Prevention better than COVID-19 cure

Much has been learned in the months since the severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, which causes COVID-19, overwhelmed an unprepared world; however, pharmacological treatment options are still very limited [1, 2]. Despite the preferred preventative approach via vaccines, COVID-19 cases still abound [3]. Most cases are mild or asymptomatic, although still contagious [4]. For those more severely affected, COVID-19 treatment aims to reduce viral load and manage and dampen the overexuberant inflammatory response that causes the often fatal acute respiratory distress syndrome (ARDS) and myocarditis [1, 5].

Essential pharmacological treatment options include antiviral agents (to reduce viral load) as well as immunomodulators and biologics [2], particularly as it is the inflammatory response and release of proinflammatory cytokines (the “cytokine storm” characteristic of ARDS) rather than SARS-CoV-2 infection per se that is fatal [5]. Of interest, some antiviral agents also act as immunomodulators [1, 6].

The COVID-19 treatment pipeline includes both “repurposed” agents already approved or developed for other indications and new compounds [1]. Benefits of the former include known adverse drug events and ready availability, but the efficacy of most in COVID-19 has been lacklustre [2, 7].

Small molecules more accessible, if supply chain works

In a pandemic setting, reliable bulk manufacture of pharmacological agents is vital; however, it is likely that supply chain issues will arise [8]. Both small molecules and biologics are being studied in COVID-19 [3]. Overall, small molecules tend to be more accessible than biologics due to stability, oral formulation and lower cost (Table 1) [8,9,10].

Table 1 Comparison of the properties of small molecules and biologics, as reviewed by Ledford [9] and Makurvet [8]
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This article reviews emerging small molecule antiviral (according to WHO ATC code or EPhMRA code) COVID-19 treatments up to mid-January 2022, with a focus on those furthest along the regulatory pathway. Discussion of the role of other small molecule classes, biologics and older immunomodulators like corticosteroids in the treatment of COVID-19 is outside the scope of this article.

Look at viral family resemblances and proteins...

Applying decades of knowledge of other coronaviruses to identify relevant, readily available drugs is seen as the fastest way to develop potential SARS-CoV-2 therapeutics [1]. The need for speed, however, should not overwhelm the need for evidence of good efficacy and safety [11].

SARS-CoV-2 is a large-genome, enveloped, positive-sense RNA virus of the genus Betacoronavirus and is closely related are SARS-CoV (for which SARS is named) and Middle East respiratory syndrome (MERS)-CoV [1, 12]. Both of these emerged in the twenty-first century to cause fatal human respiratory illness [1], but they mostly spread via nosocomial, not community, routes and pandemics were avoided [5]. SARS-CoV-2 also shares some features with unrelated viruses, e.g. HIV [13].

The SARS-CoV-2 genome codes for 4 structural proteins and 16 non-structural proteins (nsps [14]), all of which provide potential pharmaceutical antiviral targets (Table 2). Structural proteins are the three surface proteins [spike (S), membrane (M) and envelope (E)] and the two-domain, multifunctional nucleocapsid (N) protein [14]. The S protein, which has a glycan shield of uncertain significance, has S1 and S2 subunits and has been closely studied during vaccine development. The N protein, involved in RNA binding, is needed for effective viral replication [14]. Recent E protein studies indicate that its ability to affect cell polarity may correlate with viral virulence. Nsps 3-16 are similar across most coronaviruses, but nsp1 is not [15]. Some SARS-CoV-2 structural and non-structural proteins have a high degree of sequence similarity to those of SARS-CoV and MERS-CoV [1].

Table 2 SARS-CoV-2 infective life cycle and key small molecule pharmacological targets, as reviewed by Scudellari [13] and Laws [1]
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... and modify its lifecycle and immune effects

Like other viruses, SARS-CoV-2 infects humans cells by taking over host cell functions ranging from cell entry (to effect viral replication and assembly) to release from host cells (Table 2, [1, 13]). Small molecule antiviral treatments targeting these processes are accordingly broadly grouped into viral entry, replication and release inhibitors (Tables 2 and 3) [1], although the last are so far largely experimental in SARS-CoV-2 [1].

Table 3 Pharmacological features of available small molecule antivirals with potential in COVID-19, as reviewed by Laws et al [1]
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Most treatment aims to prevent or treat severe COVID-19 in high-risk patients. These include people who are older, obese or pregnant, as well as those with cancer (especially leukaemia or lymphoma), diabetes, or respiratory, cardiovascular and other comorbidities [6].

