Next Article in Journal
Comparative EPR Study on the Scavenging Effect of Methotrexate with the Isomers of Its Photoswitchable Derivative
Next Article in Special Issue
Current Status of Baricitinib as a Repurposed Therapy for COVID-19
Previous Article in Journal
Structure–Activity Relationship Analysis of Benzimidazoles as Emerging Anti-Inflammatory Agents: An Overview
Previous Article in Special Issue
Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Opinion

COVID-19: Failure of the DisCoVeRy Clinical Trial, and Now–New Hopes?

Formerly Head of the Department of Organic Chemistry (FS), University of Mons-UMONS, 7000 Mons, Belgium
Pharmaceuticals 2021, 14(7), 664; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070664
Submission received: 15 June 2021 / Revised: 4 July 2021 / Accepted: 8 July 2021 / Published: 11 July 2021
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

Abstract

:
The DisCoVeRy clinical trial aimed at the evaluation of four treatments for patients suffering from severe to critical COVID-19: Hydroxychloroquine, eventually associated with azithromycin; the combination lopinavir/ritonavir; the combination with the addition of interferon β-1a; remdesivir. The trial was discontinued due to the lack of positive results. Meanwhile, many other potential options have been considered either to target the virus itself, the interactions with the host cells, or the cytokine storm frequently observed during the infection. Several of those options are briefly reviewed. They include vaccines, small molecules, antibodies, and stem cells.

Graphical Abstract

1. Introduction

Considered as one of the worst pandemics after the Spanish flu, COVID-19 is a respiratory disease caused by a coronavirus (SARS-CoV-2), which could have emerged in humans in November–December 2019 [1,2]. First detected in Wuhan (China), SARS-CoV-2 surprised physicians and healthcare workers by the rapidity and worldwide extent of its dissemination.
Briefly, the interactions between SARS-CoV-2 and host cells are governed by the receptor-binding domain of an external glycoprotein, spike protein or S protein, of the virus and a human cellular receptor, the angiotensin-converting enzyme 2 or ACE2. S protein cleavage is then required to allow viral entry into host cells. That proteolytic cleavage is performed by the serine protease TMPRSS2 and, to a lesser extent, by the cysteine proteases cathepsin B and L (CatB/L). In the cascade of events involved in the replication of the virus, let us point out the essential role played by several viral proteins that actually constitute relevant drug targets: two polyproteins, pp1a and pp1ab, and the RNA-dependent RNA polymerase (RdRp), which are replicase proteins; the chymotrypsin-like protease 3 (3CLpro or main protease Mpro) and the papain-like protease (PLpro), which are cysteine proteases [3,4]. Importantly, human analogs of the coronavirus 3CLpro have not been reported, enabling an exceptional selectivity of its inhibitors [5].
In order to accelerate the availability of medical treatments, the logical approach was to repurpose existing drugs in order to avoid long procedures of phase studies. In that sense, the SOLIDARITY Response Fund was created, in March 2020, by the World Health Organization (WHO), the United Nations Foundation, and the Swiss Philanthropy Foundation [6]. The fund was and is still used to support adaptive international clinical trials aimed at the evaluation of “additional treatments for COVID-19 in hospitalized patients who are all receiving the local standard of care” [7,8,9,10,11]. In the beginning, four options were considered:
  • Hydroxychloroquine, eventually associated with the antibiotic azithromycin;
  • The combination lopinavir/ritonavir;
  • The combination lopinavir/ritonavir with the addition of interferon β-1a;
  • Remdesivir.

2. The DisCoVeRy Clinical Trial

DisCoVeRy [12,13] is a European study supported by the SOLIDARITY fund. It was launched by the French Institut National de la Santé Et de la Recherche Médicale (INSERM) in March 2020. In two previous publications, we gave an overview of that trial [14] and the first update of its evolution around two months after its starting date [15].
More than one year has passed now, a good time, in our opinion, to take a look at the results and perspectives.
The DisCoVeRy trial had a study start date on 22 March 2020, and, originally, it was supposed [12] to involve an estimated enrolment of 3200 patients distributed in eight countries: Belgium, France, Germany, Luxemburg, the Netherlands, Spain, Sweden, and the United Kingdom. In fact [13], most investigations were performed in France, in 40 hospitals. Five countries did not take part in that study: Germany, the Netherlands, Spain, Sweden, and the United Kingdom. Belgium and Luxemburg were poorly represented with three and two hospitals, respectively. Austria and Portugal joined the project with the participation of three and four hospitals, respectively [13]. As of 22 July 2020, 801 patients had been included in the trial, following the study chair [16].

2.1. Hydroxychloroquine, Eventually Associated with Azithromycin

The first evidence for the efficacy of hydroxychloroquine (1, Figure 1), and its structurally related analog chloroquine (2, Figure 1), in the treatment of COVID-19 were already reported by Gao et al. [17], in February 2020. A synergetic effect was expected when using hydroxychloroquine in combination with azithromycin (3, Figure 1) for preventing bacterial superinfection [18]. However, the usefulness of those drugs has been the subject of many contradictory results. Let us mention, among many others, a highly mediatized debate in France [18,19].
The modes of action of hydroxychloroquine in the treatment of COVID-19 appear to be complex and diverse, going from inhibition of the binding between the S protein and ACE2 to repression of activation of cytokines further to an increase in the pH of endosomes and lysosomes [20,21,22].
Following the U.S. National Library of Medicine of the National Institutes of Health [13,23], the study in the DisCoVeRy trial was stopped on 24 May 2020. Amazingly, a Belgian team [24] analyzed a set of data concerning 15,544 patients hospitalized in their country over a period ending on the same day! Moreover, the report concluded that a significant decrease in the number of deaths was observed in the group (4542 patients) having been treated with hydroxychloroquine.

2.2. The Combination Lopinavir/Ritonavir and the Combination with the Addition of Interferon β-1a

The combination of lopinavir (4, Figure 2) and ritonavir (5, Figure 2) is commercially available under the brand name Kaletra®. It was approved by the Food and Drug Administration (FDA) in September 2000 for the treatment of HIV-1 infection in adults and children older than 6 months [25]. In the case of COVID-19, the combination was evaluated as soon as January 2020 in a hospital in Wuhan (China). The trial involved 99 patients who did not need any respiratory support. The investigators did not find any advantage in using the combination when compared with a group of 100 patients who received standard of care alone [26]. Since then, it was demonstrated that the combination lopinavir/ritonavir targeted the 3C–like protease of SARS-CoV-2 [27].
Interferon β-1a is known to be an antiviral agent with a broad spectrum of action and there are many data [28,29,30] on its in vitro activity against coronaviruses responsible for severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). Interferon β-1a is also an essential modulator of the immune system; it is one of the first proteins released in cells in response to viral and bacterial attacks [31]. However, it was observed that SARS-CoV-2 has the capability of perturbating several pathways yielding that interferon [32,33,34], thus justifying an external supply.
Interferon β-1a, associated with lopinavir and ritonavir, exhibited some promising results in the treatment of marmosets infected by MERS-CoV [35] as well as in a small group of patients (43) hospitalized with MERS [36]. A decrease in the risk of mortality for patients with confirmed severe COVID-19 was also observed in a recent study [37].
Following the U.S. National Library of Medicine of the National Institutes of Health [13,23], both arms involving the combination lopinavir/ritonavir in the DisCoVeRy trial were stopped on 29 June 2020.

2.3. Remdesivir

Before the outbreak of SARS-CoV-2, remdesivir (6, Figure 3) was poorly studied in clinical trials. To the best of our knowledge, it had been the subject of one study only [23,38]. It was used for the treatment of people with Ebola virus disease in 2018 [38]. Mention must be made that the results were highly disappointing. Indeed, the highest number of deaths was observed in the group treated with the drug and exceeded 50% of the patients in the arm [38,39]. Consequently, it was impossible to measure any decrease in the viral load potentially induced by remdesivir.
It should be remembered that, in January 2020, the first patient suffering from COVID-19 in the United States was successfully treated with remdesivir in a hospital in the State of Washington [40]. That result was followed by the implementation of an international clinical trial in 60 locations around the world, among which 41 were in the USA. The trial, named Adaptive COVID-19 Treatment Trial (ACTT) [41], led to the conclusion, “that remdesivir (517 patients) was superior to placebo (508 patients) in shortening the time to recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection” [42]. Further to the publication of the preliminary report on 8 October 2020, the drug was approved, on 22 October 2020, by the FDA for the treatment of COVID-19 requiring hospitalization [43]. However, the approval package mentioned that clinical trials were still required by the FDA in order to administer the drug to people younger than 18, to determine side effects, and to study its efficacy against variants of SARS-CoV-2.
On the other hand, on 27 January 2021, the INSERM announced [44] that patients’ recruitment for the arm involving remdesivir in the DisCoVeRy trial had been suspended since 19 January 2021 [13]. The decision was based on an interim report describing observations obtained on a group of 389 patients that had received the drug. Nevertheless, in July 2021, the European Medicines Agency (EMA) followed the attitude of the FDA and authorized the use of remdesivir to treat COVID-19 [45].
Regarding the mode of action in the case of SARS-CoV-2, it was established that remdesivir is an inhibitor of the RNA-dependent RNA polymerase and, potentially, also of the 3C–like protease [46,47,48].

2.4. The Conclusions of the DisCoVeRy Trial

Data collected during the trial have not yet been published [18]. However, they were included in the interim WHO Solidarity trial results published on 11 February 2021 [49]. The report concluded: “These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay”.
In the case of remdesivir, results of the ACCT trial and FDA approval led the WHO to moderate its position by suggesting, “a conditional recommendation against remdesivir in hospitalized patients with COVID-19”. In the cases of hydroxychloroquine and the combination lopinavir/ritonavir, the WHO emitted “a strong recommendation against those drugs in patients with COVID-19 of any severity” [50].

3. New Hopes?

Besides the treatments initially considered by the SOLIDARITY fund, many other opportunities have emerged as potential hopes to fight COVID-19. Some of them, the most highlighted to the public, are briefly described hereafter. Evolution of the number of clinical trials registered in the U.S. National Library of Medicine of the National Institutes of Health [23] over the past 14 months for a given potential therapy, as reported in Table 1, gives a good idea of the interest it creates.
As far as possible, within each section below, drugs are listed in alphabetical order.

