FDA Grants Emergency Use Authorization to Long-Acting Antibody Combo for COVID-19 Prevention

The long-acting antibody combination of tixagevimab (AZD8895) co-packaged with cilgavimab (AZD1061; Evusheld) has been granted emergency use authorization (EUA) in the United States for the pre-exposure prophylaxis of COVID-19.¹

The combination is indicated for COVID-19 prevention in adults and adolescents, aged 12 years and older who weigh at least 40 mg, who have moderate to severe immune compromise because of a medical condition or immunosuppressive medications who may not mount an acceptable response to vaccination against the virus. The regimen is also indicated for those who are not recommended to receive the vaccination.

Importantly, individuals who are currently infected with, or who have recently been exposed to a person with, SARS-Cov-2 should not receive the combination.

The EUA is supported by primary data from the ongoing phase 3 PROVENT trial (NCT04625725), which demonstrated that the regimen significantly reduced the risk of developing symptomatic COVID-19 vs placebo. At the time of the primary analysis, the combination reduced risk by 77% (95% CI, 46-90); at a median of 6 months, one 300-mg intramuscular dose of the combination reduced risk by 83%. Moreover, protection from the virus was observed to continue for at least 6 months.

Findings from the phase 3 STORM CHASER post-exposure trial (NCT04625972) and the phase 1 trial (NCT04507256) of the combination also supported the authorization.

“Millions of people in the United States and around the world remain at serious risk for COVID-19 because their immune systems do not generate a sufficient immune response, even after receiving all recommended doses of vaccine,” Myron J. Levin, MD, professor of pediatrics and medicine at the University of Colorado School of Medicine, stated in a press release. “I am excited to offer my patients Evusheld as an easily-administered new option that provides long-lasting protection that could help them return to their everyday lives.”

The combination is comprised of 2 long-acting monoclonal antibodies and was derived from B cells donated by convalescent patients after SARS-CoV-2. This is the only antibody therapy authorized for COVID-19 prevention in the United States; it is also the only COVID-19 antibody that is administered intramuscularly, with both agents administered at a dose of 150 mg.

The regimen was originally discovered by investigators from the Vanderbilt University Medical Center. In June 2020, the antibodies were licensed to AstraZeneca.² The hypothesis was that by combining 2 monoclonal antibodies that bind to distinct portions of the SARS-CoV-2 spike protein into 1 preventative approach, the effectiveness of neutralizing the virus would be improved.

The antibodies were optimized by the biopharmaceutical company with half-life extension and reduced Fc receptor and complement C1q binding. The half-life extension more than tripled the durability of its action vs conventional antibodies and has been shown to provide the potential for up to 12 months of protection from the virus with just a single administration.^3-5

PROVENT was the first prospectively designed phase 3 trial to examine a monoclonal antibody for the prevention of symptomatic COVID-19. Investigators focused on enrolling individuals who were high risk and immunocompromised. Specifically, more than 75% of the participants had comorbidities at baseline that put them at high risk for severe infection with COVID-19; this included immunocompromised individuals and those expected to experience a reduced response to vaccination against the virus.

A total of 5197 participants were enrolled to the trial, and they were subsequently randomized 2:1 to receive the combination or placebo.⁶ The primary analysis looked at data from 5172 individuals who were not infected with SARS-CoV-2 at baseline.

At the time of the primary analysis, 25 cases of symptomatic COVID-19 were reported. However, no cases of severe COVID-19 infection or related deaths were observed in those who received the combination. In the placebo arm, 3 cases of severe COVID-19 were reported, as well as 2 associated deaths.

At a median of 6 months of follow-up, no cases of severe COVID-19 infection or related deaths were reported in those who received the combination as preventative treatment.⁷ In comparison, 2 additional cases of severe COVID-19 infection were observed in the placebo arm, which equated to a total of 5 severe infection cases and 2 related deaths.

In October 2021, positive high-level data from the phase 3 TACKLE trial (NCT04723394) indicated that a 600-mg dose of the combination given by intramuscular injection significantly reduced severe COVID-19 infection or death by 50% vs placebo in non-hospitalized patients with mild-to-moderate, symptomatic infection, meeting the primary end point of the research.⁸

A total of 18 events were recorded in the combination arm (n = 18/407) vs 37 events in the placebo arm (n = 37/415). The regimen was found to be generally well tolerated.

Moreover, a prespecified analysis of those who received treatment within 5 days of symptom onset demonstrated that the combination resulted in a 67% reduction in the risk of developing severe infection or death compared with placebo. Here, 9 events were reported with the combination (n = 9/253) vs 27 events with placebo (n = 27/251).

A month later, in November 2021, data from an exploratory analysis of the trial showed that one 600-mg intramuscular dose of the combination resulted in a 88% reduction in the risk of developing severe COVID-19 infection compared with placebo in patients who had been symptomatic for 3 days or less at the time of treatment.7

“We are proud to play a leading role in fighting the COVID-19 pandemic and, with Evusheld, we now have the first antibody therapy authorized in the United States to prevent COVID-19 symptoms before virus exposure, while also providing long-lasting protection with a single dose,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D at AstraZeneca, added in the release.

References

1. Evusheld (formerly AZD7442) long-acting antibody combination authorised for emergency use in the US for pre-exposure prophylaxis (prevention) of COVID-19. News release. AstraZeneca; December 8, 2021. Accessed January 5, 2022. https://bit.ly/31whiPc
2. Advancing our discovery of novel coronavirus-neutralising antibodies against COVID-19. News release. AstraZeneca; June 9, 2020. Accessed January 5, 2022. https://bit.ly/31rX4WE
3. Robbie GJ, Criste R, Dall’acqua WF, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. 2013;57(12):6147-6153. doi:10.1128/AAC.01285-13
4. Griffin MP, Khan AA, Esser MT, et al. Safety, tolerability, and pharmacokinetics of MEDI8897, the respiratory syncytial virus prefusion F-targeting monoclonal antibody with an extended half-life, in healthy adults. Antimicrob Agents Chemother. 2017;61(3):e01714-e01716. doi:10.1128/AAC.01714-16
5. Domachowske JB, Khan AA, Esser MT, et al. Safety, tolerability, and pharmacokinetics of MEDI8897, an extended half-life single-dose respiratory syncytial virus prefusion F-targeting monoclonal antibody administered as a single dose to healthy preterm infants. Pediatr Infect Dis J. 2018;37(9):886-892. doi:10.1097/INF.0000000000001916
6. AZD7442 PROVENT phase III prophylaxis trial met primary endpoint in preventing COVID-19. News release. AstraZeneca; August 20, 2021. Accessed January 5, 2022. https://bit.ly/3t0P1eH
7. New analyses of two AZD7442 COVID-19 phase III trials in high-risk populations confirm robust efficacy and long-term prevention. News release. AstraZeneca; November 18, 2021. Accessed January 5, 2022. https://bit.ly/3EVvEWL
8. AZD7442 reduced risk of developing severe COVID-19 or death in TACKLE phase III outpatient treatment trial. News release. AstraZeneca; October 11, 2021. Accessed January 5, 2022. https://bit.ly/3t5Lv33