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A new antibody treatment offers long-awaited hope for immunocompromised patients, if Omicron doesn't get here first
When Laura Burns went to get her first Covid-19 shot last January, no one had warned her that the vaccines might not work for her.

Burns, the recipient of a double-lung transplant in 2016, knew to be careful about the medicines she took. She consulted with her transplant team when the Pfizer and Moderna shots were authorized and only signed up after being told the vaccines would likely be safe for her, which they were.

None of the doctors, though, mentioned that the immune-suppression drugs she took to make sure her body didn’t reject her lungs could render the vaccine ineffective. She only learned after getting the results from antibody tests after the second dose: Zero.

Laura Burns
“That was a gut punch,” said Burns, a retired documentary filmmaker.

Burns became one of the millions of immunocompromised Americans who felt left behind in 2021 as the vaccines rolled out and the country slowly reopened. Guidance for these patients was slim, alternatives nearly non-existent. Many say they ended up educating their own doctors.

Burns, who went on to receive five shots over 10 months in hopes of mounting an immune response, has lived the year in March 2020 on repeat. She sees her friends exclusively over Zoom and leaves only for the grocery store and drug store. Once, she went to a concert and fretted she might die for a week afterward. In 20 months, she’s hugged three people.

“The other thing I miss is human touch,” she said. “I don’t touch anyone.”

But nearly two years after the pandemic began, there will finally be an option for Burns and the millions of other immunocompromised Americans left unprotected or only partially protected by vaccines. On Thursday, the FDA authorized a monoclonal antibody cocktail developed by AstraZeneca that’s designed to give six months or more protection against Covid-19.

The therapy, consisting of two intramuscular injections, would effectively act as ersatz inoculation, providing a stable supply of antibodies for those who can’t make their own. Estimates vary, but up to 3% of Americans fall into this category, including virtually all transplant recipients, people with certain genetic conditions, and those on certain cancer drugs like rituximab.

“This feels like such a game-changer,” said Kavita Patel, a primary care physician and a scholar with the USC-Brookings Schaeffer Initiative for Health Policy, who emailed her transplant patients immediately about the news. “For some people, this can actually mean freedom,” she said.

Although other antibody treatments have been authorized for patients infected or exposed to the virus, AstraZeneca’s is the first designed and authorized to give long-term, day-to-day protection.

Like many pandemic breakthroughs, though, the antibody comes with unanswered questions. Although the US government said it expects to have 700,000 doses of the therapy “beginning within a few weeks,” it’s unclear whether that will be enough for the target population or how states will ensure those doses get to the right people. Antibody distribution, experts note, has been patchy and uneven throughout the pandemic.

And then there’s Omicron. AstraZeneca and academic labs are now racing to see how well the antibody combo holds up against the variant, and most believe it will retain some level of efficacy. But there’s a non-zero chance that, after nearly two years of development, the treatment will become available just as the virus learns how to evade it.

“That’s a concern,” said James Crowe, the Vanderbilt researcher who invented the antibodies. “I’m worried.”

‘We just decided, OK, we need to do this. This is real’

The idea of using lab-grown antibodies to protect the vulnerable is an old one. One of the first antibody drugs ever approved was Synagis, an anti-RSV antibody OK’d in 1998 for high-risk infants.

In the 2010s, the Defense Department made these antibodies a key part of the US’ pandemic preparedness, not only for the immunocompromised but to guard healthcare workers (and soldiers) before vaccines became available. Crowe, who had been developing antibodies against bugs since the late 1990s, headed one of four teams DARPA selected in 2017 to design a platform capable of building antibodies against an outbreak in 60 days.

In January 2020, Crowe’s lab had just finished a test run on Zika and was preparing a second test on avian flu when news of a coronavirus in China went from concerning to alarming.

“And on the fly, we just decided, OK, we need to do this. This is real,” Crowe said. “So we launched a real discovery campaign, using the technology we had.”

Crowe couldn’t conjure an antibody from thin air, though. Like most antibody discovery technologies, his technique relied on extracting and cloning antibodies survivors naturally made in response to infection. And, in January 2020, survivors were in short supply.

Early on, he managed to obtain a blood sample from the Seattle patient who was the first reported American infection. But it took days to reach Nashville and wasn’t handled perfectly in the interim.

“The sample was basically dead by the time we got it,” he said.

