Therapeutics for COVID-19: established and in development

The aim of treatment for COVID-19 is to reduce disease severity and prevent mortality. Therapeutics may also be used to prevent or abort infection (pre- or post-exposure prophylaxis) and reduce post-infectious complications (Figure 1). In Australia, the National COVID-19 Clinical Evidence Taskforce has been established to review rapidly emerging evidence in real-time and maintain a ‘living document’ for COVID-19 management guidelines², available at https://covid19evidence.net.au/#living-guidelines. Interventions may be grouped into those targeting the virus and those targeting the immune response (Figure 2, Table 1). Adjunctive therapies including anticoagulation and optimising oxygenation are also critical elements of management but are beyond the scope of this review.

Figure 1.  Course and severity of COVID-19 disease. COVID-19 illness ranges from asymptomatic, mild-moderate illness, severe/critical then either recovery or death. There are limited current strategies to reduce both the spread and progression of COVID-19 disease. Future strategies include vaccines, pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). mAb, monoclonal antibody. Adapted from ¹.

Figure 2.  SARS-CoV-2 replication cycle and stages where various antiviral drug activity occurs. ACE2, angiotensin converting enzyme 2; ER, endoplasmic reticulum: E, envelope; mAb, monoclonal antibody; M, membrane; N, nucleocapsid; RdRP, RNA-dependent RNA polymerases; S, spike; TMPRSS2, transmembrane serine protease 2; 3CL, 3C-like protease. Figure was created with BioRender.com.

Table 1.  Therapeutics for COVID-19 (selected).

In a Phase III randomised placebo-controlled trial (ACTT-1, NCT04280705) including 1063 adults with COVID-19 with lower respiratory tract infection, participants receiving up to 10 days of remdesivir had shorter time to recovery than those in the placebo group (median 11 and 15 days, rate ratio for recovery 1.32; 95% CI 1.12–1.55, P < 0.001)⁵. Stratification by severity showed improved time to recovery for patients receiving oxygen at baseline, but not for those receiving no oxygen nor for those receiving high-flow oxygen or mechanical ventilation. There was no significant difference in mortality rates, although further follow-up data is awaited.

Questions remain about the optimal time and duration of administration of remdesivir. In one study (n = 397), 10 days treatment was associated with better outcomes than 5 in those going on to need mechanical ventilation; however, no control arm was included (mortality 17% with 10 days (n = 41), 40% with 5 days (n = 25))⁶. Whether there is incremental benefit above treatment with dexamethasone is not yet clear. Studies are ongoing including use of inhaled remdesivir (NCT04480333) and use in combination with other agents.

Favipiravir is an oral RNA-dependent RNA polymerase inhibitor with in vitro antiviral activity at high concentrations⁷. An open-label study in mild-moderate COVID-19 (n = 80) in combination with inhaled interferon-α reported positive results, and favipiravir was approved for marketing in China for COVID-19 in March 2020⁸. Multiple phase 2 trials are active including in Australia⁹. Concerns exist about the pharmacokinetics of favipiravir, with low trough levels in critically ill patients and potential for the emergence of resistance¹⁰.

Umfenovir (Arbidol) is a non-nucleoside antiviral targeting the viral spike (S-)protein-ACE2 host receptor interactions, inhibiting membrane fusion of the viral envelope¹⁰. Umfenovir may also promote interferon synthesis. Published results so far are inconclusive^12,13, with randomised studies in progress.

Type I interferons have broad antiviral activities and recombinant IFN-I proteins (parenteral and inhaled) are being trialled in COVID-19^14,15. Use of interferons in acute infection needs to be explored carefully, as type I interferons have been associated with exacerbation of inflammation in progression to severe COVID-19, with potential to worsen disease^16,46. Timing may be critical. In a retrospective study in COVID-19 (n = 446), late use of IFN-α led to increased mortality and delayed recovery, whilst earlier use was associated with reduced mortality¹⁷.

Ivermectin (used to treat infections such as strongyloidiasis, scabies and onchocerciasis), and nitazoxanide (used in giardia and cryptosporidium) have in vitro activity against SARS-CoV-2 and are in preclinical early clinical trials against COVID-19¹⁸. Nitazoxanide also has reported immunomodulatory activity, suppressing murine IL-6 levels^18,19.

