Combo Anti-Spike Protein Antibody for Mild to Moderate COVID-19 Save

JAMA has published the BLAZE-1 study, showing significant SARS-CoV-2 viral load reduction at day 11 and less COVID-19 progression when combination anti-spike monoclonal antibody therapy (bamlanivimab and etesevimab) was given to mild to moderate, non-hospitalized COVID-19 patients.

Bamlanivimab and etesevimab are potent COVID-19 antispike neutralizing monoclonal antibodies derived from 2 patients who recovered from COVID-19 in North America and China. These bind to different epitopes and can neutralize resistant variants with mutations. It is thought that combining these 2 neutralizing monoclonal antibodies may enhance viral load reduction and decrease treatment-emergent resistant variants.

The BLAZE-1 trial included 49 US centers who enrolled ambulatory patients (N = 613) positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), or the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156).

The primary end point was change in SARS-CoV-2 log viral load at day 11. Of the 577 patients randomized and treated, 92%  completed the efficacy evaluation period (day 29).

The change in log viral load from baseline at day 11 was:

• Bamlanivimab 700mg –3.72  (NS, not significant vs PBO)
• Bamlanivimab  2800 mg –4.08  (NS) 
• Bamlanivimab 7000 mg –3.49 (NS)
• Combination treatment –4.37 (p=0.01)
• Placebo –3.80

Secondary outcomes included COVID-19–related hospitalizations or ED visits

• PBO: 5.8% (9 events)
• Bamlanivimab 700mg 1.0% (1 event)
• Bamlanivimab  2800 mg1.9% (2 events) 
• Bamlanivimab 7000 mg 2.0% (2 events) 
• Combination treatment 0.9% (1 event)

While the number of COVID-19–related hospitalizations or emergency department visits was numerically lower in both the monotherapy and the combination therapy groups (vs placebo), the difference was only significant for the combination group. It is unknown if the greater reduction in viral load by combination therapy translates to better clinical outcomes compared with monotherapy.

Safety signals included: immediate hypersensitivity reactions in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo) and there were no deaths.

Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.

These findings raise questions about the indications for use of monoclonal antibodies in early COVID-19 infection and about optimal primary endpoints. The FDA has issued Emergency Use Authorizations for both bamlanivimab and for the combination of casirivimab and imdevimab for outpatients with mild to moderate symptoms of COVID-19 and risk factors for progression to severe disease (such as advanced age, obesity, diabetes, chronic kidney disease, and immunosuppression).