Eli Lilly said it has paused patient enrollment in an up-to-10,000-patient Phase III trial of LY-CoV555, its lead COVID-19 antibody therapy, citing an undisclosed safety concern that arose during the study. The action comes only six days after the company requested an emergency use authorization (EUA) from the FDA for the therapy.

The pause affects the ACTIV-3 trial (NCT04501978), sponsored by the NIH’s National Institute of Allergy and Infectious Diseases. ACTIV-3 is designed to assess the safety and effectiveness of LY-CoV555 compared with Gilead Sciences’ Veklury™ (remdesivir) and placebo in people who have been hospitalized with COVID-19.

The trial had recruited 326 participants before the pause, NIAID said in a statement. The agency added that ACTIV-3 was paused at the recommendation of 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. The safety board will re-review the data on October 26 at an already-scheduled meeting, and will then recommend whether ACTIV-3 should resume enrolling participants.

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

“Safety is of the utmost importance to Lilly,” the company insisted in a statement. “We are aware that, out of an abundance of caution, the ACTIV-3 independent data safety monitoring board (DSMB) has recommended a pause in enrollment.”

“Lilly is supportive of the decision by the independent DSMB to cautiously ensure the safety of the patients participating in this study,” the company added.

“Hopefully a brief pause”

Eric Topol, MD, director of the Scripps Research Translational Institute, tweeted that he found it “surprising that Lilly’s monoclonal antibody has a safety concern to pause trials, as the safety issue has not manifested in their program or Regeneron’s previously.

“Hopefully a brief pause and we’ll get details quickly. Good to be cautious,” Topol added.

LY-CoV555 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.

LY-CoV555 is among 19 “front runner” candidates among the 230+ COVID-19 therapeutics detailed in GEN’s updated “COVID-19 Drug & Vaccine Candidate Tracker.”

ACTIV-3 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.

Stage 2 or bust

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.

In the initial stage of ACTIV-3, approximately 300 volunteers were enrolled who had been hospitalized with mild to moderate COVID-19 with fewer than 13 days of symptoms. Once their COVID-19 infections were confirmed and they consented to take part in the trial, participants were randomly assigned to receive an infusion of either intravenous LY-CoV555 or placebo. Participants also received standard care for COVID-19, including the antiviral remdesivir.

The trial protocol also called for assessing after five days the symptoms of participants, as well as their need for supplemental oxygen, mechanical ventilation, or other supportive care. Volunteers were to be followed for 90 days after enrollment, receive regular examinations, and have blood samples taken periodically to analyze their response to the investigational therapeutic they were assigned.

After five days, researchers were to decide whether the investigational therapeutic would be administered to a larger group of volunteers. Should LY-CoV555 appear to be safe and appears to be effective, NIAID said in August, the trial was to enroll an additional 700 participants—and begin enrolling more severely ill participants, such as those with organ failure requiring mechanical support, or COVID-19-associated dysfunction of organs other than the lungs.

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

“Significant and comprehensive”

“Studying the impact of this investigational therapeutic on multiple patient populations at the same time is critical to determining whether it can help COVID-19 patients with differing levels of disease severity,” said NIAID director Anthony S. Fauci, MD. “These concurrent trials have the potential to yield significant and comprehensive clinical data.”

On October 7, Lilly announced plans to file an 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 (NCT04427501). 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%).

Jens Lundgren, MD, of the University of Copenhagen and Rigshospitalet, serves as the principal investigator of ACTIV-3.

Lead investigators for collaboration partners of NIAID in ACTIV-3 include James Neaton, PhD, of the International Network for Strategic Initiatives for Global HIV Trials (INSIGHT) network; Taylor Thompson, MD, of the Prevention & Early Treatment of Acute Lung Injury (PETAL) network; Annetine Gelijns, PhD, and Alan Moskowitz, MD, of the Cardiothoracic Surgical Trials Network (CTSN); and Rachel Ramoni, DMD, ScD, of the U.S. Department of Veterans Affairs.

LY-CoV555 is also under study in another ongoing NIAID study, the Phase II/III ACTIV-2 trial (NCT04518410), designed to study the Lilly antibody’s safety and efficacy in people with mild to moderate symptoms of COVID-19 who have not been hospitalized.