days. A linear relationship was observed between increasing concentrations of MK-1654 and increasing SNA. Clinical trial simulations predict that a single dose of ≥75 mg of MK-1654 will provide >75% efficacy for the prevention of RSV MALRI for a duration of 5 months in infants.
Conclusions/Learning Points:
These findings support the continued evaluation of MK-1654 in ongoing Phase 3 studies.