Could tixagevimab–cilgavimab prevent progression to severe COVID-19 in unvaccinated adults?

The combination of tixagevimab and cilgavimab, two SARS-CoV-2 neutralizing monoclonal antibodies, appeared to protect against progression to severe disease or death in non-hospitalized, unvaccinated adults presenting with mild-to-moderate COVID-19, results of the ongoing phase III TACKLE trial showed.

The multinational, double-blind trial included 903 non-hospitalized adults (mean age 46.1 years, 50 percent female, 62 percent White, mean BMI 29 kg/m²) with RT-PCR- or antigen test-confirmed SARS-CoV-2 detected ≤3 days of enrolment who were not vaccinated against COVID-19 and had a WHO Clinical Progression Scale score of >1 to <4. They were randomized 1:1 to receive a single dose of tixagevimab–cilgavimab (comprising two consecutive 3 mL intramuscular injections, one each of tixagevimab 300 mg and cilgavimab 300 mg) or placebo administered ≤7 days (mean 5 days) of onset of self-reported fever or mild-to-moderate COVID-19 symptoms.

Exclusion criteria included current or prior hospitalization and prior receipt of a monoclonal antibody or biologic for COVID-19 prevention. Ninety percent of patients were considered at high risk of COVID-19 progression and 89 percent had ≥1 risk factors for severe COVID-19.

At day 29, the composite of progression to severe COVID-19* or any-cause death in the modified full analysis set** was significantly reduced among patients in the tixagevimab–cilgavimab compared with placebo group (4 percent vs 9 percent; relative risk [RR] reduction, 50.5 percent, 95 percent confidence interval [CI], 14.6–71.3 percent; p=0.0096), with an absolute risk reduction of 4.5 percent (95 percent CI, 1.1–8.0 percent; p<0.0001). [Lancet Respir Med 2022;doi:10.1016/S2213-2600(22)00180-1]

Early administration of tixagevimab–cilgavimab appeared to confer the greatest benefit in preventing disease progression or death, with RR reductions of 88.0, 78.4, 66.9, 64.1, and 50.5 percent when treatment was administered at ≤3, ≤4, ≤5, ≤6, and ≤7 days, respectively, of symptom onset.

Fewer patients in the tixagevimab–cilgavimab than placebo group experienced respiratory failure (1 percent vs 3 percent; RR reduction, 71.9 percent, 95 percent CI, 0.3–92.1 percent; p=0.036). In exploratory analysis, there were fewer hospitalizations due to COVID-19 or its complications in the tixagevimab–cilgavimab vs placebo group by day 29 (4 percent vs 10 percent). In addition, fewer patients in the tixagevimab–cilgavimab vs placebo group required admission to the intensive care unit due to COVID-19, admission to an inpatient hospital setting or acute at-home hospital care, or admission to the emergency department for >24 hours.

“[This finding supports] tixagevimab–cilgavimab utility across a variety of healthcare settings,” the researchers said.

In a subset of patients who were assessed for antidrug antibodies at 84 days following receipt of study drug, six tixagevimab–cilgavimab recipients developed treatment-emergent antidrug antibodies (median titre 120).

After a median follow-up of 84 days, adverse event (AE) rate was comparable between the tixagevimab–cilgavimab and placebo groups (29 percent vs 36 percent), with COVID-19 pneumonia the most common AE (6 percent vs 11 percent). Serious AEs were reported in 7 and 12 percent, respectively, with COVID-19 pneumonia the most common. Most AEs were mild or moderate in severity. The most common AE of special interest was injection-site pain which affected 2 percent of each group. COVID-19–related deaths occurred in three and six patients in the tixagevimab–cilgavimab and placebo groups, respectively, while any-cause death occurred in six patients in each group.

Another potential COVID-19 treatment

“[T]hese data support the potential of tixagevimab–cilgavimab to provide a new treatment option for individuals who require protection from severe COVID-19 outcomes,” said the researchers. “[The combination] contributes to the armamentarium against COVID-19, which is crucial for reducing the burden on healthcare systems.”

While other monoclonal antibodies have shown benefit as treatment for COVID-19, the intramuscular administration of the tixagevimab–cilgavimab combination may be advantageous in the outpatient setting, they continued. Furthermore, the combination has a long half-life (90 days) compared with other therapies and as such, “could potentially also confer long-term protection against symptomatic COVID-19.”

They acknowledged that the low number of immunocompromised (5 percent) and elderly patients (13 percent aged ≥65 years) in this study was a limitation. They also called for further study into the effect of the tixagevimab–cilgavimab combination in individuals who have received COVID-19 vaccination.