Candidate: Bamlanivimab (LY-CoV555)

Category: ANTIBODY

Type: Anti-SAR-CoV-2 antibody based on AbCellera’s rapid pandemic response platform

Status: Eli Lilly and UnitedHealth Group said December 4 they would partner on a “pragmatic” study of bamlanivimab in high-risk, COVID-19 infected individuals. The study will draw upon both UnitedHealth Group’s UnitedHealthcare health benefits business and its Optum health services business to detect and treat high-risk symptomatic patients who test positive for COVID-19 with bamlanivimab. Patients will receive daily symptom tracking, in-home SARS-CoV-2 testing and in-home infusion services allowing them to stay quarantined and at home, minimizing the potential spread of COVID-19.

A day earlier, Lilly said that the U.S. government exercised its option to purchase another 650,000 vials of bamlanivimab from the company for $812.5 million through January 31, 2021, under the contract through which the government bought an initial 300,000 vials 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.

In another Operation Warp Speed contract, the U.S. Department of Health and Human Services on December 2 selected CVS Health for a pilot program designed to administer a limited supply of bamlanivimab to eligible COVID-19 patients at-risk of severe infection or complications from the virus.

Coram, the specialty pharmacy and infusion care business of CVS Health with more than 800 cetified nurses nationwide, will administer the intravenous therapy in patients’ homes or long-term care facilities. Coram agreed to administer 1,000 doses of monoclonal antibody therapies for COVID-19 in seven cities and their surrounding communities starting December 3, including Boston, Chicago, Cleveland, Los Angeles, Milwaukee, Minneapolis and Tampa, FL.

Eli Lilly joined Samsung Biologics on November 17 to announce a global, long-term manufacturing partnership for bamlanivimab and other Lilly COVID-19 antibody therapies. The value of the agreement was not disclosed, though the companies did say they entered into their partnership in May.

Since then, Samsung manufactured and delivered an initial supply of active pharmaceutical ingredients (API) meeting GMP and regulatory standards within five months of contract signing. The timeline for tech transfer was reduced dramatically to less than three months.

Emergency Use Authorization granted November 9 — The FDA on November 9 granted an emergency use authorization (EUA) to bamlanivimab 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 for administration 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.

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.

On October 27, the U.S. Army awarded a $312.5 million firm-fixed-price contract  to Lilly (W911QY-21-C-0016) covering an unspecified quantity of bamlanivimab to be made at a Lilly production site in Indianapolis. Funds for the contract, awarded by U.S. Army Contracting Command, will come from the Coronavirus Aid, Relief, and Economic Security (CARES) Act, enacted March 27.

Eli Lilly and the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) acknowledged in separate statements October 26 that the agency halted the up-to-10,000 patient Phase III ACTIV-3 trial (NCT04501978). ACTIV-3 is designed to assess the safety and effectiveness of Lilly’s LY-CoV555, recently renamed bamlanivimab, compared with Gilead Sciences’ Veklury™ (remdesivir) and placebo in people who have been hospitalized with COVID-19.

The trial’s independent data safety monitoring board reviewed data October 26 at a scheduled meeting–data that suggested that bamlanivimab is unlikely to help hospitalized COVID-19 patients recover from the advanced stage of their disease.

Lilly said all other trials of LY-CoV555 were continuing, and noted that ACTIV-3 focused on hospitalized patients who were being treated with other drugs and were more severely ill than those in its other trials. The other trials include BLAZE-1; ACTIV-2 (NCT04518410), an NIH-sponsored study in recently diagnosed mild to moderate COVID-19 patients; and BLAZE-2 (NCT04497987), Lilly’s Phase III study of bamlanivimab for the prevention of COVID-19 in residents and staff at long-term care facilities.

Participants in the multicenter, adaptive, randomized, blinded, controlled trial were randomized to treatment with LY-CoV555 plus current standard of care (SOC), remdesivir plus current SOC, or placebo plus current SOC.

Eli Lilly confirmed to Reuters it received an “Official Action Indicated” (OAI) notice from the FDA after its inspectors found quality control problems at a company facility in Branchburg, NJ, that is gearing up to manufacture LY-CoV555.