3.1. Vaccines

In order to prepare the immune system to efficiently respond to a SARS-CoV-2 infection, vaccination emerged as the most promising and the most privileged tool [51,52]. As indicated in Table 1, the number of studies has been continuously increasing for more than 1 year. Three strategies have been considered:
  • Use of mRNA encoding a fragment of the spike protein;
  • Use of a harmless virus that will produce spike proteins and consequently induce the immune response;
  • Use of spike proteins themselves.
Among the six vaccines actively considered in Western countries (Table 2), the Sanofi/GSK product (still in clinical trials) is the sole vaccine requiring an adjuvant, the GSK AS03 adjuvant manufactured by GSK. The adjuvant contains squalene, DL-α-tocopherol, and polysorbate [53].
Actually, experts agree on the fact that vaccination does not prevent transmission of the virus but limits the manifestations of the disease. However, many points are still awaiting some clarifications, among which duration of the immunization [54]; efficacy against variants of concern [55]; side effects at short, mid, and long term [56]; transmission rate after administration [57]; age of the population to vaccinate [58].
Nevertheless, following the Reuters agency, on 15 June 2021, at least 199 countries have started vaccinating against COVID-19 and more than 2.4 billion doses have been injected [59]. Regarding the number of doses, let us mention that, as of 20 May 2021, the European Union had secured the purchase of 4.4 billion shots. They are distributed among manufacturers as indicated in Table 2 [60]. The price paid per dose by the European Union was unveiled by an indiscretion from a Belgian politician [61].
Table 2. Vaccines ordered by the European Union (EU): quantity and price [60,61].
Table 2. Vaccines ordered by the European Union (EU): quantity and price [60,61].
Vaccine
(Manufacturer)
Type of VaccineNumber of ShotsNumber of Doses
Secured by the EU
Price per Dose in Euros (Tax Excluded)
Vaxzevria
(AstraZeneca/Oxford)
Viral vector2400 million1.78
Comirnati
(BioNTech/Pfizer)
mRNA22.4 billion12.00
CVnCoV
(CureVac)
mRNA2405 million10.00
Johnson & Johnson
(Janssen)
Viral vector1400 million7.08
Spikevax
(Moderna)
mRNA2460 million15.00
VAT00008
(Sanofi/GSK)
Protein-vector2300 million7.56

3.2. Small Molecules

It is worth mentioning that, in the frame of the DisCoVeRy trial, all evaluated small molecules were antiviral agents and they were all administered to hospitalized patients, most of them having been categorized as severely ill. At that stage of the illness, decreasing the viral load is not sufficient because, in most cases, it is an excessive immune response (cytokine storm) that is responsible for the degradation of health and eventually a fatal outcome. Therefore, three therapeutic strategies are globally possible:
  • Early inhibition of the interaction virus-host cells;
  • Action on the virus replication;
  • Late control of the cytokine storm.

3.2.1. Inhibition of the Interaction Virus-Host Cells

Camostat mesylate (7, Figure 4) is a serine protease inhibitor marketed in Japan since 2006 for the treatment of chronic pancreatitis [62,63]. Kawase et al. [64] as well as Zhou et al. [65], among others, had already observed that the drug was able to inhibit the growth of several coronaviruses, including SARS-CoV, by interacting with the spike protein. The idea was further exploited by Hoffmann et al. [3] who demonstrated that the entry of SARS-CoV-2 can be blocked by camostat mesylate in vitro and in vivo. The blockade was attributed to an interaction with the human protease TMPRSS2 producing a decrease in the activity of the enzyme. That led to the ironic title of a post in ScienceMag: “These drugs don’t target the coronavirus—they target us” [66].
In a more recent publication [67], it was reported that, in vivo, camostat mesylate is rapidly hydrolyzed to form 4-(4-guanidinobenzoyloxy) phenylacetic acid (8, Figure 4), a metabolite that is also active against SARS-CoV-2.
Hoffmann et al. [68] and Ko et al. [69] evaluated the inhibitory effect of nafamostat (9, Figure 4), a structural analog of camostat, which is a non-FDA approved serine protease inhibitor also. The drug is more efficient than camostat, in vitro, with EC50 values in the low nanomolar range.
Actually, there are few results on the efficacy of camostat and nafamostat for the treatment of COVID-19. Conclusions from large trials are impatiently awaited.
Umifenovir (10, Figure 4) is known under the brand name Arbidol® (hydrochloride salt). It is commercially available, at low cost, in Russia and China for the treatment of influenza. Umifenovir is an indole derivative exhibiting good efficacy against a large panel of viruses [70]. In the case of SARS-CoV-2 (multiplicity of infection of 0.05), Wang et al. determined an EC50 of 4.11 μM when 10 was tested in a culture of infected African green monkey kidney cells, Vero E6 (ATCC-1586) [71]. Following molecular dynamics simulations, umifenovir targets the virus by exhibiting a higher affinity than the angiotensin-converting enzyme 2 for the receptor-binding domain of the spike protein [72,73]. Because the drug is not approved by the FDA and is of limited access worldwide, the substance is poorly involved in large clinical trials and some contradictory results, obtained on small cohorts, have been reported [74,75,76].

3.2.2. Action on the Virus Replication

Favipiravir (11, Figure 5) is a pyrazinecarboxamide commercialized in Japan, under the name Avigan®, for the treatment of influenza. It acts as a prodrug: after a metabolic transformation into its 4-ribonucleoside 5′-triphosphate form (12, Figure 5), it inhibits the RNA-dependent RNA polymerase (RdRp) [77,78]. The drug exhibited an anti-SARS-CoV-2 efficacy in hamster models but at high doses [79,80]. Despite the poor availability of the drug in Western countries, favipiravir is seeing a renewed interest in recent months (see Table 1). In that way, its efficacy at an early stage of the disease is evaluated in France under the title “Home treatment of elderly patients with symptomatic SARS-CoV-2 infection (COVID-19: a multiarm, multi-stage (MAMS) randomized trial to assess the efficacy and safety of several experimental treatments to reduce the risk of hospitalization or death” [81]. A similar trial was launched in the USA and Canada, with the approval of the FDA. It aims at determining the potential of favipiravir as a chemoprophylactic agent or a treatment agent in long-term care homes [82]. The wave was followed in April 2021 by the National Institute for Health Research (UK), which added favipiravir to the panel of drugs involved in the PRINCIPLE clinical trial [83]. The study focuses on a possible treatment for patients recovering at home [84].
Ivermectin is made of two components differing by one methylene group in the side chain in position 25 of the skeleton (13 and 14; Figure 5). The substance was approved by the FDA in 1996 as an anthelmintic agent [85]. More recent works reported an effective in vitro capability of ivermectin to reduce the replication of several viruses, including SARS-CoV-2 [86,87,88,89,90].
Despite encouraging results for prophylaxis and treatment in clinical trials [91,92,93], the WHO recommends “not to use ivermectin in patients with COVID-19 except in the context of a clinical trial.” [50] The recommendation was justified by “the high degree of uncertainty in the most critical outcomes such as mortality and need for mechanical ventilation”. The substance remains, however, of interest, as revealed by the numbers indicated in Table 1.

3.2.3. Control of the Cytokine Storm

Baricitinib (15, Figure 6) is the active ingredient of Olumiant®, commercialized by Eli Lilly and Co (Indianapolis, IN, USA). It was approved by the FDA on 31 May 2018 for the treatment of rheumatoid arthritis [94,95,96]. The drug is a selective and reversible inhibitor of JAK1 and JAK2, which acts by blocking some cytokine pathways. The COV-BARRIER clinical trial [97] is a clinical trial sponsored by Incyte Co (Alapocas, DE, USA) and Eli Lilly and Co, the developers of baricitinib. In April 2021, they disclosed results indicating that baricitinib did not improve the development of COVID-19 for hospitalized patients with severe illness when compared to a group receiving a placebo and standard of care. However, the study indicated that a significant reduction of death (38%) was observed in the arm of patients receiving baricitinib in addition to corticosteroids and/or remdesivir [98,99]. Those combinations are now recommended by the US National Institutes of Health [100]. The efficacy of the combination baricitinib/remdesivir had been already observed in another clinical trial (ACTT-2) funded by the National Institute of Allergy and Infectious Diseases (USA) [101,102]. Encouraged by those results, the EMA is evaluating the possibility of including baricitinib in the potential treatments of COVID-19 in European hospitals [103].
Colchicine (16, Figure 6) is a plant alkaloid used for centuries because of its anti-inflammatory properties. It is widely prescribed in the treatment of gouty arthritis. In April 2020, it was suggested to consider colchicine as a potential drug in cases of COVID-19 [104]. Besides encouraging results demonstrating that, “colchicine reduced the length of both supplemental oxygen therapy and hospitalization”, the investigators of a small clinical trial in Brazil admitted that, “it is not possible to ensure that colchicine reduced mortality of COVID-19” [105]. On the other hand, the investigators of the Canadian trial COLCORONA [106] reported, in a preprint, that, “among non-hospitalized patients with COVID-19, colchicine reduces the composite rate of death or hospitalization” [107]. The study was performed on a group of 2235 patients receiving colchicine and a group of 2253 patients receiving a placebo. In both groups, the median age was 54 ± 10 years. It is noteworthy that the data focused on non-hospitalized people, contrary to most other trials. On 3 March 2021, the National Institute for Health Research (UK) decided to include colchicine in an arm of its PRINCIPLE clinical trial [83]. The drug might be administered to patients aged 18–64 with moderate symptoms of recent COVID-19 infection and to participants aged over 65 [108]. Despite those hopes, a statement of the chief investigators of the RECOVERY trial, published on 5 March 2021, underlined that “To date there has been no convincing evidence of the effect of colchicine on clinical outcomes in patients admitted to hospital with COVID-19” [109].
Corticosteroids are well-known for their anti-inflammatory properties [110]. Therefore, because SARS-CoV-2 can trigger a cytokine storm of the host, numerous studies have been dedicated to the evaluation of their efficiency in the treatment of COVID-19. Dexamethasone (17, Figure 6), hydrocortisone (18, Figure 6; the synthetic analog of the naturally produced cortisol), methylprednisolone (19, Figure 6), and prednisone (20, Figure 6) are among the derivatives that received the greatest interest. Among them, dexamethasone emerged as first-line therapy because of its long-lasting action. However, those corticosteroids are recommended for severely ill patients requiring respiratory support only. In addition, the use of corticosteroids was associated with a lower risk of mortality compared with the use of standard care or placebo [111]. The terms “lower risk” reflect the fact that mortality was reduced from 415/1000 for the groups receiving standard care to 328/1000 for the groups receiving corticosteroids [50]. That moderate optimism was confirmed by results collected in the RECOVERY clinical trial [112,113] sponsored by the University of Oxford (UK). Indeed, the study concluded that, “overall, 482 patients (22.9%) in the dexamethasone group (2104 patients) and 1110 patients (25.7%) in the usual care group (4321 patients) died within 28 days after randomization” [114].

