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The United States has allocated more than 641,000 monoclonal antibody treatments for outpatients to ease pressure on strained hospitals, but officials from Operation Warp Speed report that more than half of that reserve sits unused as clinicians grapple with best practices.
There are space and personnel limitations in hospitals right now, Janet Woodcock, MD, therapeutics lead on Operation Warp Speed, acknowledges to Medscape Medical News. "Special areas and procedures must be set up." And the operation is in the process of broadening availability beyond hospitals, she points out.
But for frontline clinicians, questions about treatment efficacy and the logistics of administering intravenous drugs to infectious outpatients loom large.
More than 50 monoclonal antibody products that target SARS-CoV-2, the virus that causes COVID-19, are now in development. The US Food and Drug Administration (FDA) has already issued Emergency Use Authorization (EUA) for two such drugs on the basis of phase 2 trial data — bamlanivimab, made by Eli Lilly, and a cocktail of casirivimab plus imdevimab, made by Regeneron — and another two-antibody cocktail from AstraZeneca, AZD7442, has started phase 3 clinical trials. The Regeneron combination was used to treat President Donald Trump when he contracted COVID-19 in October.
Monoclonal antibody drugs are based on the natural antibodies that the body uses to fight infections. They work by binding to a specific target and then blocking its action or flagging it for destruction by other parts of the immune system. Both bamlanivimab and the casirivimab plus imdevimab combination target the spike protein of the virus and stop it from attaching to and entering human cells.
Targeting the Spike Protein Out of the Hospital
The antibody drugs covered by EUAs do not cure COVID-19, but they have been shown to reduce hospitalizations and visits to the emergency department for patients at high risk for disease progression. They are approved to treat patients older than on 12 years with mild to moderate COVID-19 who are at high risk of progressing to severe disease or hospitalization. They are not authorized for use in patients who have been hospitalized or who are on ventilators. The hope is that antibody drugs will reduce the number of severe cases of COVID-19 and ease pressure on overstretched hospitals.
This is important because it targets the greatest need in COVID-19 therapeutics, says Rajesh Gandhi, MD, an infectious disease physician at Harvard Medical School in Boston, who is a member of two panels evaluating COVID-19 treatments: one for the Infectious Disease Society of America and the other for the National Institutes of Health. "Up to now, most of the focus has been on hospitalized patients," he says, but "most COVID-19 patients are outpatients, so we need something to keep them from getting worse."
Both panels have said that despite the EUAs, more evidence is needed to be sure of the efficacy of the drugs and to determine which patients will benefit the most from them.
These aren't the mature data from drug development that guideline groups are accustomed to working with, Woodcock points out. "But this is an emergency and the data taken as a whole are pretty convincing," she says. "As I look at the totality of the evidence, monoclonal antibodies will have a big effect in keeping people out of the hospital and helping them recover faster."
High-risk patients are eligible for treatment, especially those older than 65 years and those with comorbidities who are younger. Access to the drugs is increasing for clinicians who are able to infuse safely or work with a site that will.
In the Boston area, several hospitals, including Massachusetts General where Gandhi works, have set up infusion centers where newly diagnosed patients can get the antibody treatment if their doctor thinks it will benefit them. And Coram, a provider of at-home infusion therapy owned by the CVS pharmacy chain, is running a pilot program offering the Eli Lilly drug to people in seven cities — including Boston, Chicago, Los Angeles, and Tampa — and their surrounding communities with a physician referral.
Getting that referral could be tricky, however, for patients without a primary care physician or for those whose doctor isn't already connected to one of the institutions providing the infusions. The hospitals are sending out communications on how patients and physicians can get the therapy, but Gandhi says that making information about access available should be a priority. The window for the effective treatment is small — the drugs appear to work best before patients begin to make their own antibodies, says Gandhi — so it's vital that doctors act quickly if they have a patient who is eligible.
And rolling out the new therapies to patients around the world will be a major logistical undertaking.
The first hurdle will be making enough of them to go around. Case numbers are skyrocketing around the globe, and producing the drugs is a complex time- and labor-intensive process that requires specialized facilities. Antibodies are produced by cell lines in bioreactors, so a plant that churns out generic aspirin tablets can't simply be converted into an antibody factory.
"These types of drugs are manufactured in a sterile injectables plant, which is different from a plant where oral solids are made," says Kim Crabtree, senior director of pharma portfolio management for Henry Schein Medical, a medical supplies distributor. "Those are not as plentiful as a standard pill factory."
The doses required are also relatively high — 1.2 g of each antibody in Regeneron's cocktail — which will further strain production capacity. Leah Lipsich, PhD, vice president of strategic program direction at Regeneron, says the company is prepared for high demand and has been able to respond thanks to its rapid development and manufacturing technology, known as VelociSuite, which allows it to rapidly scale-up from discovery to productions in weeks instead of months.
"We knew supply would be a huge problem for COVID-19, but because we had such confidence in our technology, we went immediately from research-scale to our largest-scale manufacturing," she says. "We've been manufacturing our cocktail for months now."
The company has also partnered with Roche, the biggest manufacturer and vendor of monoclonal antibodies in the world, to manufacture and supply the drugs. Once full manufacturing capacity is reached in 2021, the companies expect to produce at least 2 million doses a year.
