%0 Journal Article
%T Adjunctive pascolizumab in rifampicin-susceptible pulmonary tuberculosis: proof-of-concept, partially-randomised, double-blind, placebo-controlled, dose-escalation trial.
%A Paton NI
%A Gurumurthy M
%A Lu Q
%A Leek F
%A Kwan P
%A Koh HWL
%A Molton J
%A Mortera L
%A Naval S
%A Abu Bakar Z
%A Pang YK
%A Lum L
%A Lim TK
%A Cross GB
%A Lekurwale G
%A Choi H
%A Au V
%A Connolly J
%A Hibberd M
%A Green JA
%A
%J J Infect Dis
%V 0
%N 0
%D 2024 Mar 25
%M 38527849
%F 7.759
%R 10.1093/infdis/jiae104
%X BACKGROUND: Interleukin-4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanised anti-IL-4 monoclonal antibody) as adjunctive tuberculosis treatment.
METHODS: Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo; and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts: [1] non-randomised 0.05 mg/kg (n = 4); [2] non-randomised 0.5 mg/kg (n = 4); [3] randomised 2.5 mg/kg (n = 9) or placebo (n = 3); [4] randomised 10 mg/kg (n = 9) or placebo (n = 3). Co-primary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE); in all cohorts (1-4). Co-primary efficacy outcome was week-8 sputum culture time-to-positivity (TTP); in randomised cohorts (3-4) combined.
RESULTS: Pascolizumab levels exceeded IL-4 50% neutralising dose for 8 weeks in 78-100% of participants in cohorts 3-4. There were no study-drug-related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (p = 0.185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 [95% Bayesian credible interval 0.006 to 0.015] log10TTP/day.
CONCLUSIONS: There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti-IL-4 interventions for tuberculosis in larger phase 2 trials.