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Clinical Trial
. 2022 Jul;15(7):1753-1763.
doi: 10.1111/cts.13290. Epub 2022 May 17.

A phase I study to evaluate safety, pharmacokinetics, and pharmacodynamics of respiratory syncytial virus neutralizing monoclonal antibody MK-1654 in healthy Japanese adults

Yuji Orito  1 , Naoyuki Otani  2 , Yuki Matsumoto  1 , Katsukuni Fujimoto  1 , Nobuyuki Oshima  1 , Brian M Maas  3 , Luzelena Caro  3 , Antonios O Aliprantis  3   4 , Kara S Cox  3 , Osamu Tokumaru  2 , Masaaki Kodama  2 , Hideo Kudo  2 , Hiromitsu Imai  2 , Naoto Uemura  2
Affiliations
Clinical Trial

A phase I study to evaluate safety, pharmacokinetics, and pharmacodynamics of respiratory syncytial virus neutralizing monoclonal antibody MK-1654 in healthy Japanese adults

Yuji Orito et al. Clin Transl Sci. 2022 Jul.

Abstract

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this unmet medical need, MK-1654, a half-life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo-controlled, single-site, double-blind trial of MK-1654 in 44 healthy Japanese adults. The safety, tolerability, pharmacokinetics, antidrug antibodies (ADAs), and serum neutralizing antibody (SNA) titers against RSV were evaluated for 1 year after a single intramuscular (i.m.) or intravenous (i.v.) dose of MK-1654 or placebo in five groups (100 mg i.m., 300 mg i.m., 300 mg i.v., 1000 mg i.v., or placebo). MK-1654 was generally well-tolerated in Japanese adults. There were no serious drug-related adverse events (AEs) reported in any MK-1654 recipient and no discontinuations due to any AEs in the study. The half-life of MK-1654 ranged from 76 to 91 days across dosing groups. Estimated bioavailability was 86% for 100 mg i.m. and 77% for 300 mg i.m. One participant out of 33 (3.0%) developed detectable ADA with no apparent associated AEs. The RSV SNA titers increased in a dose-dependent manner among participants who received MK-1654. These data support the development of MK-1654 for use in Japanese infants.

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Conflict of interest statement

Y.O., Y.M., K.F., N.O., B.M.M., L.C., and A.O.A. are employees (or were at the time of the study) of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may hold stock in Merck & Co., Inc., Rahway, NJ, USA. K.S.C. is an employee of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, may hold stock in Merck & Co., Inc., Rahway, NJ, USA, and is named on an issued patent related to the discovery of the RSV antibody. N.U. reports payments as a Primary Investigator for the study, is a paid consultant to MSD K.K. for general clinical pharmacology matters at the time of the conduct study, and holds stock in Merck & Co., Inc., Rahway, NJ, USA. All other authors declared no competing interest for this work. As an Associate Editor for Clinical & Translational Science, Naoto Uemara was not involved in the review or decision process for this paper.

Figures

FIGURE 1
FIGURE 1
Mean serum concentration‐time profiles after a single intravenous (i.v.) or intramuscular (i.m.) dose of MK‐1654 in healthy Japanese male adults. Arithmetic mean serum concentrations for each group versus time in days after administration. Error bars represent the standard deviation. Data include the 1000 mg i.v. group (N = 9), 300 mg i.v. group (N = 9), 300 mg i.m. group (N = 9), and 100 mg i.m. (N = 6). IM, intramuscular injection; IV, intravenous infusion over 2.5 h
FIGURE 2
FIGURE 2
RSV‐neutralizing antibody titers following a single intravenous (i.v.) or intramuscular (i.m.) administration of MK‐1654 or placebo in healthy Japanese male adults. RSV serum neutralization 50% inhibitory concentration (IC50) titers in log2 scale versus time. A titer of greater than 30 (4.9 in log2 scale) indicates the presence of RSV neutralizing antibody. Points represents the geometric mean of each group and error bars represent the 95% confidence intervals. Data include the 1000 mg i.v. group (N = 9), 300 mg i.v. group (N = 9), 300 mg i.m. group (N = 9), 100 mg i.m. (N = 6) and placebo (combined i.m. and i.v., N = 11). IM, intramuscular injection; IV, intravenous infusion over 2.5 h
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