Tixagevimab/cilgavimab (Evusheld) and bebtelovimab are likely ineffective against approximately 60% of currently circulating Omicron variants, creating a big gap in protection, particularly for immunocompromised individuals, researchers from a Harvard Medical School-led consortium said at a briefing on Thursday.
This is a “big loss,” said Jacob Lemieux, MD, PhD, of the Massachusetts Consortium on Pathogen Readiness and Massachusetts General Hospital in Boston, noting that tixagevimab-cilgavimab has become an extremely important tool to ward off severe COVID and death in immunocompromised patients.
Tixagevimab-cilgavimab — which was granted an emergency use authorization in December 2021 as pre-exposure prophylaxis (PrEP) for COVID-19 in immunocompromised individuals and those with a history of a severe vaccine reaction — has lost potency against BQ.1 and BQ.1.1, as well as BA.4.6, BF.7, BA.5.2.6, and BA.2.75.2. As of November 12, these variants make up about 60% of the current circulating Omicron variants.
Bebtelovimab — which was authorized for emergency use by the FDA in February for non-hospitalized patients with mild to moderate COVID-19 who are at risk for developing severe disease — has lost its potency against the subvariants BQ.1 and BQ.1.1, which are currently spreading in the U.S., because they contain spike K444T and R346T substitutions.
“These are our last functional monoclonal antibodies,” Lemieux noted. “So I think it’s fair to say that the virus has outrun the current generation of monoclonal antibodies. This race probably will continue — hopefully there’ll be some new products in the pipeline.”
Consortium co-leader Jeremy Luban, MD, of the University of Massachusetts Chan Medical School in Worcester, pointed out that patients with cancer receiving active treatment, transplant recipients, and those receiving immunosuppressive therapy are all going to feel the loss of these effective drugs.
“If you know anyone who has cancer or is immunocompromised for some other reason, it’s pretty scary not having this,” he said. “It’s a big problem.”
Recommendations from the NIH COVID-19 Treatment Guidelines Panel were recently updated to reflect the lack of alternative options for PrEP and the waning efficacy of bebtelovimab in the face of these emerging strains.
“The panel continues to recommend the use of tixagevimab plus cilgavimab as PrEP for eligible individuals,” panel members wrote. However, the decisions to use the drugs should be based on “the regional prevalence of the resistant subvariants, the individual patients’ risks, the available resources, and logistics.”
Furthermore, people receiving the treatment, “should take precautions to avoid exposure to SARS-CoV-2,” they added.
The panel only recommends bebtelovimab “when the majority of circulating Omicron subvariants in the region are susceptible.”
However, one of the challenges is knowing how to treat a patient when you don’t know what variant they have, said consortium co-leader Kathryn Stephenson, MD, MPH, of Beth Israel Deaconess Medical Center in Boston. “It’s been pretty much one variant replaces the one before in a slice of time, so you almost always know [what variant someone has]. These days, it’s a little more interesting in the sense that there’s more diversity of virus circulation or variants and it’s become really relevant.”
“It will be interesting to see if we can have faster diagnostics for sequencing — it would be nice to know in real time” what my patient has, she added. “But that’s not something in clinical practice we typically do.”
Vaccination is still the most effective tool out there, Stephenson said. “Now that most people in the U.S. have had a primary vaccine series, their risk of progression to severe disease has gone down.”
The bigger problem is with immunocompromised individuals, she noted. “We’re going to have to go to other things because the monoclonals are not going to be useful for us for now.”
According to the NIH panel recommendations, ritonavir-nirmatrelvir (Paxlovid) and remdesivir (Veklury) remain the preferred therapies (in order of preference) for patients who do contract COVID-19 and are at risk of severe disease.