Despite significant funding and research effort, a vaccine against Covid-19 is unlikely to be ready until 2021. Similarly, novel drug development is too slow and impractical a progress to effectively tackle this global pandemic, which, at the time of writing, has killed almost 185,000 people globally
A more immediate alternative approach is repurposing existing drugs; a strategy often used in the oncology space. Borrowing drugs from other indications is a time saver because these drugs will already have proven themselves to be safe in pre-clinical and early clinical testing, meaning they can be fast-tracked straight into the final stage of clinical development, Phase III, to evaluate their safety and efficacy as Covid-19 treatment.
The expediency of this strategy has captured the imagination of pharma companies and university researchers committed to quickly resolving the Covid-19 pandemic. According to the Austrian Institute for Health Technology Assessment, the majority of the 155 drugs in the pipeline for Covid-19 were already developed. Given the clear popularity of this approach, what are the most promising drugs being recycled that could effectively tackle Covid-19?
Remdesivir: an early hope against Covid-19
Within a month of the novel coronavirus dominating headlines, and around the same time that the first Covid-19 cases were reported in the US, at the end of February pharma giant Gilead Sciences announced the start of two Phase III studies for its anti-viral drug remdesivir in the US, Asia and Europe. These trials are studying this broad-spectrum nucleotide analogue in both severe and moderate Covid-19 patients.
Originally developed to treat Ebola, remdesivir was never actually approved for this indication as it was inferior to other treatments developed against the 2014 epidemic in West Africa. Following its discontinuation for Ebola, the drug demonstrated in vitro and in vivo activity against two other coronaviruses, MERS and SARS; this is where its potential as a treatment against Covid-19 originated from.
Research from the University of Alberta, Canada, has shown that the reason remdesivir has been successful against other coronaviruses, and could be effective against the SARS-CoV-2 virus that causes Covid-19, is because it blocks RNA synthesis, which is needed for replication of the virus.
Gilead announced positive interim data from one of its Phase III studies, the SIMPLE trial, at the end of April. These findings are consistent with early results from patients being treated with remdesivir on compassionate use grounds, which have been incredibly promising to date. According to Gilead, more than 1,800 patients have been treated through this free-of-charge programme across the world.
In mid-April, analysis of 53 patients hospitalised with Covid-19 and receiving remdesivir on a compassionate use basis showed the majority demonstrated clinical improvement. Remdesivir treatment caused 68% of patients to improve their oxygen support class, led to more than half on mechanical ventilation to extubated and allowed 47% to be discharged from hospital.
Remdesivir was also proven to prevent disease progression in a pre-clinical study coordinated by the US National Institute of Allergy and Infectious Diseases (NIAID). This institute is leading a Phase II study of the Ebola drug. Although full results are not expected until May, NIAID announced early positive data; the remdesivir group had a 31% faster time to recovery than the placebo arm, meaning the trial met its primary endpoint.
As a result of these two sets of positive results, the US Food and Drug Administration (FDA) granted remdesivir emergency use authorisation (EUA) on 1 May; this represents a huge vote of confidence for this antiviral. The European Medicines Agency and the UK’s Medicines and Healthcare products Regulatory Agency has followed suit.
In addition, the Japanese Ministry of Health, Labour and Welfare approved remdesivir for Covid-19. Gilead Sciences chief medical officer Merdad Parsey said: “The Japanese approval of remdesivir is in recognition of the urgent need to treat critically ill patients in Japan. It is a reflection of the exceptional circumstances of this pandemic.”
Combating the deadly cytokine storm
As Covid-19 transitioned from an epidemic to a pandemic, researchers began to investigate what makes this viral disease so severe and deadly in certain patient populations. One of the reasons is because of SARS-CoV-2’s ability to activate a patient’s immune system into overdrive, leading to a cytokine storm and hyper-inflammation. This creates a situation where healthy cells in the lungs can be damaged and destroyed, which can be life-threatening, particularly in patients with underlying, chronic health conditions. It seems that younger people often have less developed immune systems, meaning they are less at risk of over-activation of cytokines, and the subsequent symptoms.
Although there is a lack of understanding about precisely how viruses manage to send cytokines into overdrive, many drugs have been developed for other conditions characterised by inflammation caused by the immune system; some of these drugs are now being repurposed against Covid-19.
