Will a repurposed drug help treat COVID-19?

There are 344 registered interventional clinical trials under way for the treatment and prevention of COVID-19. The WHO is looking at four of them.

At the time of press on 22 May, there are more than 5.2 million confirmed cases of novel coronavirus disease 2019 (COVID-19) around the world.¹ COVID-19 is caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2).²

Approximately 80% of infections with clinical presentations will cause mild respiratory illness and people will recover without hospital care.³ Another 15% will present with moderate to severe pneumonia requiring hospital care, and 5% will need intensive care due to critical illness.³ At this stage, it is not known how many people are asymptomatic and infected. Additionally, it is unclear if succumbing to COVID-19 is a result of the virus itself or the innate immune response.⁴

Given the global emergency and the speed at which the virus has spread, drug repurposing has obvious advantages, particularly given the amount of time usually required to take a molecule from drug discovery to regulatory approval.

Some of these agents have received more media interest than others, e.g. hydroxychloroquine (Plaquenil), following social media tweets by people such as US President Donald Trump. This led to excessive attempts to acquire the medicine, resulting in the introduction of restrictions to ensure supply only to those with a therapeutic need (e.g. rheumatoid arthritis, lupus).

While numerous therapies are being tested all around the world, there are no pharmacological agents approved for either the treatment or prevention of COVID-19. In Australia, the consensus guidelines state: ‘For patients with COVID-19, only administer antiviral medications or other disease-modifying treatments in the context of clinical trials with appropriate ethical approval.’²

A recent review looked at the registered interventional clinical trials for the treatment and prevention of COVID-19.⁵ As of 20 March 2020, 344 studies were registered, of which 100 involved the use of traditional Chinese medicine, e.g. herbal medicines and acupuncture. The remainder include⁵:

• Antiviral treatments – most have focused on using therapies that have shown efficacy against SARS-CoV-1 and MERS-CoV. Lopinavir/ritonavir (protease inhibitors used for the treatment of HIV) is the most commonly explored combination.
• Antimalarial treatments – in vitro work showed chloroquine and hydroxychloroquine to have inhibitory effects on viral cell entry and replication.
• Immunosuppressants/immunomodulators – a hyperinflammatory response contributes significantly to mortality. Some studies are looking at the effect of corticosteroids in COVID-19. Other studies are focusing on immune stimulation.
• Cell and plasma-based therapy – some studies are looking at the use of mesenchymal stem cells for their immunomodulatory and tissue repair effects. Plasma, which may contain disease specific antibiotics, from patients who have recovered from COVID-19, is also under investigation.
• Other pharmacological treatments, e.g. pirfenidone (used for idiopathic pulmonary fibrosis), bevacizumab (anti-angiogenic), thalidomide.
• Other clinical trials registered include those looking at modifying the gut microbiome, and holistic approaches such as physiotherapy, psychology and nutritional interventions.

However, evidence for these as treatments for COVID-19 remain to be seen. Often, the barrier is due to the small number of patients in each trial, along with inconsistent trial protocols and endpoints, making it difficult to compare findings. To this end, the World Health Organization (WHO) announced an international clinical trial – ‘Solidarity’ – to help find an effective treatment for COVID-19.⁶

Four treatments have been selected, though the WHO has stated that other drugs can be added based on emerging evidence. The four are:

• remdesivir (an investigational nucleotide analogue with broadspectrum antiviral activity,⁷ previously tested as an Ebola treatment)
• lopinavir/ritonavir
• lopinavir/ritonavir with interferon beta-1a (used for management of multiple sclerosis), and
• chloroquine or hydroxychloroquine.⁶

This coordinated effort looks to overcome issues with speed and scale usually associated with clinical trials. The intent is for this approach to reduce the time taken by 80%, which will allow clinicians and researchers to urgently gather evidence for the clinical utility of these agents for COVID-19.⁶

References

1. Johns Hopkins University and Medicine. Coronavirus Resource Center: John Hopkins University. 2020. At: coronavirus.jhu.edu/map.html
2. Australian National COVID-19 Clinical Evidence Taskforce. Australian guidelines for the clinical care of people with COVID-19. 2020. At: app.magicapp.org/app#/guideline/4167
3. Thevarajan I, Buising K, Cowie B. Clinical presentation and management of COVID-19. Med J Aust 2020. Epub 2020 Apr 8. At: www.mja.com.au/journal/2020/clinical-presentation-and-management-covid-19
4. Ledford H. How does COVID-19 kill? Uncertainty is hampering doctors’ ability to choose treatments. Nature 2020;580:311–12. At: nature.com/articles/d41586-020-01056-7
5. Lythgoe M, Middleton P. Ongoing clinical trials for the management of the COVID-19 pandemic. Cell 2020. Epub 2020 Apr 11. At: cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(20)30070-5
6. World Health Organization. “Solidarity” clinical trial for COVID-19 treatments. 2020. At: who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
7. Gilead Sciences. About Remdesivir. 2020. At: gilead.com/purpose/advancing-global-health/covid-19/about-remdesivir