Dan Barouch, MD, PhD (Center for Virology and Vaccine Research, BIDMC) discusses delays faced in getting routing items while working to develop a COVID-19 vaccine.

Wall Street Journal – November 10, 2020

How Eli Lilly Developed Covid-19 Drug in Pandemic’s Long Shadow

When Covid-19 struck, drug companies around the world began racing to find vaccines and treatments. One factor has gummed up their efforts: They have to work in an environment transformed by the very problem they are trying to tackle.

At Eli Lilly & Co., the chief of a laboratory, quarantining at home after he contracted Covid-19, had to use a robot equipped with an iPad to patrol his lab. When shipping constraints threatened to delay testing of an experimental drug, Lilly repurposed its corporate jet to get vials to test sites. Lab technicians had to relearn basic procedures.

“We’re fighting something that’s fighting back,” said Daniel Skovronsky, Lilly’s head of research and development. “We’ve had people get sick, and I’ve been afraid that, ‘What if they contaminate everyone at work, and all the scientists get sick, and what happens to our work?’ “

The rush to fight Covid-19 is intense. On Monday, Pfizer Inc. revealed promising results in its work on a vaccine. Later in the day, U.S. regulators authorized emergency use of a new Covid-19 treatment from Lilly, the first aimed at keeping mild cases from turning serious.

What Lilly has gone through to get to this point reflects not only the common challenges all businesses face in the pandemic, but also unique ones that push drugmakers to the limit of their ability to operate.

Roche Holding AG’s Genentech unit divided its on-site workforce into small teams to minimize the risk of viral spread and monitored their adherence to its distancing and masking rules. It hired cargo planes to deliver raw materials to U.S. factories from Europe when commercial flights were grounded.

A Boston laboratory helping Johnson & Johnson develop a vaccine faced delays getting routine items because suppliers were poorly staffed and fewer workers were handling the lab’s receiving areas.

“Everything about working is an order of magnitude more difficult,” said Dan Barouch, who leads the lab, at Beth Israel Deaconess Medical Center, and is a Harvard Medical School professor.

When states began locking down in March, Lilly followed suit. That meant suspending work on some potentially lifesaving treatments. Lilly’s maintenance staff powered down elaborate lab instruments. The company put off enrollment of patients for a study of an ulcerative colitis treatment and delayed starting a test of whether an experimental diabetes drug helps with weight loss.

The company decided at the time that it wasn’t worth risking the infection of employees except for research projects aimed at the virus. Lilly has since resumed most clinical trials.

Like many companies, Lilly told most employees to work remotely. Some scientists found they missed the way that face-to-face encounters with colleagues can sometimes result in subtle insights.

“We don’t like virtual meetings; you don’t know how to interpret the silence,” said Robert Christie, who researches diabetes.

Lilly kept some employees coming to work in its labs, offices and manufacturing plants, though it put an end to the many meetings normally held. To reduce the risk of viral spread, manufacturing workers paired up with a single colleague for joint tasks. The company’s precautions couldn’t prevent people from getting exposed elsewhere, and it has grappled with how to keep projects advancing at times when infected or exposed employees were sidelined.

Andrew Schade, a pathologist who leads the clinical-diagnostic laboratory, quarantined at home for a time in March after testing confirmed that his cough and shortness of breath meant Covid.

Lilly had volunteered his laboratory to process coronavirus tests for Indiana residents. Dr. Schade found it hard to address remotely the challenges that arose, such as getting test supplies, so after a few days at home, he jury-rigged a solution. He had colleagues mount an iPad carrying a live video stream on a wheeled robot, which then roamed the lab at his command.

“Less optimal, definitely,” Dr. Schade said. While it was straightforward to review data virtually, he found it hard to discuss with colleagues how to solve problems that popped up via his contraption.

Lilly set out to make a Covid-19 treatment modeled on the antibodies produced by survivors of the disease. It partnered with AbCellera Biologics Inc. of Vancouver, British Columbia, which analyzed a blood sample taken from an early survivor, in collaboration with the U.S. National Institute of Allergy and Infectious Diseases. They scoured the blood for an antibody and cloned it for use as a drug known as a monoclonal antibody.