3.3. Antibodies

3.3.1. Convalescent Plasma

Convalescent plasma transfusion is an option considered to fight COVID-19. However, due to the diversity of the samples, large statistical studies can hardly be realized. Many factors must be considered, among which availability of samples, quality of the blood of the donors (infection-free), transfused volumes, and titers of antibodies [115]. In addition, several mechanisms of action are possible, starting from neutralization of the virus to regulation of the immune responses [116].
A rapid survey of the literature indicates that the efficacy of convalescent plasma in the treatment of COVID-19 is based essentially on the exploitation of the high content of antibodies. Consequently, such a therapy should be of particular interest when restricted to an early administration in moderately ill patients [117,118]. Conflicting results were published when convalescent plasma was transfused to hospitalized patients [119,120]. In particular, as part of the RECOVERY clinical trial [112,113], 11,558 patients distributed in 177 UK hospitals received either standard of care alone or standard of care and convalescent plasma. The study, extended from 28 May 2020 to 15 January 2021 concluded: “in patients hospitalized with COVID-19, high-titer convalescent plasma did not improve survival or other prespecified clinical outcomes” [120]. Interestingly, no particular side effect associated with the therapy is expected, except those linked to the transfusion itself.

3.3.2. Monoclonal Antibodies

Monoclonal antibodies may be considered as therapeutic tools in the treatment of COVID-19 either at the early stage of the disease by targeting the spike protein or for hospitalized patients by modulating the cytokine storm [121,122,123].

Inhibition of the Interaction Virus-Host Cells

Bamlanivimab (LY-CoV555, LY3819253) alone and in combination (1/2; w/w) with etesevimab (LY-CoV016, JS016, LY3832479) are under evaluation in the clinical trial BLAZE-1 [124]. The trial is sponsored by Eli Lilly in collaboration with AbCellera Biologics (Vancouver, BC, Canada) and Junshi Biosciences (Shanghai, China). Preliminary results indicated that the combination only, administered as an IV infusion, is able to reduce the viral load in patients with mild to moderate COVID-19 [125]. A more detailed analysis of the data collected by the group indicated that, in fact, bamlanivimab is more efficacious than etesevimab against the Wuhan variant of SARS-CoV-2. On the other hand, etesevimab is more efficiacious (than bamlanivimab) against recent variants [125]. Nevertheless, the FDA estimated that the combination is unlikely to be active against the beta (B.1.351; South Africa) and gamma (P.1; Brazil) variants [126]. Consequently, the US government has halted distribution of the monotherapy at the end of March 2021 [127].
Regdanvimab or CT-P59 is manufactured by the Korean company Celltrion Healthcare (Incheon, Korea). The antibody exhibited an anti-SARS-CoV-2 activity, in vitro, with an IC50 value of 8.4 ng/mL against a Korean clinical isolate. In vivo studies, performed in ferrets, golden Syrian hamsters, and rhesus monkeys, confirmed the antiviral efficacy [128]. Regdanvimab appeared to be poorly active in vitro against the beta variant but animal experiments clearly indicated a decrease in the viral load in the respiratory tract of infected ferrets [129]. Celltrion Healthcare announced that, further to a Phase 1 clinical trial, regdanvimab is a safe and efficacious treatment for patients with mild COVID-19 [128]. Additional data are still awaited but the company is already working on the possibility of using that antibody in combination with others [130]. At the end of March 2021, the EMA allowed its use, but with caution [131].
REGN-COV2 is certainly the most popular combination of monoclonal antibodies used in the treatment of COVID-19 since it was administered to Donald Trump, former president of the USA, and to some politicians of his party also. REGN-COV2, a combination of casirivimab (REGN10933) and imdevimab (REGN10987), is marketed by Regeneron Pharmaceuticals (Tarrytown, NY, USA). Interim results from a study on 275 patients were published by Weinreich et al. and demonstrated the safety and efficacy of the combination [132]. Because both antibodies target two different regions of the receptor-binding domain of the spike protein, it is expected that the combination will remain efficacious against variants of SARS-CoV-2 [132,133].
Sotrovimab, also known as VIR-7831 and GSK4182136, is a monoclonal antibody developed by Vir Biotechnology, Inc (San Francisco, CA, USA) and GlaxoSmithKline (Brentford, UK). There is little literature on VIR-7831, which is an evolution of an antibody (S309) isolated from a patient who recovered from SARS in 2003 [134]. Interestingly, VIR-7831 appeared to keep its efficacy, in vitro, against the beta (B.1.351; South Africa) and gamma (P.1; Brazil) variants of SARS-CoV-2 [134]. It was granted authorization of emergency use by the FDA [135], further to interim results of the clinical trial COMET-ICE [136]. Progression of COVID-19 was reduced by 85% in a cohort of 291 patients having received the antibody when compared with the cohort (292 patients) having received a placebo. A study, BLAZE-4, aimed at evaluating the potential of a combination with bamlanivimab, is currently in progress [137].

Control of the Cytokine Storm

It was established that interleukin 6 (IL-6), a pleiotropic cytokine, is produced at a too elevated level in response to the SARS-CoV-2 infection. Sarilumab and tocilizumab are two monoclonal antibodies that are able to block the receptor of IL-6. Both of them are FDA-approved and prescribed in the treatment of rheumatoid arthritis. Because of their known efficacy, they were rapidly involved in clinical trials for patients hospitalized with severe or critical COVID-19.
Sarilumab (kevzara® by Regeneron Pharmaceuticals and Sanofi (Paris, France)) did not reach the initial expectations. No significant difference was observed between patients receiving the antibody or standard of care. Faster recovery [138] and synergetic effect with the administration of corticosteroids [139] are claimed, but, in general, no significant difference was observed between patients receiving the antibody or standard of care [138,139,140].
As soon as at the end of March 2020, the FDA authorized Genentech (South San Francisco, CA, USA), a member of the Roche group, to conduct a Phase 3 clinical trial for Tocilizumab (actemra®, licensed by Hoffmann-La Roche (Basel, Switzerland)) [141]. The study (COVACTA [142]) did not reach all expectations of the company because the antibody could decrease the time of hospitalization but did not improve the status of the patients nor reduce mortality [143]. Many other trials were initiated by Hoffmann-La Roche but, roughly, tocilizumab alone did not constitute an efficient treatment. The antibody was also evaluated in combination with remdesivir (REMDACTA [144]), but without more success [145]. A synergetic effect could be observed when patients receive tocilizumab in addition to a corticosteroid (dexamethasone) [112,113,146]. In their latest COVID-19 treatment guidelines [100], the US National Institutes of Health (NIH) recommended “using tocilizumab in combination with dexamethasone alone or dexamethasone plus remdesivir for the treatment of COVID-19 in hospitalized patients on high-flow oxygen or noninvasive ventilation who have evidence of clinical progression or increased markers of inflammation.” This statement was followed (24 June 2021) by an announcement of the FDA authorizing an emergency use of the antibody for, “the treatment of hospitalized adults and pediatric patients (2 years of age and older) who are receiving systemic corticosteroids and require supplemental oxygen” [147]. Tocilizumab emerges as one of the most investigated monoclonal antibodies, as indicated by the number of ongoing clinical trials involving it (Table 1).
Siltuximab (Sylvant®, Janssen Biotech (Horsham, PA, USA)) is a monoclonal antibody that directly blocks interleukin 6. It is poorly studied in the case of COVID-19. Results acquired with an observational cohort of 30 participants in Italy [148,149] opened some hopes but confirmations remain awaited. A combination with corticosteroids is also under study [150].
Anakinra, whose brand name is Kineret®, is manufactured by Swedish Orphan Biovitrum (Solna, Sweden) and is known for its anti-inflammatory action in the treatment of rheumatoid arthritis. The antibody, produced in Escherichia coli, is a recombinant form of the naturally occurring interleukin-1 receptor antagonist. Its usefulness in the management of the cytokine storm was recently reviewed by Metha et al. [151]. Several studies indicated that anakinra was safe and could reduce the need for ventilation as well as mortality for patients hospitalized with severe COVID-19 [152,153,154,155,156]. On the other hand, its efficacy in the treatment of mild infections is doubtful [156]. However, all authors underlined that more randomized clinical trials are required to confirm those conclusions.

3.4. Mesenchymal Stem Cells

Before the outbreak of COVID-19, the therapeutic potential of mesenchymal stem cells in the treatment of lung injuries had been already recognized [157]. The approach has the combined advantages of modulating the immune response (cytokine storm) and regenerating impaired cells [158]. In addition, mesenchymal stem cells are deprived of the angiotensin-converting enzyme 2 (ACE2) and consequently cannot be attacked by SARS-CoV-2 [3]. Several reports in the treatment of severely ill patients are promising, as reported by Mahandiratta et al. [159]. However, such a cell therapy is known to be cost-effective and time-consuming, thus limiting its applicability at large clinical stages.

4. Official Status of the Potential Treatments

The most recent official recommendations on potential treatments cited in this manuscript are gathered in Table 3. They were published by the WHO, the FDA, and the EMA.