Investigations show that cytokines that drive the most severe illness include interleukins (ILs) 2, 6, 7 and 8, tumour necrosis factor (TNF)-⍺ and interferon (INF)-ɣ [5, 6]; for some of these cytokines, antagonists already exist [5]. Granulocyte-colony stimulating factor, INF-γ-inducible protein 10, macrophage inflammatory protein 1-α (MIP-1α), and monocyte chemoattractant protein-1 (MCP-1) are also of interest [5]. Clinical trials indicate that a low level of type 1 IFN is also a poor prognostic factor, as are elevated C-reactive protein and D-dimer levels [5, 16].

Mutating genes, resistance and safety matter

The potential for drug resistance, particularly for those to be used as monotherapy, needs to be considered when developing antivirals for the treatment of COVID-19. The propensity of SARS-CoV-2 for drug resistance is inversely proportional to its genetic stability [1]. Although its structural proteins are very stable [14], the mutations that do occur in the S1 subunit explain some of the increased infectivity of the ⍺, δ and omicron SARS-CoV-2 variants [13, 17]. Despite this, experience with SARS-CoV suggests resistance may not be a significant problem for viral entry inhibitors [1]. Resistance is also less of an issue with agents that directly target host cell, rather than viral, factors (Table 2). These agents may, helpfully, also reduce ARDS via immune modulation (Table 2). Nevertheless, resistance to remdesivir (an RdRp inhibitor) has been reported after emergence of an E802D mutation during treatment of an immune-deficient patient with COVID-19 (Table 3) [18].

The choice of antiviral agent may depend on the potential for drug–drug interactions, particularly in patients who are being treated for underlying health issues and therefore may be at high risk of developing severe COVID-19 [19, 20]. Among the small molecule antivirals that are currently available for the treatment of COVID-19, nirmatrelvir-ritonavir [21,22,23] has numerous and complex drug–drug interactions (including with over-the-counter medicines and herbal supplements) because of the ritonavir component, which is required to achieve effective nirmatrelvir concentrations (Tables 3 and 4). For clinicians who are not experienced in prescribing ritonavir-boosted therapies, consultation with an expert should be considered [24]. In contrast, remdesivir [25, 26] and molnupiravir [27, 28] and their active metabolites do not inhibit or induce major drug metabolising enzymes and are not inhibitors of major drug transporters, so interaction with concomitant medications is unlikely (Tables 3 and 4).

Table 4 Preliminary data on efficacy and tolerability of small molecule antivirals approved/with EUA in COVID-19 and/or other indications
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Don’t gloss over gaps in pharmacology

Pharmacological features of several approved or almost-approved COVID-19 therapies are still being elucidated (Table 3), with ideal dosages sometimes unclear [4, 29, 30]. Investigations into several repurposed antivirals, such as favipravir [4, 29, 30], suggest the plasma and lung concentrations needed to treat COVID-19 may be higher than for influenza or HIV and perhaps closer to those required for Ebola treatment [4, 29]. Inhaled formulations of drugs used to treat COVID-19 infection can deliver the drug directly to the site of activity, avoid first-pass metabolism and have less systemic toxicity, so may be of benefit [31]. Clinically, the best constant plasma drug concentration may be at least the identified in vitro EC90; combinations of antivirals are also often preferred [30].

From a safety perspective, the ideal antiviral has an effective or inhibitory trough concentration (EC50 or IC50) well below the half-cytotoxic concentration [CC50] (Table 3) [4] and will not cause serious adverse drug events at the highest clinically effective dose (Table 4). Both the in vitro selectivity index and, especially for oral agents that will be used mostly at home, the clinical therapeutic index [4] are important. At this stage, clinical results (Table 4) are driving many decisions [11, 32].

