COVID-19 Treatment: Investigational Drugs and Other Therapies

Updated: Jun 29, 2021
  • Author: Scott J Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP; more...
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Overview

Overview

Coronavirus disease 2019 (COVID-19) is defined as illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; formerly called 2019-nCoV), which was first identified amid an outbreak of respiratory illness cases in Wuhan City, Hubei Province, China. [1] It was initially reported to the World Health Organization (WHO) on December 31, 2019. On January 30, 2020, the WHO declared the COVID-19 outbreak a global health emergency. [2, 3] On March 11, 2020, the WHO declared COVID-19 a global pandemic, its first such designation since declaring H1N1 influenza a pandemic in 2009. [4]  

Utilization of programs established by the FDA to allow clinicians to gain access to investigational therapies during the pandemic has been essential. The expanded access (EA) and emergency use authorization (EUA) programs allowed for rapid deployment of potential therapies for investigation and investigational therapies with emerging evidence. A review by Rizk et al describes the role for each of these measures and their importance to providing medical countermeasures in the event of infectious disease and other threats. [5]

As of October 22, 2020, remdesivir, an antiviral agent, is the only drug fully approved for treatment of COVID-19. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. [6]  An emergency use authorization (EUA) remains in place for treat pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg. [7] An EUA for convalescent plasma was announced on August 23, 2020. [8]

The FDA issued an emergency use authorization (EUA) for outpatient monoclonal directed therapies (ie, sotrovimab, casirivimab plus imdevimab, bamlanivimab plus etesevimab) for individuals who test positive and are at high risk of severe COVID-19 or hospitalization. [9, 10]  

Baricitinib was issued an EUA on November 19, 2020 for use, in combination with remdesivir, for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized patients aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [11]  Tocilizumab, an interleukin-6 inhibitor, was granted an EUA June 24, 2021 for treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults and pediatric patients (aged >2 years) who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or ECMO.

The FDA has granted EUAs for 3 SARS CoV-2 vaccines since December 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna), whereas the third is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson).  

Information, including allocation, for COVID-19 therapies granted emergency use authorization is located at the United States Public Health Emergency webpage. 

Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies. Searching for effective therapies for COVID-19 infection is a complex process. Guidelines and reviews of pharmacotherapy for COVID-19 have been published. [12, 13, 14, 15, 16, 17, 18]  The Milken Institute maintains a detailed COVID-19 Treatment and Vaccine Tracker of research and development progress. 

Information, including allocation, for COVID-19 therapies granted emergency use authorization is located at the United States Public Health Emergency [link https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Pages/default.aspx] webpage. 

The urgent need for treatments during a pandemic can confound the interpretation of resulting outcomes of a therapy if data are not carefully collected and controlled. Andre Kalil, MD, MPH, writes of the detriment of drugs used as a single-group intervention without a concurrent control group that ultimately lead to no definitive conclusion of efficacy or safety. [19]

Rome and Avorn write about unintended consequences of allowing widening access to experimental therapies. First, efficacy is unknown and may be negligible, but, without appropriate studies, physicians will not have evidence on which to base judgement. Existing drugs with well-documented adverse effects (eg, hydroxychloroquine) subject patients to these risks without proof of clinical benefit. Expanded access of unproven drugs may delay implementation of randomized controlled trials. In addition, demand for unproven therapies can cause shortages of medications that are approved and indicated for other diseases, thereby leaving patients who rely on these drugs for chronic conditions without effective therapies. [20]  

Drug shortages during the pandemic go beyond off-label prescribing of potential treatments for COVID-19. Drugs that are necessary for ventilated and critically ill patients and widespread use of inhalers used for COPD or asthma are in demand. [21, 22]

It is difficult to carefully evaluate the onslaught of information that has emerged regarding potential COVID-19 therapies within a few months’ time in early 2020. A brief but detailed approach regarding how to evaluate resulting evidence of a study has been presented by F. Perry Wilson, MD, MSCE. By using the example of a case series of patients given hydroxychloroquine plus azithromycin, he provides clinicians with a quick review of critical analyses. [23]

