How did we get here? A historical look at the early clinical trial data investigating Covid-19 monoclonal antibody therapy and implications for the future

Date

2023

Authors

Healy, Jack
Finkenstaedt, Samantha
Frangenberg, Alexander
Tandon, Saloni
Chou, Eric

ORCID

0000-0002-3600-4455 (Healy, Jack)
0000-0003-2695-6433 (Tandon, Saloni)

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Abstract

BACKGROUND: The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic to mild, moderate, severe, and clinical illness. Current recommendations for the use of monoclonal antibody (mAb) therapy - including Ritonavir-boosted Nirmatrelvir, Remdesivir, and Molnupiravir - for the treatment of SARS-CoV-2 infection include use in patients who are at risk of progressing to severe COVID-19. Given the unprecedented process and speed of research conducted on the use of antibody therapies, beginning with polyclonal antibodies developed from patients recovered from COVID-19 to the development of monoclonal antibodies targeting the spike protein(s) of various COVID-19 variants, it is important to reflect on early data to better understand the early challenges pertaining to mAb and early COVID 19 research.

METHODS: Articles published between January 1, 2019 and October 1, 2021 were identified from keyword search of Medline (via PubMed). Clinical trials evaluating the outcomes of monoclonal antibody (MAB) therapy for the treatment of Covid-19 infection were included. This study was IRB-exempt.

RESULTS: Initial search results yielded 493 papers. After title and abstract screen, full articles were read in their entirety. A total of 21 articles were included in this analysis, representing 7833 patients. Eight studies found a statistically significant benefit to MAB use, 12 found no benefit, and one study did not perform formal statistical hypothesis testing. Primary outcomes varied between studies and included mortality rate, ICU admission, mechanical ventilation requirements, Covid-related hospitalization, supplementary oxygen use, clinical composite scores, and viral load.

DISCUSSION: Early clinical trial data was inconclusive but suggested that monoclonal antibody therapy may have reduced hospitalizations and provided a mortality benefit in some populations with COVID-19. However, several important factors may have influenced treatment response. These factors included antibody type, dose, route, therapy initiation relative to symptom onset, and disease severity, varying COVID-19 treatment protocols throughout the pandemic, possible interactions between early vaccinations and mAb, and disease severity-dependent treatment response .

It is important to look back at the early data to understand the progression to current management protocols. Previously, biologics were analyzed for approval independently of other drug applications, and could be given priority as an "orphan drug” with accelerated status for patients with rare diseases needing treatment now, allowing for rapid market mobilization.

The COVID-19 pandemic sped up the process even further. The FDA was able to issue Emergency Use Authorizations (EUA) to companies with promising pharmaceuticals and biologics for direct care of patients with COVID-19, without the confirmatory trials and tests previously required. Although the healthcare system benefited from greater access to approved biologic treatments for COVID-19, many of the biologics were revoked due to concerns about both efficacy and safety. In the end, it remains to be seen if the proper avenues for the ethical development of pharmaceuticals were neglected in favor of the streamlined approval process by the pharmaceutical companies, and thus should be considered in future international medical events.

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