CoV-2 pathophysiology influencing the current treatment paradigm.
patients or those who require supplemental oxygen. This is due to the results of a study of the mAB coadministered with remdesivir which did not demonstrate efficacy among hospitalized with COVID-19. 42 The trial had to be stopped early due to demonstrated futility of the treatment. REGN-COV2, a neutralizing monoclonal antibody cocktail consisting of casirivimab and imdevimab, was evaluated in a study in non-hospitalized patients with COVID-19. 43 The two mABs are noncompeting, neutralizing human IgG1 antibodies that target the receptor-binding domain of the SARS-CoV-2 spike protein. The study was a multicenter, randomized, double-blind, and placebo-controlled trial in which participants were assigned 1:1:1 to receive placebo or REGN-CoV-2 at two different doses. Six of 93 patients (6%) in the placebo group and 6 of 182 patients (3%) in the combined REGN-COV2 group had a medically attended visit, a relative difference of approximately 49%. The neutralizing titers achieved with REGN-COV2 were more than 1000 times the titers achievable with convalescent- phase plasma, and REGN-COV2 had a significant and rapid effect on viral load reduction. Casivirimab and imdevimab combination has gained EUA approval and is available for patient at least 12 years of age and over 140 pounds with mild to moderate SARS-CoV-2. Convalescent plasma (passive infusion of polyclonal antibodies isolated from those with prior SARS-CoV-2 infection) has been frequently administered to patients since the early days of the pandemic. Data regarding its efficacy has been mixed but support early administration during the viral response phase. PlasmAr was a randomized (2:1), double-blind, placebo-controlled, multicenter trial comparing convalescent plasma versus placebo in patients hospitalized with COVID-19. 44 In total, 228 patients were assigned to receive convalescent plasma and 105 were assigned to placebo. Median duration of symptoms prior to enrollment was 8 days. No significant differences were observed in clinical status or overall mortality at 30 days between patients treated with convalescent plasma and those who received placebo. Another randomized, double-blind, placebo-controlled trial was conducted to examine effects of high titer convalescent plasma when administered early, within 72 hours after onset of symptoms. In the study, which involved 160 pateints (80 in each arm), severe respiratory disease developed in 16% of those who received convalescent plasma 31% of those who received placebo (relative risk, 0.52). 45 Convalescent plasma currently maintains FDA EUA for treatment of SARS-CoV-2. 46
PATHOPHYSIOLOGY AND TREATMENT PARADIGM
The staged progression of COVID-19 illness was described early in the pandemic, and our current treatment paradigm is still based on this understanding of SARS- CoV-2 pathophysiology. 39 In essence, there are two phases of disease: 1) a “viral response” phase, engendered by the virus itself, which is in some cases followed by 2) a “host inflammatory response” phase, as evidenced by elevated levels of inflammatory markers including IL-6, d-dimer, ferritin, and C-reactive protein (see Figure 1). 39 The viral response phase corresponds to milder clinical symptoms such as dry cough, fever, and myalgias, while the hyperinflammatory response is characterized by shortness of breath, hypoxia, shock and/or acute respiratory distress syndrome. Results of clinical trials have mostly supported this framework for considering disease progression, i.e. anti-viral therapies have shown efficacy when administered early in disease course, while they are not effective later, while the opposite is true for immunomodulatory agents.
MONOCLONAL AND POLYCLONAL ANTIBODY TREATMENT
In the context of COVID-19, monoclonal antibodies (mABs) bind to SARS-CoV-2 spike protein and block viral entry into human cells, a process called neutralization. They function as anti-viral therapy and have been shown to prevent progression to severe disease when administered early in the course of COVID-19 infection. LY-CoV555, or bamlanivimab, has demonstrated efficacy in treating outpatients but not in those who are hospitalized. In an interim analysis of an ongoing phase 2 trial (BLAZE-1), 452 outpatients with recently diagnosed mild or moderate COVID-19 (within 3 days of first positive test) were randomized to receive a single IV infusion of one of three doses of LY-CoV555 or placebo. By day 29, viral loads were reduced in addition to reductions in hospitalization or emergency department visits in the mAB group relative to the placebo group. 40 Furthermore, in a post-hoc analysis of patients at high risk (BMI ≥35 or ≥65 years old) for disease progression, 4 of 95 patients (4%) in the mAB arm were hospitalized or visited the emergency department, compared to 7 of 48 (15%) of those in the placebo arm. 41 Bamlanivimab currently holds an EUA for treatment of mild to moderate COVID-19 in adults and children 12 years of age and older who have positive PCR-testing for SARS-CoV-2, weigh at least 40 kg), andwho are at high risk for progressing to severe COVID-19 and/or hospitalization. Consistent with our treatment paradigm for early (viral response phase) versus late (host inflammatory response phase) disease, bamlanivimab is not recommended for hospitalized
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