key: cord-0990680-s8gu83j5 authors: Chakraborty, Rohan; Parvez, Suhel title: COVID-19: An overview of the current pharmacological interventions, vaccines, and clinical trials date: 2020-07-30 journal: Biochem Pharmacol DOI: 10.1016/j.bcp.2020.114184 sha: 30d3f65f61d5991a1c8c79eaef38b8c14a2ec482 doc_id: 990680 cord_uid: s8gu83j5 COVID-19, the greatest public health emergency of the 21(st) century, has affected 215 countries and territories around the world resulting in 15,151,738 confirmed cases and 621,121 deaths. The outbreak has continued at breakneck pace despite stringent public health measures, ravaging the global economy and causing profound human casualties. Vaccination is currently the best bet for the prevention of COVID-19. Still, in its absence, there has been considerable interest in repurposing existing therapeutic agents to reduce the severity of the illness and ease the burden on the already strained healthcare systems. This review outlines the current evidence regarding proposed treatments- experimental or repurposed, for COVID-19, and gives an insight into the clinical trial landscape for drugs as well as vaccines. In late 2019, there was a sudden surge in the number of individuals being admitted to local hospitals of Wuhan, in the Hubei Province of China, with a pneumonia-like illness of unknown etiology 1 . Although results from preliminary epidemiological investigations pointed towards a zoonotic origin from a local seafood market in Huanan, the exponential increase in the number of cases suggested the possibility of human-to-human transmission 2 In the months since the novel coronavirus burst onto the scene, drug makers small and large have scrambled to put their best foot forward in an attempt to thwart the pandemic. Some are taking cues from older antivirals, while others are aiming to develop novel therapeutic agents to treat COVID-19. Vaccine development, convalescent plasma therapy, cell-based therapies and monoclonal antibodies are some of the potential approaches being targeted by researchers worldwide. However, drug development is an expensive and time-consuming endeavor with a high attrition rate 33 . The enormity of the current global health emergency means that time is of the essence. Thus, there has been considerable interest in repurposing existing drugs and expediting the development of vaccines, to allow rapid identification of suitable drug candidates. The dearth of proven clinical data on therapeutic agents for COVID-19 has led to a reliance on existing therapies for other viruses such as SARS-CoV-1, MERS-CoV, and HIV etc. It is unclear whether the data from repurposed antiviral drugs can be extrapolated to SARS-CoV-2, as unlike antibiotics, antivirals are specific for a particular virus in most cases. Table 1 lists some of the potential therapeutic agents that have been used as repurposed drugs for COVID-19 treatment. Their sites and mechanisms of action against SARS-CoV-2 are illustrated in Fig. 3 . Remdesivir, a monophosphate prodrug of an adenosine analog, was originally developed to combat the Ebola outbreak in 2014. It has been highly touted as a potential antiviral drug for COVID- 19 . It has been shown to have potent in-vitro activity against SARS-CoV-2 (EC 50 of 0.77 μM 34 ), SARS-CoV-1 and MERS-CoV 35 . Because of its high selectivity for viral polymerases, Remdesivir is less likely to cause toxicity in humans. The drug also exhibits a high genetic barrier to resistance in coronaviruses and its long intracellular half-life is conducive for once-a-day dosing 36 . There are currently 38 registered trials listed on ClinicalTrials.gov for investigating the efficacy of this drug. Preliminary results from a small cohort show clinical improvement in 68% of hospitalized patients 37 on administration of Remdesivir. However, the small sample size and the lack of a control group limit its significance. Wang et al. reported that in a randomized, double-blind, placebo-controlled, multicentre trial of 237 participants (NCT04257656), Remdesivir did not exhibit significant clinical benefits 38 . On April 29, the US NIH reported that in a high powered RCT of 1063 participants, patients in the Remdesivir group had shown a 31% faster time to recovery (median 11 days) 39 than those in the placebo group (15 days) (p<0.001). Even though the findings do not definitively reveal whether the drug is curative, Remdesivir is slated to be the new standard of care 40 for COVID-19 patients in the United States. It has also been approved