Despite an NIH move to pause enrollment in a trial testing Eli Lilly and Co.'s COVID-19 antibody candidate, LY-CoV555, after a participant's unexplained illness, at least three other studies of the candidate remain underway, the company said Oct. 14. The paused trial, testing the antibody in hospitalized patients alongside the antiviral remdesivir, won't resume until Oct. 26, at the earliest.

Lilly said the ongoing studies include the phase II BLAZE-1 trial testing LY-CoV555 as a monotherapy and in combination with LY-CoV016 in ambulatory care settings. It’s testing 700-mg, 2,800-mg and 7,000-mg doses of LY-CoV555. The phase III BLAZE-2 trial is evaluating the potential of LY-CoV555 to prevent COVID-19 in residents and staff at long-term care facilities. And the NIH-sponsored trial ACTIV-2 continues to test LY-CoV555 in recently diagnosed COVID-19 patients with mild to moderate cases of the disease.

The paused NIH-sponsored trial, ACTIV-3, is designed to evaluate the efficacy of LY-CoV555 alongside the Gilead Sciences Inc. antiviral Veklury (remdesivir) in hospitalized COVID-19 patients. But Lilly cast doubt on the potential of the candidate for such patients Oct. 14, noting in a statement that they "have been infected with the virus for a longer period of time and may have more severe symptoms” than patients studied in other trials of the antibody. Furthermore, the company said, "hospitalized patients receive different treatments for COVID-19 than earlier-stage patients.”

“For these reasons, hospitalized patients may have less benefit from neutralizing antibodies, which are a supplement to the patients' own immune system, as they may have developed their own endogenous antibody response and be in a phase of disease characterized by inflammatory responses to virus,” the company said. "This is why the use of immunosuppressive treatments is both widespread and still being investigated in hospitalized patients."

Illness still undisclosed

No further details of the illness that triggered the ACTIV-3 stop have emerged since Oct. 13. But the NIH did share a little perspective on what happened: The data safety monitoring board (DSMB) for ACTIV-3 "noted the trial reached a predefined boundary for safety at day five, meaning an overall difference in clinical status between the group receiving LY-CoV555 and the group receiving saline placebo," a spokeswoman for the National Institute of Allergy and Infectious Diseases told BioWorld.

"As a result, the DSMB recommended pausing enrollment out of an abundance of caution and continuing data collection and follow-up of current participants for safety and efficacy," she said.

The trial has enrolled 326 to date, the NIH said. It remains blinded to the investigators. Next, the DSMB will review data again at a preplanned meeting on Oct. 26, at which point it will make a recommendation on whether or not enrollment should be resumed.

The DSMB that oversees ACTIV-3 also oversees ACTIV-2. It has not recommended any changes to ACTIV-2 at this time, NIAID said.

Regulatory progress unhindered?

Lilly announced on Oct. 7 that it had requested an emergency use authorization for LY-CoV555, also known as bamlanivimab, the first products of its ongoing collaboration with Abcellera Biologics Inc.

The initial request covered LY-CoV555 monotherapy in higher-risk patients who have been recently diagnosed with mild to moderate COVID-19. At the time, another EUA request covering the combination therapy with LY-CoV016 was expected in November. Asked for updates on the EUA filing on Wednesday, a company spokeswoman referred BioWorld to the Oct. 7 statement.

Also on Oct. 7, Lilly said it expects to have data to support a BLA submission for combination therapy as early as the second quarter of 2021.

FDA inspection

Though the company has rapidly advanced its antibody candidates, the path hasn’t always been smooth. Late last year, its Branchburg, N.J., manufacturing site was inspected by the FDA as part of a routine general surveillance inspection. Earlier this year, the company received an Official Action Indicated notice in regard to the 2019 inspection, which included two findings related to control of electronic systems at the site, the company said in a statement provided to BioWorld.

“The two findings related to control of electronic systems were data deletions that were not related to any production of GMP batches at the site,” the statement said. Since then, Lilly’s team has “further strengthened our controls for this type of data. At no point was data deleted that was related to an actual production run and there has been no impact on product quality or safety,” the company said.

As part of its remediation efforts, Lilly has enlisted an external consultant to conduct a comprehensive independent review of systems at the Branchburg site. “Separately, we have increased staffing at Branchburg to manage the additional activity levels we are experiencing related to production of active pharmaceutical ingredients,” the company said.

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