The U.S. government has halted distribution of Eli Lilly’s COVID-19 antibody treatment 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.

In announcing the halt this week, the U.S. Office of the Assistant Secretary for Preparedness and Response (ASPR) said it will continue to distribute bamlanivimab in combination with etesevimab (LY-CoV16 or JS-16), another Lilly antibody. The combination won FDA authorization for emergency use last month.

ASPR said it is also continuing to distribute another antibody combination that has been granted an EUA by the FDA, Regeneron Pharmaceuticals’ two-antibody combination or “cocktail REGEN-COV™ (casirivimab and imdevimab). Healthcare providers with supplies of bamlanivimab can order etesevimab alone to create the combination.

“Using an alternative authorized monoclonal antibody therapy may reduce the risk of treatment failure should a patient be infected with a SARS-CoV-2 viral variant that is resistant to bamlanivimab alone,” ASPR stated late on Wednesday.

The FDA made a similar recommendation to healthcare providers when it recently updated the “Antiviral Resistance” section of its Fact Sheet for Healthcare Providers for the bamlanivimab emergency use authorization (EUA).

“There is a potential risk of treatment failure due to the development of viral SARS-CoV-2 variants that are resistant to bamlanivimab,” the FDA cautioned. “It is possible that bamlanivimab resistance-associated variants could have cross-resistance to other mAbs [monoclonal antibodies] targeting the receptor binding domain of SARS-CoV-2. The clinical impact is not known.”

In a statement furnished to GEN, Lilly said it developed the bamlanivimab-etesevimab combination to combat SARS-CoV-2 variants that could resist treatment with either monoclonal antibody alone.

“As previously disclosed, Lilly, in collaboration with Amgen, plans to manufacture up to 1 million doses of etesevimab for administration with bamlanivimab by mid-2021, which enables us to begin this transition to only supply product for administration of bamlanivimab and etesevimab together,” Lilly stated.

Reduced susceptibility

The FDA cited non-clinical studies using serial passage of SARS-CoV-2 and directed evolution of the spike protein. Those studies have identified several amino acid substitutions in the spike protein receptor binding domain—E484D/K/Q, F490S, Q493R and S494P—which resulted in reduced susceptibility to bamlanivimab as determined in neutralization assays using SARS-CoV-2.

F490S and S494P showed reductions of >485-fold and >71-fold, respectively, according to the FDA, while all variants showed a >100-fold reduction in a study of vesicular stomatitis virus-based pseudovirus expressing spike protein with variant substitutions.

“Reduction in susceptibility of >1,000-fold indicates that there will likely be no activity of bamlanivimab alone against these variants,” according to the FDA Fact Sheet.

In the U.K. variant lineage (B.1.1.7), testing with the key substitution N501Y showed a <5-fold reduction in susceptibility. However, a susceptibility reduction of >1,020-fold was seen when variants B.1.427 and B.1.429, both of California origin, were tested with the key substitution L452R.

Three other variant lineages showed a reduction in susceptibility to bamlanivimab of >2,360-fold after being tested with key substitution E484K:

  • The South African variant B.1.351.
  • The Brazilian variant P.1.
  • The New York variant B.1.256. However, not all isolates of the New York lineage harbored the E484K substitution as of February.

“Bamlanivimab alone is unlikely to be active against variants from this lineage,” the FDA cautioned in footnotes to all three.

The FDA also raised the possibility of COVID-19 patients contracting the disease again: “There is a theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection.”

In its Fact Sheet for REGEN-COV, the FDA disclosed that five spike protein amino acid substitutions showed reduced susceptibility to casirivimab (K417E, Y453F, L455F, F486V and Q493K), while two substitutions showed reduced susceptibility to imdevimab, K444Q and V445A.

Of 37 different RBD variants identified as the most common RBD variations circulating as of late March 2020, plus the D614G and D614N spike protein variants, casirivimab had a 4.5-fold reduced susceptibility to G476S and S494P variants, while imdevimab showed a 463-fold reduced susceptibility to the N439K variant.

Top-selling drug

Eli Lilly has issued guidance to investors projecting that bamlanivimab would generate between $1 billion and $2 billion in sales this year.

Bamlanivimab generated $871.2 million in sales last year, placing the antibody second on GEN’s A-List of Top 7 Best-Selling COVID-19 Vaccines and Drugs of 2020, published last month.

The distribution halt did not hurt Lilly’s share price, which rose 1.6% in trading Thursday, to a closing price of $183.09 from $180.17 on Wednesday.

Bamlanivimab (LY-CoV555) is a neutralizing immunoglobulin G, subclass 1 (IgG1) monoclonal antibody designed to bind to the receptor-binding domain of the spike protein of SARS-CoV-2. The antibody was first identified in a blood sample from a recovered COVID-19 patient, and discovered through the rapid pandemic response platform of partner AbCellera, in partnership with NIAID’s Vaccine Research Center.

Etesevimab (LY-CoV016, also known as JS016) is a recombinant fully human monoclonal neutralizing antibody, which specifically binds to the SARS-CoV-2 surface spike protein receptor-binding domain with high affinity and can block the binding of the virus to the ACE2 host cell surface receptor.

Etesevimab is licensed by Lilly from Junshi Biosciences after it was jointly developed by Junshi Biosciences and Institute of Microbiology, Chinese Academy of Science (IMCAS). Junshi Biosciences leads development of etesevimab in Greater China, while Lilly leads development in the rest of the world.

Earlier this month, Lilly announced positive Phase III results showing the bamlanivimab-etesevimab slashing by 87% the risk of COVID-19 related hospitalizations and deaths in high-risk patients recently diagnosed with the virus.

The EUAs for the combination and for bamlanivimab alone were both granted for the treatment of mild to moderate COVID-19 in patients aged 12 and older who are at high risk for progressing to severe COVID-19 and/or hospitalization. As with the monotherapy EUA, before patients can be treated with the combination antibody therapy, they must weigh at least 40 kilograms (about 88 pounds) and be deemed at high risk for progressing to severe COVID-19 and/or hospitalization.

Both EUAs allow for the distribution and emergency use of the antibody via a single intravenous infusion at the lowest IV dose studied, 700mg. The combination includes a 1400 mg dose of etesevimab.

Bamlanivimab monotherapy and the combination with etesevimab are among 21 “Front Runner” leading candidates among the more than 300 COVID-19 therapeutics under study in GEN’s “COVID-19 Drug & Vaccine Candidate Tracker.”

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