The FDA last night granted an emergency use authorization (EUA) to Eli Lilly’s neutralizing antibody bamlanivimab (LY-CoV555) as a treatment for adults and youths ages 12 years and older with mild-to-moderate COVID-19.

The EUA allows for the distribution and emergency use of bamlanivimab, which is administered via a single intravenous infusion at the lowest IV dose studied, 700mg. According to Lilly, bamlanivimab should be administered as soon as possible after a positive COVID-19 test and within 10 days of symptom onset.

Before patients can be treated with bamlanivimab under the EUA, 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. That high-risk category includes adults who are ages 65 or older, or who have chronic medical conditions.

“This emergency authorization allows us to make bamlanivimab available as a COVID-19 treatment for recently diagnosed, high-risk patients—adding a valuable tool for doctors fighting the now-increasing burden of this global pandemic,” Lilly Chairman and CEO David A. Ricks said in a statement.

The FDA said it based the EUA on positive data from Lilly’s ongoing Phase II BLAZE-1 (NCT04427501), a randomized, double-blind, placebo-controlled study in 465 ambulatory (non-hospitalized) patients with recently diagnosed mild to moderate COVID-19. The trial assessed both bamlanivimab as monotherapy and in combination with etesevimab (also known as LY-CoV016), another Lilly antibody against COVID-19 that binds a different epitope in the SARS-CoV-2 spike region.

In BLAZE-1, 101 patients received a 700-mg dose of bamlanivimab, 107 received a 2,800-mg dose, 101 received a 7,000-mg dose and 156 received a placebo within three days of obtaining the clinical sample for the first positive SARS-CoV-2 viral test.

The combination therapy met the trial’s primary endpoint by significantly reducing viral load at day 11, with most patients, including those receiving placebo, showing near complete viral clearance by day 11. The best outcome was in patients receiving the 2,800-mg dose, whose viral load was lowered by a factor of 3.4, according to a study published October 28 in The New England Journal of Medicine.

The study also showed that at day 29, the percentage of patients who were hospitalized with COVID-19 was 1.6% (5 of 309 patients) in the bamlanivimab group and 6.3% (9 of 143 patients) in the placebo group. The percentages in high-risk individuals was 3% for bamlanivimab patients and 10% for placebo patients.

“Physicians are likely to wonder how to define who might be at risk of hospitalization,
since the individuals who go to hospital are frequently difficult to predict (other than the relatively rare high risk co-morbid disease patients). On the other side of the indication, to be eligible you can’t be too sick, or in need of supplemental oxygen or hospital care, because then you are too advanced, and may not benefit or may suffer harm from the medicine,” Geoffrey C. Porges, MBBS, Director of Therapeutics Research and a Senior Research Analyst at SVB Leerink, wrote today in a research note.

“We expect this limited indication to be highly confusing to the community physicians and urgent care centers that see many COVID cases, and even in nursing homes and hospital ER’s this labelling and the determination of risk will be confusing,” Porges added.

Bamlanivimab performed better in the predefined secondary endpoint of COVID-19-related hospitalizations or emergency room visits within 28 days after treatment. For patients at high risk for disease progression, hospitalizations and ER visits occurred in 3% of bamlanivimab-treated patients on average compared to 10% in placebo-treated patients.

The frequency and types of adverse events in BLAZE-1 participants were similar between bamlanivimab and placebo, with most being mild to moderate in severity. Infusion reactions and other allergic hypersensitivity events have been reported.

The EUA includes a warning for hypersensitivity including anaphylaxis and infusion-related reactions.

“Expediting development”

“The FDA remains committed to expediting the development and availability of potential COVID-19 treatments and providing sick patients timely access to new therapies where appropriate, while at the same time supporting research to further evaluate whether they are safe and effective,” FDA Commissioner Stephen M. Hahn, MD, said in a statement. “Through our Coronavirus Treatment Acceleration Program, the FDA continues to work around the clock and use every tool at our disposal toward these efforts.”

Bamlanivimab is an anti-SAR-CoV-2 antibody 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.

Bamlanivimab is among 20 “Front Runner” leading candidates among the more than 300 COVID-19 therapeutics under study in GEN’s updated and just-launched “COVID-19 Drug & Vaccine Candidate Tracker.”

In granting the EUA, the FDA emphasized that bamlanivimab is not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19, since no benefit of bamlanivimab treatment has been shown in those patients.