The problems—including the deletion and improper auditing of data on the plant’s various manufacturing processes—were reported on October 13 based on a review of “heavily” redacted government inspection documents and three unnamed sources. The FDA told Reuters that it launched a “comprehensive remediation plan,” had increased staffing at the site, and was working “aggressively” to address concerns raised during the inspection. However, the agency declined to detail the manufacturing issues that led to the FDA action.

Earlier on October 13, Lilly said patient enrollment had been paused in the Phase III ACTIV-3 trial, citing an undisclosed safety concern. The trial had recruited 326 participants before the pause, which NIAID said was recommended by its independent data safety monitoring board after “an overall difference in clinical status between the group receiving LY-CoV555 and the group receiving saline placebo” was found during a planned interim analysis of safety data for the first 300 participants enrolled in the trial.

The board also recommended continuing to collect data, and following up with participants to assess their safety and the efficacy of the treatment.

Eli Lilly said October 8 it had committed to facilitating access to future Lilly therapeutic antibodies under development for to prevent and treat COVID-19 under an agreement signed with the Bill & Melinda Gates Foundation, as part of the COVID-19 Therapeutics Accelerator.

Commercial manufacturing of the antibodies will begin in April 2021 at the FUJIFILM Diosynth Biotechnologies facility in Denmark, where the Accelerator has reserved manufacturing capacity. The Gates Foundation partnered with Wellcome, and Mastercard to launch the Accelerator in order to accelerate development of and access to COVID-19 therapies.

A day earlier, Lilly said it will file an Emergency Use Authorization (EUA) application with the FDA for LY-CoV555 monotherapy in higher-risk patients recently diagnosed with mild-to-moderate COVID-19.

Lilly said it based its decision on a positive new interim analysis of data from the Phase II BLAZE-1 trial. The data showed that a combination of LY-CoV555 and LY-CoV016—another Lilly antibody that binds a different epitope in the SARS-CoV-2 spike region—reduced viral load, symptoms, and COVID-related hospitalization and ER visits.

A day later, Lilly announced additional BLAZE-1 data from an exploratory analysis which showed that the proportion of patients with persistent high viral load at day 7 for combination therapy was lower (3.0%) vs. placebo (20.8%).

BLAZE-1 assessed the two neutralizing antibodies for the treatment of symptomatic COVID-19 in the outpatient setting. The combination cohort enrolled recently diagnosed patients with mild-to-moderate COVID-19, of which 112 were assigned to 2,800 mg of each antibody, while the other 156 patients were randomized to placebo.

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.

Lilly added that the combination treatment reduced viral levels at day 3 and day 7, while also significantly reducing the time-weighted average change from baseline from day 1 to 11. An exploratory analysis showed that the proportion of patients with persistent high viral load at day 7 for combination therapy was lower (3.0%) vs. placebo (20.8%).

The rate of COVID-related hospitalization and ER visits was lower for patients treated with combination therapy (0.9%) vs. placebo (5.8%), for an 84.5% relative risk reduction, similar to LY-CoV555 monotherapy.

Lilly said it expected to submit a request in November for an EUA for the combination therapy, pending clinical trial enrollment, once additional safety data accumulate and sufficient supply is manufactured. Lilly anticipated having data to support a BLA submission for combination therapy as early as second quarter 2021.

On September 17, Lilly joined Amgen in announcing a global antibody manufacturing collaboration designed to “significantly” increase the supply capacity available for Lilly’s potential COVID-19 therapies by quickly scaling up production of LY-CoV555 and/or any other antibodies developed alone or as combination treatments. The value of the agreement was not disclosed.

A day earlier, Lilly made headlines worldwide by announcing positive proof of concept data from an interim analysis of the Phase II BLAZE-1 trial showing a reduced rate of hospitalization for mild-to-moderate recently diagnosed COVID-19 patients treated with LY-CoV555. The trial’s pre-specified primary endpoint, change from baseline in viral load at day 11, was met at the middle of three dose levels studied (2800 mg), but not the other three groups studied (700 mg, 7000 mg, and placebo).

According to Lilly, most patients—including those randomized to placebo—showed near complete viral clearance by day 11. LY-CoV555 also 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.

