Thursday, February 18, 2021

How can policymakers overcome the hurdles to scaling up antibody manufacturing?

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

In our last post, we introduced some of the clinical evidence supporting the use of therapeutic antibodies against COVID-19—including Regeneron’s casirivimab and imdevimab and Eli Lilly’s bamlanivimab—and analyzed the existing problems in the distribution and administration of those therapies. Even in just the last few weeks, further clinical evidence has supported the use of these technologies, leading the FDA to issue an additional emergency use authorization for Lilly’s bamlanivimab and etesevimab cocktail. In the near future, though, problems in administering our existing supply of these new drugs may give way to problems producing enough of them—a challenge that is also affecting the vaccine rollout. In this post, we consider the difficult manufacturing issues involved in the therapeutic antibody context (a subject we’ve previously explored regarding vaccines), and what might be done to address them.

What production challenges arise with the large-scale manufacture of therapeutic antibodies?

As we have explained, antibodies have been remarkably successful in treating diseases by specifically targeting certain foreign invaders. But antibodies are not simple chemicals that are easy to produce: they are complex proteins that are time-consuming and expensive to manufacture. Your immune system naturally produces antibodies in response to foreign bacteria and viruses; commercial antibody production attempts to replicate this biological process inside living cells.

The antibody treatments authorized for COVID-19 so far are individual monoclonal antibodies (mAbs) or combinations of mAbs. The “monoclonal” in monoclonal antibodies means that they are produced from a single cloned B-cell line and thus only produce a single antibody. This gives them high specificity to a particular target. Polyclonal antibodies, by contrast, are produced by more than one cloned B-cell line, and thus produce a number of slightly different antibodies with greater target variability. The most common commercial production platform for mAbs is the fed-batch process, in which a closed batch of cells and culture medium is fed additional nutrients as they are consumed, after which the antibodies are isolated and purified. The biopharmaceutical sector is increasingly shifting toward continuous manufacturing processes, with encouragement from the FDA, although regulatory and scientific challenges remain.

The hurdles to scaling up these processes for COVID-19 therapeutics have been long apparent. A June 2020 analysis from Duke’s Margolis Center for Health Policy noted that setting up new mAb manufacturing capacity typically takes years, and that “the fungibility of the mAb manufacturing capacity depends on the process mode and bioreactor type.” The authors argued that the “federal government could play a coordinating role,” including to help manufacturers of antibody treatments for COVID-19 “reallocate their capacity to the most promising therapies as clinical evidence emerges” without raising the “serious antitrust concerns” that such collaborations would normally raise. 

Although the federal government didn’t invest in COVID-19 antibody treatments to the same extent as vaccines, in February 2020 it entered an agreement to support Regeneron’s preclinical and clinical COVID-19 treatment development. Then in July 2020 it provided Regeneron $450 million for large-scale manufacturing, supporting the at-risk manufacture of 300,000 doses of the casirivimab and imdevimab cocktail that were allocated to states after FDA authorization in November. The federal government also entered into an advance purchase agreement for Eli Lilly’s bamlanivimab ($375 million for 300,000 doses, with the option to pay $812.5 million more for 650,000 additional doses), although the agreement came only two weeks before authorization, making it less effective for encouraging at-risk manufacturing.

The complexity of mAb manufacturing also increases costs. Regeneron’s and Eli Lilly’s drugs are cheaper than most antibody therapies, although the prices being paid by the U.S. government—over $1000 per dose for Eli Lilly’s bamlanivimab alone, not including the etesevimab that appears to make it more effective—place it out of reach of many low-income countries. These high prices and the difficulty of scaling manufacturing have raised distributional concerns that these drugs will be less available outside high-income countries. 

Part of the reason mAb manufacturing is hard and expensive is that many of the process details are kept as trade secrets. The public information about manufacturing Regeneron’s and Eli Lilly’s cocktails is limited. FDA fact sheets indicate that like the majority of commercial mAbs, the antibodies authorized for treating COVID-19 are produced using Chinese hamster ovary (CHO) cell lines. We are unaware of more detailed information about the manufacturing processes—although if you want to see some shiny metal tanks, Lilly does provide B-roll footage of bamlanivimab manufacturing for reporters.

How can policymakers help scale up antibody manufacturing?