5. Conclusions

Besides curing people at any stage of the disease, the stated goal of governments and health care professionals is to avoid saturation of the intensive care units. Consequently, most efforts were directed to the evaluation of potential treatments for severely ill patients. That led to some failures, similar to that observed in the DisCoVeRy clinical trial. Hydroxychloroquine, for example, and other antiviral agents and antibiotics [178,179] could give satisfactory results in non-severe COVID-19 cases. Otherwise, many substances used in the treatment of rheumatoid arthritis constitute a pool stimulating much interest. Monoclonal antibodies, especially tocilizumab and anakinra (Table 1), also emerged as highly promising therapeutic tools (Table 3), but they are plagued by their price. Nevertheless, today all hopes lie on the herd immunity that could be provided by a massive and worldwide vaccination.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.-R.; Zhu, Y.; Li, B.; Huang, C.-L.; et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579, 270–273. [Google Scholar] [CrossRef] [Green Version]
  2. Li, Q.; Guan, X.; Wu, P.; Wang, X.; Zhou, L.; Tong, Y.; Ren, R.; Leung, K.S.M.; Lau, E.H.Y.; Wong, J.Y.; et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med. 2020, 382, 1199–1207. [Google Scholar] [CrossRef]
  3. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krueger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020, 181, 1–10. [Google Scholar] [CrossRef]
  4. Rathnayake, A.D.; Zheng, J.; Kim, Y.; Perera, K.D.; Mackin, S.; Meyerholz, D.K.; Kashipathy, M.M.; Battaile, K.P.; Lovell, S.; Perlman, S.; et al. 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV–infected mice. Sci. Transl. Med. 2020, 12, eabc5332. [Google Scholar] [CrossRef] [PubMed]
  5. Boras, B.; Jones, R.M.; Anson, B.J.; Arenson, D.; Aschenbrenner, L.; Bakowski, M.A.; Beutler, N.; Binder, J.; Chen, E.; Eng, H.; et al. Discovery of a novel inhibitor of coronavirus 3CL protease for the potential treatment of COVID-19. BioRxiv 2021. [Google Scholar] [CrossRef]
  6. WHO. UN Foundation and Partners Launch First-of-Its-Kind COVID-19 Solidarity Response Fund. Available online: https://www.who.int/news-room/detail/13-03-2020-who-un-foundation-and-partners-launch-first-of-its-kind-covid-19-solidarity-response-fund (accessed on 15 June 2021).
  7. An International Randomized Trial of Additional Treatments for COVID-19 in Hospitalized Patients Who Are All Receiving the Local Standard of Care. Available online: https://www.who.int/publications/m/item/an-international-randomised-trial-of-additional-treatments-for-covid-19-in-hospitalised-patients-who-are-all-receiving-the-local-standard-of-care (accessed on 15 June 2021).
  8. Treatments for COVID-19: Canadian Arm of the SOLIDARITY Trial (CATCO). Available online: https://clinicaltrials.gov/ct2/show/NCT04330690 (accessed on 15 June 2021).
  9. An International Randomized Trial of Additional Treatments for COVID-19 in Hospitalized Patients Who Are All Receiving the Local Standard of Care—WHO-SOLIDARITY-GERMANY. Available online: https://clinicaltrials.gov/ct2/show/NCT04575064 (accessed on 15 June 2021).
  10. World Health Organization (WHO) COVID-19 Solidarity Trial for COVID-19 Treatments (SOLIDARITY). Available online: https://clinicaltrials.gov/ct2/show/NCT04647669 (accessed on 15 June 2021).
  11. The (Norwegian) NOR Solidarity Multicenter Trial on the Efficacy of Different Anti-Viral Drugs in SARS-CoV-2 Infected Patients. Available online: https://clinicaltrials.gov/ct2/show/NCT04321616 (accessed on 15 June 2021).
  12. Launch of a European Clinical Trial against COVID-19. Available online: https://presse.inserm.fr/en/launch-of-a-european-clinical-trial-against-covid-19/38737/ (accessed on 15 June 2021).
  13. Trial of Treatments for COVID-19 in Hospitalized Adults (DisCoVeRy). Available online: https://clinicaltrials.gov/ct2/show/NCT04315948 (accessed on 15 June 2021).
  14. Vanden Eynde, J.J. COVID-19: A brief overview of the Discovery clinical trial. Pharmaceuticals 2020, 13, 65. [Google Scholar] [CrossRef] [PubMed]
  15. Vanden Eynde, J.J. COVID-19: An update about the Discovery clinical trial. Pharmaceuticals 2020, 13, 98. [Google Scholar] [CrossRef]
  16. Ader, F.; Discovery French Trial Management Team. Protocol for the DisCoVeRy trial: Multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults. BMJ Open 2020, 10, e041437. [Google Scholar] [CrossRef]
  17. Gao, J.; Tian, Z.; Yang, X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci. Trends 2020, 14, 72–73. [Google Scholar] [CrossRef] [Green Version]
  18. Gautret, P.; Lagiera, J.-C.; Parola, P.; Hoang, V.T.; Meddeb, L.; Mailhe, M.; Doudier, B.; Courjon, J.; Giordanengo, V.; Esteves Vieira, V.E.; et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents 2020, 56, 105949. [Google Scholar] [CrossRef]
  19. Molina, J.M.; Delaugerre, C.; Le Goff, J.; Mela-Lima, B.; Ponscarme, D.; Goldwirt, L.; de Castro, N. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med. Mal. Infect. 2020, 50, 384. [Google Scholar] [CrossRef] [PubMed]
  20. Tripathy, S.; Dassarma, B.; Roy, S.; Chabalala, H.; Matsabis, M.G. A review on possible modes of action of chloroquine/hydroxychloroquine: Repurposing against SAR-CoV-2 (COVID-19) pandemic. Int. J. Antimicrob. Agents. 2020, 56, 106028. [Google Scholar] [CrossRef] [PubMed]
  21. Satarker, S.; Ahuja, T.; Banerjee, M.; Dogra, S.; Agarwal, T.; Nampoothiri, M. Hydroxychloroquine in COVID-19: Potential mechanism of action against SARS-CoV-2. Curr. Pharmacol. Rep. 2020, 6, 203–211. [Google Scholar] [CrossRef] [PubMed]
  22. Devaux, C.A.; Camoin-Jau, L.; Mege, J.-L.; Raoult, D. Can hydroxychloroquine be protective against COVID-19-associated thrombotic events? J. Microbiol. Immunol. Infect. 2021, 54, 37–45. [Google Scholar] [CrossRef] [PubMed]
  23. U.S. National Library of Medicine-Clinical Trials. Available online: https://clinicaltrials.gov/ct2/home (accessed on 15 June 2021).
  24. Catteau, L.; Dauby, N.; Montourcy, M.; Bottieau, E.; Hautekiet, J.; Goetghebeur, E.; van Ierssel, S.; Duysburgh, E.; Van Oyen, H.; Whyndham-Thomas, C.; et al. Low-dose hydroxychloroquine therapy and mortality in hospitalized patients with COVID-19: A nationwide observational study of 8075 participants. Int. J. Antimicrob. Agents 2020, 56, 106144. [Google Scholar] [CrossRef]
  25. Center for Drug Evaluation and Research. Application Numbers 21–226 and 21–251. Approval Letter. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-226_Kaletra_Approv.pdf (accessed on 15 June 2021).
  26. Cao, B.; Wang, Y.; Wen, D.; Liu, W.; Wang, J.; Fan, G.; Ruan, L.; Song, B.; Cai, Y.; Wei, M.; et al. A trial of Lopinavir–Ritonavir in adults hospitalized with severe Covid-19. N. Engl. J. Med. 2020, 382, 1787–1799. [Google Scholar] [CrossRef]
  27. Nutho, B.; Mahalapbutr, P.; Hengphasatporn, K.; Pattaranggoon, N.C.; Simanon, N.; Shigeta, Y.; Hannongbua, S.; Rungrotmongkol, T. Why are lopinavir and ritonavir effective against the newly emerged coronavirus 2019? Atomistic insights into the inhibitory mechanisms. Biochemistry 2020, 59, 1769–1779. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Spiegel, M.; Pichlmair, A.; Mühlberger, E.; Haller, O.; Weber, F. The antiviral effect of interferon-beta against SARS-Coronavirus is not mediated by MxA protein. J. Clin. Virol. 2004, 30, 211–213. [Google Scholar] [CrossRef]
  29. Hensley, L.E.; Fritz, E.A.; Jahrling, P.B.; Karp, C.L.; Huggins, J.W.; Geisbert, T.W. Interferon-β 1a and SARS coronavirus replication. Emerg. Infect. Dis. 2004, 10, 317–319. [Google Scholar] [CrossRef]
  30. Hart, B.; Dyall, J.; Postnikova, E.; Zhou, H.; Kindrachuk, J.; Johnson, R.F.; Olinger, G.; Frieman, M.B.; Holbrook, M.R.; Jahrling, P.B.; et al. Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J. Gen. Virol. 2014, 95, 571–577. [Google Scholar] [CrossRef]
  31. González-Navajas, J.M.; Lee, J.; David, M.; Raz, E. Immunomodulatory functions of type I interferons. Nat. Rev. Immunol. 2012, 12, 125–135. [Google Scholar] [CrossRef] [Green Version]
  32. Schreiber, G. The role of type I interferons in the pathogenesis and treatment of COVID-19. Front. Immunol. 2020, 11, 595739. [Google Scholar] [CrossRef]
  33. Abdolvahab, M.H.; Moradi-kalbolandi, S.; Zarei, M.; Bose, D.; Majidzadeh-A, K.; Farahmand, L. Potential role of interferons in treating COVID-19 patients. Int. Immunopharmacol. 2021, 90, 107171. [Google Scholar] [CrossRef]
  34. Monk, P.D.; Marsden, R.J.; Tear, V.J.; Brookes, J.; Batten, T.N.; Mankowski, M.; Gabbay, F.J.; Davies, D.E.; Holgate, S.T.; Ho, L.-P.; et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir. Med. 2021, 9, 196–206. [Google Scholar] [CrossRef]
  35. Chan, J.F.-W.; Yao, Y.; Yeung, M.-L.; Deng, W.; Bao, L.; Jia, L.; Li, F.; Xiao, C.; Gao, H.; Yu, P.; et al. Treatment with Lopinavir/Ritonavir or Interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J. Infect. Dis. 2015, 212, 1904–1913. [Google Scholar] [CrossRef]
  36. Arabi, Y.M.; Asiri, A.Y.; Assiri, A.M.; Balkhy, H.H.; Bshabshe, A.A.; Jeraisy, M.A.; Mandourah, Y.; Azzam, M.H.A.; Eshaq, A.M.B.; Johani, S.A.; et al. Interferon beta-1b and lopinavir–ritonavir for Middle East respiratory syndrome. N. Engl. J. Med. 2020, 383, 1645–1656. [Google Scholar] [CrossRef]
  37. Baghaei, P.; Dastan, F.; Marjani, M.; Moniri, A.; Abtahian, Z.; Ghadimi, S.; Valizadeh, M.; Heshmatnia, J.; Mirenayat, M.S.; Abedini, A.; et al. Combination therapy of IFNβ1 with lopinavir–ritonavir, increases oxygenation, survival and discharging of severe COVID-19 infected inpatients. Int. Immunol. 2021, 92, 107329. [Google Scholar] [CrossRef]
  38. Investigational Therapeutics for the Treatment of People with Ebola Virus Disease. Available online: https://clinicaltrials.gov/ct2/show/results/NCT03719586 (accessed on 15 June 2021).
