Clinicians and scientists in the UK are leading the fight against COVID-19 as an innovative platform has been launched by the University of Liverpool, the Liverpool School of Tropical Medicine and the Southampton Clinical Trials Unit. This news follows last month's news that the largest randomised controlled clinical trial for a COVID-19 treatment, funded by the UK's National Institute for Health Research (NIHR), led to the discovery of dexamethasone as the first drug to improve survival rates (NIHR, 2020).
The new drug-testing platform is called AGILE and was developed by infectious disease clinicians, clinical and preclinical pharmacologists, clinical trials specialists, as well as statisticians. Its mission is to test new drugs for COVID-19 from all over the world at an accelerated pace, identifying those compounds that can most effectively fight the virus with patient safety being the top priority, according to the Medicines and Healthcare products Regulatory Agency (MHRA) (McKee, 2020).
The AGILE platform was designed so that effective drugs can advance through large-scale trials much more rapidly than would usually be possible in order for successful therapies to be of use during the pandemic. AGILE can test drugs both for patients who are newly diagnosed with COVID-19 at home, as well as those in hospital, and has full ethical approval in the UK.
The first drug set to be trialled in AGILE was developed in the US by Ridgeback Biotherapeutics, which is a private majority-woman-owned biotechnology company based in Miami, Florida. The oral drug, which has shown promising results against coronavirus infections such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) in preclinical studies, is called EIDD-2801 and is an antiviral therapy (McKee, 2020; Robinson, 2020a).
Antivirals
Antiviral therapies would prevent the virus from multiplying. Alongside EIDD-2801 being tested on AGILE, other potential COVID-19 treatments that fall into the category of antivirals include remdesivir, chloroquine/hydroxychloroquine, lopinavir/ritonavir, favipiravir, umifenovir, ribavirin and niclosamide (Robinson, 2020a).
Remdesivir is a broad-spectrum antiviral originally developed for the treatment of hepatitis C and then tested against the Ebola virus. It is now licensed in the EU for the treatment of COVID-19 in adults and adolescents with pneumonia who require supplemental oxygen and was the first treatment to be made available for COVID-19 in the UK outside of a clinical trial (Robinson, 2020a). It was also the first treatment to receive a positive scientific opinion from the MHRA and has been recommended by the National Institute for Health and Care Excellence (NICE) (2020) for adults and young people (aged 12 years and over, weighing at least 40 kg) who are hospitalised with either suspected or laboratory-confirmed SARS-CoV-2 infection and severe disease). When compared with a placebo, remdesivir was associated with fewer serious adverse events and clinical improvements in some outcomes (NICE, 2020). However, the evidence is mixed, and further research is needed (Robinson, 2020a).
Chloroquine and hydroxychloroquine are antimalarial drugs also approved to treat rheumatoid arthritis and lupus, which have demonstrated activity against viruses in vitro, including SARS-CoV-2, the causative agent of COVID-19. Lopinavir has inhibitory activity against SARS-CoV (which causes SARS), also in vitro, and is combined with ritonavir in order to increase its half-life (Robinson, 2020a). Both chloroquine or hydroxychloroquine and the lopinavir-ritonavir combination are recommended for use in treating COVID-19 in several countries, such as Italy and France (Robinson, 2020a).
Immune modulators
The first drug that was demonstrated to prevent deaths in patients hospitalised with COVID-19 was dexamethasone, which falls into the category of immune modulator. Immune modulators help the immune system to fight the virus or stop it from overreacting in a dangerous way (Robinson, 2020a). Other immune modulators that are being considered as potential therapies for COVID-19 include convalescent plasma, which uses the antibodies from people who have recovered; azithromycin; interferons; tocilizumab; sarilumab; canakinumab; anakinra; baricitinib; ruxolitinib; acalabrutinib; brensocatib; ravulizumab; gemtuzumab ozogamicin; namilumab; infliximab; otilimab and Medi3506 (Robinson, 2020a).
Some companies are also developing novel monoclonal antibodies that could bind to SARS-CoV-2 and neutralise it. An antiviral antibody ‘cocktail’ consisting of two antibodies is being trialled to investigate whether it can improve outcomes in COVID-19 patients, as well as its potential as a preventive therapy in healthy high-risk individuals (Robinson, 2020a).
Other approaches
Approaches to potential treatments generally fall into the categories of antiviral therapy or immune modulators; however, some others being trialled behave differently or via multiple mechanisms (Robinson, 2020a). There are also a few trials taking place for patients outside of hospital in an effort to investigate potential interventions that may be effective if used earlier in the disease trajectory, before patients are sick enough to require hospital admission (Robinson, 2020b).
It is encouraging that there are thousands of clinical trials taking place to evaluate potential therapies for COVID-19 (Robinson, 2020a). Additionally, as scientists all over the world work around the clock to develop a vaccine, the World Health Organization (2020) is tracking more than 140 candidate vaccines (Gallagher, 2020).