PPA News

Posted by: Matthew Helms on Mar 4, 2021

The U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for bamlanivimab and etesevimab administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age or older weighing at least 40 kilograms [about 88 pounds]) who test positive for SARS-CoV-2 and who are at high risk for progressing to severe COVID-19. The authorized use includes treatment for those who are 65 years of age or older or who have certain chronic medical conditions. The authorized dosage is bamlanivimab 700 mg and etesevimab 1400 mg administered together. Under this EUA, bamlanivimab and etesevimab must be diluted and administered together as a single intravenous infusion as soon as possible after positive viral test for SARS-CoV-2 and within 10 days of symptom onset.

Bamlanivimab and etesevimab are not authorized for use in patients who are hospitalized due to COVID-19, who require oxygen therapy due to COVID-19, or who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity. Treatment with bamlanivimab and etesevimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab and etesevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Additional information regarding Limitations of Authorized Use can be found in the Fact Sheet for Health Care Providers linked below.

Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of bamlanivimab with and without etesevimab. Infusion-related reactions have been observed with administration of bamlanivimab and etesevimab together. These reactions may be severe or life threatening, warranting slowing or stopping the infusion and administering appropriate medications and/or supportive care. Additional information regarding these reactions can be found in the Fact Sheet for Health Care Providers linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

MOA: Bamlanivimab and etesevimab are monoclonal antibodies that are specifically directed against the spike protein of SARS-CoV-2, designed to block the virus’ attachment and entry into human cells. Bamlanivimab and etesevimab bind to different but overlapping sites on the spike protein of the virus. Using both antibodies together is expected to reduce the risk of viral resistance.

General PK: PK of bamlanivimab and etesevimab are linear and dose-proportional between 700 mg and 7000 mg following a single IV administration. There were no differences in PK of bamlanivimab between severe/moderate participants who were hospitalized and mild/moderate ambulatory participants. There were no differences in PK of etesevimab between mild/moderate ambulatory participants and healthy participants. There is no change in PK of bamlanivimab or etesevimab administered alone or together suggesting there is no interaction between the two antibodies.

Mean (90% CI) bamlanivimab Cmax was 196 µg/mL (102 to 378 µg/mL) following approximately 1 hr 700 mg IV infusion. Mean (90% CI) etesevimab Cmax is estimated to be 504 µg/mL (262 to 974 µg/mL) following approximately 1 hr 1400 mg IV infusion.

Distribution: Bamlanivimab mean volume of distribution (Vd) was 2.87 L and 2.71 L for the central and peripheral compartments, respectively; the between subject variability (%CV) was 23.2%. Etesevimab mean Vd was 2.38 L and 1.98 L for the central and peripheral compartments, respectively; %CV was 27.8%.

Elimination: Bamlanivimab and etesevimab are expected to be degraded into small peptides and component amino acids via catabolic pathways in the same manner as endogenous IgG antibodies. Bamlanivimab clearance (CL) was 0.27 L/hr (22.3%) and the mean apparent terminal elimination half-life was 17.6 days (15.8%). Etesevimab CL was 0.128 L/hr (33.8%) and the mean apparent terminal elimination half-life was 25.1 days (29.2%).

Use in Specific Populations

The PK profiles of bamlanivimab and etesevimab were not affected by age, sex, race, body weight (over
the body weight range of 41 kg to 173 kg), or disease severity. Renal impairment is not expected to impact the PK of bamlanivimab and etesevimab. There is no significant difference in PK of bamlanivimab or etesevimab in patients with mild hepatic impairment compared to patients with normal hepatic function. Bamlanivimab and etesevimab have not been studied in patients with moderate or severe hepatic impairment.

Pediatric Population
The safety and effectiveness of bamlanivimab and etesevimab administered together are being assessed in adolescent patients in ongoing clinical trials. The recommended dosing regimen is expected to result in comparable serum exposures of bamlanivimab and etesevimab in patients 12 years of age and older and weighing at least 40 kg as observed in adults, based on a PK modeling approach which accounted for effect of body weight changes associated with age on clearance and volume of distribution.

Efficacy and Safety

The issuance of an EUA is different than an FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of available scientific evidence and carefully balances any known or potential risks with any known or potential benefits of the product for use during an emergency. Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that bamlanivimab and etesevimab administered together may be effective in treating certain patients with mild or moderate COVID-19. When used to treat COVID-19 for the authorized population, the known and potential benefits of these antibodies outweigh the known and potential risks.

Efficacy and Rationale for Authorized Dose
In a clinical trial of patients with COVID-19 at high risk for disease progression, a single intravenous infusion of bamlanivimab 2800 mg and etesevimab 2800 mg administered together significantly reduced COVID-19-related hospitalization and death during 29 days of follow-up compared to placebo. The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continue to be evaluated. Detailed information on the clinical trials and supporting data for this EUA can be found in the Fact Sheet for Health Care Providers linked below.

The authorized dosage of 700 mg bamlanivimab and 1400 mg etesevimab administered together is based on analyses of available preclinical, clinical, and virologic data, as well as PK and pharmacodynamic modeling, which, in totality, support that the authorized dosage is expected to have a similar clinical and virologic effect to 2800 mg bamlanivimab and 2800 mg etesevimab administered together.

The most common adverse events in the clinical trial were nausea, dizziness, and rash. These
events each occurred in 1% of subjects treated with bamlanivimab and etesevimab and in 1% of placebo subjects. Across ongoing, blinded clinical trials, a case of anaphylaxis and other cases of serious infusion-related reactions were reported with infusion of bamlanivimab with and without etesevimab. The infusions were stopped. All reactions required treatment, one required epinephrine. All events resolved. Information regarding other immediate hypersensitivity events (e.g., flushing, infusion-related reactions, pruritis, rash) can be found in the Fact Sheet for Health Care Providers linked below.

Additional adverse events associated with bamlanivimab and etesevimab, some of which may be serious, may become apparent with more widespread use.

Additional Information

The Fact Sheet for Health Care Providers provides essential information about using bamlanivimab and etesevimab administered together in treating COVID-19 as authorized and is available at https://go.usa.gov/xs8ch. A fact sheet for patients, parents, and caregivers is available at https://go.usa.gov/xs8xC and contains information for understanding the potential risks and potential benefits of taking bamlanivimab and etesevimab, including side effects.

The EUA authority allows FDA to help strengthen the nation’s public health protections against chemical, biological, radiological, and nuclear threats by facilitating the availability and use of medical countermeasures needed during public health emergencies. For additional information on the EUA authority and EUAs for COVID-19, please visit https://go.usa.gov/xs8x4.

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This communication was prepared by the Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.