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For decades, the drug class has been a highly promising yet selectively used agent in a litany of disease. Its necessity in the pandemic has provided lessons in how it could be utilized in the future.
St. Peter’s Health Partners launched its makeshift COVID-19 monoclonal antibody clinic in Albany, NY, on December 3, 2020.
It had been 2 weeks since the US Food and Drug Administration (FDA) granted emergency use authorization (EUA) to Regeneron’s combined monoclonal antibodies carsirivimab and imdevimab for mild to moderate COVID-19 in patients 12 years and older at greater risk of progressing to severe COVID-19.
On that early December day, in a first-of-its-kind unit for the area, Melissa Fiorini, MD, and colleagues administered infusion treatment to 10 patients—a new record in a day for the St. Peter’s team.
In just 2 months, the clinic will have surpassed 650 patients treated with any of the authorized monoclonal antibody infusions, whether it be combination carsirivimab-imdevimab, or bamlanivimab, from Eli Lilly and Company.
There is no cure for COVID-19, or at least any current drug that could provide curative benefit, an expert told HCPLive® earlier this year. Antivirals, steroids, convalescent plasma, and other classes have varied in benefit in differing patients at differing stages of infection. Vaccines, particularly the mRNA platform products from Pfizer and Moderna, have been revelatory in their record-pace production, research, and rollout—but are as limited as any prophylaxis is by wavering public vaccine buy-in.
The diligently-processed biologic drug class, an otherwise high-priced and selectively administered commodity in nearly every specialty of medicine, has become the premiere agent in COVID-19 response—tested out of promising benefit from the beginning, available before any vaccine, and efficacious in its particular indication.
It could be suggested that monoclonal antibodies, for their most apparent COVID-19 benefit of reduced risk of severe disease progression, have become the most hopeful treatment during the pandemic.
With streamlined regulatory rollout and distribution plans, and dedicated treatment teams established by experienced clinicians including Fiorini, US healthcare may have found means to make the drug class more accessible for COVID-19 in ways that could be applicable to other diseases.
“There's a lot of obstacles still to many patients getting this treatment that we have to figure out,” Fiorini told HCPLive®. “But I do think that we're on the right track.”
Nearly 3000 miles southwest from Fiorini’s clinic is a large research tent posted outside of Keck Hospital of USC. At the time of speaking with HCPLive in mid-February, infectious disease specialist Saahir Khan, MD, PhD, and his colleagues were facing nearly 10,000 new cases in Los Angeles daily. One month earlier, the rate was greater than 40,000 daily—by far, the most significantly affected city in the US at the most recent peak of new cases.
Here, in a tent facility at a COVID-19 epicenter, Khan and his team observed what difference monoclonal antibodies could make in the pandemic.
Since late 2020, the research facility participated in the randomized, double-blind ACTIV-2 trial, observing bamlanivimab in symptomatic adult outpatients positive for SARS-CoV-2 who had not yet been hospitalized by the disease.
The National Institute of Allergy and Infectious Diseases (NIAID)-sponsored trial provided one-time infusions to eligible patients at the tent, then monitored their status through a series of clinician follow-ups and patient-logged symptom diaries.
The study has progressed in past months, Khan said. Beyond primary observations that bamlanivimab is associated with an approximate two-thirds reduced risk of COVID-19 hospitalization, investigations are now assessing intramuscular administration and newer antibodies.
While the sheer rate of infections and worsening cases in the Los Angeles area has been a crisis at points during the pandemic, institutions including Keck have counted themselves fortunate in at least being able to provide and assess this drug class.
“We were lucky in that we had a research tent set up for doing studies with COVID patients,” Khan said. “And we were able to repurpose that as a site where we could do monoclonal antibody infusions for outpatient treatments that had received FDA authorization. And I understand not every healthcare setting has access to those types of resources.”
Beyond resourcing and financially-supported trial participation, Keck was also able to provide the staffing necessary for an infusion clinic. Skilled nurses, Khan said—already valuable members of COVID-19 response teams—were necessary for administering and monitoring the therapies.
“That was another challenge: competing for staff, essentially, with acute care facilities,” Khan said.