As an example of the number of compounds being evaluated, Gordon et al identified 332 high-confidence SARS-CoV-2 human protein-protein interactions. Among these, they identified 66 human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and/or preclinical compounds. As of March 22, 2020, these researchers are in the process of evaluating the potential efficacy of these drugs in live SARS-CoV-2 infection assays. [24]

How these potential COVID-19 treatments will translate to human use and efficacy is not easily or quickly understood. The question of whether some existing drugs that have shown in vitro antiviral activity might achieve adequate plasma pharmacokinetics with current approved doses was examined by Arshad et al. The researchers identified in vitro anti–SARS-CoV-2 activity data from all available publications up to April 13, 2020, and recalculated an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). The researchers also calculated the unbound drug to tissue partition coefficient to predict lung concentrations that would exceed their reported EC50 levels. [25]

The NIH Accelerating Covid-19 Therapeutics Interventions and Vaccines (ACTIV) trials public-private partnership to develop a coordinated research strategy has several ongoing protocols that are adaptive to the progression of standard care.

Another adaptive platform trial is the I-SPY COVID-19 Trial for treating critically ill patients. The clinical trial is designed to allow numerous investigational agents to be evaluated in the span of 4-6 months, compared with standard of care (supportive care for ARDS, remdesivir backbone therapy). Depending on the time course of COVID-19 infections across the US. As the trial proceeds and a better understanding of the underlying mechanisms of the COVID-19 illness emerges, expanded biomarker and data collection can be added as needed to further elucidate how agents are or are not working. [26]

The WHO developed a blueprint of potential therapeutic candidates in January 2020. WHO has embarked on an ambitious global "megatrial" called SOLIDARITY in which confirmed cases of COVD-19 are randomized to standard care or one of four active treatment arms (remdesivir, chloroquine or hydroxychloroquine, lopinavir/ritonavir, or lopinavir/ritonavir plus interferon beta-1a). In early July 2020, the treatment arms in hospitalized patients that included hydroxychloroquine, chloroquine, or lopinavir/ritonavir were discontinued owing to the drugs showed little or no reduction in mortality compared with standard of care. [27]  Interim results released mid-October 2020 found the 4 aforementioned repurposed antiviral agents appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. The 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). [28]  

Next:

Antiviral Agents

Remdesivir

Remdesivir (Veklury) was the first drug approved by the FDA for treating the SARS-CoV-2 virus. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. The broad-spectrum antiviral is a nucleotide analog prodrug. Full approval was preceded by the US FDA issued an EUA (emergency use authorization) on May 1, 2020 to allow prescribing of remdesivir for severe COVID-19 (confirmed or suspected) in hospitalized adults and children prior to approval. [29]  Upon approval of remdesivir in adults and adolescents, the EUA was updated to maintain the ability for prescribers to treat pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg. [7] As of October 1, 2020, remdesivir is available from the distributor (ie, AmerisourceBergen). Wholesale acquisition cost is approximately $520/100-mg vial, totaling $3,120 for a 5-day treatment course. 

It was studied in clinical trials for Ebola virus infections but showed limited benefit. [30] Remdesivir has been shown to inhibit replication of other human coronaviruses associated with high morbidity in tissue cultures, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. Efficacy in animal models has been demonstrated for SARS-CoV and MERS-CoV. [31]

Several phase 3 clinical trials have tested remdesivir for treatment of COVID-19 in the United States, South Korea, and China. Positive results were seen with remdesivir after use by the University of Washington in the first case of COVID-19 documented on US soil in January 2020. [32]  An adaptive randomized trial of remdesivir coordinated by the National Institute of Health (NCT04280705) was started first against placebo, but additional therapies have been added to the protocol as evidence emerges. The first experience with this study involved passengers of the Diamond Princess cruise ship in quarantine at the University of Nebraska Medical Center in February 2020 after returning to the United States from Japan following an on-board outbreak of COVID-19. [33] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing.

