Monoclonal Antibodies for the Treatment of COVID-19—Every Day You Fight Like You’re Running Out of Time

Scientists across the globe have fervently searched for safe and effective therapies for COVID-19 since the advent of the pandemic. Ideal qualities of treatments include effectiveness in preventing hospitalization and death, safety and tolerability for patients, easy administration in the outpatient environment, and cost-effectiveness. Monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 fit the safety and efficacy profile in early randomized clinical trials.^1-3 Despite the challenges of outpatient administration and associated costs, mAbs were a mainstay of the COVID-19 armamentarium from November 2020, when bamlanivimab first received US Food and Drug Administration emergency use authorization (EUA), through November 2022, when the bebtelovimab EUA was revoked.

Elsewhere in JAMA Network Open, Ambrose et al⁴ evaluated the association of several SARS-CoV-2 neutralizing mAb therapies with adverse outcomes of COVID-19 in subpopulations at high risk of poor outcomes and across multiple variant epochs. A population of 167 183 patients met study inclusion criteria, of whom 25 241 (15.1%) received mAb treatment. All patients were nonhospitalized, had an EUA-defined risk factor for progression to severe disease, and received no other outpatient therapy for COVID-19. From November 2020 through January 2022, mAb treatment was associated with reductions in the odds of hospitalization of almost 50% and the odds of emergency department visits by 24% compared with no mAb treatment. The odds of 30-day all-cause death were reduced by 86% (OR, 0.14; 95% CI, 0.10-0.20). After adjusting for confounders, the number needed to treat (NNT) to prevent the composite outcome of hospitalization or death at 30 days was 42. This association was observed against a backdrop of remarkable safety, with only 0.2% of patients experiencing any kind of adverse event.

The association of mAb therapy with improved outcomes was not uniform across all SARS-CoV-2 variants or across all patients. Patients who were unvaccinated or immunocompromised benefited the most from mAb therapy. The NNT to prevent 1 hospitalization at 14 days was 35 in the unvaccinated group and 17 in the immunocompromised group compared with 60 in the fully vaccinated group. In addition, the authors found that the mAb treatment effect size increased incrementally among patients with greater probability of poor outcomes (ie, those with multiple or more severe comorbidities). It is unclear whether any patient in the study received tixagevimab-cilgavimab for prevention of COVID-19; however, this long-acting mAb combination was granted EUA in early December 2021 and was not widely distributed until February 2022. Therefore, it is unlikely that its use substantially overlapped with the study period. Regardless, the authors’ findings⁴ are consistent with most other studies of COVID-19 therapies wherein patients who were seronegative at baseline were more likely to progress to severe disease and benefit from treatment. For immunocompromised individuals, the safety and efficacy of mAbs are especially notable because many of these patients have drug interactions or contraindications to other recommended outpatient COVID-19 therapies.⁵

Unfortunately, at the time of publication, there are no mAb therapies available for the treatment or prevention of COVID-19. All EUAs were revoked or paused due to the emergence of substantial in vitro drug resistance among currently circulating SARS-CoV-2 variants. The question of whether in vitro potency directly correlates with clinical efficacy remains unanswered. In the absence of clinical data, regulatory bodies had to make decisions to offer or withdraw therapies relying on laboratory data alone. For example, the EUAs for both bamlanivimab-etesevimab and casirivimab-imdevimab were revoked on January 26, 2022, due to inability to neutralize Omicron variants. Intriguingly, Ambrose et al⁴ found that casirivimab-imdevimab was associated with decreases in 14-day hospitalization (OR, 0.05; 95% CI, 0.01-0.42) in a small sample of 115 patients infected with sequence-confirmed Omicron BA.1 despite the significantly reduced in vitro neutralizing ability of this mAb against this variant. Only 7.6% of patients received sotrovimab (which was expected to retain in vitro neutralization against early Omicron variants) despite approximately 25% of the patients being diagnosed in the Omicron era. When the Omicron-era analysis was limited to patients who received sotrovimab, the treatment was associated with significant reductions in the odds of death within 30 days (bamlanivimab-etesevimab and casirivimab-imdevimab were not).

What should clinicians and researchers do with these results, which describe 14 months of safe and effective therapy that is no longer available? Monoclonal antibodies provide important lessons that inform our future research and practice. First is the salient reminder to evaluate both the relative and absolute treatment effects when allocating scarce health care resources and/or determining the economic value of any given treatment. For instance, while the relative odds of 14-day hospitalization were exactly 49% lower in both unvaccinated and fully vaccinated groups, the NNT was notably smaller and more impactful in the unvaccinated group (NNTs of 35 vs 60, respectively).

The second lesson is that the magnitude of a treatment’s effectiveness may change over time if the disease evolves. As Ambrose et al⁴ astutely comment, if severe disease and death decrease substantially between initial and later cases, treatments will have reduced effectiveness in preventing the same outcomes. For example, sotrovimab was associated with significant decreases in the odds of death within 30 days, but its NNT had increased to 666 by the Omicron era.

Third, effective treatments are only effective if they can be readily administered to patients. Early in the pandemic, the outpatient infrastructure of US health care systems was not prepared or equipped to operationalize the rapid administration of intravenous infusions to highly contagious patients after diagnosis. Establishing processes to deliver mAb treatment was challenging, but the reward was great.⁶ Future investment in these therapies is even more important now that the infrastructure is in place to deliver them.

Fourth, mAb therapies highlighted the importance of rapid diagnostic and/or point-of-care testing. Patients with symptoms needed quick access to SARS-CoV-2 testing with rapid turnaround times. Because real-time variant sequencing was not available in the clinical setting, clinicians had to make challenging decisions about whether to continue providing mAbs for treatment based on forecasting per geographic region. With point-of-care precision testing, more treatments could have been administered for longer periods, which is particularly important during times of scarce resources.

While ethical allocation of scarce resources is challenging on many levels, it does bring into focus the fifth important lesson of mAb therapy: using risk-stratification strategies to optimize patient outcomes. These data from Ambrose et al⁴ further confirm that not all risk of COVID-19 progression is equal. Understanding this risk, ideally to the point of knowing patient-specific baseline immunity, would facilitate precision medicine and would be the gold standard for deploying optimal, equitable, and value-based care.

Ambrose and colleagues⁴ found that mAb therapy allowed us to consistently keep patients out of the hospital and alive. Acknowledging that mAb development and implementation seems like a constant race against the clock, scientists and manufacturers will need incentives to produce safe and effective therapies that are at risk of becoming obsolete. Authorizations for use of these therapies should focus on the patients most likely to benefit. Systematic efforts should continue to focus on both clinical and implementation science to capture clinical practice results as expeditiously as possible, which will allow us to effectively adapt to an ever-changing landscape.

Published: April 24, 2023. doi:10.1001/jamanetworkopen.2023.9702

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 McCreary EK et al. JAMA Network Open.

Corresponding Author: Erin K. McCreary, PharmD, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, UPMC, Forbes Tower, 3600 Forbes Ave, Pittsburgh, PA 15213 (mccrearye3@upmc.edu).

Conflict of Interest Disclosures: Dr McCreary reported receiving personal fees from Merck & Co and Shionogi outside the submitted work. Dr Escobar reported receiving personal fees from Akceso Advisors and kc2 Medical Communications outside the submitted work. Dr Justo reported receiving personal fees from bioMérieux, Entasis Therapeutics, Gilead Sciences, Merck & Co, Shionogi, and Spero Therapeutics and owning stock in Vaxart outside the submitted work.