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FDA issues Emergency Use Authorization for bamlanivimab/etesevimab combination

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On February 9, 2021, the U.S. Food and Drug Administration 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 who test positive for SARS-CoV-2 and who are at high risk for progressing to severe COVID-19. Developed by Eli Lilly and Company, bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target overlapping regions of the SARS-CoV-2 spike protein.

The EUA was based on a randomized, double-blind, placebo-controlled clinical trial in 1,035 non-hospitalized adults with mild to moderate COVID-19 symptoms who were at high risk for progressing to severe COVID-19. Of these patients, 518 received a single infusion of bamlanivimab (2.8 g) and etesevimab (2.8 g) together, and 517 received placebo. The primary endpoint was COVID-19 related hospitalizations or death by any cause during 29 days of follow-up.  Hospitalization or death occurred in 11 (2%) patients treated the mAb combination vs. 36 (7%) patients who received placebo. All 10 deaths (2%) occurred in the placebo group.

The authorized dosage of 700 milligrams bamlanivimab and 1400 milligrams etesevimab administered together is based on analyses of available preclinical, clinical, and virologic data, as well as pharmacokinetic and pharmacodynamic modeling, which, in totality, support that the authorized dosage is expected to have a similar clinical and virologic effect to the dose evaluated in the clinical trial. Use of the mAb combination is not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19.

In November 2020, FDA issued an EUA for a single infusion of 700 mg bamlanivimab for the treatment of mild-to-moderate COVID-19 in adult and certain pediatric patients. Since the monotherapy and the combination treatment are expected to benefit patients at high risk of disease progression, both 700 milligrams bamlanivimab alone and the combination of 700 milligrams bamlanivimab and 1,400 milligrams etesevimab administered together will be available under an EUA.

Anti-SARS-CoV-2 casirivimab and imdevimab (REGN-COV2) authorized in the US for COVID-19

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On November 20, 2020, the US Food and Drug Administration authorized the emergency use of casirivimab and imdevimab (REGN-COV2), both of which are recombinant human IgG1 monoclonal antibodies that target the receptor binding domain of the spike protein of SARS-CoV-2. This antibody cocktail has been shown to reduce COVID-19-related hospitalization or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo.

After reviewing the analysis of Phase 1 and 2 data from the ongoing Phase 1/2/3 NCT04425629 study, the agency concluded that “it is reasonable to believe that casirivimab and imdevimab, administered together, may be effective for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization, and that, when used under the conditions described in this authorization, the known and potential benefits of casirivimab and imdevimab, administered together, outweigh the known and potential risks of such product.”

The EUA letter further states that distribution of REGN-COV2 will be directed by the U.S. government, and its EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic is terminated or the EUA is revoked. The authorized dosage is 1,200 mg of casirivimab and 1,200 mg of imdevimab administered together as a single intravenous (IV) infusion over at least 60 minutes via pump or gravity as soon as possible after positive viral test for SARS-CoV-2 and within 10 days of symptom onset.

Regeneron was granted a $450 million contract to manufacture and supply REGN-COV2 by the US government, which has committed to making the doses available to Americans for free. The agreement covers a fixed number of bulk lots, as well as fill/finish and storage activities. Delivery of REGN-COV2 drug product started during the third quarter of 2020, and the company expects to have ~ 80,000 doses available by the end of November, ~200,000 total doses ready by the first week of January 2021, and ~ 300,000 total doses ready by the end of January 2021.

Emergency use authorization requests for anti-SARS-CoV-2 antibodies under FDA review

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On October 7, 2020, Eli Lilly and Company and Regeneron announced that they have submitted requests to the  U.S. Food and Drug Administration (FDA) for emergency use authorizations (EUA) of their anti-SARS-CoV-2 monoclonal antibodies.

Lilly’s EUA request is for bamlanivimab (LY-CoV555) monotherapy in higher-risk patients who have been recently diagnosed with mild-to-moderate COVID-19. According to the company, up to 100,000 doses of 700 mg LY-CoV555 monotherapy may be available in October, and one million doses available in Q4 2020.

The combination of LY-CoV555 and LY-CoV016, which bind complementary regions of the SARS-CoV-2 spike protein, for the treatment of symptomatic COVID-19 in an outpatient setting is also being evaluated. Lilly anticipates submission of an EUA request for combination therapy in November, and may have data to support a biologics license application submission for combination therapy as early as Q2 2021.

