Friday, January 29, 2021

Why aren’t therapeutic antibodies being used more to treat COVID-19?

By Nicholson Price, Rachel Sachs, Jacob S. Sherkow, and Lisa Larrimore Ouellette

When former President Donald Trump contracted COVID-19 in fall 2020, he was treated with monoclonal antibodies, touted as potentially miraculous treatments. Unlike other treatments so touted, there is some rigorous evidence to support these assertions: antibody drugs look like the best treatments currently available to prevent COVID cases from progressing to hospitalization. But months later, the drugs are in limited use and seem to be only a moderately important part of the COVID-19 response. Why aren’t antibodies making more of a difference for ordinary Americans?

What are therapeutic antibodies, and how are they being developed for COVID-19 treatment?

Antibodies are a type of protein produced by immune cells in response to infection. Unlike broad-spectrum drugs, antibodies’ utility lies in their specificity: they target only a minute spot on a foreign invader. This specificity makes antibodies workhorses of molecular biology research. Scientists can also engineer antibodies—to make them pharmaceutically tolerable, for example—for use as therapy. This approach has been wildly successful. In 2019, six of the top ten selling therapeutics in the U.S. are antibodies or fragments of antibodies.

Researchers have been developing numerous antibodies that may treat COVID-19 by mimicking the body’s immune response to thwart infection. To date, there are at least 21 anti-COVID-19 antibody treatments either in or about to begin clinical studies. Two have already received Emergency Use Authorizations (EUAs) from the FDA: Eli Lilly’s bamlanivimab and Regeneron’s cocktail of casirivimab and imdevimab. These two antibody treatments have received substantial interest from the federal government, which has pre-ordered 950,000 doses from Lilly and 300,000 doses from Regeneron. Recently, the FDA issued potency guidelines for future antibody development.   

Recent clinical trial data suggests that antibodies may be quite effective in treating early cases of COVID-19. One treatment from Lilly—a combination of the company’s bamlanivimab and another antibody, etesevimab—appears to decrease COVID-19 hospitalizations by 70% in some measures, a crucially important resource given the disease’s crushing effect on the health care system. Regeneron’s antibody combination treatment had similar results. At the same time, the EUA issued for Lilly’s antibody treatment was for bamlanivimab, alone, and predicated on a smaller patient population, complicating a robust assessment of their ultimate real-world impact. Some, consequently, have criticized the data for single antibody treatments as being “soft” in comparison to that for antibody cocktails.

In addition, a recent, nagging question is how well the authorized antibodies—or those currently in development—will treat new variants of the virus that causes COVID-19; the very specificity of antibodies may limit their effectiveness against changed targets. Eli Lilly’s antibody seems to fare poorly against the South African variant (B.1351), though testing is underway. Preliminary evidence suggests that Regeneron’s cocktail, at least, retains efficacy against the South African and UK (B.1.1.7) variants.

What is limiting the administration of antibody treatments?

As of January 19, states had received over 550,000 doses of Lilly’s and Regeneron’s antibody treatments, but only about 30% of available doses have been administered to patients. Given the promising results described above and the record-breaking case loads over the past month, why haven’t more doses been used?

The problem isn’t affordability. Because of generous federal coverage, including for uninsured patients, price does not appear to be a significant barrier to the use of antibody treatments in the United States so far—which is important given the socioeconomic disparities in COVID-19 infections and deaths. Nor is the problem insufficient manufacturing—at least not yet. States have doses available and more on the way, and the federal government has contracted for 2.5 million doses so far. Rather, as with the COVID-19 vaccines discussed in our most recent post, the immediate hurdle is administration to patients. But the administration problems for antibody treatments are very different from those for vaccines.

Administering an antibody drug to a patient is complex and time-consuming. As explained in instructions to providers for both Lilly’s bamlanivimab and Regeneron’s casirivimab and imdevimab, the drugs need to be infused via IV for at least 60 minutes and then the patients must be monitored for adverse reactions, which requires trained professionals. And the drugs are not authorized for patients who are already hospitalized or who require oxygen therapy—rather, they will only be administered if patients at high risk of severe COVID-19 come to the infusion site for the lengthy infusion process within 10 days of symptom onset, before hospitalization becomes necessary. Those infectious patients also must be sequestered from non-COVID patients requiring IV-administered drugs, many of whom are immunocompromised. 

Navigating these distribution challenges is daunting. Hospitals are swamped with patients who have already developed severe COVID-19, leading many hospitals to refuse their antibody allocations. Testing delays and lack of coordination between testing sites and hospitals mean that patients who might benefit are often not identified in time. States also have differing financial resources for implementing distribution programs, raising important equity concerns. Scarce resources are more likely to be funnelled to triaging the sickest patients rather than treating patients earlier in the disease course. 

These failures in distribution mean that patients often need to advocate for themselves to receive access to the antibody treatments. But many patients don’t know that they need to, or how to do so. Few patients think they should go to the hospital to get an IV drug to keep them out of the hospital. Even resourceful patients who have sought antibody treatments have often had difficulty accessing them, and these access concerns loom even larger for disadvantaged and marginalized communities.

How can policymakers promote access to distributed antibody treatments?

As with vaccines, developing a novel health technology isn’t the end of the process: distributing and administering the new technology to patients in need is critical. Policymakers must consider whether investment in the infrastructure for distributing and administering the product is also necessary, in addition to any investments they have made in the development of the technology itself. Policymakers ought to keep in mind two particular issues as they consider antibody administration: reimbursement and transparency.

Policymakers should think carefully about different strategies for using reimbursement to encourage antibody administration, not merely distribution. Early on, CMS quickly recognized the need to ensure that Medicare would pay many different types of providers to administer these antibodies, and that patients should not pay anything out of pocket for this experience (even if the latter principle was legally more questionable to impose at the time). But given the challenges that resource-constrained state and local officials are facing, additional grants to ensure that facilities have the incentives and infrastructure to administer these products may be an important part of the strategy as well. 

Transparency and coordination will also be critical to improving patient access to distributed antibodies. Many newly diagnosed COVID-19 patients do not know that these treatments are available, and even patients who do know about them and ask their providers about them often have not been able to access them. Patients must be provided with information about how to obtain access to these new therapies, but this type of information could be provided in many different ways. Perhaps people who receive a positive test could also receive information about accessing antibody treatment along with that positive test. Or perhaps states could publicize information about how to obtain these treatments, along with their public information about vaccine distribution and access. 

Policymakers at the state and federal level might also consider encouraging private sector actors to develop novel distribution pathways to lower the logistical barriers to accessing care, some of which is already occurring. As part of their clinical trial, Eli Lilly retrofitted RVs as mobile infusion clinics to allow them to reach residents of nursing homes more easily. Several chains of dialysis clinics, which have the ability to provide outpatient infusions, have begun to administer the new drugs. Pharmaceutical firms may also be encouraged to invest in developing versions of these drugs which are easier to administer, such as inhaled antibody products. 

The rapid development of therapeutic antibodies, like the rapid development of effective vaccines, is a triumph of biomedical innovation. But ultimately, even the best products won’t help unless they make it to patients.  Ensuring the last step is just as critical as facilitating the steps that come before.

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

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