The HIV protease inhibitor lopinavir has in vitro activity against SARS-CoV-1 and MERS, and possible activity in vivo²⁰. In vitro activity was demonstrated against SARS-CoV-2²¹, but no benefit in treatment of COVID-19 was reported in randomised published studies or in press release of results from the large UK ‘RECOVERY’ (Randomised Evaluation of COVID-19 Therapy) and WHO ‘Solidarity’ Trials^13,22–24. Other studies are ongoing with lopinavir/ritonavir and other antiretrovirals including nelfinavir, tenofovir, lamivudine and others, either alone or in combination.

Hydroxychloroquine (licensed as an antimalarial and anti-arthritis agent) and chloroquine were widely used in the early days of the COVID-19 pandemic, due to their potential to block viral entry, immunomodulatory impact and in vitro activity against SARS-CoV-2²⁵. Potential toxicities include prolonged QT interval, lowered convulsive threshold, retinopathy and cardiac myopathy. Randomised trials in mild, moderate and severe disease show no benefit in COVID-19^26–29 and the WHO have discontinued the hydroxychloroquine arm in the ‘Solidarity’ trial. A US federal drug administration (FDA) emergency use authorisation (EUA) for hydroxychloroquine in COVID-19 issued in March was revoked in June. Hydroxychloroquine has also been shown not effective for SARS-CoV-2 post-exposure prophylaxis²⁸. Studies investigating its utility for prevention of COVID-19 in healthcare workers are continuing, including in Australia³⁰.

SARS-CoV-2 uses the acetylcholinesterase (ACE)-2 receptor for cell entry, and serine protease TMPRSS2 for S-protein priming, both potential targets for antiviral intervention³¹. Agents that block these interactions are in clinical trials, including the serine protease inhibitor nafamostat mesylate which also has anticoagulant activity and is approved in Japan for treatment of pancreatitis^32,33.

The upregulation of ACE-2 receptors with use of the common anti-hypertensive agents ACE-inhibitors and angiotensin receptor blockers (ARB) was theorised to potentially lead to poorer outcomes in COVID-19 by enhancing viral entry; however, this has not been borne out by clinical data⁴⁷. Conversely, ARBs could provide benefit via receptor blockade, impairing viral cell entry⁴⁸.

In Ebola and HIV, pathogen-targeting antibodies have been identified and cloned for therapeutic use³⁴. Regeneron Pharmaceuticals (USA) published their discovery of several antibodies highly potent in suppressing SARS-CoV-2 replication in mouse models³⁵. REGN-CoV-2 (includes both REGN10933 and REGN10987) is designed to bind to two points on the SARS-CoV-2 S-protein to prevent it entering healthy cells. It is being assessed for safety and efficacy in preventing secondary infection or symptom onset amongst 2000 household contacts of people with SARS-CoV-2³⁶.

Another investigational monoclonal antibody LY-CoV555, developed after identification from blood from a patient who had recovered from COVID-19, is being studied in COVID-19 under an adaptive trial master protocol (‘ACTIV-2’ (outpatients) and ‘ACTIV-3’ (inpatients)) designed to enable phase 2 testing of investigational agents with the capacity to expand smoothly to phase 3³⁷.

In SARS, improved outcomes with convalescent plasma were reported in small retrospective case series³⁸. A randomised trial in severe COVID-19 suggests no benefit, although the study was stopped early due to insufficient numbers, and plasma was given late (median 30 days from symptoms onset)³⁹. Many other randomised studies are in progress. Meanwhile, over 50 000 patients have received convalescent plasma for treatment of COVID-19, mainly outside of clinical trial settings and an FDA EUA was issued on 23 August for its use in COVID-19.

