AZD7442: New player emerges in the COVID-19 treatment field

The phase III TACKLE trial highlights a new player in the COVID-19 treatment field – AZD7442 (tixagevimab/cilgavimab) – which demonstrated favourable efficacy and safety for nonhospitalized individuals with mild to moderate symptoms of the disease.

“[This is] a study of a new intervention for COVID-19 [comprising] two human-derived monoclonal antibodies modified to extend their longevity,” said Dr Hugh Montgomery from University College London, UK, at ECCMID 2022.

“The administration of the two monoclonals appeared to be safe,” he noted. Any adverse events (AEs) were slightly less common with the active agent compared with placebo (29 percent vs 36 percent). A similar trend was seen in terms of moderate AEs (8 percent vs 11 percent) and any SAE (including death; 7 percent vs 12 percent). [ECCMID 2022, abstract 00870]

Other AEs (mild AEs, those likely drug-related, any AEs of special interest, total deaths) were balanced.

“The good news was, in terms of COVID-related mortality, that was halved in the group that received the active agent – there being three deaths, and six in the placebo group,” Montgomery stressed.

Moreover, this 50-percent reduction was reflected in the composite endpoint of hospitalization, severe disease, or death, given the divergence appearing at around day 5 in the days post-dosing (4 percent vs 9 percent; hazard ratio, 0.49; p=0.01).

Early treatment = better outcomes

Also, earlier treatment was associated with even greater benefit. “[T]he earlier the dosing was given, the better the outcome: those receiving dosing within 2 days were essentially completely protected,” added Montgomery. “[This implies that] treating mild-to-moderate COVID-19 earlier in the disease course with AZD7442 leads to more favourable outcomes, potentially leading to reductions in healthcare system burden.”

The percent reductions in severe COVID-19 or death from any cause through day 29 from days 3 through 6 were 88, 78, 67, and 64 percent. There was still a 50-percent benefit if treatment was started within 7 days of symptom onset.

Primary endpoints met

“[In summary,] TACKLE met its primary endpoints – a one-time single AZD7442 600-mg IM dose provided statistically significant protection against severe COVID-19 or death vs placebo and was well tolerated,” said Montgomery.

TACKLE is an early outpatient treatment study wherein 903 participants (mean age 46 years, 50 percent female) were randomized 1:1 within 7 days of symptom onset to receive two sequential 3-mL IM injections of AZD7442 600 mg (300 mg each of tixagevimab and cilgavimab) or placebo.

“The patient population was specifically and deliberately enriched with those at slightly greater risk of progression to severe COVID-19 (89.6 percent) – they were mostly obese, smokers, hypertensive, slightly older, diabetic, and suffered from chronic lung disease or asthma, cardiovascular disease, and specific immunocompromised state,” noted Montgomery.

At the time of primary analysis, median follow-up was 84 days for both study arms.

Protection against new variants?

There were five different variants sequentially as the trial progressed, Montgomery shared. “There was good efficacy against all of them, but Omicron has been a much more recent [variant,] particularly the BA.2 variant. But the good news is, the in vitro studies show no diminution at all of the neutralizing capacity,” Montgomery noted.

“We are hoping as well that with two different epitopes being targeted, [AZD7442] will offer downstream protection with new variants as they appear,” he continued.