Endpoints evolving in “learn-as-we-go” trials

Currently, the most prominent small molecule antivirals in clinical use are remdesivir [58], which has full approval for COVID-19 treatment in a number of countries (Tables 3 and 4) and molnupiravir and nirmatrelvir-ritonavir, which have either conditional approval or are in the regulatory preregistration or emergency use authorisation (EUA) phase of approval (Tables 3 and 4) [20]. Along with dexamethasone, remdesivir is often now the “standard of care” (SOC) comparator in clinical trials (Table 4). Lopinavir/ritonavir or hydroxychloroquine were common early SOCs [59], but newer meta-analyses and reviews do not support their use in COVID-19 [60,61,62]

Aside from some doubtful SOCs, comparing different agents is complex, as primary endpoints vary and have evolved with emerging understanding of COVID-19 [68]. In early trials, virological cure, preferably measured with the reverse transcription polymerase chain reaction (RT-PCR), was often the primary endpoint, but it was seldom achieved [60, 62]. Clinical primary endpoints are now more common (Table 4) and these may change during a trial (e.g. to day 29 from the original day 15 primary endpoint in the remdesivir ACCT-1 trial in severe disease [68]). Recent disappointments (e.g. for AT-527 [88] and eicosapentaenoic acid [7]) have resulted in a further rethink and/or a focus on narrower patient subgroups [89]. Drug dosages used in the treatment of patients with COVID-19 have also come under the spotlight [73, 90].

Newer COVID-19 studies are also taking place against a changing patient backdrop. Better understanding of COVID-19’s clinical course and consequent treatment protocols have contributed to significantly improved patient outcomes since the pandemic started [2, 91]. Between March 2020 and April 2021, COVID-19 mortality rates in selected US hospitals decreased from approximately 18% to 4% and length of stay from 12 to 7 days [92]. In-hospital patient demographics have also changed, with one US study reporting mild disease in almost half of those diagnosed with COVID-19 in early 2021, versus 36% during 2020 [93].

In terms of patient selection, criteria for mild, moderate and severe disease range from WHO and other ordinal scales to oxygen saturations (SpO2 %) and/or clinical descriptions [68, 69, 80]. As far as possible, disease severity in Table 4 is based on outpatient or hospital status and SpO2 as follows:

  • mild: non-hospitalised and sometimes asymptomatic, SpO2 ≥ 95%;

  • moderate: hospitalised but not needing active COVID-19 therapy or oxygen, SpO2 ≥ 94%;

  • moderate-severe: hospitalised, on supplemental oxygen but not mechanical ventilation, SpO2 ≥ 93%; or

  • severe-critical: requiring mechanical ventilation, SpO2 < 93%.

Two network meta-analyses [60, 62], which enable comparisons in the absence of head-to-head trials, assessed all-cause mortality, virological cure [60, 62], mechanical ventilation, hospital discharge and/or adverse drug events in 46 [60] and 222 [62] randomised, controlled trials reported in peer reviewed journals. Proxalutamide, nitazoxanide and remdesivir (Tables 3 and 4) improved some outcomes, as did the combination of remdesivir and baricitinib [60, 62].

A multitude of studies, but relatively few results

Hundreds of small molecule COVID-19 therapy studies are underway [1], with some preliminary efficacy and tolerability data now available (Table 5) and a range of registered trials in progress (Tables 4, 5 and 6).

Table 5 Early trial results for emerging small molecule antivirals in phase 2/3 or 3 trials in adults for treatment of COVID-19. Drugs are oral formulations, unless specified. Standard of care in most hospitalised patients is now remdesivir and/or dexamethasone
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Table 6 Small molecule antivirals with phase 2 or 2/3 COVID-19 trials in progress and/or not yet reported [72]
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Take home messages

  • Three small molecule antivirals, intravenous remdesivir, oral molnupiravir and oral nirmatrelvir-ritonavir are among the available COVID-19 treatments; other small molecule antivirals and immune modulators are urgently needed.

  • Small molecule antiviral therapies are practical pandemic options, as they are usually more easily manufactured, stable, orally available, less costly and may be repurposed from studies or use in viruses other that COVID-19, especially those closely related to SARS-CoV-2.

  • While COVID-19 treatments are a pressing need, approved medications should meet high efficacy and safety standards and there are many gaps in current knowledge.

  • Many small molecule antivirals show some promise in selected groups of COVID-19 patients, but large, randomised efficacy and safety studies of both monotherapy and combined antiviral agents are needed.

  • New small molecule antivirals have been designed with a high barrier for drug resistance; real-world data are required to confirm this. Combination therapy using small molecule antivirals with different mechanisms of action may be required to overcome drug resistance in the future.

  • Other administration routes for small molecule antivirals, including via inhalation, are a possibility.