  39. Mulangu, S.; Dodd, L.E.; Davey, R.T., Jr.; Tshiani Mbaya, O.; Proschan, M.; Mukadi, D.; Lusakibanza Manzo, M.; Nzolo, D.; Tshomba Oloma, A.; Ibanda, A.; et al. A randomized, controlled trial of Ebola virus disease therapeutics. N. Engl. J. Med. 2019, 381, 2293–2303. [Google Scholar] [CrossRef] [PubMed]
  40. Holshue, M.L.; DeBolt, C.; Lindquist, S.; Lofy, K.H.; Wiesman, J.; Bruce, H.; Spitters, C.; Ericson, K.; Wilkerson, S.; Tural, A.; et al. First Case of 2019 Novel Coronavirus in the United States. N. Engl. J. Med. 2020, 382, 929–936. [Google Scholar] [CrossRef]
  41. Adaptive COVID-19 Treatment Trial (ACTT). Available online: https://clinicaltrials.gov/ct2/show/NCT04280705 (accessed on 15 June 2021).
  42. Beigel, J.H.; Tomashek, K.M.; Dodd, L.E.; Mehta, A.K.; Zingman, B.S.; Kalil, A.C.; Hohmann, E.; Chu, H.Y.; Luetkemeyer, A.; Kline, S.; et al. Remdesivir for the treatment of Covid-19—Final report. N. Engl. J. Med. 2020, 383, 1813–1826. [Google Scholar] [CrossRef] [PubMed]
  43. Center for Drug Evaluation and Research. Approval Package. Application Number 214787Orig1s000. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/214787Orig1s000Approv.pdf (accessed on 15 June 2021).
  44. Press Release—INSERM Press Room: Discovery Stops Testing Remdesivir against Covid-19 for Lack of Evidence of Its Efficacy. Available online: https://presse.inserm.fr/en/discovery-stops-testing-remdesivir-against-covid-19-for-lack-of-evidence-of-its-efficacy/42034/ (accessed on 15 June 2021).
  45. European Commission Authorises First Treatment against COVID-19. Available online: https://ec.europa.eu/commission/presscorner/detail/en/mex_20_1266 (accessed on 15 June 2021).
  46. Kokic, G.; Hillen, H.S.; Tegunov, D.; Dienemann, C.; Seitz, F.; Schmitzova, J.; Farnung, L.; Siewert, A.; Höbartner, C.; Cramer, P. Mechanism of SARS-CoV-2 polymerase stalling by remdesivir. Nat. Commun. 2021, 12, 279. [Google Scholar] [CrossRef]
  47. Cao, Y.C.; Deng, Q.X.; Dai, S.X. Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence. Travel Med. Infect. Dis. 2020, 35, 101647. [Google Scholar] [CrossRef] [PubMed]
  48. Nguyen, H.L.; Thai, N.Q.; Truong, D.T.; Li, M.S. Remdesivir strongly binds to both RNA-dependent RNA polymerase and Main protease of SARS-CoV-2: Evidence from molecular simulations. J. Phys. Chem. B 2020, 124, 11337–11348. [Google Scholar] [CrossRef] [PubMed]
  49. WHO Solidarity Trial Consortium. Repurposed antiviral drugs for Covid-19—Interim WHO Solidarity trial results. N. Engl. J. Med. 2021, 384, 497–511. [Google Scholar] [CrossRef] [PubMed]
  50. Therapeutics and COVID-19. Living Guideline. 31 March 2021. Available online: https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2021.1 (accessed on 15 June 2021).
  51. Kumar, A.; Kumar, A. Mucosal and transdermal vaccine delivery strategies against SARS-CoV-2. Drug Deliv. Transl. Res. 2021. [Google Scholar] [CrossRef]
  52. Olliaro, P.; Torreele, E.; Vaillant, M. COVID-19 vaccine efficacy and effectiveness—The elephant (not) in the room. Lancet Microbe 2021. [Google Scholar] [CrossRef]
  53. Francica, J.R.; Flynn, B.J.; Foulds, K.E.; Noe, A.T.; Werner, A.P.; Moore, I.N.; Gagne, M.; Johnston, T.S.; Tucker, C.; Davis, R.L. Vaccination with SARS-CoV-2 spike protein and AS03 adjuvant induces rapid anamnestic antibodies in the lung and protects against virus challenge in nonhuman primates. BioRxiv 2021. [Google Scholar] [CrossRef]
  54. Blain, H.; Tuaillon, E.; Gamon, L.; Pisoni, A.; Miot, S.; Picot, M.-C.; Bousquet, J. Spike antibody levels of nursing home residents with or without prior COVID-19 3 weeks after a single BNT162b2 vaccine dose. JAMA 2021, 325, 1898–1899. [Google Scholar] [CrossRef]
  55. Edara, V.V.; Hudson, W.H.; Xie, X.; Ahmed, R.; Suthar, M.S. Neutralizing antibodies against SARS-CoV-2 variants after infection and vaccination. JAMA 2021, 325, 1896–1898. [Google Scholar] [CrossRef]
  56. Menni, C.; Klaser, K.; May, A.; Polidori, L.; Capdevila, J.; Louca, P.; Sudre, C.H.; Nguyen, L.H.; Drew, D.A.; Merino, J. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: A prospective observational study. Lancet Infect. Dis. 2021. [Google Scholar] [CrossRef]
  57. Keehner, J.; Horton, L.E.; Pfeffer, M.A.; Longhurst, C.A.; Schooley, R.T.; Currier, J.S.; Abeles, S.R.; Torriani, F.J. SARS-CoV-2 infection after vaccination in health care workers in California. N. Engl. J. Med. 2021, 348, 18. [Google Scholar] [CrossRef]
  58. Zimet, G.D.; Silverman, R.D.; Fortenberry, J.D. Coronavirus disease 2019 and vaccination of children and adolescents: Prospects and challenges. J. Pediatr. 2021, 231, 254–258. [Google Scholar] [CrossRef] [PubMed]
  59. COVID-19. Vaccination Tracker. Available online: https://graphics.reuters.com/world-coronavirus-tracker-and-maps/vaccination-rollout-and-access/ (accessed on 15 June 2021).
  60. Safe COVID-19 Vaccines for Europeans. Available online: https://ec.europa.eu/info/live-work-travel-eu/coronavirus-response/safe-covid-19-vaccines-europeans_en (accessed on 15 June 2021).
  61. Dyer, O. Covid-19: Countries are learning what others paid for vaccines. BMJ 2021, 372, n281. [Google Scholar] [CrossRef]
  62. FOIPAN® Tablets 100 mg. Available online: http://www.shijiebiaopin.net/upload/product/201272318373223.PDF (accessed on 15 June 2021).
  63. Motoo, Y. Antiproteases in the treatment of chronic pancreatitis. JOP J. Pancreas 2007, 8, 533–537. [Google Scholar]
  64. Kawase, M.; Shirato, K.; van der Hoek, L.; Taguchi, F.; Matsuyama, S. Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J. Virol. 2012, 86, 6537–6545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Zhou, Y.; Vedantham, P.; Lu, K.; Agudelo, J.; Carrion, R., Jr.; Nunneley, J.W.; Barnard, D.; Phoelmann, L.; McKerrow, J.H.; Renslo, A.R.; et al. Protease inhibitors targeting coronavirus and filovirus entry. Antivir. Res. 2015, 116, 76–84. [Google Scholar] [CrossRef] [PubMed]
  66. Kupferschmidt, K. These drugs don’t target the coronavirus—They target us. ScienceMag 2020. Available online: https://www.sciencemag.org/news/2020/04/these-drugs-don-t-target-coronavirus-they-target-us (accessed on 15 June 2021). [CrossRef]
  67. Hoffmann, M.; Hofmann-Winkler, H.; Smith, J.C.; Krueger, N.; Arora, P.; Sørensen, L.K.; Søgaard, O.S.; Hasselstrøm, J.B.; Winkler, M.; Hempel, T.; et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine 2021, 65, 103255. [Google Scholar] [CrossRef]
  68. Hoffmann, M.; Schroeder, S.; Kleine-Weber, H.; Müller, M.A.; Drosten, C.; Pöhlmann, S. Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19. Antimicrob. Agents Chemother. 2020, 64, e00754-20. [Google Scholar] [CrossRef] [Green Version]
  69. Ko, M.; Jeon, S.; Ryu, W.-S.; Kim, S. Comparative analysis of antiviral efficacy of FDA-approved drugs against SARS-CoV-2 in human lung cells. J. Med. Virol. 2020, 93, 1403–1408. [Google Scholar] [CrossRef]
  70. Blaysing, J.; Polyak, S.J.; Pécheur, E.-I. Arbidol as a braod spectrum antiviral: An update. Antivir. Res. 2014, 107, 84–94. [Google Scholar] [CrossRef]
  71. Wang, X.; Cao, R.; Zhang, H.; Liu, J.; Xu, M.; Hu, H.; Li, Y.; Zhao, L.; Li, W.; Sun, X.; et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discov. 2020, 6, 28. [Google Scholar] [CrossRef]
  72. Vankadari, N. Arbidol: An antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein. Int. J. Antimicrob. Agents 2020, 56, 105998. [Google Scholar] [CrossRef]
  73. Padhi, A.K.; Seal, A.; Khan, J.M.; Ahamed, M.; Tripathi, T. Unraveling the mechanism of arbidol binding and inhibition of SARS-CoV-2: Insights from atomistic simulations. Eur. J. Pharmacol. 2021, 894, 173836. [Google Scholar] [CrossRef] [PubMed]
  74. Nojomi, M.; Yassin, Z.; Keyvani, H.; Makiani, M.J.; Roham, M.; Laali, A.; Dehghan, N.; Navaei, M.; Ranjbar, M. Effect of arbidol (umifenovir) on COVID-19: A randomized controlled trial. BMC Infect. Dis. 2020, 20, 954. [Google Scholar] [CrossRef] [PubMed]
  75. Huang, D.; Yu, H.; Wang, T.; Yang, H.; Yao, R.; Liang, Z. Efficacy and safety of umifenovir for coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. J. Med. Virol. 2021, 93, 481–490. [Google Scholar] [CrossRef] [PubMed]
  76. Khodashahi, R.; Naderi, H.; Bojdy, A.; Heydari, A.A.; Sani, A.T.; Ghabouli, M.J.; Sarvghad, M.R.; Nateghi, M.H.; Arian, M.; Jahanian, S. Comparison the effect of arbidol plus hydroxychloroquine vs. hydroxychloroquine alone in treatment of COVID-19 disease: A randomized clinical trial. Curr. Respir. Med. Rev. 2021, 16, 252–262. [Google Scholar] [CrossRef]
  77. Sangawa, H.; Komeno, T.; Nishikawa, H.; Yoshida, A.; Takahashi, K.; Nomura, N.; Furuta, Y. Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. Antimicrob. Agents Chemother. 2013, 57, 5202–5208. [Google Scholar] [CrossRef] [Green Version]
  78. Shannon, A.; Selisko, B.; Le, N.-T.-T.; Huchting, J.; Touret, F.; Piorkowski, G.; Fattorini, V.; Ferron, F.; Decroly, E.; Meier, C.; et al. Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis. Nat. Commun. 2020, 11, 4682. [Google Scholar] [CrossRef]
  79. Kaptein, S.J.F.; Jacobs, S.; Langendriesa, L.; Seldeslachts, L.; ter Horst, S.; Liesenborghs, L.; Hens, B.; Vergote, V.; Heylen, E.; Barthelemy, K.; et al. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas hydroxychloroquine lacks activity. Proc. Natl. Acad. Sci. USA 2020, 117, 26955–26965. [Google Scholar] [CrossRef]
  80. Driouich, J.-S.; Cochin, M.; Lingas, G.; Moureau, G.; Touret, F.; Petit, P.-R.; Piorkowski, G.; Barthélémy, K.; Laprie, C.; Coutard, B.; et al. Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model. Nat. Commun. 2021, 12, 1735. [Google Scholar] [CrossRef]
  81. EU Clinical Trials Register: EudraCT Number: 2020-001435-27. Available online: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001435-27/FR (accessed on 15 June 2021).