Two weeks ago on October 26, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) halted the up-to-10,000 patient Phase III ACTIV-3 trial (NCT04501978) it was conducting to assess the safety and effectiveness of bamlanivimab, compared with Gilead Sciences’ Veklury® (remdesivir) and placebo in people who have been hospitalized with COVID-19.

The halt came after the trial’s independent data safety monitoring board reviewed data suggesting that bamlanivimab was unlikely to help hospitalized COVID-19 patients recover from the advanced stage of their disease, NIAID and Lilly stated at the time. NIAID earlier paused patient enrollment in the Phase III ACTIV-3 trial, citing an undisclosed safety concern.

The clinical setback was one of a couple of hurdles bamlanivimab climbed en route to EUA authorization.

Also last month, the FDA gave Lilly an “Official Action Indicated” (OAI) notice after inspectors found quality control problems at a company facility in Branchburg, NJ, that is gearing up to manufacture the antibody treatment, including the deletion and improper auditing of data on the plant’s various manufacturing processes. In addition, Lilly faced competition among leading COVID-19 antibody treatments from Regeneron Pharmaceuticals’ two-antibody “cocktail REGN-COV2, which gained worldwide attention after it was one of the treatments taken by President Donald Trump after he was diagnosed with COVID-19.

“We had low expectations for this approval, and certainly didn’t expect it to occur before Regeneron’s REGN-CoV2 doublet antibody. Lilly’s antibody was approved despite only marginal efficacy at the interim analysis of its Phase II trial in mild to moderate COVID patients,” Porges wrote.

Investors today sent Lilly shares 3% higher in early trading, to $146.73 as of 10 a.m.

Washington commits Up to $1.5B

The same week that NIAID halted ACTIV-3, Washington committed up to $1.5 billion in a pair of agreements toward bamlanivimab.

On October 28, Lilly said the U.S. government agreed to buy an initial 300,000 vials of bamlanivimab over two months for $375 million—$1,250 a vial—to be provided by the Biomedical Advanced Research and Development Authority (BARDA) partnered with the DoD Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and Army Contracting Command.

The contract is part of Operation Warp Speed, the Trump administration’s program designed to accelerate the development, manufacturing, and distribution of COVID-19 diagnostics, drugs, and 300 million doses of vaccines. The contract also includes an option for the federal government to buy another 650,000 vials from Lilly for up to an additional $812.5 million through the end of June 2021.

A day after that purchase agreement, the U.S. Department of Defense (DoD) disclosed that the Army awarded Lilly a firm-fixed-price contract of $312.5 million  covering an unspecified quantity of bamlanivimab to be made at a Lilly production site in Indianapolis. Funds for the Lilly contract came from the Coronavirus Aid, Relief, and Economic Security (CARES) Act, enacted March 27.

Lilly said it anticipated manufacturing up to one million doses of bamlanivimab 700 mg by the end of 2020, for use worldwide through early next year. Beginning in the first quarter of 2021, Lilly added, its supply of bamlanivimab is expected to increase “substantially,” as additional manufacturing resources come online throughout the year. In September, Lilly announced a manufacturing partnership with Amgen of undisclosed value, with the goal of “significantly” increasing the supply capacity available for Lilly’s potential COVID-19 therapies.

Bamlanivimab is the seventh COVID-19 treatment for which the FDA has granted six emergency use authorizations, one of which has since been revoked.

The revoked EUA was the first one issued by the FDA for a COVID-19 therapeutic. On March 28, the agency authorized emergency use of the anti-malarial drugs chloroquine phosphate and its less toxic metabolite hydroxychloroquine sulfate. That authorization was repealed on June 15, with the FDA citing a lack of consistent replication of earlier promising results and a randomized controlled clinical trial that showed no clinical benefit for hydroxychloroquine.

The second and oldest COVID-19 therapeutic-related EUA still in effect was granted May 1 for Gilead Sciences’ Veklury®—the antiviral better known by its generic name of remdesivir. Veklury won full FDA approval on October 23, albeit for a smaller population than allowed under its EUA.

The other EUAs for COVID-19 therapeutics were issued to:

  • Fresenius Kabi for Propoven 2% Emulsion, indicated to maintain sedation via continuous infusion in patients greater than 16 years old who require mechanical ventilation in an Intensive Care Unit (ICU) setting (EUA issued May 8).
  • Baxter Healthcare for REGIOCIT replacement solution containing citrate for regional citrate anticoagulation of the extracorporeal circuit (August 13).
  • The U.S. Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, for convalescent plasma for hospitalized COVID-19 patients (August 23).
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