For Fiorini, the issues of staffing a COVID-19 antibody infusion clinic came down to representation. It occurred to her quickly that an emergency department or critical care team wouldn’t be able to manage the growing demand on their own.
“You need everyone from finance, nursing, pharmacy—even maintenance, to make the area better ventilated than it was before they started seeing COVID-19 patients,” she explained. “Every department has to be on board for setting up a clinic like that.”
As a member of both the emergency room (ER) and critical care teams, Fiorini has access to both patient databases to identify new SARS-CoV-2 cases. Promotion of the monoclonal antibody clinic was minimal at the very beginning, so it was her, as the clinical lead, making cold calls to at-risk patients within a week of their positive test, educating them on the drug class’ benefit and setting up an appointment.
Once the clinic became more popularized, those phone calls shifted from 20-minute crash course to a streamlined scheduling system. “I joke that they don’t want to talk to you anymore,” Fiorini said. “They just want a certain time and date that they have to show up.”
During that shift in public knowledge and interest around monoclonal antibody care, clinic runners like Fiorini and Khan were still refining the optimal utility of the newly authorized products. Fiorini found herself bucking against the nearly yearlong message of “stay home unless your symptoms worsen,” to telling high-risk patients to get tested as soon as possible—the confirmed test could assure an infusion.
That time between a patient believing they have COVID-19 under control and them seeking emergency care for severe symptoms can be startlingly brief, and is absolutely vital for monoclonal antibodies to serve their purpose, Khan said.
An unfortunate irony of the pandemic is that the most affected patients will sometimes ask for a cure, anything to end their symptoms. Khan and colleagues believe the agent closest to providing a cure is monoclonal antibodies—but by the time a patient is severely ill, it’s too late. Timing is everything.
The history of viral pandemics, even as recently as the frequently-compared 1918 Flu Pandemic, has reflected a constantly unmet want to have a curative drug for adaptive viruses. The reality is that the most transmissible respiratory viruses tend to reach at least endemic status. Thus, the overall expectation for therapies including monoclonal antibodies should reflect that limitation.
Outside COVID-19, the drug class has already appeared to reach its limitations in benefit across a litany of uses, though some groups believe there’s more to be gained from the drug class.
The production of monoclonal antibodies—conducted for 50-plus years but truly refined in the latter half of that time—requires living cells, contrasted against a standard drug’s production with smaller molecules. The latter can generally be produced in a laboratory at a massive scale, the former requires an assurance of quality that lessens the production count and raises the cost.
But innovation is helping to make monoclonal antibodies more readily produced. Ayesha Sitlani, PhD, associate vice president of Antibody Strategy at the International AIDS Vaccine Initiative (IAVI), explained to HCPLive that Chinese Hamster Ovary (CHO) cells have become a leading platform for increasing antibody expression levels in production, thereby cutting the cost of production significantly.
The average antibody was produced for up to $300 per gram as recently as 5 years ago, Sitlani said. They now cost about $100 per gram—and some companies are hoping to again halve that price. But even with that reduction, patients around the world are challenged to monoclonal antibody access due to competitive company pricing and licensing terms.
“They haven’t really made inroads into global access,” Sitlani said. “Eighty-five percent of the global population really only sees 20% of the sales.”
Even in countries where the drug class is highly available, costs are significant for the average patient. Per IAVI, the average cost for annual antibody cancer treatment is approximately $150,000.
“They've been able to demand these high prices, I think partly because of the complexity of producing them—and the efficacy,” Sitlani said. “Antibodies are very safe, they're very targeted, and they have limited side effects relative to small molecules.”
In other fields in which monoclonal antibodies are still becoming more established, physician prescribing is also lagging, mostly due to confidence in the unique process. J. Allen Meadows, MD, the immediate past president of the American College of Allergy, Asthma & Immunology (ACAAI), told HCPLive he doesn’t prescribe antibodies for immunodeficiencies, as they would be used in his field.
Though that’s more due to his small practice’s patients than preference, he understands why colleagues would be reticent to pursue prescribing for such uses in patients with specific presentations.
“It's not like ordering an inhaler, or a pill. I mean, there's work to order in these,” Meadows said. “And if you're not used to ordering these types of drugs, it may seem daunting to some physicians.”
