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Background: The henipaviruses, Hendra virus and Nipah virus, are emerging zoonotic pathogens of bat origins that have been associated with poor clinical outcomes in humans. The monoclonal antibody (mAb) m102∙4 is a potent fully human antibody that neutralizes Hendra and Nipah viruses in vitro and in vivo. Clinical trials in humans represent the next stage in the utilization of this antibody in the prophylactic treatment and prevention of deaths from henipavirus infections. Methods: We performed a randomised, double-blind, placebo-controlled, singlecentre, dose escalation phase 1 study using the human monoclonal antibody m102∙4. Healthy adults aged 18-50 years with a body-mass index of 18.0 to ≤35.0 kg/m2 were assigned to one of five cohorts. A sentinel pair for each cohort was randomised in a 1:1 ratio to receive either active treatment or placebo. The remaining participants in each cohort were randomised 5:1 to receive m102∙4 or placebo. Cohorts 1 to 4 received a single intravenous infusion of m102∙4 at doses of 1, 3, 10, and 20 mg/kg respectively, and were monitored for 113 days. Cohort 5 received two infusions of 20 mg/kg, 72 hours apart, with monitoring for 123 days. The primary objective was to assess the safety and tolerability of single and multiple IV doses of m102∙4 mAb. We also assessed pharmacokinetics, immunogenicity, and virus neutralisation. Analyses were completed according to protocol. Findings: Between April 15, 2015 and June 16, 2016, 77 healthy adults were screened and 40 participants were enrolled in the study; eight were assigned to each cohort (six randomised to receive m102∙4, and two randomised to receive placebo per cohort). A total of 86 treatment-emergent adverse events were reported by the 40 participants with similar rates between placebo and active treatment groups. Thirty-one events reported in 20 participants (50%) receiving m102∙4 were considered treatment-related, and six events were reported in five participants (50%) receiving placebo. A possible trend of treatment-related headaches with m102∙4 was noted; this was reported in 66.7% of participants administered singledose m102∙4 compared with 10% of those administered placebo. There was no increase in treatment-related headaches among those with repeat dosing. There were no deaths or severe adverse events leading to withdrawals or premature discontinuations during the study. Pharmacokinetics based on those receiving active treatment (n=30) were linear, with the mean halflife ranging from 16.5 to 27.6 days across Cohorts 1-4. There was small to moderate accumulation of monoclonal antibody in those receiving a repeat dose (Cohort 5), with elimination kinetics that were comparable to those receiving a single dose. Anti-m102∙4 antibodies were not detected at any time-point during the study. All serum samples at all time points exhibited virus-neutralisation activity when tested in vitro for both HeV and NiV. Interpretation: m102∙4 single and repeated dosing of up to two doses separated by 3 days appears to be safe and well tolerated when administered to healthy adult volunteers. A standard pharmacokinetic profile was observed with linear elimination kinetics. There was no evidence of an immunogenic response to m102∙4. Exploratory virus neutralisation studies confirmed that m102∙4 remained active for at least 8 days following administration of a clinically relevant dose. This study will inform future dosing regimens for m102∙4 to achieve prolonged exposure for systemic efficacy against henipaviruses. Trial Registration: The study was registered on the Australian New Zealand Clinical Trials Registry, registration number ACTRN12615000395538. Funding Statement: Queensland Department of Health, the National Health and Medical Research Council and the National Hendra Virus Research Program. Declaration of Interests: CCB is a US federal employee; and CCB and DSD are co-inventors on US patent Nos. 7,988,971 and 8,313,746 “Human monoclonal antibodies against Hendra and Nipah viruses”; assignees are The United States of America as represented by the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. (Bethesda, MD). All other authors declare no competing interests. Ethics Approval Statement: Ethics approval was obtained from the study site’s Human Research Ethics Committee at the QIMR Berghofer Medical Research Institute before participant enrolment commenced. The study was conducted under the Therapeutic Goods Administration (TGA) Clinical Trial Notification Scheme (CTN) and in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and the National Health and Medical Research (NHMRC) statement on ethical conduct in human research. |