The EUA for remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT) was announced April 29, 2020. The final analysis included 1,062 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients treated with 10-days of remdesivir recovered faster than similar patients who received placebo. Results showed that patients who received remdesivir had a 31% faster time to recovery compared with those who received placebo (P < 0.001). Specifically, the median time to recovery was 10 days in patients treated with remdesivir compared with 15 days in those who received placebo (P < 0.001). Patients with severe disease (n = 957) had a median time to recovery of 11 days compared with 18 days for placebo. A statistically significant difference was not reached for mortality by day 15 (remdesivir 6.7% vs placebo 11.9%) or by day 29 (remdesivir 11.4% vs placebo 15.2%). [34]

The final ACTT-1 results for shortening the time to recovery differed from interim results from the WHO SOLIDARITY trial for remdesivir. These discordant conclusions are complicated and confusing as the SOLIDARITY trial included patients from ACTT-1.  In SOLIDARITY, over 11,000 hospitalized patients with COVID-19 (from 405 hospitals and 30 countries) were randomized between whichever study drugs (up to 4 options) were locally available and open control. [28] An analysis by Sax describes variables to consider when interpreting the results. The ACTT-1 trial included a placebo arm and was blinded, providing stronger evidence of remdesivir efficacy. Also, remdesivir worked for patients with shorter duration of symptoms and in those requiring oxygen. When the SOLIDARITY trial began in March 2020, it was a time during much of the enrollment period where patients tried to avoid hospitalization. The issue of when the drug was initiate in relationship to the stage of infection is an important factor. Duration of symptoms is not reported in the preliminary SOLIDARITY trial, a critical piece of information. [35]  An editorial by Harrington et al, notes the complexity of the SOLIDARITY trial and the variation within and between countries in the standard of care and in the burden of disease in patients who arrive at hospitals. The editorial also mentions that trials solely focused on remdesivir were able to observe nuanced outcomes (ie, ability to change the course of hospitalization), whereas the larger, simple randomized SOLIDARITY trial focused on more easily defined outcomes. [36]

The ACTT results also differed from a smaller randomized trial conducted in China and published hours before the press release by the NIH about the study. Results from this other randomized, double-blind, placebo-controlled, multicenter trial (n = 237; 158 to remdesivir and 79 to placebo; 1 patient withdrew) found remdesivir was not associated with statistically significant clinical benefits, measured as time to clinical improvement, in adults hospitalized with severe COVID-19. Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less. The authors concluded that numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. This study was underpowered owing to dropping case numbers in China as the study was starting. [37]

A phase 3, randomized, open-label trial showed remdesivir was associated with significantly greater recovery and reduced odds of death compared with standard of care in patients with severe COVID-19. The recovery rate at day 14 was higher in patients who received remdesivir (n = 312) compared with those who received standard of care (n = 818) (74.4% vs 59%; P< 0.001). The mortality rate at day 14 was also lower in the remdesivir group (7.6% vs 12.5%; P = 0.001). [38]

The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanical ventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimen on day 14 (OR: 0.75 [95% CI 0.51-1.12]). In this study, 65% of patients who received a 5-day course of remdesivir showed a clinical improvement of at least 2 points on the 7-point ordinal scale at day 14, compared with 54% of patients who received a 10-day course. After adjustment for imbalances in baseline clinical status, patients receiving a 10-day course of remdesivir had a distribution in clinical status at day 14 that was similar to that of patients receiving a 5-day course (P = 0.14). The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with the current supply of remdesivir. The trial is continuing with an enrollment goal of 6,000 patients. [39]

Data presented at the virtual COVID-19 Conference in July 2020 included a comparative analysis of clinical recovery and mortality outcomes from the phase 3 SIMPLE trials versus a real-world cohort of patients with severe COVID-19 receiving standard of care. The analysis showed remdesivir was associated with a 62% reduction in the risk of mortality compared with standard of care. Subgroup analyses found these results were similar across different racial and ethnic groups. While these data are important, they require confirmation in prospective clinical trials. [40]

