Viral clearance, pharmacokinetics and tolerability of ensovibep in patients with mild to moderate COVID-19: A phase 2a, open-label, single-dose escalation study.

AIM: To assess viral clearance, pharmacokinetics, tolerability and symptom evolution following ensovibep administration in symptomatic COVID-19 outpatients. METHODS: In this open-label, first-in-patient study a single dose of either 225 mg (n = 6) or 600 mg (n = 6) of ensovibep was administered intravenously in outpatients with mild-to-moderate COVID-19 symptoms. Pharmacokinetic profiles were determined (90-day period). Pharmacodynamic assessments consisted of viral load (qPCR and cultures) and symptom questionnaires. Immunogenicity against ensovibep and SARS-CoV-2-neutralizing activity were determined. Safety and tolerability were assessed throughout a 13-week follow-up. RESULTS: Both doses showed similar pharmacokinetics (first-order) with mean half-lives of 14 (SD 5.0) and 13 days (SD 5.7) for the 225- and 600-mg groups, respectively. Pharmacologically relevant serum concentrations were maintained in all subjects for at least 2 weeks postdose, regardless of possible immunogenicity against ensovibep. Viral load changes from baseline at day 15 were 5.1 (SD 0.86) and 5.3 (SD 2.2) log10 copies/mL for the 225- and 600-mg doses, respectively. COVID-19 symptom scores decreased from 10.0 (SD 4.1) and 11.3 (SD 4.0) to 1.6 (SD 3.1) and 3.3 (SD 2.4) in the first week for the 225- and 600-mg groups, respectively. No anti-SARS-CoV-2 neutralizing activity was present predose and all patients had SARS-CoV-2 antibodies at day 91. Adverse events were of mild-to-moderate severity, transient and self-limiting. CONCLUSION: Single-dose intravenous administration of 225 or 600 mg of ensovibep appeared safe and well tolerated in patients with mild-to-moderate COVID-19. Ensovibep showed favourable pharmacokinetics in patients and the pharmacodynamic results warrant further research in a larger phase 2/3 randomized-controlled trail.

Accelerating vaccine trial conduct in a pandemic with a hot spot-based inclusion strategy using trial and epidemic simulation.

Clinical development of vaccines in a pandemic situation should be rigorous but expedited to tackle the pandemic threat as fast as possible. We explored the effects of a novel vaccine trial strategy that actively identifies and enrolls subjects in local areas with high infection rates. In addition, we assessed the practical requirements needed for such a strategy. Clinical trial simulations were used to assess the effects of utilizing these so-called "hot spot strategy" compared to a traditional vaccine field trial. We used preset parameters of a pandemic outbreak and incorporated realistic aspects of conducting a trial in a pandemic setting. Our simulations demonstrated that incorporating a hot spot strategy shortened the duration of the vaccine trial considerably, even if only one hot spot was identified during the clinical trial. The active hot spot strategy described in this paper has clear advantages compared to a "wait-and-see" approach that is used in traditional vaccine efficacy trials. Completion of a clinical trial can be expedited by adapting to resurgences and outbreaks that will occur in a population during a pandemic. However, this approach requires a speed of response that is unusual for a traditional phase III clinical trial. Therefore, several recommendations are made to help accomplish rapid clinical trial setup in areas identified as local outbreaks. The described model and hot spot vaccination strategy can be adjusted to disease-specific transmission characteristics and could therefore be applied to any future pandemic threat.