Coincidentally, Meadows got his first experience in prescribing an infusion, not for a patient’s uncontrolled asthma or inflammation-driven disease—but for one with suspected COVID-19, whose symptoms were at risk of worsening due to severe asthma. The successful and somewhat simplistic experience won him over.
“What they do for an allergist, immunologist, is supportive care,” Meadows said. “And a good thing that’s come out of COVID-19 is that more of us learned how really easy it is to prescribe them.”
The prescribing confidence is also influenced by top-down guidance and health authority recommendation, Sitlani said. Monoclonal antibodies offer greater efficacy in treating cancer and autoimmune diseases than most competing drug classes—and they do so with greater half-lives, meaning patients require fewer administrations over a long period.
All of these benefits are offset by the steeped price tags in the eyes of national and global health authorities and policy makers, Sitlani explained.
But just as vaccines benefitted from advocacy campaigns in the last decade-plus of preventable outbreaks, Sitlani has hope COVID-19 will drive awareness to worldwide antibody access. What’s more, the expedited pathway from antibody development to research to FDA regulation may be a model for application across other fields.
“That's not to say we should be registering antibodies in 9 months for every disease, but it doesn't have to be 10 years,” Sitlani said. “And it doesn't have to be 20 years before the rest of the globe sees it—and that’s what the situation is right now for other diseases.”
Of course, much of that depends on healthcare continuing to practice the collaborative systems that COVID-19 made necessary, from the private-public development and research partnerships that Sitlani observes, to the multi-department care teams that Fiorini and Khan help set.
There are still some immediate refinements necessary in COVID-19 monoclonal antibody care. For herself, Fiorini has been weighing the means by which treatment-eligible patients may best travel to the clinic and receive their care while assuring everyone’s safety from transmission. She also believes there could be optimization in infusion duration, and even administration—subcutaneous doses for antibodies may be available for COVID-19 treatment eventually.
“I think once those things happen, then it'll be much easier to give widespread use, but we're not there yet,” Fiorini said.
The logistics of infusion therapy and the limited supplies of antibodies are the primary reasons why Khan does not see the drug class as a game changer for COVID-19. He’s still waiting to see the authorized regimens become more scaled up, noting the overall benefit it could provide burdened areas such as his own.
“I mean, if we could take away two-thirds of all hospitalized cases of COVID-19, that would be a game changer,” he said, “but the number of patients that have been treated so far has not been enough.”
Beyond the indicated use, monoclonal antibodies may even provide preventive benefit—so as long as more agents become available. With more doses, Khan suggested areas with the greatest-risk COVID-19 patents, such as nursing homes or long-term care facilities, could provide infusions or injections as prophylaxis in the event of any possible outbreaks. It’s a more realistic scenario than his actual hope for the drug class: that anyone with a positive COVID-19 test, regardless of risk, is able to receive antibody treatment from well-resourced clinics.
But monoclonal antibody availability for the pandemic may be hindered in the very near future by emerging SARS-CoV-2 variants. Just as proven vaccines may need adjustment or new booster doses made available, these agents may need to be updated to assure absolute benefit in reducing risk of progression to severe disease.
At the very least, virus evolution may force drug producers to continue producing large counts of beneficial therapies on the incentive of legislative partnerships. The pandemic has created a unique scenario where creating the most potent drug for the highest price is not the priority. Though monoclonal antibody developers will return to this mindset in due time, Sitlani hopes a combination of global interest in the agents, continued improvement of production via CHO, and greater public-private partnerships will at least help decrease the disparity of worldwide availability.
“They have their limitations, and the availability and affordability summarizes that,” she said.
There’s a wide chasm between the world where monoclonal antibodies have been appropriated for greatest-risk COVID-19 patients in ad hoc clinics, and the world where the same agents are selectively prescribed, lesser resourced, and often inaccessibly priced.
The absolute benefit for the drug class—in optimal utility, availability, prescribing confidence, production, and cost—is likely a collection of strategies and ideas adopted by these 2 worlds. It make take years still to reach, but the necessities of COVID-19 may have help set course toward it.
“The time that it has taken from discovery of antibodies to approval is beyond anyone's imagination,” Sitlani said. “I mean, it's so rapid, that I think we can learn lessons from that to streamline how we develop and register antibodies for all diseases.”