Repurposing drugs for treatment of COVID-19.

Although the COVID-19 vaccine programme continues to be rolled out globally, there is still a need to identify effective treatments, particularly in countries where vaccine uptake is slow, and with the insidious threat of mutations resulting in vaccine escape. With the urgency of the pandemic making the timely discovery of new drugs almost impossible, the idea of repurposing existing drugs to treat COVID-19 is an attractive strategy, especially if they are already approved (for other indications) and have well established safety profiles.

Hundreds of medications have been trialled in mainly hospitalised patients with COVID-19, creating a huge amount of data of differing qualities. A central data repository called the CORONA Project was launched by the Castleman Disease Collaborative Network (Paso Robles, CA, USA) and the Center for Cytokine Storm Treatment & Laboratory (CSTL; Philadelphia, PA, USA) in early 2020 to track all treatments that have been used for COVID-19. The project, discussed by CSTL director David Fajgenbaum in a recent podcast with the ASCO Daily News, contains data for 443 medications that have been given to more than 340 000 patients. A panel of physicians and researchers assigns grades to all the drugs based on their effectiveness in randomised trials and whether they met their pre-specified primary endpoint. The grades range from A (established effectiveness; endorsement by professional societies) to F (unlikely to be effective; all or nearly all randomised trials are negative).

As Fajgenbaum describes in the podcast, “out of those over 400 drugs that have been tried, just a few of them have been definitively shown to be effective”. The database has ranked only four drugs with a grade A: baricitinib, remdesivir, dexamethasone, and tocilizumab.

Guidance issued globally follows these data to some degree. For example, US guidelines recommend the use of dexamethasone in hospitalised patients who require supplemental oxygen or mechanical ventilation, and state that the addition of tocilizumab to dexamethasone improves survival. They also recommend the use of remdesivir in hospitalised patients with COVID-19 who require supplemental oxygen but not those who require mechanical ventilation. UK guidelines recommend offering dexamethasone to patients who need supplemental oxygen; or tocilizumab to those who need supplemental oxygen. They make conditional recommendations to consider remdesivir for adults with COVID-19 pneumonia on supplemental oxygen but not those on mechanical ventilation.

The clinical trial data are also important for ruling out drugs that have not been effective for COVID-19. Platform trials, such as RECOVERY and SOLIDARITY, testing multiple drugs showed that hydroxychloroquine, lopinavir–ritonavir, and interferon did not reduce mortality. Also, on the basis of trial data, the European Medicines Agency, the US National Institutes of Health, and WHO have advised against using ivermectin outside clinical trials, since higher than approved doses would be needed for efficacy against the virus, which increases the risk of side effects. Azithromycin is also not recommended for the management of patients in hospital with COVID-19, on the basis of negative data from trials such as RECOVERY.

Yet, some repurposed drugs showing a lack of effectiveness have been among the most widely used treatments; almost one in three patients globally has received hydroxychloroquine, despite only one of 18 randomised trials showing an effect or benefit. Fajgenbaum commented in the podcast “[This] highlights why it's so important to centralise the data in one place.”

Trials for repurposed drugs in patients in hospital are ongoing; in the RECOVERY trial alone, drugs that have been added for testing include aspirin, colchicine, and dimethyl fumarate. There is also a move towards testing repurposed drugs for early management of COVID before hospitalisation. In the USA, the phase 3 ACTIV-6 trial will begin shortly, testing self-administered medications for patients who are not sick enough to be hospitalised. And in the UK, the PRINCIPLE trial is ongoing, testing community treatments to enable patients with symptoms to recover before they need to go to hospital. On the basis of results from PRINCIPLE, the UK NHS stated that inhaled budesonide can reduce the recovery time for patients managed within primary care and might be considered for use in the community setting. The importance of early treatment has been highlighted not only in COVID-19 but also in other respiratory diseases such as influenza. Additionally, as mutations dominate the outbreak, variants of concern might be more susceptible to treatment than wild-type strains, especially when treatment is started early.

Felix Hammann (University Hospital Bern, Bern, Switzerland) commented “Repurposing will continue to play an important role, and we must keep funding this, collaborate, and openly publish raw research data to allow for data mining and pooling of trials.” He continued, “Repurposing may be the most straightforward way to deliver a pharmacological treatment. Every mutation SARS-CoV-2 acquires brings it a step closer to vaccine escape. If the variants of concern are more susceptible to treatment, we will have something on our hands should an escape ever occur.”