Similarly, the phase 3 SIMPLE II trial in patients with moderate COVID-19 disease (n = 596) showed that 5 days of remdesivir treatment had a statistically significant higher odds of a better clinical status distribution on Day 11 compared with those receiving standard care (odds ratio, 1.65; p = 0.02). Improvement on Day 11 did not differ between the 10-day remdesivir group and standard of care (P = 0.18). [41]

Real-world analysis

Three retrospective real-world studies presented at the 2021 World Microbe Forum showed remdesivir-treated hospitalized patients had significantly lower risk for mortality compared with matched controls. The studies included 98,654 patients and results are summarized below. [42]

Aetion and HealthVerity: Remdesivir-treated patients (n = 24,856) had a 23% lower mortality risk compared with controls (n = 24,856), regardless of baseline oxygen requirement from May 1, 2020 to May 3, 2021. Patients who received a 5-day regimen also had a significantly greater likelihood of discharge by day 28. 

Premier Healthcare: Assessed mortality in hospitalized patients who were initiated remdesivir (n=28,855) within the first 2 days of hospitalization versus matched patients not receiving remdesivir (n=16,687) between August and November 2020. Patients were matched on baseline level of oxygenation, hospital, within a 2-month hospital admission period, and all stayed in the hospital for a minimum of 3 days after initiating treatment. Remdesivir-treated patients had a significantly lower risk of mortality at Day 14 (p < 0.0001) and Day 28 (P = 0.003) compared with those not given remdesivir. 

SIMPLE-Severe: Compared outcomes in patients receiving 10-days of remdesivir in the extension phase of the open-label SIMPLE-Severe trial. Regardless of baseline oxygen requirements, treatment with remdesivir results in a 54% lower mortality risk at Day 28 compared with the control group (P < 0.001). 

Remdesivir use in children

Remdesivir emergency use authorization includes pediatric dosing that was derived from pharmacokinetic data in healthy adults. Remdesivir has been available through compassionate use to children with severe COVID-19 since February 2020. A phase 2/3 trial (CARAVAN) of remdesivir was initiated in June 2020 to assess safety, tolerability, pharmacokinetics, and efficacy in children with moderate-to-severe COVID-19. CARAVAN is an open-label, single-arm study of remdesivir in children from birth to age 18 years. [43]

Data were presented on compassionate use of remdesivir in children at the virtual COVID-19 Conference held July 10-11, 2020. Results showed most of the 77 children with severe COVID-19 improved with remdesivir. Clinical recovery was observed in 80% of children on ventilators or ECMO and in 87% of those not on invasive oxygen support. [44]

For additional information, see Coronavirus Disease 2019 (COVID-19) in Children.

Remdesivir use in pregnant women

Outcomes in the first 86 pregnant women who were treated with remdesivir (March 21 to June 16, 2020) have been published. Recovery rates were high among women who received remdesivir (67 while pregnant and 19 on postpartum days 0-3). No new safety signals were observed. At baseline, 40% of pregnant women (median gestational age 28 weeks) required invasive ventilation compared with 95% of postpartum women (median gestational age at delivery 30 weeks). Among pregnant women, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women, 89% were extubated, 89% recovered, and 84% were discharged. There was 1 maternal death attributed to underlying disease and no neonatal deaths. [45]

Data continue to emerge. A case series of 5 patients describe successful treatment and monitoring throughout treatment with remdesivir in pregnant women with COVID-19. [46]

Drug interactions with remdesivir

Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine. Based on in vitro data, chloroquine demonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir. [7]

