Combination therapies for COVID‐19: An overview of the clinical trials landscape

Abstract

The COVID‐19 pandemic has driven an unprecedented level of global activity in drug discovery and clinical development for effective therapeutics targeting the coronavirus disease. There are currently 744 therapeutics being tested in 2879 clinical trials globally. Almost 90% of these clinical trials are focused on monotherapies. Combination therapies are the mainstay of antiviral therapeutics to increase the potency of the individual compounds and to combat the rapid evolution of resistance, although combination therapies have inherently complex clinical and regulatory development challenges. Increased understanding of the SARS‐CoV‐2 lifecycle and COVID‐19 pathology provides a scientific rationale for evaluating the effectiveness of different combinations. In this paper, we provide an overview of the current clinical trial landscape for combination therapeutics targeting COVID‐19 through weekly scanning of national and international clinical trial registries. Our analysis delves specifically into dual combination therapies in what can be defined as “pivotal clinical trials” (active, randomised, controlled and at least phase II), with a focus on new and repurposed therapeutic candidates that have shown positive signals and/or been granted authorisation for emergency use based on positive efficacy and safety data.

Drug-Target Network Study Reveals the Core Target-Protein Interactions of Various COVID-19 Treatments

“…Their targets and involved pathways are mainly related to anti-cytokine activity and inhibiting viral entry, which explains the functions of the module genes enriched in the immune cell membrane receptors and the downstream cellular signaling cascade. Nevertheless, many antiviral agents and anti-inflammatory drugs have been reported for combination use [ 70 , 71 , 72 ], providing better treatment efficacy than monotherapies.…”

Repurposing Multiple-Molecule Drugs for COVID-19-Associated Acute Respiratory Distress Syndrome and Non-Viral Acute Respiratory Distress Syndrome via a Systems Biology Approach and a DNN-DTI Model Based on Five Drug Design Specifications

“…Additionally, combination therapies deployed with repurposed drugs have also been considered as therapeutic interventions for COVID-19. At present, thousands of repurposed clinical trials are being tested for COVID-19 [ 27 , 28 , 29 ]. Although most of them are monotherapy, the importance of accelerating the evaluation efficacy should not be neglected.…”

Computational pharmacology: New avenues for COVID-19 therapeutics search and better preparedness for future pandemic crises

“…The initial therapeutic management of COVID-19 was limited and the urgent nature of the pandemic prompted clinicians to try different approaches [ 3 ]⁠. A variety of protocols were developed to provide treatment and aid patient recovery where the therapeutic options included antiviral drugs, anti-inflammatory drugs, immunomodulators and other types of intervention [ 3 , 5 , 6 ]⁠. As more information was collected and emergency approvals for clinical trials produced data, the clinical strategies were further refined [ 3 , 5 , 6 ]⁠.…”

“…A variety of protocols were developed to provide treatment and aid patient recovery where the therapeutic options included antiviral drugs, anti-inflammatory drugs, immunomodulators and other types of intervention [ 3 , 5 , 6 ]⁠. As more information was collected and emergency approvals for clinical trials produced data, the clinical strategies were further refined [ 3 , 5 , 6 ]⁠. This also presented an opportunity to explore drug repurposing and search for effective clinical management options capturing both infection prevention and the alleviation of symptoms [ 2 , 7 , 8 ]⁠.…”

“…Intriguingly, looking into the extended networks of drug targets, we found rich clusters of shared features. This allowed us to hypothesise that a direct drug-target interaction will have an effect on other associated interactors and this information could be used to assess drugs under investigation that share a predicted network [ 5 , 6 , 10 , [23] , [24] , [25] ]⁠. Moreover, this approach could be used to select combination therapy regimens.…”