  82. Control of COVID-19 Outbreaks in Long Term Care. Available online: https://clinicaltrials.gov/ct2/show/NCT04448119 (accessed on 15 June 2021).
  83. Principle. Platform Randomized Trial of Treatments in the Community for Epidemic and Pandemic Illnesses. Available online: https://www.principletrial.org/ (accessed on 15 June 2021).
  84. National Institute for Health Research. Favipiravir. Available online: https://www.nihr.ac.uk/news/favipiravir-to-be-investigated-as-a-possible-covid-19-treatment-for-at-home-recovery-in-the-principle-trial/27426 (accessed on 15 June 2021).
  85. Center for Drug Evaluation and Research. Approval Package for Application Number 050742. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/050742ap.pdf (accessed on 15 June 2021).
  86. Wagstaff, K.M.; Sivakumaran, H.; Heaton, S.M.; Harrich, D.; Jans, D.A. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem. J. 2012, 443, 851–856. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Lundberg, L.; Pinkham, C.; Baer, A.; Amaya, M.; Narayanan, A.; Wagstaff, K.M.; Jans, D.A.; Kehn-Hall, K. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antivir. Res. 2013, 100, 662–672. [Google Scholar] [CrossRef] [PubMed]
  88. Tay, M.Y.; Fraser, J.E.; Chan, W.K.; Moreland, N.J.; Rathore, A.P.; Wang, C.; Vasudevan, S.G.; Jans, D.A. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antivir. Res. 2013, 99, 301–306. [Google Scholar] [CrossRef] [PubMed]
  89. Götz, V.; Magar, L.; Dornfeld, D.; Giese, S.; Pohlmann, A.; Höper, D.; Kong, B.-W.; Jans, D.A.; Beer, M.; Haller, O.; et al. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci. Rep. 2016, 6, 23138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Caly, L.; Druce, J.D.; Catton, M.G.; Jans, D.A.; Wagstaff, K.M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir. Res. 2020, 178, 104787. [Google Scholar] [CrossRef]
  91. Chaccour, C.; Casellas, A.; Blanco-Di Matteo, A.; Pineda, I.; Fernandez-Montero, A.; Ruiz-Castillo, P.; Richardson, M.-A.; Rodríguez-Mateos, M.; Jordan-Iborra, C.; Brew, J.; et al. The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine 2021, 32, 100720. [Google Scholar] [CrossRef] [PubMed]
  92. Ivermectin, Aspirin, Dexamethasone and Enoxaparin as Treatment of COVID-19 (IDEA). Available online: https://clinicaltrials.gov/ct2/show/NCT04425863 (accessed on 15 June 2021).
  93. Prophylactic Ivermectin in Covid-19 Contacts. Available online: https://clinicaltrials.gov/ct2/show/NCT04422561 (accessed on 15 June 2021).
  94. Center for Drug Evaluation and Research. Approval Package for Application Number 207924Orig1s000. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000Approv.pdf (accessed on 15 June 2021).
  95. Smolen, J.S.; Genovese, M.C.; Takeuchi, T.; Hyslop, D.L.; Macias, W.L.; Rooney, T.; Chen, L.; Dickson, C.L.; Riddle Camp, J.; Cardillo, T.E.; et al. Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment. J. Rheumatol. 2019, 46, 7–18. [Google Scholar] [CrossRef] [Green Version]
  96. Mayence, A.; Vanden Eynde, J.J. Baricitinib: A 2018 novel FDA-approved small molecule inhibiting JAK kinases. Pharmaceuticals 2019, 12, 37. [Google Scholar] [CrossRef] [Green Version]
  97. A Study of Baricitinib (LY3009104) in Participants with COVID-19 (COV-BARRIER). Available online: https://clinicaltrials.gov/ct2/show/NCT04421027 (accessed on 15 June 2021).
  98. Lilly and Incyte Announce Results from the Phase 3 COV-BARRIER Study of Baricitinib in Hospitalized COVID-19 Patients. Available online: https://investor.lilly.com/news-releases/news-release-details/lilly-and-incyte-announce-results-phase-3-cov-barrier-study (accessed on 15 June 2021).
  99. Marconi, V.C.; Ramanan, A.V.; de Bono, S.; Kartman, C.E.; Krishnan, V.; Liao, R.; Piruzeli, M.L.B.; Goldman, J.D.; Alatorre-Alexander, J.; de Cassia Pellegrini, R. Baricitinib plus standard of care for hospitalized adults with COVID-19. MedRxiv 2021. [Google Scholar] [CrossRef]
  100. The COVID-19 Treatment Guidelines Panel’s Statement on Baricitinib for the Treatment of Adults with COVID-19. Available online: https://www.covid19treatmentguidelines.nih.gov/statement-on-baricitinib/ (accessed on 15 June 2021).
  101. Adaptive COVID-19 Treatment Trial 2 (ACTT-2). Available online: https://clinicaltrials.gov/ct2/show/NCT04401579 (accessed on 15 June 2021).
  102. Kalil, A.C.; Patterson, T.F.; Mehta, A.K.; Tomashek, K.M.; Wolfe, C.R.; Ghazaryan, V.; Marconi, V.C.; Ruiz-Palacios, G.-M.; Hsieh, L.; Kline, S.; et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N. Engl. J. Med. 2021, 384, 795–807. [Google Scholar] [CrossRef]
  103. EMA Starts Evaluating Use of Olumiant in Hospitalised COVID-19 Patients Requiring Supplemental Oxygen. Available online: https://www.ema.europa.eu/en/news/ema-starts-evaluating-use-olumiant-hospitalised-covid-19-patients-requiring-supplemental-oxygen (accessed on 15 June 2021).
  104. Deftereos, S.; Giannopoulos, G.; Vrachatis, D.A.; Siasos, G.; Giotaki, S.G.; Cleman, M.; Dangas, G.; Stefanadis, C. Colchicine as a potent anti-inflammatory treatment in COVID-19: Can we teach an old dog new tricks? Eur. Heart J. Cardiovasc. Pharmacother. 2020, 6, 255. [Google Scholar] [CrossRef]
  105. Lopes, M.I.; Bonjorno, L.P.; Giannini, M.C.; Amaral, N.B.; Menezes, P.I.; Dib, S.M.; Gigante, S.L.; Benatti, M.N.; Rezek, U.C.; Emrich-Filho, L.L.; et al. Beneficial effects of colchicine for moderate to severe COVID-19: A randomised, double-blinded, placebo-controlled clinical trial. RMD Open 2021, 7, e001455. [Google Scholar] [CrossRef]
  106. Colchicine Coronavirus SARS-CoV2 Trial (COLCORONA) (COVID-19). Available online: https://clinicaltrials.gov/ct2/show/NCT04322682 (accessed on 15 June 2021).
  107. Tardif, J.-C.; Bouabdallaoui, N.; L’Allier, P.L.; Gaudet, D.; Shah, B.; Pillinger, M.H.; Lopez-Sendon, J.; da Luz, P.; Verret, L.; Audet, S.; et al. Efficacy of colchicine in non-hospitalized patients with COVID-19. MedRxiv 2021, 21250494. [Google Scholar] [CrossRef]
  108. PRINCIPLE COVID-19 Treatments Trial Widens to Under 50s and Adds Colchicine. Available online: https://www.principletrial.org/news/principle-covid-19-treatments-trial-widens-to-under-50s-adds-colchicine (accessed on 15 June 2021).
  109. RECOVERY Trial Closes Recruitment to Colchicine Treatment for Patients Hospitalised with COVID-19. Available online: https://www.recoverytrial.net/news/recovery-trial-closes-recruitment-to-colchicine-treatment-for-patients-hospitalised-with-covid-19 (accessed on 15 June 2021).
  110. Barnes, P.J. Inhaled corticosteroids. Pharmaceuticals 2010, 3, 514–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19. A meta-analysis. JAMA 2020, 324, 1330–1341. [Google Scholar] [CrossRef] [PubMed]
  112. Randomised Evaluation of COVID-19 Therapy (RECOVERY). Available online: https://clinicaltrials.gov/ct2/show/NCT04381936 (accessed on 15 June 2021).
  113. RECOVERY. Randomised Evaluation of COVID-19 Therapy. Available online: https://www.recoverytrial.net/ (accessed on 15 June 2021).
  114. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N. Engl. J. Med. 2021, 384, 693–704. [Google Scholar] [CrossRef]
  115. Katz, L.M. (A little) Clarity on convalescent plasma for Covid-19. N. Engl. J. Med. 2021, 384, 666–668. [Google Scholar] [CrossRef] [PubMed]
  116. Rojas, M.; Rodriguez, Y.; Monsalve, D.M.; Acosta-Ampudia, Y.; Camacho, B.; Gallo, J.E.; Rojas-Villarraga, A.; Ramirez-Santana, C.; Diaz-Coronado, J.C.; Manrique, R.; et al. Convalescent plasma in COVID-19: Possible mechanisms of action. Autoimmun. Rev. 2020, 19, 102554. [Google Scholar] [CrossRef]
  117. Libster, R.; Pérez Marc, G.; Wappner, D.; Coviello, S.; Bianchi, A.; Braem, V.; Esteban, I.; Caballero, M.T.; Wood, C.; Berrueta, M.; et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N. Engl. J. Med. 2021, 384, 610–618. [Google Scholar] [CrossRef]
  118. Franchini, M.; Liumbruno, G.M. Convalescent plasma for the treatment of severe COVID-19. Biol. Targets Ther. 2021, 15, 31–38. [Google Scholar] [CrossRef]
  119. Duan, K.; Liu, B.; Li, C.; Zhang, H.; Yu, T.; Qu, J.; Zhou, M.; Chen, L.; Meng, S.; Hu, Y.; et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc. Natl. Acad. Sci. USA 2020, 117, 9490–9496. [Google Scholar] [CrossRef] [Green Version]
  120. The RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): A randomised controlled, open-label, platform trial. Lancet 2021, 397, 2024–2025. [Google Scholar] [CrossRef]
  121. Scourfield, D.O.; Reed, S.G.; Quastel, M.; Alderson, J.; Bart, V.M.T.; Crespo, A.T.; Jones, R.; Pring, E.; Richter, F.C. The Oxford-Cardiff COVID-19Literature Consortium and Burnell, S.E.A. The role and uses of antibodies in COVID-19infections: A living review. Oxf. Open Immunol. 2021, 2, iqab003. [Google Scholar] [CrossRef]
  122. Taylor, P.C.; Adams, A.C.; Hufford, M.M.; de la Torre, I.; Winthrop, K.; Gottlieb, R.L. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat. Rev. Immunol. 2021, 21, 382–393. [Google Scholar] [CrossRef]
  123. Deb, P.; Molla, M.A.; Saif-Ur-Rahman, K.M. An update to monoclonal antibody as therapeutic option against COVID-19. Biosaf. Health 2021, 3, 87–91. [Google Scholar] [CrossRef] [PubMed]
  124. A Study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in Participants with Mild to Moderate COVID-19 Illness (BLAZE-1). Available online: https://www.clinicaltrials.gov/ct2/show/NCT04427501 (accessed on 15 June 2021).
  125. Gottlieb, R.L.; Nirula, A.; Chen, P.; Boscia, J.; Heller, B.; Morris, J.; Huhn, G.; Cardona, J.; Mocherla, B.; Stosor, V.; et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19. A randomized clinical trial. JAMA 2021, 325, 632–644. [Google Scholar] [CrossRef] [PubMed]