Another pre-specified endpoint, COVID-19-related hospitalization or ER visit, occurred in 1.7% (5/302) of LY-CoV555 patients, pooled across dose groups, compared to 6% (9/150) of placebo patients—a 72% risk reduction, Lilly said. Most study hospitalizations occurred in patients with underlying risk factors (age or BMI), suggesting a more pronounced treatment effect for patients in these higher-risk groups, a finding that Lilly said it will seek to confirm through ongoing studies.

The BLAZE-1 trial is enrolling a larger, confirmatory cohort of higher risk patients, testing the ability of the antibody combination to reduce the number of patients with persistently high viral load and reduce COVID-19 related hospitalizations.

In August, Eli Lilly launched BLAZE-2, a Phase III trial being conducted with NIAID, the COVID-19 Prevention Network (CoVPN), and several long-term care facility networks across the country.

BLAZE-2 is designed to study the efficacy and safety of LY-CoV555 for the prevention of SARS-CoV-2 infection and COVID-19 in up to 2,400 participants—both residents and staff at U.S. nursing homes and assisted living facilities. The study will enroll residents and staff who live or work at facilities that have had a recently diagnosed case of COVID-19, and who are now at a high risk of exposure. BLAZE-2 will assess whether a single dose of LY-CoV555 reduces the rate of SARS-CoV-2 infection through four weeks, as well as complications of COVID-19 through eight weeks.

To conduct the trial, Lilly has created customized mobile research units that include a custom retrofitted recreational vehicle (RV) to support mobile labs and clinical trial material preparation, along with a trailer truck that will deliver clinical trial supplies for an on-site infusion clinic. Lilly said it will deploy its mobile research unit fleet in response to outbreaks of the virus at long-term care facilities nationwide.

Also in August, Lilly launched ACTIV-3, which uses an adaptive two-stage protocol design intended to allow for modification to test additional experimental therapeutics, as well as flexibly allow novel therapeutics to enter at either stage 1 or stage 2. Should a treatment appear to be safe and effective in the initial stage after review by the DSMB, the treatment is to be advanced to stage 2 testing, where more volunteers are enrolled. If an investigational therapeutic is unsafe or not likely to be effective, it will be dropped.

The primary endpoint of ACTIV-3 is participants’ sustained recovery for 14 days after release form the hospital.

In June, Lilly and AbCellera said the first patients were dosed in a Phase I trial (NCT04411628) assessing the safety and tolerability of LY-CoV555 in patients hospitalized with COVID-19—what the companies called the world’s first study of a potential antibody treatments for the disease. The first patients were dosed at major medical centers in the U.S., including NYU Grossman School of Medicine and Cedars-Sinai in Los Angeles. Results are set for review later this month; if successful, LY-CoV555 will advance into broader efficacy trials, the companies said. The trial began less than a week after AbCellera completed a $105 million Series B financing, whose proceeds in part will fund R&D into LY-CoV555 and other antibody treatments the companies plan to develop.

In March, Lilly and AbCellera announced plans to partner to co-develop the most promising of 500+ unique fully human antibody sequences identified in a blood sample from one of the first U.S. patients to recover from COVID-19. AbCellera said it was tapping into the expertise of NIAID’s Dale and Betty Bumpers Vaccine Research Center, which was to identify the antibodies that bind the pandemic strain of SARS-CoV-2 the best.

AbCellera and Lilly committed to equally share initial development costs towards a treatment, after which Lilly has agreed to oversee all further development, manufacturing and distribution. If successful, Lilly will work with global regulators to bring a treatment to patients.

Globally, Lilly has joined a cross-industry collaboration and the Bill & Melinda Gates Foundation to accelerate the development, manufacturing and delivery of vaccines, diagnostics and treatments for COVID-19. The consortium of 17 life sciences companies, announced by the Foundation March 25, plans to will work with regulators and the World Health Organization to ensure promising studies are quickly scaled to help people worldwide.


COVID-19: 300 Candidates and Counting

To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:

FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.

DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data

KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.

TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.

GEN has also tagged the most common treatment types:

● ANTIVIRAL
● VAX
● ANTIBODY
● RNA

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