Articles
Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial

https://doi.org/10.1016/S2213-2600(20)30320-9Get rights and content

Summary

Background

Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX-0171 is a novel trivalent Nanobody with antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in children admitted to hospital with RSV lower respiratory tract infection.

Methods

This double-blind, randomised, placebo-controlled, phase 2b trial was done in 50 hospital paediatric departments across 16 countries. Previously healthy children aged between 28 days to younger than 24 months who were admitted to hospital with RSV acute severe lower respiratory tract infection were randomly assigned in three sequential safety cohorts (3:1) to receive nebulised ALX-0171 (cohort 1 received 3 mg/kg, cohort 2 received 6 mg/kg, and cohort 3 received 9 mg/kg) or placebo once daily for 3 days using web-based randomisation in the sequential safety part (first block size 12, subsequently four). In a parallel part of the study, participants (cohort 4) were randomly assigned (parallel 1:1:1:1) to receive nebulised ALX-0171 3 mg/kg, 6 mg/kg, 9 mg/kg, or placebo (blocks of eight by restricted randomisation). Study drug masking was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. The primary outcome was to evaluate time for the RSV viral load to drop to below quantifiable limit, measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical efficacy, pharmacokinetics, viral load by RT-qPCR, and immunogenicity were secondary outcomes. Analysis, including of the primary outcome, was by modified intention to treat (participants receiving at least one dose of study drug as assigned), and safety was assessed in all children who received at least one administration of study drug, as treated. This trial is registered with EudraCT, 2016-001651-49.

Findings

Between Jan 10, 2017, and April 26, 2018, 175 children (median age 4·8 months [IQR 2·0–10·8]), received at least one dose of study drug (45 received 3 mg/kg of ALX-0171, 43 received 6 mg/kg of ALX-0171, 45 received 9 mg/kg of ALX-0171, and 42 received placebo; the modified intention-to-treat population) commencing at a mean 3·3 days (SD 1·1) from symptom onset. Median time for the viral load to drop to below quantifiable limit on plaque assay was significantly faster for the 3 mg/kg group (median 14·2 h [IQR 5·0–28·0]), 6 mg/kg group (5·1 h [4·7–28·5]), and 9 mg/kg group (5·1 h [4·6–5·9]) than the placebo group (46·1 h [25·2–116·7]; hazard ratio [HR] all ALX-0171 groups vs placebo 2·6 [1·7–3·9]; p<0·0001). Median time for the viral load to drop below quantification limit with RT-qPCR was 95·9 h (IQR 26·7 to not estimable) for the placebo group (n=35) versus 49·4 h (25·1 to 351·4) for all ALX-0171 groups (n=118). Clinical outcomes were not improved by ALX-0171 compared with placebo, with no difference in time to clinical response (oxygen saturation >92% for 4 h in room air and adequate oral feeding) in ALX-0171 groups and the placebo group (median 43·8 h [IQR 21·7–68·5] vs 47·9 h [22·5–76·4]; HR 1·1 [95% CI 0·8–1·6]) or change in the global severity score from baseline to 5 h post-dose on day 2 (−4 [IQR −6 to −2] vs −4 [–6 to −1]; difference in least-squares mean −0·45 [95% CI −1·39 to 0·49]). Serum concentrations of ALX-0171 on day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 mg/kg and 9 mg/kg doses. Treatment-emergent antidrug antibodies were detected at day 14 in 46 (34%) of 135 patients who received ALX-0171 and ten (26%) of 39 patients who received placebo. Serious adverse events were reported in five (13%) of 40 children in the placebo group and ten (7%) of 135 children in all ALX-0171 groups, leading to study drug discontinuation in three children (two in the 3 mg/kg group and one in the 6 mg/kg group). 13 of 15 serious adverse events (three of four in the 3 mg/kg group, two of three in the 6 mg/kg group, three of three in the 9 mg/kg group, and five of five in the placebo group) were related to worsening respiratory status, and none were considered to be related to the study drug.

Interpretation

Antivirals against RSV might be unable to improve clinical course once RSV lower respiratory tract infection is established. Future studies of RSV antivirals should focus on earlier intervention and more precise measurement of objective outcomes before the onset of significant lower respiratory tract inflammation.

Funding

Ablynx, a Sanofi Company.

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)

  • Diagnosis and management of bronchiolitis

    Pediatrics

    (2006)
  • JP DeVincenzo et al.

    Oral GS-5806 activity in a respiratory syncytial virus challenge study

    N Engl J Med

    (2014)
  • JP DeVincenzo et al.

    Activity of oral ALS-008176 in a respiratory syncytial virus challenge study

    N Engl J Med

    (2015)
  • D Hanfelt-Goade et al.

    A phase 2b, randomized, double-blind, placebo-controlled trial of presatovir (GS-5806), a novel oral RSV fusion inhibitor, for the treatment of respiratory syncytial virus (RSV) in hospitalized adults

    Am J Respir Crit Care Med

    (2018)
  • FM Marty et al.

    A phase 2b, randomized, double-blind, placebo-controlled multicenter study evaluating antiviral effects, pharmacokinetics, safety, and tolerability of presatovir in hematopoietic cell transplant recipients with respiratory syncytial virus (RSV) infection of the lower respiratory tract

    Clin Infect Dis

    (2019)
  • A Larios Mora et al.

    Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

    MAbs

    (2018)
  • AJ Justicia-Grande et al.

    Development and validation of a new clinical scale for infants with acute respiratory infection: the ReSVinet scale

    PLoS One

    (2016)
  • Germani MNC, Kanacher T, Stohr T, Detalle L, Wendl T, Sargentini L. A physiologically-based pharmacokinetic (PB-PK)...
  • SC Buckingham et al.

    Nasal quantity of respiratory syncytical virus correlates with disease severity in hospitalized infants

    Pediatr Infect Dis J

    (2000)
  • E Uusitupa et al.

    Association of viral load with disease severity in outpatient children with respiratory syncytial virus infection

    J Infect Dis

    (2020)
  • Cited by (0)

    Members of the RESPIRE study group are listed in the appendix

    View full text