Then there is the issue of getting the drugs from the factories to the places they will be used.
Antibodies are temperature-sensitive and need to be refrigerated during transport and storage, so a cold-chain-compliant supply chain is required. Fortunately, they can be kept at standard refrigerator temperatures, ranging from 2 °C to 8 °C, rather than the ultra-low temperatures required by some COVID-19 vaccines.
Two Million Doses a Year
Medical logistics companies have a lot of experience dealing with products like these and are well prepared to handle the new antibody drugs. "There are quite a few products like these on the market, and the supply chain is used to shipping them," Crabtree says.
They will be shipped to distribution centers in refrigerated trucks, repacked into smaller lots that can sustain the correct temperature for 24 hours, and then sent to their final destination, often in something as simple as a Styrofoam cooler filled with dry ice.
The expected rise in demand shouldn't be too much of an issue for distributors either, says Crabtree; they have built systems that can deal with short-term surges in volume. The annual flu vaccine, for example, involves shipping a lot of product in a very short time, usually from August to November. "The distribution system is used to seasonal variations and peaks in demand," she says.
The next question is how the treatments will be administered. Although most patients who will receive monoclonal antibodies will be ambulatory and not hospitalized, the administration requires intravenous infusion. Hospitals, of course, have a lot of experience with intravenous drugs, but typically only give them to inpatients. Most other monoclonal antibody drugs — such as those for cancer and autoimmune disorders — are given in specialized suites in doctor's offices or in stand-alone infusion clinics.
That means that the places best suited to treat COVID-19 patients with antibodies are those that regularly deal with people who are immunocompromised, and such patients should not be interacting with people who have an infectious disease. "How do we protect the staff and other patients?" Gandhi asks.
Protecting Staff and Other Patients
This is not an insurmountable obstacle, he points out, but it is one that requires careful thought and planning to accommodate COVID-19 patients without unduly disrupting life-saving treatments for other patients. It might involve, for example, treating COVID-19 patients in sequestered parts of the clinic or at different times of day, with even greater attention paid to cleaning, he explains. "We now have many months of experience with infection control, so we know how to do this; it's just a question of logistics."
But even once all the details around manufacturing, transporting, and administering the drugs are sorted out, there is still the issue of how they will be distributed fairly and equitably.
Despite multiple companies working to produce an array of different antibody drugs, demand is still expected to exceed supply for many months. "With more than 200,000 new cases a day in the United States, there won't be enough antibodies to treat all of the high-risk patients," says Gandhi. "Most of us are worried that demand will far outstrip supply. People are talking about lotteries to determine who gets them."
The Department of Health and Human Services (HHS) will continue to distribute the drugs to states on the basis of their COVID-19 burdens, and the states will then decide how much to provide to each healthcare facility.
Although the HHS goal is to ensure that the drugs reach as many patients as possible, no matter where they live and regardless of their income, there are still concerns that larger facilities serving more affluent areas will end up being favored, if only because they are the ones best equipped to deal with the drugs right now.
"We are all aware that this has affected certain communities more, so we need to make sure that the drugs are used equitably and made available to the communities that were hardest hit," says Gandhi. The ability to monitor drug distribution should be built into the rollout, so that institutions and governments will have some sense of whether they are being doled out evenly, he adds.
Equity in distribution will be an issue for the rest of the world as well. Currently, 80% of monoclonal antibodies are sold in Canada, Europe, and the United States; few, if any, are available in low- and middle-income countries. The treatments are expensive: the cost of producing one gram of marketed monoclonal antibodies is between $95 and $200, which does not include the cost of R&D, packaging, shipping, or administration. The median price for antibody treatment not related to COVID-19 runs from $15,000 to $200,000 per year in the United States.
Regeneron's Lipsich says that the company has not yet set a price for its antibody cocktail. The government paid $450 million for its 300,000 doses, but that price includes the costs of research, manufacturing, and distribution, so is not a useful indicator of the eventual per-dose price. "We're not in a position to talk about how it will be priced yet, but we will do our best to make it affordable and accessible to all," she says.
There are some projects underway to ensure that the drugs are made available in poorer countries. In April, the COVID-19 Therapeutics Accelerator — an initiative launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard to speed-up the response to the global pandemic — reserved manufacturing capacity with Fujifilm Diosynth Biotechnologies in Denmark for future monoclonal antibody therapies that will supply low- and middle-income countries. In October, the initiative announced that Eli Lilly would use that reserved capacity to produce its antibody drug starting in April 2021.
In the meantime, Lilly will make some of its product manufactured in other facilities available to lower-income countries. To help keep costs down, the company's collaborators have agreed to waive their royalties on antibodies distributed in low- and middle-income countries.
"Everyone is looking carefully at how the drugs are distributed to ensure all will get access," said Lipsich.
Brian Owens is a freelance science journalist who has filed for Nature, New Scientist, and The Lancet. In 2019, he won a National Magazine Award for best news story for an article in CMAJ (Canadian Medical Association Journal).
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Cite this: Averting COVID Hospitalizations With Monoclonal Antibodies - Medscape - Jan 12, 2021.