BACKGROUND
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19), which is most frequently mild yet can be severe and life-threatening. Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization.
METHODS
In this ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19, we randomly assigned 452 patients to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes. The primary outcome was the change from baseline in the viral load at day 11. The results of a preplanned interim analysis as of September 5, 2020, are reported here.
RESULTS
At the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was −3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was −0.53 (95% confidence interval [CI], −0.98 to −0.08; P=0.02), for a viral load that was lower by a factor of 3.4. Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (−0.20; 95% CI, −0.66 to 0.25; P=0.38) or the 7000-mg dose (0.09; 95% CI, −0.37 to 0.55; P=0.70). On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19–related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group.
CONCLUSIONS
In this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11
In this preplanned interim analysis of the BLAZE-1 trial, we examined the efficacy of LY-CoV555 in the treatment of mild or moderate Covid-19. The trial was designed to enroll patients with a recent disease onset to evaluate the effect of early intervention with antibody therapy on viral-load biomarkers, symptoms, and severe clinical outcomes, such as hospitalization and death.
Among the patients who received LY-CoV555, the viral load at day 11 (the primary outcome) was lower than that in the placebo group only among those who received the 2800-mg dose. However, a decreased viral load at day 11 did not appear to be a clinically meaningful end point, since the viral load was substantially reduced from baseline for the majority of patients, including those in the placebo group, a finding that was consistent with the natural course of the disease.However, the evaluation of the effect of LY-CoV555 therapy on patients’ symptoms at earlier time points during treatment (e.g., on day 3) showed a possible treatment effect, with no substantial differences observed among the three doses. It is unclear whether RT-PCR is an accurate measure of viral neutralization, since viral RNA may persist for some time even in the absence of replication-competent virus. Since the severity of illness is primarily driven by lung injury from SARS-CoV-2 infection in the lower respiratory tract, the viral load in the air spaces would be a better reflection of the injury response than the viral load in nasopharyngeal secretions. However, assessments of the lower respiratory tract were not practical owing to precautions that were required in treating these highly infectious patients. Therefore, the nasopharyngeal viral swab was the most pragmatic way of getting a sense of viral load as a surrogate marker of the viral load in the lungs and to correlate with clinical outcomes. However, the nasopharyngeal viral load has not been validated as a predictor of clinical disease course.
An unanticipated observation in this trial was that patients with a higher viral load on day 7 had a higher rate of hospitalization than those with better clearance of viral RNA on day 7, a finding that was consistent with the delayed viral clearance that was observed in patients with more severe disease.20,22,23 On day 7, no hospitalized patient had a viral load that was below the median value of the population. If this observation is prospectively confirmed in future studies, it would suggest the potential for an agent that lowers the viral load to reduce the rate of hospitalization.
To examine the potential of LY-CoV555 to improve Covid-19 clinical outcomes, we evaluated the effect of LY-CoV555 therapy on the frequency of hospitalization, an important outcome given the association between hospitalization and subsequent mortality in patients with Covid-19.On day 29, the percentage of patients who were hospitalized was 1.6% in the LY-CoV555 group and 6.3% in the placebo group. In a post hoc analysis that was focused on high-risk subgroups (an age of ≥65 years or a BMI of ≥35), the percentage of hospitalization was 4.2% in the LY-CoV555 group and 14.6% in the placebo group.
The data regarding symptoms (as measured by the change from baseline in the symptom score) were also consistent with the hospitalization results, with findings that supported a possible reduction in symptom severity as early as day 2 in the LY-CoV555 group. This effect was maintained over time and across doses, which further supports the validity of a treatment effect on symptoms and suggests a mechanistic link between a lower viral load and a lower frequency of hospitalization. Although the differences in the effects of the three doses of LY-CoV555 were not clear, the 2800-mg dose was the only one to show evidence of accelerated viral clearance. Nevertheless, further studies should continue to assess the efficacy of lower doses.
The safety profile of patients who received LY-CoV555 was similar to that of placebo-treated patients. These data indicate that the treatment is safe. In this interim analysis, the patients who received LY-CoV555 had fewer hospitalizations and a lower symptom burden than those who received placebo, with the most pronounced effects observed in high-risk cohorts. If these results are confirmed in additional analyses in this trial, LY-CoV555 could become a useful treatment for emergency use in patients with recently diagnosed Covid-19
Reference & source information: https://www.nejm.org/
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