The ‘RECOVERY’ trial showed a reduction in 28-day mortality in patients hospitalised with COVID-19 receiving oxygen or invasive mechanical ventilation treated with dexamethasone⁴⁰. 2104 patients receiving IV/oral dexamethasone (6 mg/day up to 10 days, median 6 days) had lower mortality compared to 4321 receiving usual care (22.9% vs 25.7%, age adjusted rate ratio 0.83 (0.75–0.93, P < 0.0001). Mortality was reduced by 35% among those receiving invasive mechanical ventilation, 20% in those on supplemental oxygen only and no impact was seen amongst those not receiving any respiratory support at randomisation. These results are consistent with respiratory compromise being driven by an overactive inflammatory response. Patients with symptoms for over 7 days had greater mortality benefit in response to dexamethasone treatment, compared to those with more recent onset. A recent meta-analysis combines results from ‘RECOVERY’ with six other studies to demonstrate a mortality benefit of steroids (including dexamethasone and hydrocortisone) in severe COVID-19⁴¹.

IL6 plays a key role in driving the dysregulated inflammatory response in COVID-19 with higher levels associated with greater disease severity⁴⁹. IL-6 receptor antagonist tocilizumab is used to treat rheumatoid arthritis and is FDA-approved to treat cytokine release syndrome associated with CAR T-cell immunotherapy. It has beneficial effects in vitro and in animal models of sepsis and influenza⁴². Thousands of patients are reported to have been treated with tocilizumab; however, assessment of efficacy is impaired by lack of control groups and follow up.

A non-randomised study of tocilizumab in patients requiring mechanical ventilation reported a 45% reduction in hazard of death (hazard ratio 0.55 (95% CI 0.33–0.90)) in patients receiving tocilizumab (n = 78) compared to those who did not (n = 76) with follow up 47 days (median), although superinfections were more common (54% vs 26%, P < 0.001)⁴³. Another IL6 receptor blocking agent, sarilumab and IL6 antagonist siltuximab are also in phase 3 trials.

The Janus kinase (JAK) 1/2 inhibitor, baricitinib, licensed for rheumatoid arthritis, has been identified as a candidate for therapy against SARS-CoV-2 due to potent anti-inflammatory effects and possible off-target antiviral effects⁴⁴. A case series describing use in patients with moderate-severe COVID-19 reported safety and suggests improved outcomes⁴⁵. Randomised studies are in progress and will be imperative in ascertaining the benefit of these agents, particularly in combination with direct acting antivirals, and the balance with immunocompromise and adverse events.

Different factors drive disease manifestations at different stages of SARS-CoV2 infection, and optimal management may depend on stage of illness at time of presentation. Furthermore, the course of COVID-19 differs significantly amongst individuals, with higher risk of progression to severe disease seen in the elderly. Individualised therapy using informatics strategies based on stage and prediction of disease progression have been associated with improved patient outcomes⁵⁰. Therapy based on immunophenotyping has also been suggested, based on readily identifiable immunological signatures associated with different disease trajectories^51,52.

The benefit of therapeutic antiviral combinations is also being explored. In a randomised trial in early COVID-19 (<7 days onset), the combination of lopinavir/ritonavir, interferonβ-1B and ribavirin resulted in greater reduction of virus in nasopharyngeal swabs and quicker time to recovery compared to lopinavir/ritonavir alone¹⁴. Combining antiviral and immunomodulatory agents may be important in management of COVID-19 given the role of the inflammatory response in disease evolution severity. Timing of different therapeutics should be considered carefully in trial design.

Repurposing existing therapies will be the quickest way to find effective intervention and improve outcomes in COVID-19; however, bigger gains are likely through the development of new agents specific to SARS-CoV2. These are being rapidly engineered using high-throughput screening platforms. Websites tracking COVID-19 clinical trials and the development of new agents show over 300 novel agents are in pre-clinical testing. Their diverse actions reflect the range of pathology seen in COVID-19 that is a consequence of both viral action as well as immune response. Their introduction into clinical trials will be the next exciting phase of therapeutics.

JA, JS and SRL have received investigator-initiated funding for research from Gilead Sciences for work unrelated to COVID-19. SRL has received honoraria for education activities supported by Gilead Sciences and Viiv Healthcare. SRL has received research support from Gilead Sciences, Viiv Healthcare and Merck. SRL is a member of scientific advisory boards to Merck Gilead Sciences and Biotron.