Monoclonal Antibodies For COVID-19 In Africa: A Complex Web Of Opportunities And Challenges

Reported COVID-19 cases and deaths in many low- and middle-income countries (LMICs) have been fewer than initially anticipated. However, even relatively small surges in COVID-19 infections in an LMIC have the potential to devastate fragile health systems, communities, and families. Despite several promising vaccines, it may take years before immunization campaigns reach large populations in low-resource settings. Vaccines are also unlikely to be the complete solution to managing the pandemic. With new, more-transmissible and potentially more lethal variants spreading worldwide, complementary solutions, including therapeutics for treating patients with COVID-19, are essential to minimize hospitalizations and prevent complications from infection. Yet to date, we only have dexamethasone to treat critically ill patients, mixed data on the effectiveness of remdesivir, and early (positive) data on monoclonal antibodies. As cases surge in many African nations, countries urgently need a broader armory of effective drugs, particularly those that act early in the disease or as prophylaxis.

Monoclonal antibodies have been transformative for treatment of multiple oncologic, rheumatologic, and infectious diseases. Promising trials of these agents for COVID-19 have led to emergency use authorization in the United States for Regeneron’s monoclonal antibodies, casirivimab and imdevimab, and Eli Lilly’s drug bamlanivimab. Numerous other pharmaceutical companies and partners, including Vir, Celltrion, GlaxoSmithKline, Brii, Sorento, and AstraZeneca, are conducting Phase II or III trials that are underway or forthcoming. Initial evidence from Regeneron and Eli Lilly indicate that these drugs decrease hospitalizations and medical visits, as well as reduce patient viral loads. These agents have only been found effective for outpatients in the early stages of the disease and work best in high-risk patients with poor native antibody response. However, studies of new monoclonal antibodies are also ongoing in hospitalized patients (Vir and GlaxoSmithKline), so their application may be extended to these populations in the future. Additional efforts are also underway to study potential impact on transmission through trials in long-term care facilities in the United States. While promising, current candidates require intravenous formulation and early administration after infection, and require post-treatment monitoring by a health care worker. This presents a range of clinical and logistical challenges, particularly around the complexity of determining which patients should receive these drugs and where they can safely do so. These issues are further complicated by emerging concerns that single monoclonal antibody treatment, such as bamlanivimab, will not be efficacious against the B.1.351 variant due to viral escape. While antibody cocktails such as the Regeneron candidate may address this issue, additional research is needed to ensure efficacy.

The Bill & Melinda Gates Foundation and Eli Lilly recently announced an agreement to reserve some part of the supply of these agents for LMICs. The Canadian government has also committed to financially supporting UNITAID to procure three million doses of monoclonal antibodies once trials are completed. Additionally, the World Health Organization (WHO) and the Access to COVID-19 Tools Accelerator (ACT-A), led by the Wellcome Trust and UNITAID, are including monoclonal antibodies in ongoing clinical trials and are proactively planning deployment efforts. ACT-A estimates that developing LMIC-dedicated manufacturing capacity and volume guarantees through their program could “avert over 350,000 deaths, at a cost of $1,000 per death-averted and $60 per disability-adjusted life years.” Additionally, academic institutions and pharmaceutical companies are working at breakneck speed to develop more effective and efficient candidates. Examples include DARPins, small synthetic protein scaffold drugs currently in development by Molecular Partners and Novartis, and Aeronabs, a nanobody agent that is smaller in size and easier to produce than traditional monoclonal antibodies.

While these efforts are promising, many challenges will remain to effectively and rapidly rollout any supply of monoclonal antibodies for LMICs. It is critical to develop solutions to these challenges now to prevent severe delays and deepening inequities.

On December 10, 2020, the Institute for Global Health Sciences at the University of California, San Francisco hosted a digital forum and panel highlighting perspectives from global health experts on the opportunities and challenges associated with the use of monoclonal antibodies to treat COVID-19 in Africa. The challenges and potential solutions that these experts highlighted include the following: 

Evidence Generation

As of January 2021, more than 70 monoclonal antibodies are currently under development in the private and public sector, with multiple candidates in Phase II and III trials in high-income countries. With only preliminary data available from the Regeneron and Eli Lilly trials, the global community continues to await more robust data on the efficacy and optimal dosing of monoclonal antibodies to inform widespread use. To date, there has been a lack of clinical trials in low- and middle-income countries, although there are plans to add monoclonal antibodies to treatment arms in studies supported by ACT-A. While clinical trials for outpatient drugs will be challenging to conduct in resource-constrained settings during the pandemic, generating an evidence base specific to African populations is crucial to ensuring monoclonal antibodies have optimal impact. This will also help build much-needed local support and buy-in from policy makers, researchers, clinicians, and patients.

Regulatory Issues

While novel small-molecule therapeutics have well-defined regulatory pathways in LMICs, biologic agents generally do not. Monoclonal antibody products are rarely used in resource-constrained settings, and most African countries lack defined pathways for registering biologics and biosimilars. A WHO emergency use listing (EUL) could reduce long delays for the launch of monoclonal antibodies for COVID-19 across Africa once proven effective. The EUL program was developed for public health emergency scenarios in which an untested therapeutic can be given a listing after scientific assessment to facilitate availability. Additionally, to best facilitate rapid rollout at the appropriate time, donors and technical agencies should support countries in developing their own local regulatory frameworks and guidelines for relevant biologics. Developing templated registration pathways and requirements would also help to harmonize regulatory processes across Africa and could have long-lasting impact on facilitating the use of other biologics or biosimilars. Collaborative regulatory activities that already exist in Africa, such as the Southern African Development Community Collaborative Medicines Registration Initiative (ZaZiBoNa), can be used to fast-track access for multiple African countries.

