The U.S. treatment arsenal against COVID-19 has gained one new antibody, and lost two others, in recent days through regulatory actions.

The FDA has granted Genentech, a member of the Roche Group, emergency use authorization (EUA) for its marketed interleukin-6 (IL-6) receptor antagonist Actemra® (tocilizumab) as a treatment for COVID-19.

Actemra was granted an EUA on Thursday as a COVID-19 treatment for hospitalized adults and children ages two and older who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

A day later, the FDA joined with another agency within the U.S. Department of Health and Human Services to immediately pause all nationwide distribution of Eli Lilly’s antibody combination of bamlanivimab and etesevimab.

The U.S. Assistant Secretary for Preparedness and Response (ASPR) said the combination showed itself “not active” against two of the COVID-19 variants that have increasingly accounted for new cases of the disease—based on in vitro assays that assessed the susceptibility of viral variants to specific monoclonal antibodies.

Of those two variants, P.1/Gamma (first identified in Brazil) accounted for 11.2% of cases that emerged between March 14 and June 5, while the B.1.351/Beta (first identified in South Africa) accounted for 0.4%, according to the U.S. Centers for Disease Control and Prevention.

Both variants have shown significantly reduced susceptibility against bamlanivimab-etesevimab, the FDA acknowledged in its “Fact Sheet” for healthcare providers of detailed instructions for administering the antibody combination, revised May 14.

Pseudotyped virus-like particles (VLPs) expressing spike protein from B.1.351 showed a 251-fold reduced susceptibility to the bamlanivimab-etesevimab combo, improving only to >45-fold reduced susceptibility when three substitutions found in that lineage were studied (K417N, E484K, and N501Y).

The P.1 lineage showed >46-fold reduced susceptibility to the bamlanivimab-etesevimab combo—a result that worsened to >511-fold when three substitutions were assessed, (K417M, E484K, and N501Y).

(Brazil origin) or K417T + E484K + N501Y found in the P.1 lineage had reduced susceptibility to bamlanivimab and etesevimab together of >46-fold or >511-fold, respectively.

Two alternatives

On Friday, the FDA recommended that healthcare providers nationwide use two other monoclonal antibody therapies that have been granted EUAs—Regeneron Pharmaceuticals’ two-antibody “cocktail” or combination REGEN-COV™; and Sotrovimab (formerly VIR-7831), which is being developed by GlaxoSmithKline (GSK) and Vir Biotechnology.

“Based on similar in vitro assay data currently available, REGEN-COV and sotrovimab are likely to retain activity against the P.1 or B.1.351 variants,” ASPR and FDA stated.

On June 4, Regeneron cited in vitro research showing that REGEN-COV retained potency against the main variants of concern circulating within the U.S., including P.1 and B.1.351. That day, Regeneron said it expected to submit a full Biologics License Application (BLA) for REGEN-COV in non-hospitalized outpatients with COVID-19 “later this summer.”

GSK and Vir earlier this month announced the NIH’s updating its COVID-19 treatment guidelines to recommend Sotrovimab for non-hospitalized patients with mild-to-moderate COVID-19 who are at high risk of clinical progression. The NIH guidelines noted that Sotrovimab maintained neutralizing activity in vitro against P.1 and B.1.351, as well as variants B.1.1.7 (Alpha/first identified in Kent, U.K.); B.1.427/429 (Epsilon/California), and B.1.526 (Iota/New York City).

The distribution pause marks Lilly’s second regulatory setback for its COVId-19 antibodies in three months. Back in March, the ASPR halted distribution of bamlanivimab (LY-CoV555) as a monotherapy just four months after it received FDA emergency use authorization, citing a sustained increase in variants of SARS-CoV-2 that are resistant to the monotherapy.

Shares of Lilly closed down nearly 1.5% in trading Friday on the New York Stock Exchange, closing at $229.50. Shares of Roche, traded on the SIX Swiss Exchange, inched up 0.75% on Friday, closing at CHF 374.80 ($408.76).

Four trials

The FDA based its EUA of Actemra on data from four randomized, controlled studies that assessed Actemra as a COVID-19 treatment in more than 5,500 hospitalized patients. The studies suggested that Actemra may improve outcomes in patients receiving corticosteroids and requiring supplemental oxygen or breathing support.

The Phase II/III Randomized Evaluation of COVID-19 Therapy (RECOVERY; NCT04381936) Actemra study was led by researchers in the U.K. and included more than 4,000 hospitalized COVID-19 patients. Genentech-sponsored global Phase III trials included the placebo-controlled EMPACTA (NCT04372186), COVACTA (NCT04320615), and REMDACTA (NCT04409262) studies. There have been no new safety signals identified for Actemra in any of these studies, Genentech said. The most common adverse reactions seen (incidence ≥ 3%) were constipation, anxiety, diarrhea, insomnia, hypertension and nausea.

Genentech has said that RECOVERY and EMPACTA met their primary endpoints—but not REMDACTA or COVACTA.

A preprint study from RECOVERY, posted in February on bioRxiv, showed Actemra increased the probability of discharge alive within 28 days from 47% to 54%. And among patients not on invasive mechanical ventilation upon entering the trial, Actemra significantly reduced the chance of progressing to invasive mechanical ventilation or death from 38% to 33%.

However, in July 2020, the company acknowledged that Actemra failed the COVACTA trial by missing its primary endpoint of improved clinical status in hospitalized adult patients with severe COVID-19 associated pneumonia. And in March, Roche said REMDACTA—which assessed Actemra in combination with Gilead Sciences’ Veklury® (remdesivir)—also missed its primary endpoint, as measured by improved time to hospital discharge up to day 28 in patients with severe COVID-19 pneumonia receiving standard of care.

“We are committed to collaborating closely with our distribution partners to enable access to Actemra in hospitals across the country to help adults and children with COVID-19, as well as people who depend on the medicine for its FDA-approved indications,” Genentech CEO Alexander Hardy added.

First authorized by the FDA in 2010, Actemra already holds full approvals for numerous indications that include forms of rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome.

“Even with the availability of vaccines and declines in deaths from COVID-19 in various parts of the world, we continue to see new hospitalizations from severe forms of the disease,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development. “We are pleased that Actemra is now authorized as an option that may help improve outcomes for adults and children hospitalized with COVID-19 in the United States.”

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