By IDSE News Staff
The FDA revised the emergency use authorization (EUA) for tixagevimab-cilgavimab (Evusheld, AstraZeneca) to allow a higher dose for preexposure prophylaxis (PrEP) of COVID-19 in adults and children who are immunocompromised or cannot receive COVID-19 vaccination for medical reasons.
Based on the most recent information and data available, the original dose of tixagevimab-cilgavimab (150 mg each) may be less active against certain omicron subvariants, the FDA said. However, available data indicate that a higher dose of tixagevimab-cilgavimab may be more likely to prevent infection by COVID-19 omicron subvariants BA.1 and BA.1.1.
Three omicron variants dominate SARS-CoV-2 circulation in the United States as of Feb. 28: BA.1.1 makes up 75.7%; B.1.1.529 is 20.6%; and BA.2 is 3.8% of circulating virus. As omicron started overtaking delta as the most common variant, many monoclonal antibodies (mAbs) were found to be less effective against this variant.
The FDA increased the initial authorized dose to 300 mg of tixagevimab and 300 mg of cilgavimab. Patients who have already received the previously authorized dose should be contacted about receiving an additional dose of 150 mg of tixagevimab and 150 mg of cilgavimab as soon as possible to raise their antibody levels.
Tixagevimab-cilgavimab as PrEP is authorized for certain adults and children (≥12 years of age weighing ≥40 kg) who are not currently infected with SARS-CoV-2 and who have not had a known recent exposure to someone infected with SARS-CoV-2.
Tixagevimab-cilgavimab is only authorized for those:
- who are moderately to severely immunocompromised due to a medical condition or who have received immunosuppressive medications or treatments and may not mount an adequate immune response to COVID-19 vaccination; or
- for whom vaccination with any available approved or authorized COVID-19 vaccine is not recommended due to a history of severe adverse reaction (e.g., severe allergic reaction) to a COVID-19 vaccine(s) and/or COVID-19 vaccine component(s).
The duration of protection provided by tixagevimab-cilgavimab against symptomatic SARS-CoV-2 infection may not be as long as was shown in the clinical trial supporting the initial authorization, as the clinical trial data were collected before the emergence of the BA.1 and BA.1.1 subvariants, the FDA warned.
However, it is not known whether BA.1 and BA.1.1 will still be circulating in the coming months or whether another omicron subvariant, BA.2, for which tixagevimab-cilgavimab is expected to have greater neutralizing activity, will become dominant.
“Because it is unclear which SARS-CoV-2 variant or omicron subvariant will become dominant in the United States over the next few months, the recommended timing for repeat dosing cannot be provided at this time. We will continue to monitor the situation closely and will provide updates with redosing recommendations in the near future when more data are available to determine the appropriate timing of redosing [e.g., 3 months or 6 months after the prior dose],” the FDA said in a statement.
The volume of each injection for the new, higher dose will be larger, 3 mL instead of 1.5 mL, so injections should be limited to large muscles in the body that can accommodate this volume, such as the gluteal muscles.
In related news, the FDA recently issued an EUA for a new mAb, bebtelovimab (Lilly), for the treatment of mild to moderate COVID-19 in adults and children with a positive COVID-19 test, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by the FDA are not accessible or clinically appropriate.
Bebtelovimab is not authorized for patients who are hospitalized due to COVID-19 or require oxygen due to COVID-19. Treatment with bebtelovimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bebtelovimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation.
The EUA for bebtelovimab is supported by clinical and nonclinical data. The clinical data are from a phase 2, randomized, single-dose clinical trial evaluating the efficacy of bebtelovimab alone and bebtelovimab with other mAbs for treating mild to moderate COVID-19.
Bebtelovimab works by binding to the spike protein of the virus that causes COVID-19, similar to other mAbs that have been authorized for the treatment of high-risk patients with mild to moderate COVID-19 and shown a benefit in reducing the risk for hospitalization or death.
The FDA is carefully monitoring circulating viral variants and their sensitivity to authorized mAbs, including bebtelovimab. Laboratory testing showed that bebtelovimab retains activity against both the omicron variant and the BA.2 omicron subvariant.
The placebo-controlled portion of the trial enrolled 380 low-risk patients (i.e., patients without risk factors for progression to severe COVID-19 illness). Patients in this part of the trial were randomized to receive a single infusion of bebtelovimab alone, bebtelovimab with other mAbs or placebo. Treatment with bebtelovimab resulted in a reduction in time to sustained symptom resolution compared with placebo. Reduction in viral load relative to placebo was also seen on day 5 after treatment.
In another part of the trial involving mostly high-risk individuals (i.e., patients with risk factors for progression to severe COVID-19 illness), 150 patients were randomized to receive a single infusion of bebtelovimab alone or a single infusion of bebtelovimab with other mAbs. An additional 176 high-risk patients received bebtelovimab with other mAbs in an open-label treatment arm.
The rates of COVID-19–related hospitalization and death through day 29 seen in those who received bebtelovimab alone or with other mAbs were generally lower than the placebo rate reported in prior trials of other mAbs in high-risk patients. Conclusions are limited, as these data are from different trials that were conducted when different viral variants were circulating and baseline risk factors varied.
Clinical data were similar for bebtelovimab alone compared with the combination of bebtelovimab with other mAbs.
The mAb is indicated for adults and children 12 years of age and older weighing at least 40 kg, which is about 88 pounds.
Possible side effects of bebtelovimab include itching, rash, infusion-related reactions, nausea and vomiting.
—From FDA press materials
