Since the beginning of the COVID-19 pandemic, researchers have been racing to identify therapeutics that prevent the progression of SARS-CoV-2 infection to serious disease. Although vaccine rollout is ongoing, SARS-CoV-2 infection rates are increasing nationwide and there is an urgent need for life-saving interventions. Results of the BLAZE clinical trials involving LY-CoV555, an antibody against the SARS-CoV-2 spike protein, provide context on these therapeutic possibilities. This research is being conducted through multiple Baylor Scott & White Research Institute (BSWRI) sites across Texas.
The first interim results of the BLAZE-1 phase 2 clinical trial (NCT04427501) were published in October 2020 in the New England Journal of Medicine. Outpatients with mild to moderate symptoms who were recently diagnosed with SARS-CoV-2 infection were randomized to receive either the LY-CoV555 antibody (700 mg, 2800 mg, or 7000 mg) or placebo. The antibody was delivered as a single hour-long infusion within 3 days of a positive test result. The primary outcome was the change from baseline viral load at day 11 post-diagnosis, and clinical outcomes were also evaluated.
The BLAZE-1 study at BSWRI is led by Robert Gottlieb, MD, PhD, a BSWRI physician-researcher. According to Dr. Gottlieb, “We know that the safest and most efficacious time to treat a patient is before they become critically ill. It is very important to get the information about how to treat patients early in the disease course.”
By 11 days post-diagnosis, the viral load had decreased dramatically in most patients, including those in the placebo group and the treatment groups (99.7% reduction in viral RNA levels across the whole population). Nonetheless, there was a statistically significant reduction in viral load in the group receiving 2800 mg of LY-CoV555 compared to the other groups (p=0.02). Analysis at Day 3, when all the patients had higher viral loads, revealed a possible beneficial effect of antibody treatment for all doses. The authors noted limitations in the analysis of viral load, such as the possibility that nasopharyngeal swabbing coupled with RT-PCR, while practical, may not be the best way to evaluate the true levels of infectious viral particles in the lower respiratory tract and may not be an ideal surrogate for clinical efficacy.
The secondary and exploratory measures offered intriguing insights for further evaluation. The safety profile of LY-CoV555 was considered similar to that of the placebo, with the only serious adverse event occurring in a placebo-treated patient. In addition, patients with a higher viral load on day 7 were more likely to become hospitalized. Furthermore, on day 29, 1.6% of patients who received LY-CoV555 were hospitalized, compared to 6.3% of those in the placebo group. An ad hoc analysis of high risk patients (either over 65 years old or obese) also showed a promising trend toward lower hospitalization rates with LY-CoV555. Similarly, there appeared to be a more rapid decline in the symptom severity in patients receiving LY-CoV555 compared to those receiving placebo.
These results have been followed by new data published this month in the Journal of the American Medical Association (JAMA) that continue to demonstrate neutralizing antibodies show promise as effective treatments for COVID-19 for those with mild to moderate disease.
The analysis (authored by Dr. Gottlieb) from BLAZE-2 compares the effects of three doses of bamlanivimab monotherapy (700 vs 2,800 vs 7,000 mg) vs combination bamlanivimab and etesevimab vs placebo on day 11 severe acute respiratory syndrome coronavirus viral load in patients with mild to moderate COVID-19.
Researchers found that the combination therapy of bamlanivimab and etesevimab not only significantly reduced viral load at 11 days, but more importantly, resulted in fewer hospitalizations, emergency department visits, and deaths related to COVID-19 at day 29.
Single monoclonal antibody bamlanivimab or “monotherapy” has been given emergency use authorization (EUA) by the FDA for adult and pediatric outpatients (12 years and older) with mild-to-moderate COVID-19 with an initial positive test who are at high risk for progressing to severe COVID-19 and/or hospitalization due to age or comorbidity.
This combination therapy has not yet been submitted to the FDA for review and it is not yet considered a standard of treatment and not available outside of a clinical trial setting.