Drugs for SARS-CoV-2 infection (COVID-19)

COVID-19 is the disease caused by infection by SARS-CoV-2 (severe acute respiratory syndrome virus 2), the airbourne, respiratory coronavirus that was first detected in China’s city of Wuhan in late 2019. The spread of this virus rapidly became a global pandemic that has resulted in millions of deaths. The pace of the subsequent response by the medical, pharmacology, scientific and pharmaceutical research communities has been unprecedented and delvered significant advances in both vaccinations and therapeutic interventions.

Whilst vaccinations that stimulate an immune response against SARS-CoV-2 have proved effective in preventing severe respiratory complications, this section will focus on the drugs that alter disease pathology or inhibit virus infection. A huge effort has been made to understand the host factors that may affect the severity of disease experienced by individual patients, and therefore provide pharmaclogical targets with potential to modify the disease progression. Thousands of clinical trials have evaluated both existing drugs, repurposed for SARS-CoV-2 infection, or drugs that were in development for other diseases.

Initially, medical interventions for hospitalised COVID-19 patients was supportive and aimed to improve oxygenation in the face of infection-induced lung damage. In patients that progressed to acute respiratory distress syndrome (ARDS) this could extend to CPAP, intubation or extracorporeal membrane oxygenation (ECMO; although this is very limited in availability). It soon became apparent that severe COVID-19 might be accompanied by hyper-inflammation and microvascular clotting abnormalities that extended beyond the respiratory system, and that patients could experience rapid deterioration of pulmonary, cardiac, and/or neurological function. This emerging understanding of severe COVID-19 pathology led to the urgent search more targeted treatment options.

The University of Oxford-led “Randomised Evaluation of COVID-19 Therapy” (RECOVERY) trial has been instrumental in identifying therapeutic options for COVID-19 patients. RECOVERY is an international study, and as of April 2022 had provided evidence for 4 drugs that are effective COVID-19 treatments*. This page from the RECOVERY website shows the timeline of discoveries, and also (importantly) indicates some of the drugs that have shown no clinical benefit.

Therapies that are host-directed

Dexamethasone* is a widely available and relatively cheap corticosteroid (glucocorticoid receptor agonist) that targets the over-active immune response in patients with severe COVID-19. It has become the primary addition to standard care for critically ill COVID-19 patients.

Tocilizumab* is an anti-IL-6 receptor mAb, with immunosuppressive action that is approved for chronic autoimmune indications. Following many clinical studies, tocilizumab was found to decrease COVID-19 mortality, and in the UK can be used to treat critically ill COVID-19 patients in ICUs. In this setting, it is used in addition to corticosteroid therapy.

Baricitinib* is an oral Janus kinase inhibitor that has powerful anti-inflammatory activity. It is already used to treat severe rheumatoid arthritis, so its safety profile is well established. Baricitinib is indicated for hospitalised COVID-19 patients in addition to standard of care therapies such as immunomodulatory treatments (e.g. dexamethasone, tocilizumab) or the antiviral drug remdesivir.

To date the drugs that have demonstrated clinical benefit that holds up under RCT evaluation are those that modulate the inflammatory component of SARS-CoV-2 infection.

Therapies that target the virus

Anti-spike monoclonal antibodies

Several such mAbs were rapidly generated, either via analysis of plasma from recovered COVID-19 patients, and/or other mAb generation/optimisation strategies. A number of these have been authorised in different jurisdictions as COVID-19 therapies. Some are used in combinations, and work is ongoing to determine how effective they are in view of evolving SARS-CoV-2 variants.  Monoclonal antibodies are particularly useful for patients who either cannot be vaccinated or who don’t develop a strong vaccine response.

Regdanvimab is EMA authorised to treat SARS-CoV-2 positive patients with mild-moderate symptoms, who don’t require supplemental oxygen therapy, but who are at increased risk of progressing to severe disease.

Sotrovimab retains activity against the omicron (B.1.1.529) SARS-CoV-2 variant

Casirivimab + imdevimab (Ronapreve*) is a cocktail of two mAbs that have non-overlapping epitopes on the SARS-CoV-2 spike protein. Like regdanvimab, approval indicates Ronapreve use in confirmed COVID-19 patents with mild-moderate disease who are at high risk of progressing to severe disease.

A list of some other anti-spike mAbs is available on the Guide to PHARMACOLOGY

Mpro (main protease; 3CLpro)  inhibitors

Nirmatrelvir is the Mpro inhibitor component of Pfizer’s Paxlovid. Inhibiting Mpro blocks replication at an early stage in the virus' life cycle, so Paxlovid should be administered within 5 days of symptom onset. There is provisional evidence that nirmatrelvir retains activity against SARS-CoV-2 variants including delta and omicron. Paxlovid contains low dose ritonavir to inhibit CYP450-mediated metabolic clearance of nirmatrelvir.

RdRp (RNA-dependent RNA polymerase)  inhibitors

The conservation of RdRP catalytic domain between different RNA virus families means that inhibitors that were designed against other viral pathogens have some activity against the SARS coronaviruses.

One such inhibitor is remdesivir, which is a broad spectrum antiviral that was originally evaluated for anti-Ebola and anti-Marburg virus activity. In vitro activity against SARS and MERS coronaviruses had been demonstrated, so remdesivir was quickly tested for anti-SARS-CoV-2 activity. Anti-SARS-CoV-2 activity in in vitro systems and in animal models is low, and its clinical efficacy is not robust. However remdesivir was the first direct-acting antiviral to be FDA approved for COVID-19 (October 2020), in the rush to address the need for drug treatments for SARS-CoV-2 infections.