A Phase 1 Randomized, Double‐Blind, Placebo‐Controlled Trial to Assess the Safety, Tolerability, and Pharmacokinetics of a Respiratory Syncytial Virus Neutralizing Monoclonal Antibody MK‐1654 in Healthy Adults

Abstract

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection and related morbidity and mortality in infants. Passive immunization with an RSV-neutralizing antibody can provide rapid protection to this vulnerable population. Proof-of-concept for this approach has been demonstrated by palivizumab; however, the use of this antibody is generally restricted to the highest-risk infants due to monthly dosing requirements and its cost.To address the large unmet medical need for most infants, we are evaluating MK-1654, a fully human RSV-neutralizing antibody with half-life extending mutations targeting site IV of the fusion protein. In this 2-part, placebo-controlled, double-blind, first-inhuman study, 152 healthy adults were randomized 3:1 to receive a single dose of MK-1654 or placebo in 5 cohorts (100 or 300 mg as an intramuscular dose or 300, 1000, or 3000 mg as an intravenous dose). Safety, pharmacokinetics, antidrug antibodies, and RSV serum-neutralizing antibody titers were evaluated through 1 year. MK-1654 serum concentrations increased proportionally with dose and resulted in corresponding elevations in RSV serum-neutralizing antibody titers. The antibody displayed a half-life of 73 to 88 days and an estimated bioavailability of 69% at the 300-mg dose. The overall safety profile of MK-1654 was similar to placebo, and treatment-emergent antidrug antibodies were low (2.6%) with no associated adverse events. These data support the continued development of MK-1654 for the prevention of RSV disease in infants.

Passive Immunoprophylaxis against Respiratory Syncytial Virus in Children: Where Are We Now?

“…The advantage of a mAb that binds these specific epitopes consists in the neutralization and consequent protection from diverse RSV A and B strains. Preclinical studies demonstrated a potent in vivo protection in cotton rats [ 99 , 100 ]. MK-1654 can be considered an improved version of RB1.…”

“…Currently, MK-1654 is the object of clinical trials. In a double-blinded, Phase 1 study involving 152 healthy adult volunteers, it resulted safe as the placebo and its half-life amounted to an average of 73–88 days [ 100 ]. A Phase 2a trial enrolled 80 healthy adults to determine if a single intravenous dose of MK-1654, when administered at one of four dose levels, decreases viral RSV load compared to placebo.…”

Bringing Preventive RSV Monoclonal Antibodies to Infants in Low- and Middle-Income Countries: Challenges and Opportunities

“…The safety data, to date, from nirsevimab and MK-1654 studies in adults and infants, have been favorable. The overall safety profile in phase 1 studies in adults, with dosing 5 to 10 times the target infant doses, is similar to that of placebo [ 51 , 52 ]. In the phase 2b study, in which approximately 900 infants received nirsevimab, no anaphylaxis or other notable hypersensitivity reactions were observed.…”

Sendai Virus-Vectored Vaccines That Express Envelope Glycoproteins of Respiratory Viruses

“…Antibodies obtained from adults (pre-immune to HRSV) were once used routinely to passively protect infants from HRSV [17]. More recently, monoclonal antibodies are used to prevent serious infections with HRSV in vulnerable children [18][19][20]. While passive treatments can provide short-term protection, vaccines are needed to induce stable, endogenous virus-specific antibodies and T cells in young infants prior to a first virus exposure.…”

“…Messenger RNA (mRNA) vaccines have come to the forefront of vaccine development in the SARS-CoV-2 field [82,83] and will assist the generation of multiple, new vaccine candidates for the paramyxovirus and pneumovirus fields [18]. Given the extraordinary effort dedicated to vaccine development for the paramyxoviruses and pneumoviruses, one can expect that new, licensed vaccine products are in sight.…”