An observer-blind, randomised, placebo-controlled, phase 1, single ascending dose study of dengue monoclonal antibody in healthy adults in Australia.

ABSTRACT

BACKGROUND: Dengue is highly prevalent in Asia and Latin America and has no specific dengue antiviral treatment. A recombinant monoclonal antibody (VIS513) that neutralises all four serotypes of the dengue virus has been developed in India. After confirmation of safety and efficacy in preclinical studies, it was tested in a first-in-human study to assess the safety and pharmacokinetics. METHODS: This was a partially blind (observer-blind), randomised, placebo-controlled, phase 1, single ascending dose study in Australia. Participants were dengue naive, healthy adults (aged 18-45 years) with no clinically significant disorders or immunosuppressive conditions. Four dose levels of dengue monoclonal antibody (ie, 1 mg/kg, 3 mg/kg, 7 mg/kg, and 12 mg/kg; n=4 for 1 mg/kg and n=10 each for 3 mg/kg, 7 mg/kg, and 12 mg/kg doses) were assessed in a dose-ascending way with a placebo control (n=2 for each dose cohort, total n=6) for each cohort except for 1 mg/kg. Within each cohort, participants were first randomly assigned (11) in a sentinel sub-cohort and then randomly assigned (91) in an expansion sub-cohort to dengue monoclonal antibody or placebo except for the 1 mg/kg cohort. Participants, investigators, and outcome assessors were masked and treatment administrators were not masked. 40 participants received a single intravenous injection or infusion of either dengue monoclonal antibody or placebo over a period of 3 min to 2 h and were followed up until day 85. The primary outcomes were proportion of participants with adverse events and serious adverse events (SAEs) up to 84 days after dosing whereas the secondary outcomes were to assess the pharmacokinetic profile of dengue monoclonal antibody and to assess the presence of anti-drug antibody (ADA) to dengue monoclonal antibody. All participants were included in the safety analysis and the pharmacokinetic population involved participants receiving dengue monoclonal antibody. This study is registered with ClinicalTrials.gov, NCT03883620. FINDINGS: Between March 22 and Dec 23, 2019, 40 healthy adults were randomly assigned and all completed the study. There were no SAEs reported. None of the placebo recipients (n=6) reported any adverse events. 31 (91%) of 34 participants receiving dengue monoclonal antibody reported 143 adverse events (1 mg/kg four [100%] of four participants; 3 mg/kg ten [100%] of ten participants; 7 mg/kg seven [70%] of ten participants; 12 mg/kg ten [100%] of ten participants). Of these 143 adverse events, 80 were treatment-related adverse events in 28 (82%) of 34 participants. Headache (16 [47%] of 34), infusion reaction (11 [32%] of 34), lymphopenia (seven [21%] of 34), fatigue (five [15%] of 34), and pyrexia (four [12%] of 34) were the most common reactions. Infusion reactions were reduced in the 7 mg/kg (two [20%] of ten participants) and 12 mg/kg (three [30%] of ten) cohorts with paracetamol premedication compared with the 3 mg/kg cohort (five [50%] of ten). The majority of adverse events were grade 1 or grade 2 in severity, and resolved completely. Median maximum serum concentrations ranged from 28 µg/mL (1 mg/kg) to 525 µg/mL (12 mg/kg). The median elimination half-life ranged from 775 h (1 mg/kg) to 878 h (12 mg/kg). No ADA against dengue monoclonal antibody was detected. INTERPRETATION: Dengue monoclonal antibody was safe and well tolerated. It showed a dose-proportionate increase in pharmacokinetic exposure. These data support further evaluation of dengue monoclonal antibody in patients with dengue for safety and efficacy. FUNDING: Serum Institute of India.