For this type of treatment—similar to one given to President Trump, in his case a still-experimental drug from Regeneron Pharmaceuticals Inc.—manufacturing is complicated. The drugs are grown in living cells and fed nutrients to cultivate their development. Lilly produced copies in stainless-steel tanks sloshing with a liquid medium of ovary cells from Chinese hamsters, said Sarah Langan, director of a plant making the experimental Covid-19 antibody.

Readying an antibody-based drug for human testing normally takes about 17 months. Lilly wanted to do it in just a couple of months, not only given the need for a Covid-19 treatment but also in case an advancing pandemic made work in its lab perilous.

To reduce risk, Lilly cut the usual cohort of 65 workers in its antibody-drug production plant to about 20 to 30, all wearing gowns, gloves and masks. Lilly took similar steps at its plants making other drugs. One worker worried out loud about the risk of catching the virus and infecting his family, recalled Brandon Paschal, a manufacturing official. He said he reassured the worker, and that at the insulin plant he oversees, few have gotten sick.

The virus complicated even basic tasks. Lilly bought a sterile mobile lab for the final manufacturing step of filling vials, because repurposing an in-house lab would take longer. But the unfamiliar space in the mobile lab meant that Lilly pharmacists who would do the work had to rehearse their steps to avoid any mistakes. A pair of pharmacists had to stand inches apart in April practicing a key handoff of materials.

“People were fully gowned, but the first time that they physically got close to somebody, they automatically kind of withdrew,” said Matthew Waddell, director of clinical-trial manufacturing operations.

By late May, Lilly had produced enough of the antibody for a small human trial. It signed up hospitals in New York, Atlanta and Los Angeles to recruit Covid-19 patients and inject them with the experimental drug.

Lilly wanted to get it to trial sites in one day and have patients dosed that same day. Concerned that a third-party courier, its usual means of transport, couldn’t deliver quickly enough, Lilly decided it had to do the job itself.

Adam Scott, a quality-assurance manager, joined a few colleagues to carry the precious cargo on Lilly’s corporate jet. A few seats from him on the flight sat a colleague who had recovered from Covid-19. Mr. Scott worried about what would happen if he came down with it, because his Type 1 diabetes made him more vulnerable.

Adding to his concerns, he would be hand-delivering the drug to a hospital in New York City, which recently had been the U.S. epicenter of the pandemic.

“I recognized that I was headed into an area that was more impacted…. I definitely felt cautious, especially knowing I was going into a hospital,” he said.

On the ground in New York, a car service took the Lilly workers to NYU Langone Health in Manhattan, where they waited in the car because of the hospital’s visitor restrictions and the need for colleagues in Indianapolis to send a final authorization for release of the batch. Finally, a hospital pharmacist escorted Mr. Scott inside with the boxes of vials. The crew flew home the same day, toasting the mission with wine on the flight, and by the time they landed, doctors in New York had injected the first patient.

In September, Lilly said it had determined the drug reduced the rate of hospitalization in recently diagnosed Covid-19 patients. In October, it asked the Food and Drug Administration to authorize emergency use of the treatment in those with mild to moderate disease. Though this wouldn’t be full marketing approval—Lilly won’t seek that until it generates more clinical data—it would permit physicians to prescribe the drug in certain situations. Regeneron made a similar request to the FDA for its treatment about the same time.

Their drugs don’t appear to be a good option for severe cases. Researchers recently halted a study of Lilly’s drug in hospitalized patients, in combination with the approved antiviral drug remdesivir from Gilead Sciences Inc., because of a lack of benefit. Regeneron suspended a study of its antibody drug in the sickest patients.

The antibody drugs might serve as a bridge until a vaccine is available. Lilly is testing whether its version can prevent Covid-19 from spreading in a nursing home where someone has gotten sick.

In the vaccine hunt, in addition to the promising news from Pfizer, Moderna Inc. could have initial the result of a large clinical trial soon. Others running large vaccine studies that could yield results this year or early next year include AstraZeneca PLC, J & J and Novavax Inc.

Mr. Scott, the Lilly staffer who delivered the batch to the New York hospital, said several employees he manages have faced personal challenges such as having a family member get sick. He has had to help staffers deal with anxiety while working on the project.

“It was a heavy weight, but at the same time it propelled me onward, because I felt like I was contributing in some small way,” he said.