Updated: Study shows AstraZeneca's Covid-19 mAb Evusheld may not work against dominant Omicron strain
AstraZeneca’s prophylactic treatment for Covid-19, known as Evusheld, has survived where other mAbs failed, showing efficacy for the immunocompromised and others who cannot be vaccinated across multiple variants, including Delta and several Omicron subvariants.
But new correspondence published in the New England Journal of Medicine yesterday says that the dominant Omicron subvariants right now are much less susceptible to Evusheld, which is a combination of tixagevimab and cilgavimab. That data may end up resulting in a pause in the use of Evusheld, although an AstraZeneca spokesperson insists that it won’t, and HHS has not indicated that there’ll be a pause anytime soon.
An AstraZeneca spokesperson told Endpoints via email that “studies have shown that Evusheld neutralizes all known variants of concern, including BA.4/5,” adding:
- The publication data do not support that Evusheld does not work against BA.5, and the NEJM authors do not make that conclusion. The NEJM data show the combination of the two antibodies that comprise Evusheld neutralizes BA.5, with a FRNT50 (a level of an antibody’s neutralizing potency, also called IC50) of 192ng/ml. The limit of detection of the assay was 10,000ng/ml.
- In the NEJM study, the FRNT50 for Evusheld against BA.1 is 351. Therefore, it makes sense that Evusheld would remain effective against BA.5, since the FRNT50 against BA.5 is lower than for BA.1 (192 for BA.5 and 361 for BA.1; lower means higher potency)
- Evusheld started with highly potent in vitro neutralization against the original SARS-CoV-2 virus and earlier variants. Therefore, IC50/FRNT50 level differences and fold changes may be reported against certain Omicron variants even though activity is retained and above the threshold needed to neutralize the variant.
- There have been no discussions with the US FDA over a pause of use of Evusheld.
- The FDA has reviewed previous neutralization data against BA.4/.5 that are now included in the revised Evusheld Fact Sheet. That data are generally in line with the new data reported in the NEJM.
The U.S government has spent more than $1.5 billion in developing and acquiring doses of Evusheld during the pandemic, and AstraZeneca reported $469 million in worldwide sales of the mAb combo in Q1 of this year.
The researchers from Japan, the University of Wisconsin-Madison, Johns Hopkins and Icahn School of Medicine at Mount Sinai wrote that Eli Lilly’s bebtelovimab may be the only mAb left standing that’s effective against three different Omicron sublineages – BA.2.12.1, BA.4, and BA.5.
Regeneron’s combo of casirivimab and imdevimab, as well as GSK’s sotrovimab, both of which have been pulled from the US market in recent months, also may not provide effective treatment against BA.2.12.1, BA.4, or BA.5, the study shows. Lilly’s other mAb combo of bamlanivimab and etesevimab also was pulled from the market previously.
“Our findings show that the selection of monoclonal antibodies to treat patients who are infected with omicron variants should be carefully considered,” the authors wrote.
The FDA late last month authorized revisions to Evusheld’s dosing, saying that, “Nonclinical data and pharmacokinetic modeling suggest that activity against these subvariants [BA.2, BA.2.12.1, BA.4, and BA.5] may be retained for six months at drug concentrations achieved following an Evusheld dose of 300 mg of tixagevimab and 300 mg cilgavimab.”
And the agency now recommends repeat dosing every six months. But supplies of the prophylactic mAb are not running thin in the US, with HHS reporting that a little less than half of about 800,000 courses of Evusheld have been administered so far.
However, the good news, despite some limitations to the research, is that the authors found three small-molecule antiviral drugs against Covid-19 — Gilead’s remdesivir, Merck’s molnupiravir, and Pfizer’s nirmatrelvir — all still work against the latest Omicron sublineages.
“The main limitation of our study is the lack of clinical data on the efficacy of these monoclonal antibodies and antiviral drugs for the treatment of patients infected with BA.2.12.1, BA.4, or BA.5 subvariants,” the researchers added.
Editor’s note: Article updated with comment from AstraZeneca.