for therapeutic use in COVID-19 patients by the regulatory bodies of Japan, Australia, Singapore, and Europe 41 . The use of Remdesivir might prove to have a measurable impact on healthcare capacity by minimizing the length of hospital stay and reducing the overall severity of the illness. In a comparative analysis of the Phase 3 SIMPLEsevere trial and a retrospective cohort study of severe COVID-19 patients, Remdesivir has recently shown a 62% reduction in the risk of mortality as opposed to the standard of care and an improvement in clinical recovery 42 . The drug is also being tested on outpatients as an inhaled, nebulised form in a Phase 1a trial 43 . It is an antiviral combination of protease inhibitors that are used to treat HIV infections. Eighty trials are listed on clinical trial registries around the world for testing the drug as a COVID-19 treatment. As Lopinavir has insufficient oral bioavailability (it gets rapidly catabolized by the Cytochrome P450 enzyme system) 44 , ritonavir (a CYP3A4 inhibitor) is added to increase its plasma half-life. Even though LPV/r was found to be effective in retrospective studies on SARS-CoV 45 , it was far less potent than Remdesivir and Chloroquine in-vitro 46 . In a randomized openlabel study of 199 patients with COVID-19 (ChiCTR2000029308), LPV/r failed to reduce overall mortality as well as viral load 47 . Thus it is difficult to ascertain whether LPV/r may have an effective role for the treatment of COVID-19 based on the available data. LPV/r has also been discontinued from randomization in the treatment arms of the RECOVERY trial, and the SOLIDARITY trial as it did not demonstrate any beneficial effect in either clinical recovery or mortality 48,49 . Oseltamivir, a neuraminidase inhibitor, is frequently prescribed for the treatment of Influenza. It was prescribed to treat flu-like symptoms in COVID-19 patients at the onset of the outbreak in China before SARS-CoV-2 was identified as the etiologic factor. It has no scientific basis for the treatment of COVID-19 as viruses of the Coronaviridae family do not utilize the enzyme neuraminidase. Moreover, Oseltamivir does not exhibit in-vitro activity against SARS-CoV 50 . Eighteen studies are currently listed for testing the drug on COVID-19 patients. Oseltamivir was shown to be ineffective in the treatment of COVID-19 by an in silico assessment, which also included an in vitro and retrospective study 51 . Favipiravir is an RNA-dependent RNA polymerase (RdRp) inhibitor. It is used in China for the treatment of Influenza and is capable of blocking the replication of other RNA viruses 52 such as arenavirus, filovirus, bunyavirus etc. Favipiravir is activated into its phosphoribosylated form (favipiravir-RTP) in cells, which then inhibits viral RNA polymerase activity 53 . It has shown potential in-vitro activity against SARS-CoV-2 34 . There are currently 32 studies underway which are aimed at investigating the efficacy of this drug in COVID-19. Favipiravir has been approved for experimental use in COVID-19 patients in Italy, China and Russia 54, 55 . In a recent multicenter trial in Japan, Favipiravir did not show a significant benefit in mild and moderate COVID-19 cases 56 . Ribavirin, a guanosine analog prescribed for viral hemorrhagic fever and respiratory syncytial virus, inhibits viral RNA polymerase and mRNA capping. It has no in-vitro activity against SARS 50 , and is far less potent against SARS-CoV-2 in-vitro than antivirals like Remdesivir 34 . It is associated with hemolytic anemia which could lead to exacerbation of cardiac disease in comorbid patients. Further, it is also known to be teratogenic. It is a protease inhibitor that is used for the treatment of chronic pancreatitis. Camostat inhibits the host cell serine protease TMPRSS2 57 , which primes the viral S protein for entry into human cells. In mice, camostat mesylate showed a 60% survival rate following SARS-CoV infection, at dose concentrations similar to that in humans 58 . It also was found to block viral maturation and entry of SARS-Cov-2 in vitro. Eight trials on COVID-19 are currently underway around the globe. These are antimalarial drugs which are also believed to have antiviral activity 52 . Both HCQ/CQ demonstrated potent in vitro activity against SARS-CoV-2 with an EC 50 of 6.14 μM and 23.90 μM, respectively 59 . The drugs have recently gained notoriety due to much sociopolitical hype that has led to a spate of newly launched clinical trials-more than 240 studies are currently