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Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults.

ABSTRACT: Cytomegalovirus can cause debilitating and life-threatening disease in newborns infected in utero and immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody; n = 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses; n = 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses; n = 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.).

SUBMITTER: Ishida JH

PROVIDER: S-EPMC4505204 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults.

Ishida Julie H JH Burgess Tracy T Derby Michael A MA Brown Pearline A PA Maia Mauricio M Deng Rong R Emu Brinda B Feierbach Becket B Fouts Ashley E AE Liao X Charlene XC Tavel Jorge A JA

Antimicrobial agents and chemotherapy 20150608 8

Cytomegalovirus can cause debilitating and life-threatening disease in newborns infected in utero and immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The s ...[more]

PMID: 26055360

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Project description:IntroductionAdintrevimab is a fully human immunoglobulin G1 extended half-life monoclonal antibody that was developed to have broad neutralization against SARS-CoV, SARS-CoV-2, and other SARS-like CoVs with pandemic potential. Here we report the safety, pharmacokinetics (PK), serum viral neutralizing antibody (sVNA) titers, and immunogenicity results of the first three cohorts evaluated in the first-in-human study of adintrevimab in healthy adults.MethodsThis is a phase 1, randomized, placebo-controlled, single ascending-dose study of adintrevimab administered intramuscularly (IM) or intravenously (IV) to healthy adults aged ≥ 18-55 years with no current or prior SARS-CoV-2 infection. Participants were randomized 8:2 to adintrevimab or placebo in each of three dose cohorts: adintrevimab 300 mg IM (cohort 1), 500 mg IV (cohort 2), and 600 mg IM (cohort 3). Follow-up was 12 months. Blood samples were taken predose and at multiple time points postdose up to month 12 to assess sVNA, PK, and antidrug antibodies (ADAs).ResultsThirty participants received a single dose of adintrevimab (n = 24; 8 per cohort) or placebo (n = 6). All except one adintrevimab participant in cohort 1 completed the study. No participants in any treatment arm experienced a study drug-related adverse event. Across adintrevimab-treated participants, 11 (45.8%) experienced at least one TEAE. All but one TEAE were mild in severity, and all were either viral infection or respiratory symptoms. There were no serious adverse events, discontinuations due to adverse events, or deaths. Adintrevimab exhibited a linear and dose-proportional PK profile and extended serum half-life (mean 96, 89, and 100 days in cohorts 1, 2, and 3, respectively). Participants receiving adintrevimab demonstrated dose-dependent increased sVNA titers and breadth across multiple variants.ConclusionAdintrevimab at doses of 300 mg IM, 500 mg IV, and 600 mg IM was well tolerated in healthy adults. Adintrevimab demonstrated dose-proportional exposure, rapid development of neutralizing antibody titers, and an extended half-life.

Project description:BACKGROUND:VIS410, a broadly neutralizing monoclonal antibody that binds the hemagglutinin stem of influenza A viruses, was safe and efficacious in a human H1N1 virus challenge study. This study evaluated the safety and tolerability of VIS410 in non-hospitalized adult patients with uncomplicated influenza A. METHODS:Patients 18 to 65?years of age with symptom onset within 72?h were randomized 1:1:1 to receive a single intravenous infusion of VIS410 4000?mg, 2000?mg, or placebo. Neuraminidase inhibitor therapy was prohibited. Treatment-emergent adverse events (TEAEs) were evaluated up to 100?days post-infusion. Influenza symptoms were assessed daily for 10?days using the FLU-PRO tool. Nasopharyngeal virus shedding was assessed by quantitative reverse-transcription PCR (qRT-PCR) and viral culture through Day 7. FINDINGS:Of the 150 patients randomized, 148 received study drug, and 138 were confirmed influenza A positive. Median age was 42?years; median time from symptom onset to treatment was 42?h; 93% had influenza A subtype H3N2. SAFETY:TEAEs, most commonly diarrhea of mild severity, were dose-related, occurring in 55%, 35%, and 24% of the 4000?mg, 2000?mg, and placebo patients, respectively. Two serious adverse events occurred, both in placebo patients. SYMPTOM ANALYSES:Baseline FLU-PRO symptom scores were balanced among groups. Mean scores were lower by Days 3 and 4 in the pooled VIS410 treatment group versus placebo (p?<?0.023), with a tendency toward faster resolution by Kaplan-Meier analysis. VIROLOGY ANALYSES:VIS410 was associated with reduced median nasopharyngeal viral load TCID50 AUCDay7 (days?×?log10 TCID50/mL) (3.66 pooled VIS410 vs 4.78 placebo, p?=?0.08) and in the subset of patients with baseline hemagglutination inhibition (HAI) titer ?40 (overall, 74% of patients) was significantly reduced vs placebo (4.218 pooled VIS410 vs 6.152 placebo, p?=?0.009). Kaplan-Meier estimated time to resolution of viral shedding was reduced (1.9 vs 3.6?days, p?=?0.03) in VIS410 treated patients. There was a trend toward greater proportion of culture-negative patients by Day 3 (66.7% vs 51.1%, p?=?0.11); when this analysis was limited to the subset of patients with positive baseline cultures, this difference became more pronounced (63.2% vs 42.5%, p?=?0.053). No differences were observed in nasopharyngeal influenza qRT-PCR profiles, which represent both live and neutralized virus. INTERPRETATION:VIS410 was safe and well tolerated in adults with uncomplicated influenza A, with favorable effects on symptom resolution and virus replication. TRIAL REGISTRATION:Clinical Trials: NCT02989194. FUNDING:This project was funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under Contract No. HHSO100201500018C.

Project description:ObjectivesIndigenous medicines are widely used throughout Africa, despite a lack of scientific evidence for their safety or efficacy. The aims of this study were: (a) to conduct a pilot study of the safety of a common indigenous South African phytotherapy, Lessertia frutescens (Sutherlandia), in healthy adults; and (b) to contribute to establishing procedures for ethical and scientifically rigorous clinical trials of African indigenous medicines.DesignA randomized, double-blind, placebo-controlled trial of Sutherlandia leaf powder in healthy adults.SettingTiervlei Trial Centre, Karl Bremer Hospital, Bellville, South Africa.Participants25 adults who provided informed consent and had no known significant diseases or allergic conditions nor clinically abnormal laboratory blood profiles during screening.Intervention12 participants randomized to a treatment arm consumed 400 mg capsules of Sutherlandia leaf powder twice daily (800 mg/d). 13 individuals randomized to the control arm consumed a placebo capsule. Each participant received 180 capsules for the trial duration of 3 mo.Outcome measuresThe primary endpoint was frequency of adverse events; secondary endpoints were changes in physical, vital, blood, and biomarker indices.ResultsThere were no significant differences in general adverse events or physical, vital, blood, and biomarker indices between the treatment and placebo groups (p > 0.05). However, participants consuming Sutherlandia reported improved appetite compared to those in the placebo group (p = 0.01). Although the treatment group exhibited a lower respiration rate (p < 0.04) and higher platelet count (p = 0.03), MCH (p = 0.01), MCHC (p = 0.02), total protein (p = 0.03), and albumin (p = 0.03), than the placebo group, these differences remained within the normal physiological range, and were not clinically relevant. The Sutherlandia biomarker canavanine was undetectable in participant plasma.ConclusionConsumption of 800 mg/d Sutherlandia leaf powder capsules for 3 mo was tolerated by healthy adults.

Dataset Information

Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults.

Publications

Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults.

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