  126. Fact Sheet for Health Care Providers. Emergency Use Authorization (EUA) for Bamlanivimab and Etesevimab. Available online: https://www.fda.gov/media/145802/download (accessed on 29 May 2021).
  127. U.S. Stops Distribution of Lilly’s COVID-19 Therapy due to Impact of Variants. Available online: https://www.reuters.com/article/health-coronavirus-lilly-idUSL4N2LN3TS (accessed on 15 June 2021).
  128. Kim, C.; Ryu, D.-K.; Lee, J.; Kim, Y.-I.; Seo, J.-M.; Kim, Y.-G.; Jeong, J.-H.; Kim, M.; Kim, J.-I.; Kim, P.; et al. A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein. Nat. Commun. 2021, 12, 288. [Google Scholar] [CrossRef] [PubMed]
  129. Ryu, D.-K.; Song, R.; Kim, M.; Kim, Y.-I.; Kim, C.; Kim, J.-I.; Kwon, K.-S.; Tijsma, A.S.L.; Nuijten, P.M.; van Baalen, C.A.; et al. Therapeutic effect of CT-P59 against SARS-CoV-2 South African variant. BioRxiv 2021. [Google Scholar] [CrossRef]
  130. Celltrion Confirms Neutralising Potency Against Emerging SARS-CoV-2 Variants with Anti-COVID-19 Monoclonal Antibody Treatment Regdanvimab (CT-P59). Available online: https://www.celltrionhealthcare.com/en-us/board/newsdetail?modify_key=482&pagenumber=1&keyword=&keyword_type= (accessed on 15 June 2021).
  131. EMA Issues Advice on Use of Regdanvimab for Treating COVID-19. Available online: https://www.ema.europa.eu/en/news/ema-issues-advice-use-regdanvimab-treating-covid-19 (accessed on 15 June 2021).
  132. Weinreich, D.M.; Sivapalasingam, S.; Norton, T.; Ali, S.; Gao, H.; Bhore, R.; Musser, B.J.; Soo, Y.; Rofail, D.; Im, J.; et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N. Engl. J. Med. 2021, 384, 238–251. [Google Scholar] [CrossRef]
  133. Fact Sheet for Health Care Providers. Emergency Use Authorization (EUA) for REGEN-COV™ (Casirivimab with Imdevimab). Available online: https://www.fda.gov/media/145611/download (accessed on 15 June 2021).
  134. Cathcart, A.L.; Havenar-Daughton, C.; Lempp, F.A.; Ma, D.; Schmid, M.; Agostini, M.L.; Guarino, B.; Di iulio, J.; Rosen, L.; Tucker, H.; et al. The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. BioRxiv Immunol. 2021. [Google Scholar] [CrossRef]
  135. Fact Sheet for Health Care Providers. Emergency Use Authorization (EUA) for Sotrovimab. Available online: https://www.fda.gov/media/149534/download (accessed on 15 June 2021).
  136. VIR-7831 for the Early Treatment of COVID-19 in Outpatients (COMET-ICE). Available online: https://clinicaltrials.gov/ct2/show/NCT04545060 (accessed on 15 June 2021).
  137. A Study of Immune System Proteins in Participants with Mild to Moderate COVID-19 Illness (BLAZE-4). Available online: https://clinicaltrials.gov/ct2/show/NCT04634409 (accessed on 15 June 2021).
  138. Della-Torre, E.; Campochiaro, C.; Cavalli, G.; De Luca, G.; Napolitano, A.; La Marca, S.; Boffini, N.; Da Prat, V.; Di Terlizzi, G.; Lanzillotta, M.; et al. Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: An open-label cohort study. Ann. Rheum. Dis. 2020, 79, 1277–1285. [Google Scholar] [CrossRef] [PubMed]
  139. Sivapalasingam, S.; Lederer, D.J.; Bhore, R.; Hajizadeh, N.; Criner, G.; Hossain, R.; Mahmood, A.; Giannelou, A.; Somersan-Karakaya, S.; O’Brien, M.; et al. A randomized placebo-controlled trial of sarilumab in hospitalized patients with Covid-19. MedRxiv 2021. [Google Scholar] [CrossRef]
  140. Lescure, F.-X.; Honda, H.; Fowler, R.A.; Lazar, J.S.; Shi, G.; Wung, P.; Patel, N.; Hagino, O. Sarilumab in patients admitted to hospital with severe or critical COVID-19: A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir. Med. 2021, 9, 522–532. [Google Scholar] [CrossRef]
  141. FDA Approves Phase III Clinical Trial of Tocilizumab for COVID-19 Pneumonia. Available online: https://www.cancernetwork.com/view/fda-approves-phase-iii-clinical-trial-tocilizumab-covid-19-pneumonia (accessed on 15 June 2021).
  142. A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients with Severe COVID-19 Pneumonia (COVACTA). Available online: https://clinicaltrials.gov/ct2/show/NCT04320615 (accessed on 15 June 2021).
  143. Genentech Provides an Update on the Phase III COVACTA Trial of Actemra in Hospitalized Patients with Severe COVID-19 Associated Pneumonia. Available online: https://www.gene.com/media/press-releases/14867/2020-07-28/genentech-provides-an-update-on-the-phas (accessed on 15 June 2021).
  144. A Study to Evaluate the Efficacy and Safety of Remdesivir Plus Tocilizumab Compared with Remdesivir Plus Placebo in Hospitalized Participants with Severe COVID-19 Pneumonia (REMDACTA). Available online: https://clinicaltrials.gov/ct2/show/NCT04409262 (accessed on 15 June 2021).
  145. Roche Provides Update on the Phase III REMDACTA Trial of Actemra/RoActemra Plus Veklury in Patients with Severe COVID-19 Pneumonia. Available online: https://www.roche.com/media/releases/med-cor-2021-03-11.htm (accessed on 15 June 2021).
  146. The RECOVERY Collaborative Group. Tocilizumab in Patients Admitted to Hospital with COVID-19 (RECOVERY): Preliminary Results of a Randomised, Controlled, Open-Label, Platform Trial. Lancet 2021, 397, 1637–1645. [Google Scholar] [CrossRef]
  147. Coronavirus (COVID-19) Update: FDA Authorizes Drug for Treatment of COVID-19. 24 June 2021. Available online: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-treatment-covid-19 (accessed on 3 July 2021).
  148. Gritti, G.; Raimondi, F.; Bottazzi, B.; Ripamonti, D.; Riva, I.; Landi, F.; Alborghetti, L.; Frigeni, M.; Damiani, M.; Micò, C.; et al. Siltuximab downregulates interleukin-8 and pentraxin 3 to improve ventilatory status and survival in severe COVID-19. Leukemia 2021. [Google Scholar] [CrossRef]
  149. An Observational Study of the Use of Siltuximab (SYLVANT) in Patients Diagnosed with COVID-19 Infection Who Have Developed Serious Respiratory Complications (SISCO). Available online: https://www.clinicaltrials.gov/ct2/show/NCT04322188 (accessed on 15 June 2021).
  150. Anti-IL6 and Corticosteroid Monotherapy vs Combination in COVID-19. Available online: https://clinicaltrials.gov/ct2/show/NCT04486521 (accessed on 15 June 2021).
  151. Mehta, P.; Cron, R.Q.; Hartwell, J.; Manson, J.J.; Tattersall, R.S. Silencing the cytokine storm: The use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol. 2020, 2, e358–e367. [Google Scholar] [CrossRef]
  152. Cavalli, G.; De Luca, G.; Campochiaro, C.; Della-Torre, E.; Ripa, M.; Canetti, D.; Oltolini, C.; Castiglioni, B.; Din, C.T.; Boffini, N.; et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: A retrospective cohort study. Lancet Rheumatol. 2020, 2, e325–e331. [Google Scholar] [CrossRef]
  153. Franzetti, M.; Forastieri, A.; Borsa, N.; Pandolfo, A.; Molteni, C.; Borghesi, L.; Pontiggia, S.; Evasi, G.; Guiotto, L.; Erba, M.; et al. IL-1 Receptor antagonist anakinra in the treatment of COVID-19 acute respiratory distress syndrome: A retrospective, observational study. J. Immunol. 2021, 206, 1569–1575. [Google Scholar] [CrossRef]
  154. Kooistra, E.J.; Waalders, N.J.B.; Grondman, I.; Janssen, N.A.F.; de Nooijer, A.H.; Netea, M.G.; van de Veerdonk, F.L.; Ewalds, E.; van der Hoeven, J.G.; Kox, M.; et al. Anakinra treatment in critically ill COVID-19 patients: A prospective cohort study. Crit. Care 2020, 24, 688. [Google Scholar] [CrossRef]
  155. Pasin, L.; Cavalli, G.; Navalesi, P.; Sella, N.; Landoni, G.; Yavorovskiy, A.G.; Likhvantsev, V.V.; Zangrillo, A.; Dagna, L.; Monti, G. Anakinra for patients with COVID-19: A meta-analysis of non-randomized cohort studies. Eur. J. Intern. Med. 2021, 86, 34–40. [Google Scholar] [CrossRef] [PubMed]
  156. The CORIMUNO-19 Collaborative Group. Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): A randomised controlled trial. Lancet Respir. Med. 2021, 9, 295–304. [Google Scholar] [CrossRef]
  157. Harrell, C.R.; Sadikot, R.; Pascual, J.; Fellabaum, C.; Jankovic, M.G.; Jovicic, N.; Djonov, V.; Arsenijevic, N.; Volarevic, V. Mesenchymal stem cell-based therapy of inflammatory lung diseases: Current understanding and future perspectives. Stem Cells Int. 2019, 4236973. [Google Scholar] [CrossRef] [PubMed]
  158. Basiri, A.; Mansouri, F.; Azari, A.; Ranjbarvan, P.; Zarein, F.; Heidari, A.; Golchin, A. Stem cell therapy potency in personalizing severe COVID-19 treatment. Stem Cell Rev. Rep. 2021, 17, 193–213. [Google Scholar] [CrossRef] [PubMed]
  159. Mahandiratta, S.; Bansal, S.; Sarma, P.; Kumar, H.; Choudhary, G.; Kumar, S.; Prakash, A.; Sehgal, R.; Medhi, G. Stem cell therapy in COVID-19: Pooled evidencefor SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS: A systematic review. Biomed. Pharmacother. 2021, 137, 111300. [Google Scholar] [CrossRef] [PubMed]
  160. FDA Cautions against Use of Hydroxychloroquine or Chloroquine for COVID-19 Outside of the Hospital Setting or a Clinical Trial due to Risk of Heart Rhythm Problems. Available online: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or#:~:text=Hydroxychloroquine%20and%20chloroquine%20are%20FDA,in%20adults%2C%20and%20rheumatoid%20arthritis (accessed on 4 July 2021).
  161. COVID-19: Chloroquine and Hydroxychloroquine Only to be Used in Clinical Trials or Emergency Use Programmes. Available online: https://www.ema.europa.eu/en/documents/press-release/covid-19-chloroquine-hydroxychloroquine-only-be-used-clinical-trials-emergency-use-programmes_en.pdf (accessed on 15 June 2021).
  162. FAQ: COVID-19 and Ivermectin Intended for Animals. Available online: https://www.fda.gov/animal-veterinary/product-safety-information/faq-covid-19-and-ivermectin-intended-animals (accessed on 4 July 2020).
  163. EMA Advises against Use of Ivermectin for the Prevention or Treatment of COVID-19 Outside Randomised Clinical Trials. Available online: https://www.ema.europa.eu/en/news/ema-advises-against-use-ivermectin-prevention-treatment-covid-19-outside-randomised-clinical-trials (accessed on 15 June 2021).
