Chapter 4: Repurposing Therapies for COVID-19

INTRODUCTION

New drug development is expensive, requires at least 10 years, and has a success rate of only 2.01%.¹ There are a large number of compounds to be tested and large number of randomized control trials with no clinical benefit or with toxicities.^2,3 There would also be a significant gap between the need and the availability of treatment. During the coronavirus disease 2019 (COVID-19) pandemic, drug repurposing was used to identify new indications of existing drugs.^4–6 It has been suggested that 75% of known drugs can be used for repurposing, re-profiling, re-tasking, or rescue.⁶ Safety of these drugs have already been tested. Therefore, this technique is less expensive, and allows faster utilization via phase II and III clinical trials and compassionate use.

METHODS TO IDENTIFY REPURPOSED DRUGS

The concept of repurposing is that a single drug can interact with multiple targets and the targets are associated with a number of biological processes.⁵ In other words, one drug that targets one disease might target another through a shared protein-protein interaction network.⁶ Due to the repository of medical knowledge in the form of gene expression, drug target interactions, protein networks, electronic medical records, clinical trials, and adverse event reports, computational methods are able to integrate and identify potential new drug mechanisms and indications.⁵

During COVID-19, there were computational-based repurposing approaches with network, structure, and artificial intelligence (AI).⁷ Network approaches rely on clusters and propagation to find drug–disease, drug–drug, and drug–target relationships.⁷ Therefore, medical knowledge graphs relations between diseases, drugs, and proteins and predicts new links.² The structural approach uses known or predicted 3D structure to see how chemicals bind to targets. AI uses linear and non-linear transformation in hierarchical way and biological sequencing.⁷

CHALLENGES OF REPURPOSED DRUGS

Considerations in new treatment targets for repurposed drugs include the heterogenous patient population with many genetic variations, drug mechanisms, stage of the disease, pharmacokinetics and pharmacodynamics, and disease course. Repurposed drugs also have additional challenges. Cellular or animal assays are not the same as the human environment, and repurposed drugs are not necessarily optimized for the new indication.² Expedited trials often have a small number of patients and lack clinical endpoints. The drug should target the particular severity of the disease; therefore, patients with milder forms of the disease might require analysis with greater sensitivity.²

REPURPOSED DRUGS FOR COVID-19 (MONOTHERAPY AND COMBINATION THERAPY)

Drugs that do not have retrospective or prospective studies in peer-reviewed journals as of March 1, 2021 are not included. Large randomized control trials currently in pre-print are included. These drugs are nitazoxanide, elbasvir, mefuparib, bevacizumab, melatonin, imatinib, darutinib, ibrutinib, dasutinib, cepharantine, camostat mesylate, fingolimod, pirfenidone, bamlanivimab, and auranofin.

Acalabrutinib

Acalabrutinib is a bruton tyrosine kinase ...