Lumicitabine, an orally administered nucleoside analog, in infants hospitalized with respiratory syncytial virus (RSV) infection: Safety, efficacy, and pharmacokinetic results

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. There were no significant differences between the lumicitabine groups and placebo in reducing viral load, time to viral non-detectability, and symptom resolution. No emergent resistance-associated substitutions were observed at the RSV L-gene positions of interest. In summary, lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia and failed to demonstrate antiviral activity in RSV-infected hospitalized infants. This contrasts with the findings of the previous RSV-A adult challenge study where significant antiviral activity was noted, without incidence of neutropenia. Trial registration ClinicalTrials.gov Identifier: NCT02202356 (phase 1b); NCT03333317 (phase 2b).

Fig 1. Patient disposition in SAD and MAD phases of Study 1.

eMV, Need for endotracheal mechanical ventilation; ITT, intent-to-treat; MAD; multiple-ascending dose; SAD, single-ascending dose. Percentages based on the total number of patients randomized and treated in each treatment group. Patients completed SAD phase through Day 7 visit and completed MAD phase through Day 28 visit. *1 patient randomized but not treated. ^#Event of Neutropenia.

Fig 2. Patient disposition in Study 2.

Fig 3

Median Change from Baseline in RSV RNA Log₁₀ Viral Load Over Time in MAD Phase (Study 1, Full Analysis Set)–(A) Nasal Aspirates and (B) Nasal Swabs. MAD, multiple-ascending doses; PFUe, plaque-forming unit equivalents; RNA, ribonucleic acid; RSV, respiratory syncytial virus.

Fig 4

Time to RSV Non-Detectability in MAD Phase (Study 1, Full Analysis Set)–(A) Nasal Aspirates and (B) Nasal Swabs. MAD, multiple-ascending dose; RSV, respiratory syncytial virus. Time to non-detectability was defined as the relative time in hours from the first dose of study drug until the first post-baseline time point when the viral load reached non-detectability. Subjects whose viral load did not reach non-detectability were censored at their last RSV assessment. Time to non-detectability was not defined if a subject did not have any post-baseline viral load result.

Fig 5. Time from first dose to RSV symptom resolution in MAD phase (Study 1, full analysis set).

MAD, multiple-ascending dose; RSV, respiratory syncytial virus.

Fig 6. Mean (±SE) change from baseline in RSV RNA log₁₀ viral load over time (Study 2, ITT analysis set).

ITT, intent-to-treat; LD, loading dose; MD, maintenance dose; RNA, ribonucleic acid; RSV, respiratory syncytial virus; SE, standard error.RSV-A viral load LOQ (limit of quantification) = 3.00 log₁₀ copies/mL., LOD (limit of detection) = 2.79 log₁₀ copies/mL. RSV-B viral load LOQ = 2.40 log₁₀ copies/mL., LOD = 1.90 log₁₀ copies/mL. Results <LOQ and >LOD (target detected) are imputed with 2.90 or 2.15 log₁₀ copies/mL for resp. RSV-A or RSV-B. Results <LOD (target not detected) are imputed with 1.90 log₁₀ copies/mL.