Abbie Oey, Matthew McClure, Julian A. Symons, Sushmita Chanda, John Fry, Patrick F. Smith, Kathia Luciani, Michael Fayon, Kulkanya Chokephaibulkit, Rattapon Uppala, Jolanta Bernatoniene, Kenji Furuno, Thorsten Stanley, Dymphy Huntjens, James Witek ,on behalf of the 503 and RSV2004 Study Groups
Abstract
Respiratory syncytial virus (RSV) infection is the leading cause of infant hospitalizations and mortality. Lumicitabine, an oral nucleoside analog was studied for the treatment of RSV. The phase 1b and phase 2b studies reported here assessed the safety, pharmacokinetics, and pharmacodynamics of lumicitabine in infants/neonates hospitalized with RSV. In the phase 1b study, infants (≥1 to ≤12 months) and neonates (<28 days) received a single-ascending or multiple-ascending doses (single loading dose [LD] then 9 maintenance doses [MD] of lumicitabine, or placebo [3:1]). In the phase 2b study, infants/children (28 days to ≤36 months old) received lumicitabine 40/20 mg/kg, 60/40 mg/kg LD/MD twice-daily or placebo (1:1:1) for 5 days. Safety, pharmacokinetics, and efficacy parameters were assessed over 28 days. Lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia. Plasma levels of ALS-008112, the active nucleoside analog, were dose-proportional with comparable mean exposure levels at the highest doses in both studies.
Introduction
Respiratory Syncytial Virus (RSV), a ribonucleic acid (RNA) virus belonging to the Pneumoviridae family, has two serotypes, A and B, which co-circulate [1]. Lower respiratory tract infections due to RSV are among the leading global health ailments with an annual occurrence of 34 million cases, leading to significant morbidity and mortality [2]. According to the World Health Organization, RSV accounts for >60% of acute respiratory infections in children globally, and >80% of lower respiratory tract infections in infants annually during the peak of the viral season [3]. Children and infants with heart or lung medical conditions or adults with chronic obstructive pulmonary disease or asthma are the most vulnerable to lower respiratory tract-associated complications with increased risk of hospitalizations [4].
Materials and method
Study 1 was a randomized, double-blind, placebo-controlled, 2-part, phase 1b study to assess the safety, PK and PD of single- and multiple-ascending doses (SAD/MAD) of oral lumicitabine in neonates and infants (aged 1 to 12 months) hospitalized with RSV infection. The starting dose of lumicitabine was selected based on an estimation of human efficacious doses projected to be the lowest potential therapeutic dose from the pediatric PK modeling.
Results
In the SAD phase of Study 1, 70 patients were randomized and treated in 8 countries: United Kingdom (n = 16), Panama (n = 13), Thailand (n = 13), France (n = 10), Chile (n = 6), New Zealand (n = 6), Colombia (n = 5), and Australia (n = 1). Of these, 53 were randomized to 1 of 4 doses of lumicitabine (1.37 mg/kg, n = 18; 4.1 mg/kg, n = 18; 12 mg/kg, n = 14; 25 mg/kg, n = 3), while 17 were randomized to placebo. In all, 66 patients completed the SAD phase of the study (Fig 1). In the MAD phase, 113 patients were randomized in 11 countries: Japan (n = 38), USA (n = 22), Thailand (n = 14), Panama (n = 12), United Kingdom (n = 6), Chile (n = 6), Taiwan (n = 5), France (n = 4), New Zealand (n = 3), Colombia (n = 2), and Australia (n = 1). Of the 113 patients, 79 were randomized to 1 of 6 regimens of lumicitabine (4.1/1.37 mg/kg, n = 5; 10/2 mg/kg, n = 15; 30/6 mg/kg, n = 8; 30/10 mg/kg, n = 17; 40/20 mg/kg, n = 18; 60/40 mg/kg, n = 16), whereas 34 were randomized to placebo.
Discussion
The given phase 1b and phase 2b studies evaluated the safety, PK, and efficacy of lumicitabine in infants hospitalized with RSV infection. They were undertaken following promising outcomes from preclinical studies and an RSV-A human challenge study in healthy adults [10, 11, 14]. This challenge study demonstrated that lumicitabine treatment resulted in more rapid RSV clearance, and a greater reduction in the RSV viral load and the RSV symptom score compared with placebo. Additionally, lumicitabine was found to be generally safe; AEs were balanced in terms of frequency and intensity across treatment arms with no evidence of drug-related hematologic abnormalities.
Acknowledgments
We acknowledge Hein Fennema, PhD for statistical analysis. Vaibhav Deshpande, PhD (SIRO Clinpharm Pvt. Ltd.) provided medical writing assistance. Bradford Challis, PhD and Robert Achenbach (Janssen Global Services, LLC) provided additional editorial support for this manuscript. The authors thank the study participants and their parents, without whom this study would not have been accomplished, as well as the investigators and study coordinators for their contributions to this study. RSV503 and RSV2004 Study Group Members: Mina Pastagia, Leen Vijgen: Janssen Research & Development, LLC; Keith Nieforth: Certara Strategic Consulting, Parsippany, NJ, USA; Jeff Sorbel: Triangle, Biostatistics LLC, Raleigh, NC, USA; John P DeVincenzo MD: University of Tennessee Health Sciences Center, Memphis, TN, USA; Jolanta Bernatoniene: Upper Maudlin Street, Bristol BS2 8AE, UK.
Citation: Oey A, McClure M, Symons JA, Chanda S, Fry J, Smith PF, et al. (2023) Lumicitabine, an orally administered nucleoside analog, in infants hospitalized with respiratory syncytial virus (RSV) infection: Safety, efficacy, and pharmacokinetic results. PLoS ONE 18(7): e0288271. https://doi.org/10.1371/journal.pone.0288271
Editor: Satyajit Mohapatra, SRM Medical College Hospital and Research Centre, INDIA
Received: January 19, 2022; Accepted: April 25, 2023; Published: July 19, 2023
Copyright: © 2023 Oey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files. All data generated or analyzed during this study are included in this published article and its supplementary information files. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access [YODA] Project site at http://yoda.yale.edu.
Funding: This work was supported by Janssen Research & Development, LLC. The sponsor was responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Competing interests: Abbie Oey, Matthew McClure, Julian A. Symons, Sushmita Chanda, John Fry, Dymphy Huntjens, and James Witek are current or former employees of Janssen Research & Development and may own stock/stock options in Johnson & Johnson. Patrick Smith works for Certara, a consulting firm in integrated drug development and has directly consulted with a variety of not‐for‐profit global health organizations, biotechnology, and pharmaceutical companies and governments with an interest in medical countermeasures against respiratory virus infections. Kathia Luciani, Michael Fayon, Kulkanya Chokephaibulkit, Rattapon Uppala, Jolanta Bernatoniene, Kenji Furuno, and Thorsten Stanley have no potential conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0288271#abstract0
