Among patients with mild to moderate Covid-19 who were not hospitalized, combination treatment with two investigational anti-spike neutralizing monoclonal antibodies was associated with a significant reduction in viral load compared to placebo treatment in interim findings from a multicenter randomized trial.
The anti-spike monoclonal antibodies bamlanivimab and etesevimab were derived from 2 patients — one in North America and one in China — who had recovered from Covid-19.
In final phase II analysis of the ongoing phase 2/3 BLAZE-1 study, published online Thursday in JAMA, patients who received the two monoclonal antibodies, but not bamlanivimab alone, showed statistically significant reductions in SARS-CoV-2 viral load at post-infusion day 11.
In all, 5.8% of placebo-treated patients and 0.9% of the combination-treatment group experienced Covid-19-related hospitalizations or emergency department visits at day 29.
Also on Thursday, bamlanivimab developer Eli Lilli and Company released phase 3 results from it BLAZE-2 trial of the drug, which included 965 nursing home residents and staff who tested negative for SARS-CoV-2 at baseline.
The participants received either 4,200 mg of bamlanivimab or placebo and were followed for 8 weeks, with the active-treatment group showing significantly lower frequency of Covid-19 during follow-up (odds ratio 0.43; P=0.00021).
These findings have not yet been reported in a peer-reviewed medical journal.
In a previously reported BLAZE-1 trial analysis, monotherapy with 2,800 mg of bamlanivimab (also known as LY-CoV555) was associated with significant reductions in viral load, compared to placebo. Viral load among patients receiving lower (700 mg) and higher (7,000 mg) infusions of the monoclonal antibody were not statistically different from placebo.
Last November, bamlanivimab was granted emergency use authorization (EUA) status by the U.S. Food and Drug Administration for the treatment of mild to moderate Covid-19 in adults and children age 12 years and older.
In commentary published with the latest analysis of the BLAZE-1 data, JAMA associate editor Preeti N. Malani, MD, and deputy editor Robert M. Golub, MD, wrote that the different results may be due to an extra month of placebo group follow-up in the newly reported findings. Malani and Golub noted that the comparison of the monotherapy groups against the final results for the placebo group led to changes in the effect sizes, “and the loss of previously reported statistical significance in the group that received 2,800 mg of bamlanivimab.”
“During normal times, an interim analysis of an ongoing clinical trial usually would not be published, but these are not normal times,” they wrote, adding that while monoclonal antibodies likely improve clinical outcomes in selected patients, “the studies needed to answer remaining questions on the utility of treatment (which patients can benefit and in what circumstances) are unlikely to become available in a timely manner.”
The BLAZE-1 study is a randomized phase II/III trial being conducted at 49 U.S. centers involving patients who tested positive for SARS-CoV-2 and had 1 or more mild to moderate symptoms.
Enrollment of patients in the bamlanivimab monotherapy or placebo arms was conducted between June 17 and Aug. 21, 2020 and enrollment of those treated with the combination of bamlanivimab and etesevimab or placebo occurred between Aug. 22 and Sept. 3.
Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2,800 mg [n = 107], or 7,000 mg [n = 101]), the combination treatment (2,800 mg of bamlanivimab and 2,800 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 (±4 days), and nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo.
Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29).
The updated analysis found that:
- The change in log viral load from baseline at day 11 was −3.72 for 700 mg, −4.08 for 2,800 mg, −3.49 for 7,000 mg, −4.37 for combination treatment, and −3.80 for placebo.
- Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, −0.35 to 0.52; P=0.69) for 700 mg, −0.27 (95% CI, −0.71 to 0.16; P=0.21) for 2,800 mg, 0.31 (95% CI, −0.13 to 0.76; P=0.16) for 7,000 mg, and −0.57 (95% CI, −1.00 to −0.14; P=0.01) for combination treatment.
- The proportion of patients with Covid-19–related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2,800 mg, 2.0% (2 events) for 7,000 mg, and 0.9% (1 event) for combination treatment.
Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo) and no deaths occurred among the cohort.
In their editorial, Malani and Golub wrote that while the BLAZE-1 investigators used the objective and measurable primary end point of change in viral load, “this end point does not translate easily into tangible clinical outcomes.”
“Viral load decreases naturally during illness, and statistically significant differences in this outcome may occur only if treatment is given early during the course of illness,” they wrote. “Rather, the prespecified secondary outcomes of Covid-19-related hospitalizations or emergency department visits likely are most meaningful to patients and families.”
“As has been the case throughout the pandemic, clinicians face an ever-changing treatment narrative and must make decisions based on the best information available. While the world waits for widespread administration of effective vaccines and additional data on treatments, local efforts should work to improve testing access and turnaround time and reduce logistical barriers to ensure than monoclonal therapies can be provided to patients who are most likely to benefit.”
Among patients with mild to moderate Covid-19 who were not hospitalized, combination treatment with two investigational anti-spike neutralizing monoclonal antibodies was associated with a significant reduction in viral load compared to placebo treatment.
In final phase II analysis of the ongoing phase 2/3 BLAZE-1 study, patients who received the two monoclonal antibodies, but not bamlanivimab alone, showed statistically significant reductions in SARS-CoV-2 viral load at post-infusion day 11.
Salynn Boyles, Contributing Writer, BreakingMED™
Funding for this trial was provided by Eli Lilly and Company, which was responsible for the study design and collection, management, analysis and interpretation of the data, as well as preparaton, review and approval of the manuscript. The company did not have the right to veto publication or to control the decision regarding submission of the paper to journals. All final content decisions were made by the reseachers.
Researcher Robert L. Gottlieb reported receiving personal fees and nonfinancial support from Gilead Sciences, and serving on an advisory board for Sentinel. Other researchers reported being employees or shareholders in Eli Lilly or receiving consulting or other fees from the company.
Cat ID: 190
Topic ID: 79,190,728,932,730,933,190,926,192,927,151,928,925,934