Can existing drugs be effectively combined to treat COVID-19?
The key outtake underpinning all three papers is that, as there does not appear to be one truly effective repurposed antiviral for COVID-19, combined agents must be explored – particularly in the absence of a vaccine.
The team has used viral cell cycle modelling to take a deep dive into not only which drugs should be explored for therapeutic treatment, but also when in the disease course intervention might be most effective.
Featured across three leading journals: The Lancet, British Journal of Clinical Pharmacology and the American Journal of Tropical Medicine and Hygiene, the investigators are acting on an urgent need to evaluate combination therapies for COVID-19, given the current lack of effective antiviral monotherapies.
In the British Journal of Clinical Pharmacology study, the investigators described application of viral cell cycle mathematical models of the SARS-CoV2 built from patient data, to explore the potential of various viral cell cycle check-points as therapeutic intervention targets. The investigators showed that outcome improves with earlier intervention, irrespective of pharmacological target, highlighting the importance of initiating antiviral therapy as soon as possible in the disease course.
The investigators also found that drugs such as camostat or nafamostat that may impact ‘viral attachment’ are best used for prevention and very early treatment. Drugs like remdesivir, lopinavir/ritonavir and favipiravir that reduce the production of virus from infected cells are also most effective in early disease but may also continue to reduce viral shedding as the disease progresses. Furthermore, the study found that combining repurposed agents may provide an alternative pathway to identifying effective antiviral interventions for COVID-19.
Dr. Craig Rayner, an Adjunct Associate Professor at Monash University and President of Integrated Drug Development at Certara, says that because there does not appear to be a silver bullet repurposed treatment, the team’s primary goal is to explore approaches to achieve clinical efficacy by using combined agents informed by the viral life cycle.
“Given the lack of effective antiviral monotherapies for COVID-19, the need to evaluate combinations, as outlined by the World Health Organisation in the initial coronavirus roadmap, is being re-emphasised.” says Dr Rayner. “It is not efficient, cost effective or ethical to apply a blind ‘trial and error’ approach to selecting combinations for clinical evaluation against COVID-19. Establishing a robust clinical and quantitative pharmacological rationale to guide clinical evaluation of repurposed combinations is a very high priority.”
In a second study, published in the Lancet Global Health, the team of researchers warn against the oversimplification of the COVID-19 disease process, highlighting the critical need to evaluate therapeutic interventions aligned with pathophysiology. Importantly, the authors flag that antivirals shown to be ineffective in hospitalised patients should not stop evaluations earlier in the infection, where viral replication is the primary driver of disease.
In the American Journal of Tropical Medicine and Hygiene, the investigators described a novel strategy to accelerate antiviral combination evaluation for COVID-19 by using an adaptive combination platform clinical trial approach in early disease. This approach challenges traditional drug development practices. It leverages combination selection informed by viral cell cycle modelling and is supported by an advisory committee of expert clinical pharmacologists and infectious disease physicians.
“We need to reinvent the way we do clinical trial evaluations of combinations in the urgency of COVID-19. Adaptive platform trial designs offer flexibility to begin with high potential combinations and if effective, continue to simplify regimens in parallel with other patients having the potential to receive an effective treatment regimen,” says Dr Rayner.
The next step for the team is to harness the hypotheses proposed from this framework and test in preclinical and clinical investigations.
Dr Edward Mills, Principal Scientist from Cytel and Professor at McMaster University and Principal Investigator of the Together Platform Trial says, “Our global Together Platform trial in early treatment is designed to rapidly evaluate antiviral combination approaches in an adaptive framework. The trial is rapidly recruiting in Brazil, USA and South Africa and will be used to evaluate additional combination regimens. Results of trial arms will be shared on a rolling basis.”
Contact: Kate Carthew