Supply And Cost

Monoclonal antibody supplies will be limited by their highly technical manufacturing requirements in animal cells in temperature-sensitive bioreactors. Improving yields from cell lines, developing more efficient bioreactors, and creating thermostable formulations would facilitate increased production. Improving production efficiency (and reducing cost) of monoclonal antibodies should also include process intensification and optimization steps, and should be prioritized at an early stage by companies with monoclonal antibody development programs. Additionally, new technologies that help to streamline and decentralize manufacturing, including prefabricated podular or modular manufacturing, could increase production capacity. Developing local or regional manufacturing capacity would also facilitate production of greater supply, although admittedly ensuring optimal product quality across multiple manufacturing sites would be challenging.

Companies willing to scale-out the production of monoclonal antibodies would benefit from a clear technology transfer assistance program. This program should help identify potential manufacturing partners in Africa that companies can work with over time to engage in technology transfer to prevent individual companies from having to navigate these challenging issues without guidance.

While supply has, to date, actually outstripped demand in the US, in the future LMICs may face fierce competition for treatment courses from wealthy countries if more robust efficacy is proven in ongoing trials. In comparison to small-molecule drugs with long shelf lives, accurate forecasting and allocation for biologics such as monoclonal antibodies are even more critical to ensure countries have the appropriate number of treatment courses to prevent wasted supply. Finally, using African initiatives (such as the Africa Supply Management Platform) could provide individual countries with more efficient ways to organize coordinated procurement across countries, facilitating delivery to locations where these drugs are needed.

While the costs of COVID-19 monoclonal antibody candidates remain unknown, estimates range from US$50 to $1,250 per dose, not including costs associated with administration. Many LMICs will struggle to find the budgets for these costs and will need support from donors and/or will have to face trade-offs with other essential investments for mitigating the deadly impact of pandemic. The combination of limited supply and high prices means that most countries will likely receive far fewer doses than they need. In anticipation of this reality, countries and their partners should adopt clear, evidence-based prioritization frameworks that allocate limited doses to where they will have the greatest and most equitable impact. Such frameworks should take into account the complexities of administering these drugs and the realities of local health systems. Countries should also explore collaborating on procurement initiatives that increase purchased volumes to reduce the price of monoclonal antibodies.

Distribution And Administration

Monoclonal antibodies require properly refrigerated transportation and storage to ensure product quality and integrity. While this adds additional complexity to landing and delivering these drugs, similar processes have been used for vaccine and immunization programs for decades and can be adapted for COVID-19 monoclonal antibodies. As mentioned above, current evidence indicates that monoclonal antibody candidates are only effective for outpatients in the early stages of the disease and work best in high-risk patients with poor native antibody response. These two factors will make it difficult to determine which patients should receive these drugs. Targeting is further complicated by intravenous formulation and administration currently limited to inpatient settings. To manage this complexity, countries will need to develop robust roll-out plans that address these key components:

• Administration locations: It is likely that the use of these drugs will be limited to tertiary care centers in large urban areas due to the (small) risk of drug reactions and hour-long intravenous administration. Finding physical locations for safe administration of hour-long infusions will also require re-allocation of hospital or clinic space.
• Patient identification: Without scientific evidence for efficacy in African populations, policy and guideline makers may need to extrapolate data from US studies to determine which high-risk patients should receive these drugs, while simultaneously collecting information on local use and care.
• Diagnostic pathways: Monoclonal antibodies are only effective early in the disease course and should be administered within the first 10 days of infection. Therefore, robust diagnostic testing programs and community engagement and education will be needed to ensure that patients are able to access care early enough to guarantee treatment efficacy.
• Provider training: Given that monoclonal antibodies are only used in a limited capacity in many African countries, physicians, nurses, and pharmacists will need training on administration and side-effect profiles, as well as devote increased attention to pharmacovigilance reporting systems.

An Urgent Imperative

The pandemic has further exposed deep global inequities. The current situation with monoclonal antibodies is a glaring example. Wealthy individuals in high-income countries will be treated with novel antibodies, while a series of barriers may prevent patients in LMICs from accessing these drugs for months or years. Similar to what has been done for HIV/AIDS and other diseases, the global community should support LMICs to close this gap as a matter of urgency, while simultaneously urging the pharmaceutical industry to facilitate LMIC’s access to monoclonal antibodies.

With plans for deployment of doses of Eli Lilly’s drug to LMICs in the first half of 2021, planning must begin now to maximize their impact. The challenges identified herein are surmountable, and overcoming them will require focused technical support and adequate funding. Optimal solutions to challenges involving expedited regulatory pathways, manufacturing capacity, and prioritization of limited supply remain unclear. Countries and their partners should analyze and debate the options for each of these issues. Given COVID-19’s unmitigated spread, the only approach that should be tolerated is immediate action.

The Bill & Melinda Gates Foundation, the ACT-A consortium, and other partners have already taken important steps in exploring effective, rapid solutions. If trial evidence continues to confirm the potential for monoclonal antibodies to prevent hospitalizations, other donors and organizations should build on these initial actions and provide LMICs with the support they need to roll these drugs out rapidly and globally. With multiple novel COVID-19 treatments in development, investing now to prepare in-country treatment pathways has potential for broad impact in the future. Finally, while our collective attention remains focused on COVID-19 in this moment, investing in the future capacity of these systems now will also lead to improved access to lifesaving monoclonal antibody drugs that treat other diseases in the future.