New findings from a pivotal study raise concerns about the efficacy and safety of the monoclonal antibody Covid-19 treatment bamlanivimab in hospitalized patients whose immune systems have mounted a SARS-CoV-2 neutralizing antibody response.
In the ACTIV-3/TICO study, which compared bamlanivimab to placebo in combination with remdesivir in patients hospitalized with Covid-19, half of the randomized patients showed evidence of endogenous production of anti-spike neutralizing antibodies (nAb) prior to treatment.
The latest findings from the trial, published online Dec. 20 in Annals of Internal Medicine, confirm the occurrence of worse sustained recovery and greater adverse outcomes—including death, organ failure, or serious adverse events—in these patients seropositive for endogenous neutralizing antibodies at study entry.
Previously reported ACTIV-3 findings, published last March in NEJM, showed no significant difference in cumulative incidence of sustained recovery among bamlanivimab- and placebo-treated patients overall, which contrasted with findings from studies in non-hospitalized patients with mild-to-moderate Covid-19.
Late in 2020, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) to bamlanivimab for the treatment of adult and pediatric patients ages 12 years and older with mild-to-moderate Covid-19 at elevated risk for progressing to severe disease. Early this month, the EUA was extended to include younger children and infants.
Combination treatment with bamlanivimab and etesevimab also recently receive EUA status for post-exposure prophylaxis to prevent Covid-19 in those at high risk.
The lack of efficacy reported in the patients hospitalized with Covid-19 treated with bamlanivimab led the ACTIV-3-TICO investigators to hypothesize that the null effect “could be due to enrolling patients who had already started to mount an effective nAb response at baseline, compared with patients earlier in the course of their infection.”
Researcher Jens Lundgren, MD, of the University of Copenhagen, and ACTIV-3-TICO colleagues further hypothesized that treatment with exogenous nAb “could be redundant in hospitalized patients.”
“In support of such an explanation, we found a positive trend for recovery for the bamlanivimab group among the subset of patients (50% of the total) without nAbs at study entry and a trend in the opposite direction for those with nAbs. A similar pattern was observed across subgroups according to total nucleocapsid antigen antibodies.”
Specifically, the analysis showed that among the 314 randomized study participants, including 163 treated with the bamlanivimab-remdesivir combination and 151 receiving placebo plus remdesivir, the median time to sustained recovery was 19 days.
Bamlanivimab was administered as a single intravenous infusion at a dosage of 7,000 mg on the day of randomization.
Median time to recovery did not differ significantly between the bamlanivimab and placebo groups (sub-hazard ratio [sHR], 0.99; 95% CI, 0.79-1.22]; sHR>1 favors bamlanivimab).
Half of the study participants (50%) demonstrated production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1,000 ng/L.
The analysis confirmed that:
- Among study participants without and with nAbs at study entry, the sHRs were 1.24 (95% CI, 0.90-1.70) and 0.74 (95% CI, 0.54-1.00), respectively (nominal P for interaction=0.018).
- The sHR (bamlanivimab versus placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and were greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48; 95% CI, 0.99-2.23) or viral RNA (sHR, 1.89; 95% CI, 1.23-2.91).
- Hazard ratios for the composite safety outcome also differed by serostatus at entry: 0.67 (95% CI, 0.37-1.20) among those without and 1.79 (95% CI, 0.92-3.48) among those with nAbs.
- The composite outcome of mortality, organ failure serious infections, serious adverse event or grade 3 or 4 adverse events occurred in 28% of bamlanivimab-treated patients and 19% of placebo-treated patients.
- For the 90-day composite safety outcome, the HRs (bamlanivimab versus placebo) were 0.67 (CI, 0.37 to 1.20) for those who were negative for nAb at entry and 1.79 (CI, 0.92-3.48) for those who were positive at study entry.
The researchers concluded that while the findings suggest the efficacy and safety of bamlanivimab may differ depending on whether endogenous nAb response has been mounted, “the limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting.”
The researchers noted that the trial’s subgroup analysis was “prematurely stopped because of futility; small sample size; [and] multiple subgroups analyzed.”
The latest findings from the ACTIV-3-TICO trial confirm the occurrence of worse sustained recovery and greater adverse outcomes—including death, organ failure, or serious adverse events—in patients seropositive for endogenous neutralizing antibodies at study entry.
Median time to recovery did not differ significantly between the bamlanivimab and placebo groups in the trial population overall.
Salynn Boyles, Contributing Writer, BreakingMED™
This study was funded by the U.S. government’s Operation Warp Speed program and the National Institute of Allergy and Infectious Disease. Corresponding researcher Jens Lundgren reported no relevant disclosures.
Cat ID: 125
Topic ID: 79,125,730,933,125,926,192,927,151,928,925,934
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