On November 9, 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) to Eli Lilly for bamlanivimab (LY-CoV555), an investigational monoclonal antibody therapy, for the treatment of mild to moderate COVID-19 in adult and pediatric patients 12 years or older weighing at least 40 kg and who are at high risk for progressing to severe COVID-19 and/or hospitalization. Monoclonal antibodies could potentially be associated with worsening outcomes when used in hospitalized patients with severe COVID-19, therefore bamlanivimab is not authorized for use in patients that have already been hospitalized or require oxygen therapy due to COVID-19. Bamlanivimab must be administered as a single dose intravenously by trained healthcare providers. [1], [2]
Prior to the FDA issuance of EUA, Eli Lilly company has conducted a randomized, double-blind, placebo-controlled, phase II study, BLAZE-1, to evaluate the efficacy and safety of bamlanivimab alone or in combination with a second antibody for the treatment of outpatient COVID-19. Included patients were not hospitalized, had symptoms of mild or moderate COVID-19, and confirmed positive for SARS-CoV-2 within 3 days. Patients were to be given bamlanivimab 700 mg, 2,800 mg, 7,000 mg, or placebo. The primary outcome of this study is the change from baseline to day 11 in the SARS-CoV-2 viral load. The data from this interim analysis has been published with promising results [Table 1]. A phase III study, BLAZE-2, is also ongoing with the hope of using bamlanivimab as prevention of COVID-19 in long-term care facilities. [3], [4]
A phase III randomized, double-blind, placebo-controlled trial (BLAZE-2) is currently being conducted with 2,400 enrolled participants. This study is looking to evaluate whether bamlanivimab can prevent SARS-CoV-2 infection and COVID-19 in residents and staff in skilled nursing or assisted living facilities. Inclusion criteria includes resident or staff in skilled nursing or assisted living facilities with at least one confirmed case of direct SARS-CoV-2 detection ≤7 days and men or non-pregnant women. Exclusion criteria include a history of confirmed COVID-19 and previously treated with monoclonal antibodies or received an investigational vaccine. Participants are randomized to receive either bamlanivimab IV or placebo. The primary outcome is the percentage of participants with SARS-CoV-2 infection. The primary outcome is estimated to complete by March 8, 2021, with the overall study estimated to be completed by June 29, 2021. [5]
On November 21, the FDA granted an emergency use authorization (EUA) to antibody cocktail casirivimab and imdevimab based on the positive phase 2 data announced by Regeneron in September and October press release. Preliminary data from the phase 1/2/3 trial of REGN-COV2 reported data on the first 275 patients included. The trial included non-hospitalized (outpatient) adults with COVID-19. Symptoms must have been onset less than 7 days from randomization. Participants were then randomized to a lower dose (2.4 g) casirvimab/imdevimab antibody cocktail, higher dose (8 g) casirvimab/imdevimab antibody cocktail, or placebo. The clinical endpoints were time to symptom alleviation and the proportion of patients with medically-attended visits through 29 days; the virologic endpoint was the change from baseline viral load from day 1 to day 7. [6], [7], [8]
Participants were stratified based on their antibody status at baseline. Patients showed a 0.51 log10 copies/mL greater reduction in nasopharyngeal viral load with the higher dose (P=0.0049) from baseline and 0.23 log10 copies/mL greater reduction with the lower dose (P=0.20) compared to placebo by day 7. The viral load reduction was greater in patients who were seronegative at baseline. Additionally, patients with higher baseline levels correlated with greater viral load reductions by day 7. The time to symptom alleviation was 6 days in the low dose group, 8 days in the high dose group, and 9 days with placebo. In patients who were seronegative at baseline, the time to symptom alleviation was 6 days in the low dose group (P=0.09), 8 days in the high dose group (P=0.22), compared to 13 days with placebo. [7]
An additional press release revealed data from 524 additional patients who received casirvimab/imdevimab (N=799). The overall primary endpoint of reduced COVID-19 related medical visits by day 29 was significantly lower with casirvimab/imdevimab (2.8% combined dose groups; 6.5% placebo; P=0.024). Treatment with casirvimab/imdevimab reduced COVID-19 related medical visits by 72% in patients with one or more risk factor (including being over 50 years of age; body mass index greater than 30; cardiovascular, metabolic, lung, liver or kidney disease; or immunocompromised status) (combined dose groups; nominal P=0.0065). [8]
Clinical trials of casirvimab/imdevimab aim to study safety (proportion of patients with serious adverse events) and clinical status of patients on a 7-point ordinal scale (from "death" to 'not hospitalized"). Another clinical trial is assessing the prophylactic use of casirvimab/imdevimab with a primary endpoint of positive SARS-CoV-2 tests up to 1 month after receiving the study drug. [9], [10]