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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.

Anti-SARS-CoV-2 bamlanivimab authorized in the US for emergency use

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On November 9, 2020, the US Food and Drug Administration authorized the emergency use of anti-SARS-CoV-2 bamlanivimab (LY-CoV555, LY3819253). The agency stated that “it is reasonable to believe that bamlanivimab may be effective for the treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, 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 bamlanivimab when used to treat COVID-19 in such patients outweigh the known and potential risks of such product.”

Bamlanivimab is a human IgG1 antibody directed against the receptor binding domain of the spike protein of the SARS-CoV-2 coronavirus. AbCellera and Eli Lilly and Company partnered on the discovery and development of the antibody, which was derived from B cells of convalescent patients. The EUA was based on review of the topline data from the planned interim analysis of BLAZE-1 (NCT04427501), an ongoing randomized, double-blind, placebo-controlled, Phase 2 dose-finding trial of bamlanivimab monotherapy in outpatients with mild to moderate COVID-19.

The EUA letter indicates that distribution of the authorized bamlanivimab (700 mg/20 mL) will be controlled by the United States Government for use consistent with the terms and conditions of the EUA, and that the EUA is effective only while circumstances exist justifying the authorization of emergency use during the COVID-19 pandemic.

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.

First study results for anti-SARS-CoV-2 antibody LY-CoV555

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On September 16, 2020, Eli Lilly and Company announced proof of concept data from an interim analysis of the Phase 2 BLAZE-1 clinical trial (NCT04427501) of LY-CoV555 (also known as LY3819253), an anti-SARS-CoV-2 IgG1 antibody. The randomized, double-blind, placebo-controlled study included 4 arms (placebo, 700 mg, 2800 mg, and 7000 mg administered intravenously (IV)), and enrolled mild-to-moderate recently diagnosed COVID-19 patients. Treatment is provided in an outpatient setting. The study was initiated on June 17, 2020 and has an estimated primary completion date of September 20, 2020.

  • The prespecified primary endpoint, change from baseline in viral load at day 11, was met at the 2800 mg dose level, but not the others. Additional analyses of viral data demonstrated that LY-CoV555 improved viral clearance at an earlier time point (day 3) and reduced the proportion of patients with persistently high viral load at later time points. Most patients, including those receiving placebo, demonstrated near complete viral clearance by day 11.
  • Analysis of pooled data from all dose groups indicated the rate of hospitalizations and ER visits was 1.7% (5/302) for LY-CoV555 vs. 6% (9/150) for placebo. Across all treatment groups (including placebo), no patients progressed to mechanical ventilation or died.
  • Viral RNA sequencing revealed putative LY-CoV555-resistance variants in placebo and all treatment arms. The rate of resistance variants was numerically higher in treated patients (8 percent) versus placebo (6 percent).
  • LY-CoV555 was well-tolerated, with no drug-related serious adverse events reported. Treatment emergent adverse events were similar across all dose groups and comparable to placebo.

Details for the BLAZE-1 study were updated on August 21, 2020 to include an experimental treatment arm comprising LY3819253 + LY3832479 (also known as LY-CoV016) administered IV.  LY-CoV016 binds a different epitope in the SARS-CoV-2 spike region compared to LY-CoV555. Across all treatment arms, the trial will enroll an estimated 800 participants.

Summary data for all anti-SARS-CoV-2 antibodies in clinical studies can be found here.

Fighting the Forever-war Against Infectious Diseases

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Author: Nick Hutchinson, Mammalian Cell Culture, Business Steering Group Lead, FUJIFILM Diosynth Biotechnologies (nick.hutchinson@fujifilm.com)

The COVID-19 crisis has had a devastating impact on populations across the world and caused the death of hundreds of thousands of people. The Antibody Society spoke to Dr. Jacob Glanville, CEO and President of Distributed Bio, Inc. to learn how his company has approached the development of new antibody therapeutics against the SARS-CoV-2 Coronavirus. He described how the crisis has stimulated innovation that may revolutionize the way we approach antibody discovery and development once the current pandemic is under control.

Dr Glanville explained, “The problem, when we think of every major outbreak, such as Ebola, SARS, MERS, Swine Flu, Avian Flu, is that the time it takes to develop a new drug is too long compared to the speed with which we need it. De novo discovery is too slow.”

To develop antibody therapeutics against COVID-19 as quickly as possible, Distributed Bio identified anti-SARS antibodies from almost 20 years ago that researchers had already shown would neutralize the SARS virus in vitro, protect mice from lethal challenge, and had known crystal structures. These antibodies have been studied extensively but were eventually too late to have an impact on the SARS crisis of 2003. It was Glanville’s idea to take advantage of the detailed functional research already performed on these antibodies and, try to retrofit them to bind to the new version of their original target the virus SARS-CoV-2. For this purpose, Distributed Bio applied their Tumbler technology, a computationally-guided antibody optimization method, capable of producing a library of billions of variants of individual antibodies exploring variations of all six complementarity-determining regions simultaneously.

“The novel coronavirus has around 74% homology in identity with the SARS receptor binding domain. I knew exactly how similar they were to the novel coronavirus as we had crystal structures of the SARS epitope. I believed that if we took five anti-SARS antibodies, there was going to be a pretty good chance that we would be able to adapt them to be a potent medicine against COVID-19,” said Glanville. “We already knew that they had the correct function, that they bound the right epitope in the right orientation with the right elbow angles. I believed that we could optimize them and enhance their affinity by making billions of versions of the antibodies within the library,” he continued.

According to Glanville, this is crucially important because historically, with outbreaks such as Ebola, the first antibodies launched were essentially prototypes with low potency or had inferior characteristics such as poor thermostability. It was the best-in-class not the first antibody that was successful, ultimately.

Distributed Bio were able to adapt all five antibodies in just nine weeks, a testament to the remarkable speed of these novel technologies. They sent a set of the most promising candidates to five laboratories which independently confirmed their ability to bind to the new SARS-CoV-2. The company then selected the two most potent antibodies for in-vivo testing, and two laboratories confirmed independently that both candidates protected healthy, as well as immuno-compromised animals using hamster models.

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