Investigational antivirals

Molnupiravir

Molnupiravir (MK-4482 [previously EIDD-2801]; Merck) is an oral antiviral agent that is a prodrug of the nucleoside derivative N4-hydroxycytidine. It elicits antiviral effects by introducing copying errors during viral RNA replication of the SARS-CoV-2 virus. Preliminary results from the phase 2a dose-ranging MOVe-OUT study (n = 2020) showed at an average of 10 days after symptom onset, 24% of patients in the placebo group remained culture positive for SARS-CoV-2; whereas, no infectious virus could be recovered at study day 5 in any molnupiravir-treated outpatients. The inpatient molnupiravir study (MOVe-IN) has been halted, but the phase 3 trial in outpatients who have at least 1 risk factor for poor outcomes (eg, advanced age, obesity, diabetes) will proceed with patients receiving 800 mg orally twice daily. [47]

Favipiravir

Favipiravir (Avigan; Appili Therapeutics) is an oral antiviral approved for treatment of influenza in Japan. It is approved in Russia for treatment of COVID-19.

Favipiravir selectively inhibits RNA polymerase, which is necessary for viral replication. An adaptive, multicenter, open label, randomized, phase 2/3 clinical trial of favipiravir compared with standard of care I hospitalized patients with moderate COVID-19 was conducted in Russia. Both dosing regimens of favipiravir demonstrated similar virologic response. Viral clearance on Day 5 was achieved in 25/40 (62.5%) patients on in the favipiravir group compared with 6/20 (30%) patients in the standard care group (p = 0.018). Viral clearance on Day 10 was achieved in 37/40 (92.5%) patients taking favipiravir compared with 16/20 (80%) in the standard care group (p = 0.155). [48]  

In the United States, the phase 3 PRESECO (Preventing Severe COVID Disease) study is evaluating use in patients with mild-to-moderate symptoms to prevent disease progression and hospitalization. The phase 3 PEPCO (Post Exposure Prophylaxis for COVID-19) study will look at asymptomatic individuals with direct exposure (within 72 hours) to an infected individual. A study in hospitalized patients is also underway. [49, 50]  Additionally, the phase 2 CONTROL study is evaluating use to control outbreaks of COVID-19 in Canadian long-term care facilities. [51]

Clinical trials of existing drugs with antiviral properties

Nitazoxanide

Nitazoxanide extended-release tablets (NT-300; Romark Laboratories) inhibit replication of a broad range of respiratory viruses in cell cultures, including SARS-CoV-2. Two phase 3 trials for prevention of COVID-19 are being initiated in high-risk populations, including elderly residents of long-term care facilities and healthcare workers. In addition to the prevention studies, a third trial for early treatment of COVID-19 is planned. [52, 53]  Another multicenter, randomized, double-blind phase 3 study was initiated in August 2020 for treatment of people aged 12 years and older with fever and respiratory symptoms consistent with COVID-19. Efficacy analyses will examine those participants who have laboratory-confirmed SARS-CoV-2 infection. [54]  

Niclosamide 

Niclosamide (FW-1002 [FirstWave Bio]; ANA001 [ ANA Therapeutics]) is an anthelmintic agent used primarily for tapeworms for nearly 50 years. Niclosamide is thought to disrupt SARS-CoV-2 replication through S-phase kinase-associated protein 2 (SKP2)-inhibition, by preventing autophagy and blocking endocytosis. 

A proprietary formulation that targets the viral reservoir in the gut to decrease prolonged infection and transmission has been developed, specifically to decrease gut viral load. It is being tested in a phase 2 trial. [55]  A phase 2/3 trial is testing safety and the potential to improved outcomes and reduce hospital stay by reducing viral load. [56]  

Table 1. Other Investigational Antivirals for COVID-19 (Open Table in a new window)

Antiviral Agent Description
PF-07304814 (Pfizer) [57]   IV SARS-CoV2-3CL protease inhibitor in phase 1b clinical trial in hospitalized patients.
PF-07321332 (Pfizer) [58]   Oral SARS-CoV2-3CL protease inhibitor in phase 1 clinical trial.
Ensovibep (MP0420; Molecular Partners and Novartis) [59]   [60] A designed ankyrin repeat protein (DARPin) engineered to contain domains that bind to the same epitope region within the SARS-CoV-2 spike glycoprotein RBD but with 3 different antigen-binding sequences. Part of NIH ACTIV-3 global phase 3 trial investigating safety and efficacy of ensovibep in adults hospitalized with COVID-19 in addition to existing standard of care, including remdesivir. 
Rintatolimod (Poly I:Poly C12U; Ampligen; AIM ImmunoTech) [61] Toll-like receptor 3 (TLR-3) agonist that is being tested as a potential treatment for COVID-19 by the National Institute of Infectious Diseases (NIID) in Japan and the University of Tokyo. A clinical trial for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), also call ‘Long Haulers’ syndrome, was announced in December 2020. It is a broad-spectrum antiviral agent with immunologic properties.
Bemcentinib (BerGenBio ASA) [62] Selective oral AXL kinase inhibitor, has previously been reported to exhibit potent antiviral activity in preclinical models against several enveloped viruses, including Ebola and Zika virus. Recent data have expanded this to SARS-CoV-2. A phase 2 study of bemcentinib in hospitalized patients with COVID-19 is planned as part of the UK’s Accelerating COVID-19 Research and Development (ACCORD) initiative.
Plitidepsin (Aplidin; PharmaMar) Member of the compound class known as didemnins. In vitro studies from Spain report plitidepsin potentially targets EF1A, which is key to multiplication and spread of the virus. [63]
VIR-2703 (ALN-COV; Vir Biotechnology Inc and Alnylam Pharmaceuticals, Inc) [64] In vitro data shows the drug targets small interfering RNA (siRNA). RNA interference (RNAi) is a natural cellular process of gene silencing. The siRNA molecules mediate RNAi function by silencing messenger RNA (mRNA). mRNA is the genetic precursor that encodes for disease-causing proteins. The companies plan to advance development of the drug candidate as an inhalational formulation.
Emetine hydrochloride (Acer Therapeutics) [65] Active ingredient of syrup of ipecac (given orally to induce emesis), has been formulated as an injection to treat amebiasis. Clinical trials have been conducted for viral hepatitis and varicella-zoster virus infection. Several in vitro studies have demonstrated potency against DNA and RNA-replicating viruses, including Zika, Ebola, Rabies Lyssavirus, CMV, HIV, influenza A, echovirus, metapneumovirus, and HSV2. It is also a potent inhibitor of multiple genetically distinct coronaviruses. Plans are underway to evaluate the safety and antiviral activity of emetine with an adaptive design phase 2/3 randomized, blinded, placebo-controlled multicenter trial in high-risk symptomatic adults with confirmed COVID-19 not requiring hospitalization.
AT-527 (Atea Pharmaceuticals) [66] Oral purine nucleotide prodrug designed to inhibit RNA polymerase enzyme. It has demonstrated in vitro and in vivo antiviral activity against several enveloped single-stranded RNA viruses, including human flaviviruses and coronaviruses. IND for phase 2 study accepted by FDA for patients hospitalized with moderate COVID-19.
Trabedersen (OT-101; Mateon Therapeutics, Oncotelic) [67] Antisense oligonucleotide that inhibits transforming growth factor (TGF)-beta2 expression. Viral replication requires cell cycle arrest that is mediated by viral induction of TBF-beta. Phase 2 trials initiated in India and Peru.
Stannous protoporphyrin (SnPP; RBT-9; Renibus Therapeutics) [68] Antiviral agent in phase 2 trial for treatment of COVID-19 in patients who are at high risk of deteriorating health owing to age or comorbid conditions (eg, kidney or cardiovascular disease).
Antroquinonol (Hocena; Golden Biotechnology Corp) [69] Antiviral/anti-inflammatory agent. Reduces viral nucleic acid replication and viral protein synthesis in both cell and animal experiments. Prevention of organ and tissue damage was also observed with antroquinonol when treating mice with excessive inflammation. The FDA has accepted the IND for a phase 2 clinical trial in patients with mild-to-moderate COVID-19 pneumonia.
Apilimod dimesylate (LAM-002A; AI Therapeutics) [70] Inhibits the lipid kinase enzyme PIKfyve. It disrupts lysosome dysfunction and interferes with the entry and trafficking of the SARS-CoV-2 virus in cells. Phase 2 trial is starting at Yale University in late July 2020.
Remdesivir inhaled (Gilead Science) [71] A phase 1b trial of inhaled nebulized remdesivir initiated in late June 2020 to determine if remdesivir can be used on an outpatient basis and at earlier stages of disease.
Brequinar (Clear Creek Bio, Inc) [72] Orally available dihydroorotate dehydrogenase (DHODH) inhibitor.  Shown in vitro to inhibit of viral SARS-CoV-2 viral replication, as well as a broad spectrum of RNA viruses. Inhibition of the DHODH enzyme causes pyrimidine depletion and reduces mitochondrial electron transport needed for viral replication. The phase 2 study (CRISIS2) in hospitalized patients was initiated in November 2020.
Brilacidin (Innovation Pharmaceuticals) [73]   [74] Host defense protein mimetic with antiviral, anti-inflammatory and antibacterial properties. It’s anti-inflammatory effects are attributed to inhibition of of IL-6, IL-1beta, TNF-alpha, and other proinflammatory cytokines. Potent in vitro antiviral activity against SARS-CoV-2 has been demonstrated. 
Sangivamycin (TNX-3500; Tonix Pharma) Preclinical phase. Demonstrated broad-spectrum antiviral activity in laboratory-based assays against the coronaviruses SARS-CoV-2 and MERS-CoV. 
Tempol (Adamis Pharmaceuticals) [75]   Identified as potential oral antiviral agent for treating COVID-19 infection. The drug demonstrated an ability to limit SARS-CoV-2 infection by impairing the activity of a viral enzyme RNA replicase. A phase 2/3 study is ongoing.
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Immunomodulators and Other Investigational Therapies

Various methods of immunomodulation are being quickly examined, mostly by repurposing existing drugs, in order to blunt the hyperinflammation caused by cytokine release. Interleukin (IL) inhibitors, Janus kinase inhibitors, and interferons are just a few of the drugs that are in clinical trials. Ingraham et al provide a thorough explanation and diagram of the SARS-CoV-2 inflammatory pathway and potential therapeutic targets. [76]  A review of pharmaco-immunotherapy by Rizk et al summarizes the roles and relationships of innate immunity and adaptive immunity, along with immunomodulators (eg, interleukins, convalescent plasma, JAK inhibitors) prevent and control infection. [77]  

NIH immune modulators trial 

In October 2020, the NIH launched an adaptive phase 3 trial (ACTIV-Immune Modulators [IM]) to assess safety and efficacy of 3 immune modulator agents in hospitalized patients with Covid-19. The three drugs are infliximab (Remicade), abatacept (Orencia), and cenicriviroc, a late-stage investigational drug for hepatic fibrosis associated with nonalcoholic steatohepatitis.  

Infliximab

Monoclonal antibody that inhibits TNF, a proinflammatory cytokine that may cause excess inflammation during advanced stages of COVID-19. Initially approved in 1998 to treat various chronic autoimmune inflammatory diseases (eg, rheumatoid arthritis, psoriasis, inflammatory bowel diseases). 

Abatacept

Selective T-cell costimulatory immunomodulator. The drug consists of the extracellular domain of human cytotoxic T cell-associated antigen 4 fused to a modified immunoglobulin. It works by preventing full activation of T cells, resulting in inhibition of the downstream inflammatory cascade.

