Clinical Progress of Anti-SARS-CoV-2 Neutralizing Antibody (NAb)—PART II

In this article, we'll continue talking about the nAb drugs that have entered the clinical trials. LY-CoV555 and LY-CoV016 LY-CoV555 (also known as LY3819253, recently named bamlanivimab) is a fully human neutralizing IgG1 mAb developed by AbCellera and the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center in cooperation with Eli Lilly, which targets the SARS-CoV-2 S RBD (https://www.creativebiolabs.net/symbolsearch_SARS-CoV-2%20%282019-nCoV%29%20S%20RBD.htm). Another monoclonal antibody, LY-CoV016 (also known as LY3832479, recently named etesevimab), targets a different spike epitope and was developed by Eli Lilly to achieve synergy with LY-CoV555. In August 2020, the Phase I clinical trial of LY-CoV555 (NCT04411628) was completed on 24 COVID-19 hospitalized patients, and the safety, tolerability, and pharmacokinetics and pharmacodynamics of intravenous administration were evaluated. The phase II clinical trial BLAZE-1 (NCT04427501) is currently in progress investigating the efficacy and safety of the combined application of LY-CoV555 and LY-CoV016 on outpatients diagnosed with mild to moderate COVID-19. The preliminary results of the BLAZE-1 study showed that compared with the placebo group, patients taking the 2800mg dose had a significantly lower viral load on day 11 (the primary endpoint). The 29-day hospitalization rate (including emergency admissions) decreased (1.6% in the LY-CoV555 group and 6.3% in the placebo group), and the symptom severity gradually decreased from day 2 to day 11, and it was well tolerated. Among the three doses (700mg, 2800mg, and 7000mg), a statistically significant difference in viral load reduction was observed on the 11th day of the intermediate dose, which, however, may not be clinically significant because it might be related to the natural course of COVID-19. On the other hand, the decrease in hospitalization rate or emergency admission rate on the 29th day is more related to the efficacy. Eli Lilly announced in October 2020 an emergency use authorization (EUA) application for combined treatment of patients with mild to moderate COVID-19. The ongoing Phase III trial BLAZE-2 (NCT04497987) plans to enroll 2,400 patients to evaluate the effectiveness of using LY-CoV555 to prevent SARS-CoV-2 infection among skilled nursing staff, auxiliary living facility staff, and resident physicians. In addition, the Phase II/III placebo-controlled trial (ACTIV-2, NCT04518410) aims at outpatients who were tested positive for COVID-19 to evaluate whether LY-CoV555 can prevent the spread of infection and disease development. Finally, the Phase III trial of ACTIV-3 (NCT04501978) is comparing the effectiveness and safety of this mAb with Remdesvir. On October 13, 2020, the trial suspended patient registration based on the recommendation of the Independent Data Security Monitoring Committee (IDMC) because of the need to investigate unspecified safety issues. On October 26, 2020, the ACTIV-3 data assessment showed no significant difference in the safety results between the two groups. On November 10, 2020, the FDA issued an emergency use authorization for bamlanivimab for the treatment of mild to moderate COVID-19 in adult and pediatric patients, which is the first nAb authorized for clinical use. BGB-DXP593 BGB-DXP593 was jointly developed by BeiGene and Singlomics, which was obtained at the Advanced Innovation Center of Genomics at Peking University by identifying blood samples from convalescent COVID-19 patients through high-throughput single-cell sequencing. The exact mechanism by which BGB-DXP593 neutralizes SARS-CoV-2 is still unclear, which may act by inhibiting the virus from entering cells through ACE2. A randomized, double-blind, and placebo-controlled Phase II study (NCT04551898) is conducted to evaluate its efficacy and safety in patients with mild to moderate COVID-19, which will recruit approximately 180 participants (18 to 65 years old) who had COVID-19 symptoms (such as fever, cough, shortness of breath, sore throat, diarrhea, dysgeusia, and vomiting) within 7 days before treatment. The study consists of four treatment groups, three of which are designed to test three different doses of antibodies (low, medium, and high doses), and one control group. All subjects will receive the designated treatment on day 1, and follow up for safety within 85 days. The main purpose is to study the safety and tolerability of single-dose intravenous administration of BGB-DXP593 in patients with mild to moderate COVID-19, and the main results will be the evaluation of the change from baseline to D8 virus spread by RT-PCR in nasopharyngeal swabs. In this trial, from baseline to d15, 29, and 85, 8 secondary results will be evaluated.