ArticlesNebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial
Introduction
Respiratory syncytial virus (RSV) is a common respiratory tract pathogen associated with annual epidemics, leading to increased requirement for health care in vulnerable populations (children, older people, and people with compromised immune systems) and substantial mortality in developing countries.1 Although RSV is the most common lower respiratory tract pathogen in children, an effective therapeutic option remains elusive2 and, as a consequence, is a global health priority.3, 4 Ribavirin, a nucleoside analogue with broad spectrum antiviral activity, has poor antiviral efficacy in treating RSV,5 and clinical guidelines do not recommend its use.6 RSV therapeutics, including vaccines, long-duration monoclonal antibodies, and antivirals are in a rapid phase of development.7 The novel candidate antivirals, presatovir and lumicitabine, have demonstrated significant RSV antiviral activity when tested in adult human challenge models,8, 9 but so far these antivirals have not been able to demonstrate similar antiviral or clinical efficacy in target populations10, 11 (EudraCT results 2013-005104-33).
Nanobodies are a novel class of therapeutic proteins, based on the naturally occurring smallest functional fragments of single-chain antibodies in the Camelidae family. ALX-0171 is a trivalent Nanobody directed towards the RSV fusion protein, designed to prevent viral entry into host cells. Because RSV causes lower respiratory tract infection in humans, ALX-0171 was developed as a nebulisation solution to enable direct deposition at the site of infection. Nebulised ALX-0171 was able to reduce viral load in airway secretions and improve clinical symptoms and lung pathology in a newborn lamb model infected with human RSV, even when commenced 3 days after infection to mirror use in infants.12 In a preparatory multicentre phase 1/2a study in 53 otherwise healthy young children admitted to hospital with RSV lower respiratory tract infection, nebulised ALX-0171 (target dose of 1·2 mg/kg) demonstrated a rapid reduction in nasal RSV viral titres (assessed by a plaque assay) with no safety concerns (EudraCT 2014-002841-23). We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in otherwise healthy young children admitted to hospital with RSV lower respiratory tract infection (the RESPIRE trial).
Section snippets
Study design and participants
We did a double-blind, randomised, placebo-controlled, phase 2b trial in 50 hospital paediatric departments in 16 countries (appendix p 1).
Otherwise healthy children were eligible if they were aged between 28 days and younger than 2 years with gestational age of 33 weeks or more, and admitted to hospital with a lower respiratory tract infection within 4 days of onset of symptoms, supported by a positive local RSV diagnostic test. Children also needed to fulfil at least two of three RSV disease
Results
Between Jan 10, 2017, and April 26, 2018, 301 children were screened and 180 of these children were randomised (figure 1). 45 children in the 3 mg/kg group, 43 children in the 6 mg/kg group, 45 children in the 9 mg/kg group, and 42 children in the placebo group received at least one dose of study drug (modified intention-to-treat population). Two children who were assigned to placebo each received one dose of active treatment by error and were included in the modified intention-to-treat
Discussion
ALX-0171 was effective in rapidly and significantly reducing the time for infectious RSV viral load to drop below the quantification limit, as measured in mid-turbinate nasal swabs in children younger than 24 months who were admitted to hospital for an RSV lower respiratory tract infection. The observed decline in RSV viral load was not associated with a correspondingly earlier clinical improvement.
To our knowledge, nebulised ALX-0171 is the first RSV-specific therapeutic for which antiviral
Data sharing
Qualified researchers can request access to patient-level data and related documents (including, for example, the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications). Patient-level data will be anonymised, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data-sharing criteria, eligible studies, and process for requesting access can be found at //www.clinicalstudydatarequest.com
References (41)
- et al.
Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study
Lancet
(2017) - et al.
Determining the burden of respiratory syncytial virus disease: the known and the unknown
Lancet
(2017) - et al.
Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics
Lancet Respir Med
(2015) - et al.
Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial
Lancet
(2015) - et al.
Determining the outcomes of interventions to prevent respiratory syncytial virus disease in children: what to measure?
Lancet Respir Med
(2018) - et al.
A phase 2b randomized controlled trial of presatovir, an oral RSV fusion inhibitor, for the treatment of respiratory syncytial virus (RSV) in lung transplant (LT) recipients
J Heart Lung Transplant
(2018) - et al.
Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial
Lancet
(2020) Viral bronchiolitis in children
N Engl J Med
(2016)- et al.
Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study
Lancet
(2019) - et al.
Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children
Cochrane Database Syst Rev
(2007)