underway around the world. There is very limited data to advocate the use of HCQ/CQ as therapeutic options in COVID- 19 . In a small open-label non-RCT of 36 patients (20 treated/ 16 controls), significantly improved virologic clearance was observed in the HCQ (N=14) group. All six patients in the HCQ plus Azithromycin group had significantly better viral clearance 60 . However, six patients in the HCQ group were removed from the study due to adverse effects or intolerance of the medication. A study in Brazil (NCT04323527) was forced to prematurely halt patient recruitment due to the high fatality rate in the CQ group 61 . The authors of the study opined that treatment providers should refrain from administering high doses of CQ to critically ill patients with COVID-19 because of its potential safety hazards. There was also no reported evidence of a decrease in viral load or improvement in other clinical outcomes. A recent multinational observational study on more than 96,000 patients across six continents reported an increased occurrence of ventricular arrhythmias in patients who received hydroxychloroquine or chloroquine, when used alone or in conjunction with macrolides 62 . The authors reported that the drug regimen did not have any beneficial effect on treatment outcomes in COVID-19 patients, and exhibited an increased risk of mortality in the treatment group as compared to the control. HCQ/CQ has several potential Adverse Drug Reactions (ADR), such as the risk of cardiac arrhythmias (e.g., QT prolongation), GI Disturbances, ECG abnormalities, hypoglycemia, and retinal damage upon long-term/high dose use. In a recent single-center study on 2541 patients, treatment with HCQ alone and HCQ + Azithromycin demonstrated a significant reduction in mortality among hospitalized COVID-19 patients 63 . However, a randomized double-blind placebo-controlled trial which tested HCQ as postexposure prophylaxis did not find the drug to be effective in preventing COVID-19 after a high-risk exposure 64 . Hydroxychloroquine was discontinued from the RECOVERY trial owing to no evidence of beneficial effect on either mortality or clinical improvement outcomes 65 . The WHO also discontinued the Hydroxychloroquine trial arm of the SOLIDARITY trial as it did not produce any reduction in mortality of COVID-19 patients when compared to the standard of care 49 . Similarly, the FDA has warned against the use of HCQ/CQ as therapeutic interventions against COVID-19 due to the risk of potential ADRs, and has revoked its status as an emergency-use drug for hospitalized patients who are not enrolled in registered clinical trials 66 . Tocilizumab is a recombinant monoclonal antibody that inhibits IL-6 receptors and is used for the treatment of rheumatoid arthritis and the "cytokine storm" immune overresponse in cancer patients. IL-6 is implicated in immunologic response in patients with Cytokine-release syndromes (CRS). Elevated levels of IL-6 have been associated with hyperinflammatory states and CRS in severe COVID-19 cases and can potentially lead to increased rates of mortality 67 . Patients with thrombocytopenia and neutropenia are at a greater risk of possible ADRs of this drug, which include GI perforation and hepatotoxicity. Sixety two registered trials are currently testing the safety and efficacy of Tocilizumab on COVID-19 patients. A recent study reported that Tocilizumab improved survival, as well as clinical markers in patients with CRS 68 . The drug was also reported to be associated with lower mortality in a cohort of mechanically ventilated COVID-19 patients 69 . However, a retrospective cohort study reported that Tocilizumab did not show a significant difference versus standard care in either clinical improvement or mortality 70 . IL-6 Receptor-Inhibiting Monoclonal Antibody that has been previously used in the treatment of Rheumatoid arthritis. It is currently being tested in more than fifteen registered trials targeted at managing the "cytokine storm" immune response in severely ill COVID-19 patients. Results from a recent Phase 3 trial showed that Sarilumab did not meet any of the primary or secondary endpoints of the study and is thus ineffective in COVID-19 patients requiring mechanical ventilation 71 . Ruxolitinib has been found to be effective against inflammatory and autoimmune diseases, and is in late-stage development as a topical ointment for atopic dermatitis. Twenty trials are currently testing the efficacy of the drug in COVID-19 patients. IFX-1 is a monoclonal