Adjunctive Pascolizumab in Rifampicin-Susceptible Pulmonary Tuberculosis: Proof-of-Concept, Partially-Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial

• Published in: The Journal of infectious diseases Vol. 230; no. 3; pp. 590 - 597
• Main Authors: Paton, Nicholas I, Gurumurthy, Meera, Lu, Qingshu, Leek, Francesca, Kwan, Philip, Koh, Hiromi W L, Molton, James, Mortera, Lalaine, Naval, Sullian, Bakar, Zamzurina Abu, Pang, Yong-Kek, Lum, Lionel, Lim, Tow Keang, Cross, Gail B, Lekurwale, Ganesh, Choi, Hyungwon, Au, Veonice, Connolly, John, Hibberd, Martin, Green, Justin A
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 23.09.2024
• Subjects: Adult; Animal models; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Antitubercular Agents - administration & dosage; Antitubercular Agents - adverse effects; Antitubercular Agents - therapeutic use; Bayesian analysis; Clinical trials; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Drug Therapy, Combination; Female; Humans; Interleukin 4; Male; Mathematical models; Middle Aged; Monoclonal antibodies; Placebos; Placebos - administration & dosage; Proof of Concept Study; Rifampin; Rifampin - administration & dosage; Rifampin - therapeutic use; Sputum; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary - drug therapy; Young Adult; interleukin-4; clinical trial; host-directed therapy; pascolizumab; tuberculosis
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiae104

Abstract 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 (humanized 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) nonrandomized 0.05 mg/kg (n = 4); (2) nonrandomized 0.5 mg/kg (n = 4); (3) randomized 2.5 mg/kg (n = 9) or placebo (n = 3); and (4) randomized 10 mg/kg (n = 9) or placebo (n = 3). Coprimary safety outcome was study-drug–related grade 4 or serious adverse event (G4/SAE) in all cohorts (1–4). Coprimary efficacy outcome was week 8 sputum culture time-to-positivity (TTP) in randomized cohorts (3–4) combined. Results Pascolizumab levels exceeded IL-4 50% neutralizing 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 = .185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 log10 TTP/day; 95% Bayesian credible interval 0.006 to 0.015 log10 TTP/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. Clinical Trials Registration NCT 01638520. We evaluated pascolizumab (anti–IL-4 monoclonal antibody) as adjunctive tuberculosis treatment. There were no pascolizumab-related serious or grade 4 adverse events. The rate of increase in time to positivity on serial sputum samples was consistent with faster clearance with pascolizumab. Graphical Abstract Graphical Abstract This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/adjunctive-pascolizumab-in-rifampicin-susceptible-pulmonary-tuberculosis-proof-of-concept-partially-randomised-double-blind-placebo-controlled-dose-escalation-trial-9e594d9e-cf68-436a-9ba9-28da9c59f211