Antispike nMAb combo reduces viral load in COVID-19 outpatients

A combination of two potent antispike neutralizing monoclonal antibodies (nMAbs) – bamlanivimab and etesevimab – significantly reduced viral load in nonhospitalized individuals with mild-to-moderate COVID-19, the phase II/III BLAZE-1* trial has shown.

“[Our findings show that] treatment with bamlanivimab-etesevimab combination therapy, but not bamlanivimab monotherapy, resulted in a reduction in SARS-CoV-2 log viral load at day 11 [in this patient setting],” said the researchers.

Bamlanivimab was derived from a recovered COVID-19 patient in North America. [bioRxiv 2020;doi:10.1101/2020.09.30.318972] It has been recently authorized for emergency use (at a 700-mg dose) in the US and Canada for mild-to-moderate COVID-19. Etesevimab was also derived from another recovered COVID-19 patient in China. [Nature 2020;584:120-124] “Combining these two nMAbs in clinical use may enhance viral load reduction and decrease treatment-emergent resistant variants,” said the researchers.

The study comprised 577 ambulatory individuals (mean age 44.7 years, 55 percent female) who tested positive for SARS-CoV-2. Participants received either single, 1-hour IV infusions of bamlanivimab 700, 2,800, or 7,000 mg (n=101, 107, and 101, respectively); a combination of bamlanivimab 2,800 mg and etesevimab 2,800 mg (n=112); or placebo (n=156) within a median 4 days of symptom onset. [JAMA 2021;325:632-644]

At day 11, baseline log viral load dropped the most with the combination regimen, generating a significant difference when compared against placebo (mean change, –4.37 vs –3.80; p=0.01).

Fewer patients on the combination regimen had COVID-19-related hospitalizations or emergency department (ED) visits at day 29 compared with those on placebo (0.9 percent vs 5.8 percent; p=0.049).

In a post hoc analysis, hospitalization rate was lower in older (≥65 years) and morbidly obese (BMI ≥35) patients on combination therapy vs placebo (0 percent vs 13.5 percent; p=0.04). “[However], these preliminary data are hypothesis-generating and suggest the need for further study to determine whether [these high-risk] patients … should be prioritized for this particular treatment,” said the researchers.

There was only one serious adverse event reported with combination therapy, and two incidences of immediate hypersensitivity reactions that were mild and not dose-related.

However, the population was small, and day 11 may have been “too late in the immune response to optimally detect treatment effects,” the researchers noted. “An earlier timepoint (ie, day 3 or 7) [may] have been more appropriate to measure viral load.”

“[Also, as] the antiviral activity of etesevimab monotherapy or different combination doses was not investigated, it is difficult to determine whether the greater reduction in viral load [with combination therapy] was due to additive or synergistic effects vs differential efficacy of etesevimab,” they noted.

Different interim results?

Moreover, interim results show that statistical significance was achieved with bamlanivimab 2,800 mg for the primary outcome. [N Engl J Med 2020;doi:10.1056/NEJMoa2029849] However, follow-up during this time was incomplete (database lock, September 5, 2020), noted Dr Preeti Malani from the University of Michigan, Ann Arbor, Michigan, US, and Dr Robert Golub, JAMA Deputy Editor, in an editorial. [JAMA 2021;325:644-645]

“In the [current] analysis … the database was locked on October 6, 2020 … [T]he longer follow-up for the placebo group, which is now complete, resulted in changes in the primary outcome [in] that group,” said Malani and Golub. “The comparison of the monotherapy arms against the final results for the placebo arm led to changes in the effect sizes, and the loss of the previously reported statistical significance in the … bamlanivimab 2,800 mg [arm].”

However, they noted that the primary endpoint, while “objective and measurable”, does not clearly translate to 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. [T]he prespecified secondary outcomes of COVID-19-related hospitalizations or ED visits likely are most meaningful to patients and families.”

More studies needed

Further exploration is warranted to determine whether the viral load reduction with the combination regimen would translate to clinical benefit, noted the researchers.

It is imperative to ascertain the clinical potential of nMAbs for COVID-19 to augment the current treatment armamentarium, as only remdesivir is approved by the US FDA. [Lancet 2020;395:1569-1578; N Engl J Med 2020;383:1813-1826] As an alternative, steroids have been used by some professional medical societies and organizations, including the WHO. [JAMA 2020;324:1292-1295]

The phenotypic and genotypic evaluations of BLAZE-1 is underway.