antibody designed to induce an anti-inflammatory response by blocking the biological activity of human complement factor C5a. One trial (NCT04333420) is currently being held in the Netherlands to test its efficacy in patients with severe COVID-19, with preliminary results expected by December 31, 2020. It will soon be studied in a Phase 3 trial on patients with severe COVID-19 induced pneumonia after promising results in the earlier phases 72 . It is a corticosteroid with potent anti-inflammatory properties which is prescribed for the treatment of arthritis, and has potential benefit in the management of pneumonia. However, data for its use in severe coronavirus diseases is inconclusive and controversial as it shows no impact on clinical outcomes in SARS 73 . Moreover, the benefits are often outweighed by the risks 74 of secondary infection and delayed viral clearance. It is a glucocorticoid that has been used for several years in the treatment of various inflammatory and autoimmune diseases. Preliminary results from the RECOVERY trial have shown that Dexamethasone reduces mortality by one-third in mechanically ventilated patients hospitalized with severe COVID-19, and by one-fifth in patients requiring oxygen without mechanical ventilation 75 . The drug did not improve survival in patients not requiring respiratory support. Dexamethasone has been approved for use as a COVID-19 treatment in the UK 76 . As is the case with other corticosteroids, Dexamethasone suppresses the immune system and could thus potentially exacerbate viral infections. However, its immunosuppressant effects might benefit COVID-19 patients who experience CRS. NKG2D is an activating receptor for the immune system's natural killer (NK) cells. SARS-CoV-2 binds to the ACE-2 receptor using its S protein. By targeting the S protein of the virus and NKG2DL on the surface of infected cells with ACE-2 and NKG2D respectively, it is expected that SARS-CoV-2 can be eliminated from the infected cells. Moreover, ACE2 CAR-NK cells can competitively inhibit infection of ATII cells by SARS-CoV-2 through ACE2 receptors, thereby preventing the production of infectious virus particles. A multicenter, randomized Phase 1/2 trial (NCT04324996) is currently testing this cell therapy. These drugs are being trialled to study their cardioprotective effect and prevent direct damage to the heart muscle that appears to exacerbate the severity of COVID-19 in certain patients. The Randomized, open label trial (NCT04333407) will include 3170 patients and will be conducted in the United Kingdom, with a completion date of March 30, 2021. 11.1 IMMUNOGLOBULIN THERAPY Inducing passive immunization by infusion of CP is a potential therapeutic option in the absence of a proven anti-viral agent or vaccine. In CP therapy, blood plasma of patients who have recovered from COVID-19 is transfused into patients who are currently ill, in the hope that the freshly-made antibodies will help overcome the virus. Convalescent plasma has previously been used in the treatment of viral diseases such as poliomyelitis, influenza, SARS, and MERS. A case series of five critically ill COVID-19 patients with ARDS reported clinical improvements after the administration of convalescent plasma 77 . Another study on ten severely ill patients in China showed that the clinical symptoms improved significantly within three days, and that the viral load was undetectable after seven days of transfusion 78 . A recent study on more than 20,000 COVID-19 patients who received CP therapy reported that transfusion of CP is safe and does not heighten the risk of adverse events 79 Adverse effects associated with plasma transfusion include pathogen transmission and allergic transfusion reactions. The greatest obstacle for a large scale rollout of plasma therapy is to find prospective donors with high levels of neutralizing antibody titer (>1:640) 78 . Studies on SARS have reported that the level of specific neutralizing antibodies titer decreased rapidly within four months of recovery 82 , suggesting that immune protection may wane over time. Such shortlasting humoral immune response suggests that plasma from recently recovered patients is more effective for plasma therapy. The presence of antibodies points to a past infection. However, further research is needed to know more about the type and concentration of virus-neutralizing antibodies that protect against a new infection, and the duration for which the immunity might last. Current data is still insufficient on whether or not mild or asymptomatic infections generate adequate antibody responses or protection to COVID-19. Vaccination is the best bet for COVID-19 control. DNA plasmids, epitopes, mRNA, and artificial antigen-presenting cells (aAPCs) are some of the biotechnological platforms on which the hunt for a global vaccine is based 83 . Currently, there are no FDA-approved vaccines for COVID-19. There is limited information on the specific antigens used in the development of vaccines against SARS-CoV-2. Most candidate vaccines are aimed at inducing neutralizing antibodies against the viral spike (S) protein, which prevents its uptake via the ACE2 receptor. Table 2 provides an overview of the global landscape of COVID-19 vaccine development activity for active clinical trials 84 . The chain of events from conception to market availability of a vaccine usually takes over ten years, and has a mere 6% probability of successful market entry 85 . If a commercially-available SARS-CoV-2 vaccine were to be made available for use in 12-18 months, assuming its path from the lab to the market is unhindered, it would represent a seismic change from the traditional vaccine development pathway. This would require a multipronged strategy involving novel vaccine development paradigms, flexible development phases, ramping up existing manufacturing capacity, unprecedented scale and speed of global R&D, and radical changes in regulatory processes. It will also require careful evaluation of safety and efficacy every step of the way. The sheer volume of clinical trials that are investigating prospective treatment options for COVID-19 emphasizes the need to expedite the production of effective measures to curb its spread and provide much-needed relief to patients and healthcare providers the world over. The SOLIDARITY trial is an international collaborative clinical trial initiated by the WHO to help find an effective treatment for COVID-19 in over 100 countries. The trial will assess the efficacy of four treatment options against COVID-19, namely: Remdesivir; LPV/r; LPV/r with The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is a multi-centre, randomised controlled trial of over 11,000 patients across the UK. The treatment arms include LPV/r (discontinued due to lack of efficacy), Dexamethasone, HCQ (discontinued), Azithromycin, Tocilizumab, and Convalescent plasma 48 . In order to understand the long-term impact of COVID In summary, SARS-CoV-2 is a highly contagious novel coronavirus that has rapidly brought about a global pandemic, destroying lives and livelihood at an alarming pace. Even though much is known about its genetic sequence and virology due to our knowledge of its predecessors, Credit Author Statement: This table looks at the interventional trials that have been completed and listed on ClinicalTrials.gov. 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(Infectious Diseases Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19 A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19 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 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Tocilizumab for treatment of mechanically ventilated patients with COVID-19 Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study Provide Update on Kevzara® (sarilumab) Phase 3 U.S. Trial in COVID-19 InflaRx Announces Decision to Enter Phase III Development of IFX-1 in Severe COVID-19 Induced Pneumonia Systematic Review of Treatment Effects On the use of corticosteroids for 2019-nCoV pneumonia Effect of Dexamethasone in Hospitalized Patients with COVID-19 World first coronavirus treatment approved for NHS Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma Effectiveness of convalescent plasma therapy in severe COVID-19 patients Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients Potential Antiviral Options against SARS-CoV-2 Infection Rush for plasma therapy as Covid-19 cases rise Disappearance of Antibodies to SARS-Associated Coronavirus after Recovery The SARS-CoV-2 Vaccine Pipeline: an Overview DRAFT landscape of COVID-19 candidate vaccines Risk in Vaccine Research and Development Quantified Federally-funded clinical studies related to COVID-19 Solidarity" clinical trial for COVID-19 treatments WHO Director-General's opening remarks at the media briefing on COVID-19 COVID-19: A Brief Overview of the Discovery Clinical Trial Altered Lipid Metabolism in Recovered SARS Patients Twelve Years after Infection The authors have no conflicts of interest.