In March, though, after weeks of efforts, they obtained a sample from a patient who had been infected roughly 50 days prior, enough time for them to have mounted and refined their immune response. A small team of scientists went to work, quarantining in the lab as the world shut down and working 20 hours a day to extract the best antibodies. Vanderbilt hauled in sleeper sofas so they could rest.

After 25 days, they emerged with a set of potent antibodies. That left the question of who would manufacture and put them in clinical trials, too tall a task for any academic lab.

After talking with over 40 companies, Vanderbilt announced an agreement to license six antibodies to AstraZeneca, a company Crowe was familiar with as one of the other three organizations in the DARPA program.

The decision would prove consequential. AstraZeneca had spent the last few years testing a technology, called YTE, designed to substantially lengthen the amount of time antibodies stay in the bloodstream. The pharma engineered YTE into two of Crowe’s antibodies and put them in the clinic as a combo, potentially conferring six months protection where others lasted one.

The US government focused first on treatments in 2020, giving a $450 million contract to Regeneron that June. But that October, HHS signed a $486 million deal with AstraZeneca to acquire up to 100,000 doses of the Crowe antibody, promising they would be used for a “high-risk population that may not benefit from a vaccine.”

‘A lot of us feel very on our own’

As the vaccines were proven effective, debated and authorized last fall, officials offered little guidance for the immunocompromised. Vaccine trials excluded them, so no one knew quite how the shots would work in some of the patients most vulnerable to the virus.

Many patients knew or suspected they wouldn’t respond. Some found their doctors and public health departments were less informed than they hoped, or learned their risks by reading the fine print on medicine bottles.

After the vaccine, “my oncologist was like, ‘oh yeah, just go do whatever you want,’ and I’m going, ‘I’m not so sure that that is the case,'” said Diane Barron, a lymphoma patient who takes the immune cell-depleting cancer drug Gazyva.

A test subsequently showed she made no antibodies to the vaccine, shocking her doctor. “A lot of us feel very on our own,” she said.

As the world reopened, Barron, a former producer who lost two friends with lymphoma to Covid-19, found herself stuck inside her Florida home, unable to see her grandkids and afraid to hug her husband because he works in a mask-free office. She passes the time on long walks and bike rides and solo games of pickleball.

Barron considers herself lucky. Patients who work in-office jobs have had to negotiate a tougher reality as public health standards changed. Beth Trudeau, an elementary school teacher in Michigan and a 23-year long liver transplant recipient, said she was able to teach from home last year, but that wasn’t an option this fall.

She now teaches in N95s, sometimes multiple, but only a couple of her students or fellow teachers wear masks. Having only partially responded to the vaccines — some antibodies but less than standard — and with the school only reporting PCR positive tests, she said she thinks about her risk “constantly.”

“A kid coughs and I’m like, OK, move away,” Trudeau said. “I feel like I’m exposed all the time.”

Slowly, options began to emerge. In the spring, stories and ultimately data emerged showing that giving a third dose of the vaccine could get some, but not all, immunocompromised patients to start producing antibodies.

Until the FDA officially authorized the third shot in October, though, third doses could be hard to come by. Sometimes transplant teams discouraged it, but patients, fearing they were unprotected and seeing the data on additional doses, scrambled for workarounds. Many went to walk-up sites, while “forgetting” their vaccine card.

A few did the same to get fourth or fifth doses if they didn’t respond to the third.

“We’re all trading notes about where you could go for walk-ins,” said one kidney transplant recipient, who declined to be named because breaking doctor guidance can jeopardize your chances of receiving a second transplant. “I had a neighbor who went to drug stores and looked for walk-ins to see which was least likely to look me up.”

In rare cases, antibody infusions were also an option. Although Regeneron’s antibody cocktail is only authorized for treating people who have been infected or exposed to the virus, a spokesperson said the company has approved “dozens” of compassionate use requests for pre-exposure prophylaxis, or PrEP, although the process is cumbersome and is only intended for those ineligible for clinical trials.

The Regeneron EUA also allows use in patients with continuous exposure in an institutional setting, a loose criteria that some doctors used to get infusions for immunocompromised patients with high-risk jobs, such as a bus or truck driver. (Some company data suggest the antibody can also offer long-term protection and the company has talked with regulators about an EUA.)

”Our institution hasn’t budged on its policies but more creative infusion centers have,” said Leonard Calabrese, a Cleveland Clinic rheumatologist.

In August, AstraZeneca finally announced results from its clinical trial for preventing infection. Across just over 3,000 high-risk patients, including many who were vaccinated, the antibody reduced the risk of developing symptomatic Covid-19 by 77%. In October, the company announced there were no severe cases within the first six months for patients who received the antibody, compared to five on placebo.

Only a fraction of the 3,000 patients were immunocomprised. Still, researchers cautiously hailed it as a breakthrough for them.

“It’s not as good as what we saw when the first vaccines came out,” said Deepali Kumar, a transplant infectious diseases physician and a professor of medicine at the University of Toronto. “But it’s very comparable to, let’s say, how the vaccines work against Delta.”

At the same time, public tragedy put a rare spotlight on the predicament people who don’t respond to vaccines face. Colin Powell, the former Secretary of State, passed away from Covid-19; although he was vaccinated, he had a weakened immune system from years dealing with multiple myeloma.

“We felt marginalized,” Barron said. “Really I think until Colin Powell passed away, and people started to realize.”

Now she’s hopeful the antibody can provide her first return to semi-normalcy since her cancer diagnosis. “It’s a real game changer in so many ways,” she said.

‘Somebody has started making decisions here’

The AstraZeneca EUA, while vaunted by patients and providers, will bring its own headaches. The US government has struggled over the last 13 months to equitably and efficiently distribute antibodies. The new treatment will only compound those questions.

An HHS official said the first doses will roll out in “the next few weeks” and an AstraZeneca spokesperson said all 700,000 doses contracted by the US will be available “within a few months.” But that still accounts for a small fraction of the millions of the immunocompromised Americans.

And neither the FDA nor the CDC have said who should be first in line: Is it anyone on an immunosuppresant? How much immunosuppresant counts? Should transplant be ahead of autoimmune disorders? Or maybe just anyone who scores below X on an antibody test after vaccination?

“Somebody has started making decisions here,” said Calabrese. “As far as I can see — and I’m actively reading 100 pages of released documents here — You know, where do you start drawing that line? I don’t think it’s in here.”

The HHS official said that, as with previous antibodies, state health departments would be responsible for getting federally directed shipments to patients. “As always, equity remains central to our planning, which is why we are encouraging states to incorporate equity considerations into their distribution plans to ensure this product reaches those who need it most,” they said.

Several patients and doctors said they called their health departments but received little guidance yet. “They said they had to get back to me, because they don’t know,” said Patel, the Brookings scholar and Maryland physician.

‘I’m just dying to hold that child’

The biggest looming threat, though, is Omicron, the heavily mutated variant already spreading widely in the US and abroad.

Initially, researchers looking at Omicron’s sequence predicted AstraZeneca’s antibody cocktail would be one of the few that retained efficacy, unlike Regeneron and Eli Lilly. But multiple lab studies have since suggested that Crowe’s work may not emerge unscathed.

That doesn’t mean the antibodies will be rendered useless, though. Laura Walker, CSO of the coronavirus antibody startup Adagio, said recipients may instead need injections of AstraZeneca’s cocktail more often.

“I think there’s uncertainty there,” she said. “I think it probably will provide some level of protection in prophylaxis, but the duration of protection is not going to be as long.”

Crowe’s lab is one of the many now trying to decipher the exact impact. If Omicron proves evasive, he suspects authorities will recommend the antibody based on whether or not that variant is common in your particular community.

He’s also beginning to look beyond Covid. Regardless of Omicron’s impact, he said, AstraZeneca’s has already shown that antibodies to protect immunosuppressed patients are viable. He has launched a center that is working to develop and store antibodies against the most likely pathogens to trigger epidemics.

It will also accelerate efforts to develop a universal flu antibody for people not protected from seasonal epidemics like the flu, he said.

“It’s like a tipping point where antibodies become comparable to vaccines for an epidemic interruption,” he said. “We’re at a historical tipping point.”

Burns, the double transplant recipient, still isn’t sure whether or not she’ll get the antibody. She saw a modest level of antibodies after her third and fourth dose, and she’s now waiting to see whether her antibody levels spiked after the fifth.

Depending on the result, she said, she might try to get the injections, in hopes that she can get to a level to see her stepdaughter in Europe and safely hug her family again. Her niece had a kid during the pandemic. She’s seen the baby twice, but only outdoors and at a distance.

“I’m just dying to hold that child,” she said.
https://endpts.com/a-new-antibody-treatment-offers-hope-for-immunocompromised-patients-if-omicron-doesnt-get-here-first/