Bamlanivimab for COVID-19 may harm patients with endogenous neutralizing antibodies

The monoclonal antibody bamlanivimab may be effective in treating hospitalized patients with SARS-CoV-2 infection if they have no detectable levels of endogenous neutralizing antibodies prior to administration, according to researchers.

However, the researchers warned that bamlanivimab (Eli Lilly & Co.) may be harmful to patients who have already mounted an endogenous neutralizing antibody response. Their findings were recently published in Annals of Internal Medicine.

In November 2020, the FDA issued an emergency use authorization (EUA) for bamlanivimab for the treatment of mild-to-moderate COVID-19. However, in April, the FDA rescinded the EUA for bamlanivimab monotherapy because of the sustained increase in COVID-19 viral variants that are resistant to bamlanivimab alone, resulting in treatment failure.

Researchers in the Accelerating COVID-19 Therapeutic Interventions and Vaccines, Inpatient Monoclonal Antibodies and Other Therapies/Therapeutics for Inpatients With COVID-19 (ACTIV-3/TICO) study group have investigated several novel agents. The analysis investigating bamlanivimab was terminated because it lacked evidence of a clinical benefit, according to Jens D. Lundgren, MD, DMSc, the director of the Centre of Excellence for Health, Immunity and Infections in Denmark, and colleagues. However, Lundgren and colleagues conducted a new review of the ACTIV-3/TICO bamlanivimab trial to investigate a hypothesis that patients without endogenous neutralizing antibodies would benefit more from bamlanivimab than those with antibodies.

In the randomized, multicenter, placebo-controlled trial, researchers administered 7,000 mg of bamlanivimab intravenously over a 1-hour period to 163 participants and a placebo to 151 participants. The median age of the participants was 61 years. Also, 44% were women, 47% were white and 52% had a BMI at or above 30 kg/m². These individuals were hospitalized with COVID-19 without end-organ failure between Aug. 5, 2020, and Oct. 13, 2020. The participants had symptoms attributable to COVID-19 for 12 or fewer days and did not receive invasive mechanical ventilation. The researchers followed participants for 90 days to determine their time to sustained recovery (discharged to home for at least 14 days) and a composite safety outcome of mortality, serious adverse events, organ failure and serious infections.

Presence of neutralizing antibodies

Overall, the median time to sustained recovery was 19 days, and it did not significantly differ between the two groups (subhazard ratio = 0.99; 95% CI, 0.79-1.22), according to the researchers. At enrollment, 50% of participants were seropositive for endogenous neutralizing antibodies and 59% had anti-nucleocapsid antibodies. Also, 95% of participants had plasma antigen levels of 3 ng/L or more at enrollment and 50% had antigen levels of 1,000 ng/L or more, according to Lundgren and colleagues. Individuals who were positive for neutralizing antibodies had median plasma antigen and viral RNA levels of 297 ng/L and 14,164 copies/mL, respectively. Those who were negative for neutralizing antibodies had median levels of 2,130 ng/L and 70,953 copies/mL.

The levels of neutralizing antibodies increased after the infusion of bamlanivimab, and nearly all patients who were seronegative at entry (97%) and were administered bamlanivimab were seropositive on day 1 after infusion compared with 32% of the placebo group (P < .001). After baseline, the placebo group progressively seroconverted. The researchers observed little difference between the two groups among those who were seropositive at entry.

Sustained recovery and safety

In total, 80% of participants in each group demonstrated sustained recovery by day 28, according to the researchers. This increased to 88% by day 90 in the bamlanivimab group compared with 90% in the placebo group (sHR = 0.99; 95% CI, 0.79-1.22).

Among patients who were negative for neutralizing antibodies, 91% in the bamlanivimab group and 85% in the placebo group achieved sustained recovery by day 90 compared with 87% and 96%, respectively, who were positive.

There was no significant difference in the composite safety outcome through day 90 in the treatment group compared with the placebo group (28% vs. 27%). However, the HRs for the composite safety outcome at day 90 were 0.67 (95% CI, 0.37-1.2) for those who were negative for neutralizing antibodies at entry and 1.79 (95% CI, 0.92-3.48) for those who were positive. The HR for death was also higher among seropositive participants (HR = 3.53; 95% CI, 0.75-16.6) compared with seronegative participants (HR = 0.45; 95% CI, 0.14-1.48).

“The data suggests that use of monoclonal neutralizing antibodies among hospitalized patients with COVID-19 pneumonia should be restricted to those patients who have not yet mounted an endogenous neutralizing antibody response,” Lundgren told Healio Primary Care.

As the antibody therapy had no neutralizing effect against the alpha and delta variants, he expects the same fallibility against the omicron variant.

“Point-of-care antibody tests that reliably assess serostatus and identify patients at risk for harm are urgently needed,” the researchers wrote.