Three noteworthy examples of drugs being repurposed to take the pressure of ventilators are AstraZeneca’s Calquence, Roche’s Actemra and Novartis and Incyte’s Jakavi.
The aim is to evaluate whether these repurposed anti-inflammatory drugs can manage this potentially deadly cytokine storm in the most at-need, severe Covid-19 patients, so they are no longer reliant on mechanical ventilation; countries across the world have been struggling with shortages of these devices and necessary oxygen supplies.
Calquence (acalabrutinib) is a blood cancer drug thattargets the Bruton’s tyrosine kinase (BTK) pathway, known to play a role in the production of inflammatory cytokines. In AstraZeneca’s global, randomised CALAVI trial, Calquence is being compared with best supportive care to reduce the need for patients to be placed on ventilators. This study is in the enrolment stage, having only been initiated in mid-April.
Targeting inflammatory pathways with Actemra and Jakavi
Interleukin-6 (Il-6) is a pro-inflammatory cytokine, which is known to play a role in causing diabetes, Alzheimer’s and rheumatoid arthritis (RA). Roche’s Actemra (tocilizumab) was the first IL-6 inhibitor approved for RA, as well as other types of arthritis and CAR-T cell-induced cytokine release syndrome (CRS); the name of the disease caused by a cytokine storm.
Roche’s subsidiary Genentech is collaborating with US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) on a Phase III COVACTA study of Actemra plus standard of care. This trial was given the go-ahead by the FDA at the end of March; results are expected in the early summer. Tocilizumab is also one of the repurposed drugs being studied in the largest Covid-19 trial, the UK’s RECOVERY trial.
Last, but not least, is Novartis and Incyte’s JAK1/JAK2 inhibitor Jakavi (ruxolitinib), indicated for polycythaemia vera, which is caused by a neoplasm in the bone marrow, rare bone marrow cancer myelofibrosis and graft-versus-host disease that might occur after an allogeneic transplant.
JAK1/JAK2 are tyrosine kinase proteins that code for certain cytokines. Novartis chief medical officer and head of global drug development John Tsai explained: “The potential that Jakavi could lead to faster recovery times for Covid-19 patients with fewer requiring intensive care and mechanical ventilation is encouraging and absolutely merits further investigation.
“We now are moving rapidly to finalize the [Phase III] study plan and then to enrol eligible patients, as well as put in place a process to provide access for patients unable to participate in the trial.”
Hydroxychloroquine: the promise of an anti-malarial?
Like remdesivir, hydroxychloroquine has received significant coverage in the media as a potential treatment for Covid-19. This antimalarial, which is also approved for lupus, has particularly captured the attention of US President Donald Trump, who described it as a ‘game changer’ in the battle against Covid-19.
His support for the drug, both alone and in combination with antibiotic azithromycin, comes despite very limited evidence in support and serious concerns about the risks of adverse cardiac events, including drug-induced cardiac death. As a result of the hype around the drug, the FDA granted it EUA, and it has been recommended for use by frontline healthcare workers in India.
Many studies are underway to try and determine if hydroxychloroquine is both safe and effective in Covid-19 patients. Two noteworthy examples focusing on hydroxychloroquine alone are US National Heart, Lung, and Blood Institute’s ORCHID study at Vanderbilt University and Novartis’s recently announced FDA-approved Phase III trial. It makes sense for the Swiss pharma giant to study this generic drug, given it is manufactured by its generics division Sandoz. In addition, the UK’s University of Oxford led RECOVERY trial will study both hydroxychloroquine and azithromycin.
Unfortunately, data released to date is not incredibly promising. At the end of April, researchers in the US published a non-peer reviewed study showing hydroxychloroquine was associated with increased overall mortality and did not reduce the overall risk of mechanical ventilation of Covid-19 patients.
Although a US National Institute of Health panel recommended against the combination of azithromycin and hydroxychloroquine, it concluded there was still insufficient evidence to recommend for or against hydroxychloroquine.
All the world can do is wait and see what the results of the large-scale studies of these repurposed drugs show; keeping our fingers crossed that at least one can help stop the pandemic in its deadly tracks.