  164. What’s New in the Guidelines. Last Updated: 11 June 2021. Available online: https://www.covid19treatmentguidelines.nih.gov/about-the-guidelines/whats-new/ (accessed on 15 June 2021).
  165. Coronavirus (COVID-19) Update: FDA Authorizes Drug Combination for Treatment of COVID-19. Available online: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19 (accessed on 4 July 2021).
  166. Corticosteroid for COVID-19. Living Guidance 2 September 2020. Available online: https://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1 (accessed on 15 June 2021).
  167. Temporary Policy for Compounding of Certain Drugs for Hospitalized Patients by Pharmacy Compounders not Registered as Outsourcing Facilities during the COVID-19 Public Health Emergency. Available online: https://www.fda.gov/media/138279/download (accessed on 4 July 2021).
  168. EMA Endorses Use of Dexamethasone in COVID-19 Patients on Oxygen or Mechanical Ventilation. Available online: https://www.ema.europa.eu/en/news/ema-endorses-use-dexamethasone-covid-19-patients-oxygen-mechanical-ventilation (accessed on 15 June 2021).
  169. Anti-SARS-CoV-2 Monoclonal Antibodies. Last Updated: 24 May 2021. Available online: https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/ (accessed on 15 June 2021).
  170. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Available online: https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf (accessed on 15 June 2021).
  171. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Monoclonal Antibody Bamlanivimab. Available online: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-monoclonal-antibody-bamlanivimab (accessed on 4 July 2021).
  172. EMA Issues Advice on Use of Antibody Combination (Bamlanivimab/Etesevimab). Available online: https://www.ema.europa.eu/en/news/ema-issues-advice-use-antibody-combination-bamlanivimab-etesevimab (accessed on 15 June 2021).
  173. Coronavirus Company News Summary. Available online: https://www.pharmaceutical-technology.com/uncategorised/coronavirus-company-news-summary-gsk-and-vir-submit-eua-application-to-fda-for-covid-19-monoclonal-antibody-treatment-ema-recommends-celltrions-regdanvimab-for-severe-covid-19/ (accessed on 4 July 2021).
  174. Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19. Available online: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19 (accessed on 4 July 2021).
  175. EMA Issues Advice on Use of REGN-COV2 Antibody Combination (Casirivimab/Imdevimab). Available online: https://www.ema.europa.eu/en/news/ema-issues-advice-use-regn-cov2-antibody-combination-casirivimab-imdevimab (accessed on 15 June 2021).
  176. Coronavirus (COVID-19) Update: FDA Authorizes Additional Monoclonal Antibody for Treatment of COVID-19. Available online: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-monoclonal-antibody-treatment-covid-19 (accessed on 4 July 2021).
  177. EMA Issues Advice on Use of Sotrovimab (VIR-7831) for Treating COVID-19. Available online: https://www.ema.europa.eu/en/news/ema-issues-advice-use-sotrovimab-vir-7831-treating-covid-19 (accessed on 15 June 2021).
  178. Raoult, D. Carnets de Guerre COVID-19; Michel-Lafon: Neuilly-sur-Seine, France, 2021. [Google Scholar]
  179. Ip, A.; Ahn, J.; Zhou, Y.; Goy, A.H.; Hansen, E.; Pecora, A.L.; Sinclaire, B.A.; Bednarz, U.; Marafelias, M.; Sawczuk, I.S. Hydroxychloroquine in the treatment of outpatients with mildly symptomatic COVID-19: A multi-center observational study. BMC Infect. Dis. 2021, 21, 72. [Google Scholar] [CrossRef]
Figure 1. Chemical structure of hydroxychloroquine (1), chloroquine (2), and azithromycin (3).
Figure 1. Chemical structure of hydroxychloroquine (1), chloroquine (2), and azithromycin (3).
Pharmaceuticals 14 00664 g001
Figure 2. Chemical structure of lopinavir (4) and ritonavir (5).
Figure 2. Chemical structure of lopinavir (4) and ritonavir (5).
Pharmaceuticals 14 00664 g002
Figure 3. Chemical structure of remdesivir (6).
Figure 3. Chemical structure of remdesivir (6).
Pharmaceuticals 14 00664 g003
Figure 4. Chemical structure of camostat mesylate (7), its metabolite (8), nafamostat (9), and umifenovir (10).
Figure 4. Chemical structure of camostat mesylate (7), its metabolite (8), nafamostat (9), and umifenovir (10).
Pharmaceuticals 14 00664 g004
Figure 5. Chemical structure of favipiravir (11), its metabolite 12, and ivermectin (1314).
Figure 5. Chemical structure of favipiravir (11), its metabolite 12, and ivermectin (1314).
Pharmaceuticals 14 00664 g005
Figure 6. Chemical structure of baricitinib (15), colchicine (16), dexamethasone (17), hydrocortisone (18), methylprednisone (19), and prednisone (20).
Figure 6. Chemical structure of baricitinib (15), colchicine (16), dexamethasone (17), hydrocortisone (18), methylprednisone (19), and prednisone (20).
Pharmaceuticals 14 00664 g006
Table 1. Evolution of the number of registered clinical trials [23] over the past 14 months for treatments cited in this opinion.
Table 1. Evolution of the number of registered clinical trials [23] over the past 14 months for treatments cited in this opinion.
Search TermAs of
28 March 202028 April 202028 September 202028 March 202128 May 2021
COVID-19202997347951705619
Hydroxychloroquine19148252275276
Azithromycin1662118126127
Lopinavir (+ritonavir)1444809193
Interferon214299140153
Remdesivir9185793103
Vaccine2271240538673
Camostat-292224
Nafamostat-1677
Umifenovir911141414
Favipiravir212375051
Ivermectin25446568
Baricitinib29141820
Colchicine28223133
Corticosteroid123573100111
Dexamethasone410306272
Hydrocortisone46151820
Methylprednisolone514405154
Prednisone24101316
Plasma42123398559593
Bamlanivimab--41213
Etesevimab--245
Regdanvimab/CT-P59--333
Regn-Cov211456
Casirivimab--379
Imdevimab--379
Sotrovimab/VIR-7831--355
Sarilumab412161717
Tocilizumab632698284
Siltuximab13444
Anakinra412243435
Mesenchymal (cells)1130627781
Table 3. Official status of some potential treatments for patients with COVID-19.
Table 3. Official status of some potential treatments for patients with COVID-19.
TreatmentWHOFDAEMA
Hydroxychloroquinea strong recommendation against use in patients with COVID-19 of any severity [50]
(31 March 2020)
FDA cautions against use outside of the hospital setting or a clinical trial [160]
(1 July 2020)
only to be used in clinical trials or emergency use programs [161]
(1 April 2020)
Lopinavir
ritonavir
a strong recommendation against use in patients with COVID-19 of any severity [50]
(31 March 2020)
No data foundNo data found
Remdesivira conditional recommendation against use in hospitalized patients [50]
(31 March 2020)
approved for adults and pediatric patients requiring
hospitalization [43]
(22 October 2020)
conditional marketing authorization [45]
(3 July 2020)
Ivermectinnot recommended in patients with COVID-19 except in the context of a clinical trial [50]
(31 March 2020)
not approved for the prevention or treatment of COVID-19 [162]
(26 April 2021)
against use for the prevention or treatment outside randomized clinical trials [163]
(22 March 2021)
Baricitinibin combination; for hospitalized patients on high-flow oxygen or noninvasive ventilation who have evidence of clinical progression or increased markers of inflammation [164]
(27 May 2021)
emergency use authorization in combination with remdesivir [165]
(19 November 2020)
EMA starts evaluating the use of Olumiant in hospitalized patients requiring supplemental oxygen [103]
(29 April 2021)
Dexamethasoneuse of systemic corticosteroids rather than no corticosteroids recommended for patients with severe or critical COVID-19 infection, use not recommended for patients with non-severe infection [166]
(2 September 2020)
in the list of drugs used for hospitalized patients [167]
(13 October 2020)
can be used in patients on oxygen or mechanical ventilation [168]
(18 September 2020)
Bamlanivimab
etesevimab
use recommended to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression [169,170]
(24 May 2021)
FDA revokes emergency use authorization [171]
(19 April 2021)
can be used in patients not requiring oxygen and at high risk of progressing to severe disease [172] (5 March 2021)
Regdanvimab
CT-P59
No data foundapplication for emergency use authorization submitted [173]
(29 March 2021)
can be used in patients not requiring oxygen and at high risk of progressing to severe disease [131] (26 March 2021)
Regn-Cov2Use recommended to treat outpatients with mild to moderate COVID-19 who
are at high risk of clinical progression [169,170]
(24 May 2021)
emergency use authorization [174]
(21 November 2020)
can be used in patients not requiring oxygen and at high risk of progressing to severe disease [175] (26 February 2021)
Sotrovimab
VIR-7831
No data foundemergency use authorization [135,176]
(26 May 2021)
can be used in patients not requiring oxygen and at high risk of progressing to severe disease [177] (21 May 2021)
Tocilizumabin combination; for hospitalized patients on high-flow oxygen or noninvasive ventilation who have evidence of clinical progression or increased markers of inflammation [164]
(27 May 2021)
emergency use authorization [147]
(24 June 2021)
No data found
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Vanden Eynde, J.J. COVID-19: Failure of the DisCoVeRy Clinical Trial, and Now–New Hopes? Pharmaceuticals 2021, 14, 664. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070664

AMA Style

Vanden Eynde JJ. COVID-19: Failure of the DisCoVeRy Clinical Trial, and Now–New Hopes? Pharmaceuticals. 2021; 14(7):664. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070664

Chicago/Turabian Style

Vanden Eynde, Jean Jacques. 2021. "COVID-19: Failure of the DisCoVeRy Clinical Trial, and Now–New Hopes?" Pharmaceuticals 14, no. 7: 664. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070664

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop