There are very few drugs that prevent people with early Covid-19 from progress to severe disease, but monoclonal antibodies may be among them.
Early study results show they may reduce the rate of hospitalizations by up to 70% if they are taken in time, which can be life-saving, especially among people who are at high risk of getting very sick.
But it seems that the word is not getting out to those who need the medications the most, or their health care providers.
Eli Lilly’s monoclonal antibody, called bamlanivimab, received an emergency use authorization from the US Food and Drug Administration in early November. Less than two weeks later, the agency granted an EUA to Regeneron’s monoclonal antibody cocktail, made up of two monoclonal antibodies, casirivimab and imdevimab, and called REGEN-COV2. It was given to President Trump when he got infected at the start of October. Former New Jersey Gov. Chris Christie and Housing and Urban Development Secretary Ben Carson were also treated with monoclonal antibody therapy.
According to the FDA, monoclonal antibodies should be given as soon as possible after symptoms emerge and a person tests positive for infection. And, because of limited supply, the authorizations are limited to high-risk patients, such as people 65 and older, those who have a BMI (body mass index) of 35 or greater and those with other health conditions like diabetes, cardiovascular disease or chronic kidney disease.
“The monoclonal antibodies we’ve authorized seem to work best for preventing hospitalization in outpatients early in their disease – typically within 10 days of the onset of symptoms, if you are a high-risk individual. So, over the age of 65, or over the age of 55 with a comorbidity, or… some preexisting illness to put you at risk,” FDA Commissioner Dr. Stephen Hahn told CNN’s Dr. Sanjay Gupta in mid-December.
“These antibodies, for the last month since authorization, have been distributed around the country. So, they should be available locally, and it’s under state jurisdiction,” Hahn said.
At a time when hospitals across the country are running out of beds and staff to care for the severely ill, monoclonal antibodies may have a real role to play. So why aren’t more people trying to access these potentially life-saving medications, especially since both the drugs are mostly free, under Operation Warp Speed?
“We’ve got to get the therapeutics used. We need patients who test positive, who are at risk of hospitalization, to get on these monoclonal antibodies. We actually have more right now than there are getting used. We’ve got to get them earlier, so we keep people out of hospitals,” Health and Human Services Secretary Alex Azar told CNN’s Jake Tapper Monday.
An HHS spokesperson confirmed that a new report showed only 5%-20% of the available supply of monoclonal antibodies are actually being used – an ironic statistic considering one big concern was that there would not be enough supply to meet demand. It is the first time HHS had requested utilization information from facilities and providers administering the drugs.
“We will continue working with stakeholders to learn more about drug utilization decisions,” the spokesperson said.
How monoclonal antibodies work
To fight infections, the immune system produces different types of antibodies that target different parts of the invader, explained Gigi Kwik Gronvall, senior scholar at the Johns Hopkins Center for Health Security.
“When you have an infection, your immune system kicks into action and you produce antibodies,” Gronvall said.
“The best antibodies stick to the pathogen – in this case, it will stick to the virus and prevent the virus from infecting your cells. So, antibodies have a real role in stopping infections.”
That’s why convalescent plasma therapy is sometimes used to treat patients infected with coronavirus. It involves taking the antibody-containing plasma from someone who has recovered from Covid-19 and infusing it into a sick person in the hopes of kickstarting their immune response. But some antibodies work better than others and different people have different levels of antibodies, so results from convalescent plasma aren’t always uniform.
Monoclonal antibodies to treat coronavirus Covid-19 are intensely focused, lab-made versions of convalescent plasma. Scientists looked for the antibodies that best blocked infection by the SARS-CoV-2 virus. “They picked a particular kind of antibody – what they call a neutralizing antibody… and made a purified version of it to be used as a medicine,” Gronvall said.
Eli Lilly’s drug uses one particular antibody and Regeneron’s drug uses a combination of two others. Early study results have shown they appear to reduce the changes of winding up in a hospital or the emergency room by between 55% and 70%.
Neither medication is fully FDA-approved and not everyone is convinced the evidence so far is strong enough to support routine use. The National Institutes of Health’s Covid-19 treatment guidelines, for example, say “there are insufficient data to recommend either for or against the use” of either product “for the treatment of outpatients with mild to moderate Covid-19.”
Similarly, a guideline panel for the Infectious Diseases Society of America “suggests against routine use of bamlanivimab for ambulatory patients with Covid-19.” However, the panel noted that some people at increased risk of progressing to severe Covid-19 “may reasonably select this treatment after careful discussion with their clinician.”
It’s important also to note that monoclonal antibodies don’t appear to help – and may actually harm – people who are hospitalized. Both Lilly and Regeneron ended trials of their drugs in severely sick patients.
Azar told reporters at an Operation Warp Speed briefing in mid-December that more than 278,000 courses of the two antibody treatments have gone out to medical facilities, and that the administration is working to send out more.
The government initially bought 300,000 doses of bamlanivimab and in early December bought an additional 650,000 doses, according to an Eli Lilly statemen, which also says it “continues to manufacture bamlanivimab for use around the world, and the supply is expected to increase substantially in 2021.”
A release from Regeneron notes it “expects to have treatment doses ready for approximately 80,000 patients by the end of November, approximately 200,000 patients by the first week of January, and approximately 300,000 patients in total by the end of January 2021.”
While that may sound like a lot of doses in total, they come at a time when new coronavirus cases in the United States alone are averaging more than 215,000 per day – although it’s important to note that not everyone who is infected has risk factors for developing severe disease and so may not be a candidate for one of these medications.
Both companies told CNN in separate emails that supply is expected to increase in 2021 as additional manufacturing resources “scale up” (Regeneron) and “come online” (Eli Lilly).
In addition to Lilly and Regeneron’s monoclonal antibody medications, there are more than 70 different antibody treatments for Covid-19 under investigation, according to BIO, an association that represents major biotechnology companies.
There are several reasons why monoclonal antibodies are in scarce supply. For one, unlike most drugs, which are made by combining specific chemical ingredients following a precise process, monoclonal antibodies are very large and complex molecules that are complicated to produce. That’s because they’re what’s known as a biologic: biologics are manufactured in a living system such as a microorganism, or plant or animal cells.
“It’s not like aspirin or just, you know, when you’re making a chemical [drug]; these are biologics and it takes a lot of work to make them, purify them and put them in a form for delivery. So there are lots of steps along the way,” says Gronvall.
According to Fouad Atouf, the vice president of global biologics at US Pharmacopeia, the nonprofit organization that sets quality standards for medicines and related products, purification is “very laborious.”
“But there is, thanks to the advances in science, specifically the recombinant-DNA technology approach, where you can use cell lines as factories. And now you can create synthetic copies of those antibodies,” he said. In other words, cells can be genetically engineered and turned into factories for churning out monoclonal antibodies.
Because of this, according to Atouf, manufacturing capacity is limited. “You can only make fewer doses at a given time.”
Another issue, he said, is sheer volume: you need to give a patient a lot more of a monoclonal antibody than, say, a vaccine or a pill.
A third issue, the one that worries him “a lot” the competition for the raw ingredients.
Despite the challenges, Atouf said monoclonal antibodies have a lot of potential. In addition to treating people with mild Covid-19, he said there are studies looking to see if they can be given prophylactically, to prevent an infection; there’s also research looking into whether they can be used against existing and emerging coronaviruses.
Access to a monoclonal antibody
There are a couple of additional hurdles that need to be overcome to get monoclonal antibodies to people in time to help. One is to decide where the limited supply of medications get shipped to.
To make access as fair as possible, the medications are allocated weekly to each state by the government, under Operation Warp Speed, based on confirmed Covid-19 cases in that state during the previous seven days. The individual state health departments are then responsible for deciding how many doses to send to which health care facilities in their state. AmerisourceBergen, a national distributor, will deliver the allotted medications directly to the health care facilities overnight.
Another challenge with monoclonal antibodies is that they are not easy to administer, requiring a one-hour IV infusion and an hour observation period in an outpatient setting. So, any location that’s going to administer these medications must be set up to keep Covid-19 patients isolated from their other patients during the two-hour infusion and monitoring process.
The FDA’s Dr. Janet Woodcock, the head of the Center for Drug Evaluation and Research and an Operation Warp Speed leader, suggested during a news conference in early November that pop-up infusion centers may be one solution.
Another solution may be partnering with pharmacy chains. HHS recently tapped CVS’s infusion care business, Coram, for a pilot program to administer 1,000 doses of bamlanivimab to qualified patients both at home and in long-term care facilities. The program launched on December 3 in seven cities and their surrounding communities, including Boston, Chicago, Cleveland, Los Angeles, Milwaukee, Minneapolis and Tampa.
Patient awareness also needs to be raised. “We’re all going to need to get the word out that people with high risk have therapeutic option now, as outpatients. Up until this point, people been told to stay home unless they get very sick,” said Woodcock.
Steve Rudner, the director of pharmacy network contracting at Vizient, a health care performance improvement company, agrees. “Like with many pharmaceutical agents or drugs, the patient might not know if they are in fact, a candidate for this,” he said.
“If you’re a health care provider and you just confirmed a case of Covid with a patient, and they fall into one of the high-risk categories … it’s your mission to make sure that that patient understands, ‘Here is a one-hour infusion that could prevent you from going in the hospital,’” he said.
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But there’s a role for patients too, said Rudner. “If a patient reads [an] article and says, ‘Wait a second: maybe I’m in one of these high-risk categories. If my physician doesn’t ask me about it, maybe I should ask him or her about it because I just I just tested positive and I don’t want to go into hospital,’” he said.
The FDA’s Hahn echoed the sentiment. “I would encourage anyone who might be in the categories I described to talk to their provider about this, because as an outpatient, these can be infused to those folks who are in high-risk populations. We know that the clinical endpoint is prevention of hospitalization,” Hahn said.
“God knows the health care systems are significantly overstressed at this point, so I would encourage your viewers to ask the providers about this.”