The most basic step in scaling up antibody manufacturing is recognizing that it is a worthwhile policy goal to pursue alongside other priorities. As noted above, policymakers under the previous administration prioritized the scale-up of vaccine manufacturing, but did not invest to the same degree in antibody manufacturing. In our view, this was a miscalculation. Weighing investment in vaccine versus antibody manufacturing, policymakers may have thought (correctly) that vaccines would be needed broadly to bring about the end of the pandemic, but that antibodies were less crucial, both because vaccines would diminish the need for effective treatments (as fewer people become ill) and because antibodies are merely one among many potential therapeutic interventions. This may be true, but investing in manufacturing scale-up for vaccines versus antibodies need not be an “either or” situation; rather, it is “both and,” especially given that we now have EUAs for multiple antibodies. Given the economic and human toll of COVID-19, we can afford to invest in both, particularly if investments in scaling up the manufacturing technology lead to broader innovations in biologics manufacturing.

So how does that investment happen? For one thing, policymakers can try to drive knowledge sharing between antibody manufacturers. In the vaccine space, knowledge transfer has emerged as a stumbling block to rapid scale-up, especially on a global scale, though there are other hurdles, especially for the novel mRNA vaccines, involving specialized ingredients and equipment. Knowledge sharing is likely a more important limiting factor for antibody manufacturing, since antibody manufacturing has been going on in some form for decades, and many manufacturers thus already possess the ingredients and equipment needed. Sharing knowledge would allow other manufacturers to increase the supply of existing antibodies, and could also allow for increased understanding and better manufacturing generally (including of other antibodies). Incentives or mandates for increased information sharing could increase innovation and efficiency in antibody manufacturing (and potentially biologic manufacturing more generally), with possible benefits beyond the pandemic. There are some indications that information sharing is happening: six companies involved in therapeutic antibody development sought and received DOJ permission to share development and manufacturing information in August (defusing antitrust concerns). Such collaborations should be lauded and pursued.

More immediately, policymakers should seriously consider employing global purchasing initiatives for biologic therapies, akin to those of COVAX, the international consortium for global purchasing of vaccines. IAVI, the nonprofit famous for its work on securing and distributing HIV therapies in Africa and India, recently announced it was working on such an initiative in partnership with the Wellcome Trust for biologic therapies, like antibodies. IAVI’s initiative, Expanding Access to Monoclonal Antibody-based Products, seeks to expand access to antibody therapies, including those for COVID-19, to middle and low-income countries, an important component of global health equity. As noted in IAVI’s report, Asia and Africa constitute less than 20% of the global market for antibodies despite comprising more than half of the world’s population and their population’s persistent need for such treatments. At the same time, IAVI’s report is short on details about how to bring about such change, other than harmonizing a number of global regulatory pathways for antibody therapies’ approval that IAVI contends will lower prices by lowering manufacturing costs. Whether such cost savings will indeed be passed on to payers in the short run remains to be seen—but lowering manufacturing costs may give payers more leverage on prices both during this pandemic and the next one (or few).

Relatedly, policymakers in the US could invest in improving manufacturing domestically. The House Energy and Commerce Committee recently introduced a legislative package that includes $500 million in funds for the FDA “to support the review, facilitate the development and post-marketing surveillance of COVID-19 vaccines and therapeutics.” This could very well be used to support advances in techniques in and regulatory oversight over continuous manufacturing, a possibility that Alexander Gaffney of Politico notes would be of great interest to FDA observers. To be sure, half-a-billion to improve biologics manufacturing seems like a lot of money—but as we’ve noted time and time again, the COVID-19 pandemic is not the time to be penny-wise and pound-foolish. As noted above, manufacturing advantages are one area where the public is likely to see advantages—bang for their collective buck—not just in the United States, but elsewhere, too.

Among other things, that $500 million fund could be used to invest, specifically, in automating and simplifying the production of biologics in manner akin to those of small molecule drugs. Researchers in the area, like James Swartz at Stanford, have researched some of these possibilities for years, labeling their efforts “cell-free manufacturing.” The necessity of cellular components in biologics manufacturing is a major technical hurdle, a source of both secret and tacit knowledge, and a cost sink. Efforts to improve cell-free manufacturing are under-encouraged, among other reasons, because profit margins for biologics remain enormously high and FDA regulations for cell-free manufacturing are, not yet, up to a sufficient level of specificity. Implementing such guidances would go a long way for both investing in the now—and in the future.

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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