Regeneron’s EUA request is for REGN-COV2, which is a combination of two anti-SARS-CoV-2 monoclonal antibodies (REGN10933 and REGN10987). Regeneron was granted a $450 million contract to manufacture and supply REGN-COV2 by the US government, which has committed to making the doses available to Americans for free. The agreement covers a fixed number of bulk lots that are intended to be completed in the fall of 2020, as well as fill/finish and storage activities. At the time of the EUA request, Regeneron had doses available for ~ 50,000 patients, and expects to have doses available for a total of 300,000 patients within several months.

The Antibody Society is tracking the progress of recombinant biologic COVID-19 interventions in preclinical and clinical studies. Summary data for all anti-SARS-CoV-2 antibodies in clinical studies can be found here.

Antibodies to Watch in a Pandemic

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The extraordinary scale of the COVID-19 pandemic has elicited extraordinary responses world-wide, but the resulting disruptions have raised concerns about delays in approval of non-COVID-19 antibody therapeutics.

As part of the virtual Antibody Engineering & Therapeutics Europe conference, Dr. Janice Reichert, Executive Director of The Antibody Society,  provided an update on non-COVID-19 antibody therapeutics approved so far in 2020, and those that might be approved by the end of the year. She also discussed the biologics currently in development for COVID-19, which includes over 50 repurposed biologics and over 80 anti-SARS-CoV-2 biologics.

Broadcast date: Thursday August 27, 2020.

Updated presentation slides can be downloaded here.

Dataset of commercially sponsored biologic COVID-19 interventions can be downloaded here.

FDA issues Emergency Use Authorization for COVID-19 convalescent plasma

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On August 23, 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for investigational COVID-19 convalescent plasma (CCP) for the treatment of COVID-19 in hospitalized patients. CCP is human plasma collected by FDA-registered blood establishments from individuals whose plasma contains anti SARS-CoV-2 antibodies, and who meet all donor eligibility requirements and are qualified. Titer levels of anti-SARS-CoV-2 antibodies are determined by the Ortho VITROS SARS-CoV-2 IgG test before units of CCP are released. Units found to have a signal-to-cutoff ratio of 12 or greater qualify as High Titer COVID-19 Convalescent Plasma.

Based on scientific evidence available, the FDA concluded CCP may be effective in treating COVID-19, and that the known and potential benefits of CCP outweigh the known and potential risks of the product. The EUA authorizes the distribution of COVID-19 convalescent plasma in the U.S. and its administration by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in hospitalized patients with COVID-19.

Data obtained from the ongoing National Convalescent Plasma Expanded Access Protocol (EAP) sponsored by the Mayo Clinic was included in FDA assessment. This uncontrolled, single-arm study was established in April 2020 to provide access to COVID-19 convalescent plasma in hospitalized subjects with severe or life-threatening COVID-19 or judged by the treating provider to be at high risk of progression to severe or life-threatening disease. As of August 13, 2020, over 90,000 patients have been enrolled. Data from the EAP posted online on August 12, 2020 reveals trends toward reduced mortality when patients receive CCP with higher antibody levels and at earlier time points. According to FDA’s decision memorandum:

  • In the subset of non-intubated patients, there was a 21% reduction in 7-day mortality (from 14% to 11%, p=0.03) in subjects transfused with high versus low titer CCP.
  • In the subgroup of patients less than 80 years of age who were not intubated and who were within 72 hours of diagnosis, a significant reduction in 7-day mortality from 11.3 to 6.3% (p = 0.0008) was observed when titers are binned to low versus high.
  • Survival trends observed at 7 days persisted over a longer time period, with significantly improved survival in non-intubated patients (p=0.032) and a larger benefit in the subset of patients not intubated at the time of treatment, less than 80 years of age, who were treated within 72 hours of diagnosis (p=0.0081)

However, there was no difference in 7-day survival in the overall population between subjects transfused with high versus low titer CCP, and there was no apparent association between neutralizing antibody titers and 7-day mortality in intubated subjects.

Information from the EUA and clinical studies of CCP may inform the development of other biologic COVID-19 interventions, such as recombinant anti-SARS-CoV-2 antibodies.  The Antibody Society is currently tracking 10 such antibodies in clinical studies or with clinical studies pending. We will report on the progress of these molecules and other COVID-19 interventions in the future.