Safety and Efficacy of Inhaled IBIO123 for Severe COVID-19: A Randomised, Double-Blind, Dose-Ascending, Placebo-Controlled, Phase 1/2 Trial

Background: COVID-19 severity is associated with its respiratory manifestations. Neutralising antibodies against SARS-CoV-2 administered systemically have shown limited clinical efficacy, especially in the hospitalised patients. However, instant, and direct delivery of neutralising antibodies via inhalation might provide immediate and additional respiratory clinical benefits. IBIO123 is a cocktail of three, fully human, neutralising monoclonal antibodies against SARS-CoV-2 that showed clinical benefits in mild-to-moderate COVID-19 participants. We aimed to assess the safety and efficacy of inhaled IBIO123 in individuals with severe COVID-19 and who were recently hospitalised.Methods: This double-blind, dose-ascending, placebo-controlled, first-in-human, phase 1/2 trial recruited symptomatic and hospitalised COVID-19 participants in South Africa and Ukraine across 5 centres. Eligible participants were adults (aged ≥18 years; men and non-pregnant women) and hospitalised within 3 days prior to enrolment with a PCR-confirmed COVID-19 (within 24 hours). Using permuted blocks of 4, Phase 1 participants were randomly assigned (1:3) to receive single dose of placebo or IBIO123 (5 mg, or 10 mg) plus local standard-of-care. In Phase 2, using permuted blocks of 3, participants were randomly assigned (1:2) to receive a once-repeated dose of placebo or 10 mg of IBIO123 at Day 1 and Day 3 plus local standard-of-care. Participants underwent serological testing to identify pre-existence of antibodies against SARS-CoV-2. Participants, investigators, and the study team were masked to treatment assignment. In Phase 1, primary outcome was the safety assessment in the safety population (ie, all participants who received an intervention). In Phase 2, the primary outcome was the mean absolute change from baseline to Day 5 in SARS-CoV-2 viral load measured by nasopharyngeal swabs analysed using a mixed model for repeated measures among the full analysis set (FAS; ie, participants with one analysable viral load value at baseline and at least one analysable viral load value at day 3 or day 5). Secondary clinical outcomes were safety through day 29 using adverse events collection, and the effect of IBIO123 on respiratory rate. For clinical endpoints in phase 2, we used a modified FAS (ie, randomised participants who received the study treatment and having a positive SARS-CoV-2 viral infection determination within 24 hours prior to randomisation). This trial is now completed and is registered with ClinicalTrials.gov NCT05303376.Findings: Between March 2022 and June 2023, 140 participants were randomised to IBIO123 (n=94) or placebo (n=46). Study was stopped prior to reaching planned accrual because of significant decline in COVID-19 incidence. In phase 1, no safety issues were observed. In Phase 2, the primary endpoint was met, showing a significantly greater reduction in SARS-CoV-2 viral load from baseline to Day 5 in the IBIO123 group than in the placebo group (adjusted mean difference in the FAS: ‑0×75 (0×37); 95% CI: -1×5, 0; p=0×049). In patients with tachypnea at baseline (mFAS: N=77 in the IBIO123 group and N=39 in the placebo group), the greatest reduction from baseline in respiratory rate was seen in the IBIO123 treatment group with symptom onset less than 5 days.Interpretation: Inhalation of IBIO123 antibody cocktail was safe. Patients treated with a repeated administration of 10 mg IBIO123 had a greater reduction in SARS-CoV-2 viral load as soon as Day 5. DespiTrial Registration: Registered with ClinicalTrials.gov NCT05303376.Funding: Funded by Immune Biosolutions BioMed Propulsion program and the Canadian Strategic Innovation Fund.Declaration of Interest: SML, BM, ML, PB, JFL, SG, AlF, AL, DG, FL, SG are all employees of Immune Biosolutions. AnF holds patents on mAbs contained in IBIO123. LDM declares no competing interests.Ethical Approval: The study was reviewed and approved by the South African Health Products Regulatory Authority (SAHPRA), and by the State Expert Center and the Ministry of Health of Ukraine. Written informed consent was obtained from all participants before completion of any procedures.