Adjunctive Pascolizumab in Rifampicin-Susceptible Pulmonary Tuberculosis: Proof-of-Concept, Partially-Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial
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 ,   Pascolizumab Tuberculosis Trial Team, Gurumurthy Meera , Molton James , Naftalin Claire , Yeo Benjamin , Papineni Padmasayee , Cross Gail , Kwan Philip , Paton Nicholas , Rutkute Kristina , Jun Ling , Pang Yan , Choi Hyungwon , Koh Hiromi Wai Ling , Townsend David , Totman John , Leek Francesca , Thomas Benjamin , Lim Tow Keang , Lum Lionel , Molton James , Cross Gail , Naftalin Claire , Pang Yan , Paton Nicholas , Xie Grace , Qi Xie , Yu Bu Duo , Lin Yuchen , Lim Yin Shan , Teoh Siang Nee , Jureen Roland , Chia Donald , Chiu Cindy , Kin Khor Lih , Hallinan James , Tee Felicia , Boon Eng Chon , Lu Qingshu , Ng Siok Ting , Quek Timothy , Tan Siew Hoon , Kee Koh Sze , Hsing Sandra , Ping Tan Choon , Suelyn Lau , Yeo Jane , Han Ho Shuet , Lekurwale Ganesh , Jie Su , Pokharkar Yogesh , Moorakonda Rajesh , Hibberd Martin , deSessions Paola , Periaswamy Bala , Chu Collins , Connolly John , Au Veonice , Chua Gerald , Lin Lin , Hian Wan , Tee Augustine , Hong Samuel , Razak Dato Abdul , Bakar Zamzurina Abu , Pang Yong-Kek , Azwin Nur , Tahir Amirah Mohamed , Jalil Abdul , Mortera Lalaine , Tadeo Megan , Tadeo Frances , Santos Fria Los , Bulicatin Alden , Del Rosario Zyra , Geronimo Anthony , Bernardino Mark , Guda Glaiza Erika , Peng Yong Wei , Gee Lim Seng , Har Tan Tiong , Low Jenny , Green Justin , Dixon Susan , Springman Nathanael , Rousell Vicki , Lee Thomas , Orr Bonnie , Chen Keguan , DeWall Stephen , Webster Alison , Cammack Nick 
Published: March 2024

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.