Evaluation of the safety and efficacy of XAV-19 in patients with COVID-19-induced moderate pneumonia: study protocol for a randomized, double-blinded, placebo-controlled phase 2 (2a and 2b) trial

Abstract

Background Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2. Methods Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population. Discussion This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis. Trial registration ClinicalTrials.gov NCT04453384, registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.

Pharmacokinetics and Safety of XAV-19, a Swine Glyco-humanized Polyclonal Anti-SARS-CoV-2 Antibody, for COVID-19-Related Moderate Pneumonia: a Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study

“…This is an ongoing, multicenter, randomized, double-blind, placebo-controlled, phase IIa to III clinical trial involving hospitalized patients with COVID-19-related moderate pneumonia requiring low-flow oxygen supplementation ( 10 ). The first part was conducted as a phase IIa, first-in-human, dose-ranging study at four sites in France to assess the pharmacokinetics and safety of XAV-19 and to select the optimal dose for the second part of the trial, designed as a phase III trial, for which recruitment is ongoing.…”

“…In an ongoing trial, we are investigating XAV-19, a swine glyco-humanized polyclonal SARS-CoV-2-neutralizing antibody ( 9 ), in hospitalized patients with COVID-19 pneumonia requiring low-flow oxygen supplementation ( 10 ). In agreement with French national authorities, it was agreed that the first-in-human study was to be performed as a phase IIa dose selection study in COVID-19 patients, to gather safety information for this population and allow rollover without a delay in a phase III study.…”

Pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal anti-SARS-CoV-2 antibody, for COVID-19-related moderate pneumonia: a randomized, double-blind, placebo-controlled, phase IIa study

“…This is an ongoing multicenter, randomized, double-blind, placebo-controlled, phase IIa-III clinical trial involving hospitalized patients with COVID-19-related moderate pneumonia requiring low-flow oxygen supplementation [10]. The first part was conducted as a phase IIa, first-in-human dose-ranging study at four sites in France, to assess the pharmacokinetics and safety of XAV-19, to select the optimal dose for the second part of the trial, designed as a phase III for which recruitment is ongoing.…”

“…In an ongoing trial, we are investigating XAV-19, a swine glyco-humanized polyclonal SARS-CoV-2neutralizing antibody [9], in hospitalized patients with COVID-19 pneumonia requiring low flow oxygen supplementation [10]. The main hypothesis is that reducing viral burden and improving specific immunity by passive antibodies administration at hospital entry of patients hospitalized for COVID-19related moderate pneumonia within 10 days of first symptom onset could lead to clinical benefit.…”

XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2 Spike receptor-binding domain, targets multiple epitopes and broadly neutralizes variants

“…Early after Covid-19 outbreak onset, many labs have been able to rapidly develop neutralizing antibodies. One year later, as of mid-2021, more than 93 clinical trials assessing the safety and benefit of mAbs and 8 of polyclonal antibodies are listed in the Clinicaltrials.gov repository ) estimated at 11.4 days24,46 . The data presented here, together with these pharmacokinetic data, indicate that XAV-19 can provide high and sustained therapeutic activity in vivo.…”