Cenicriviroc

An immunomodulator that blocks 2 chemokine receptors, CCR2 and CCR5, shown to be closely involved with the respiratory sequelae of COVID-19 and of related viral infections. It is also part of the I-SPY COVID-19 clinical trial. [26]  

Interleukin inhibitors

Interleukin (IL) inhibitors may ameliorate severe damage to lung tissue caused by cytokine release in patients with serious COVID-19 infections. Several studies have indicated a “cytokine storm” with release of IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor-alpha (TNFα) and other inflammatory mediators. The increased pulmonary inflammatory response may result in increased alveolar-capillary gas exchange, making oxygenation difficult in patients with severe illness. 

Tocilizumab and other interleukin-6 inhibitors

IL-6 is a pleiotropic proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. This cascade of events is the rationale for studying IL-6 inhibitors. [78]  

Tocilizumab was issued an EUA on June 24, 2021 for hospitalized adults and pediatric patients (aged 2 years and older) with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 

The Infectious Diseases Society of America guidelines recommend tocilizumab in addition to standard of care (ie, steroids) among hospitalized adults with COVID-19 who have elevated markers of systemic inflammation. [16]  The NIH guidelines The NIH guidelines recommend use of tocilizumab (single IV dose of 8 mg/kg, up to 800 mg) in combination with dexamethasone in recently hospitalized patients who are exhibiting rapid respiratory decompensation caused by COVID-19. [79]  These recommendations are based on the paucity of evidence from randomized clinical trials to show certainty of mortality reduction. 

The EMPACTA trial found nonventilated hospitalized patients who received tocilizumab (n = 249) in the first 2 days of ICU admission had a lower risk of progression to mechanical ventilation or death by day 28 compared with those not treated with tocilizumab (n = 128) (12% vs 19.3% respectively; p = 0.04). The data cutoff for this study was September 30, 2020. In the 7 days before the trial or during the trial, 200 patients in the tocilizumab group (80.3%) and 112 patients in the placebo group (87.5%) received systemic glucocorticoids and 55.4% and 67.2% of the patients received dexamethasone. Antiviral treatment was administered in 196 (78.7%) and 101 (78.9%), respectively, and 52.6% and 58.6% received remdesivir. However, there was no difference in incidence of death from any cause between the 2 groups. [80]  

Results from the REMAP-CAP international adaptive trial evaluated efficacy of tocilizumab 8 mg/kg (n = 353), sarilumab 400 mg (n = 48), or control (n = 402) in critically ill hospitalized adults receiving organ support in intensive care. Hospital mortality at day 21 was 28% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab, and 35.8% (142/397) for control. Of note, corticosteroids became part of the standard of care midway through the trial. Estimates of the treatment effect for patients treated with either tocilizumab or sarilumab and corticosteroids in combination were greater than for any single intervention. [81]  

The RECOVERY trial assessed use of 4,116 hospitalized adults with COVID-19 infection who received either tocilizumab (n = 2,022) compared with standard of care (n = 2,094) in the United Kingdom from April 23, 2020 to January 24, 2021. Among participants, 562 (14%) received invasive mechanical ventilation, 1686 (41%) received non-invasive respiratory support, and 1868 (45%) received no respiratory support other than oxygen. Median C-reactive protein was 143 mg/L and most patients (82% in both treatment groups) were receiving systemic corticosteroids at randomization. The primary outcome of all-cause mortality within 28 days of randomization occurred in 35% of the usual care group compared with 31% of those who received tocilizumab (p = 0.0028). Tocilizumab mortality benefits were clearly seen among those who also received systemic corticosteroids. Patients in the tocilizumab group were more likely to be discharged from the hospital within 28 days (57% vs 50; p < 0.0001). Among those not receiving invasive mechanical ventilation at baseline, patients who received tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; p < 0.0005). [82]  

Conversely, the COVACTA study, 452 with COVID-19 (oxygen saturation, 93% or less) were randomly assigned in a 2:1 ratio to receive 1 dose of tocilizumab or placebo. At day 28, no significant difference was observed for mortality between the tocilizumab group and placebo (19.7% vs 19.4%, respectively). [83]

An editorial by Rubin et al discusses the discordant results of the RECOVERY and REMAP-CAP trials compared with the COVACTA trial. One significant difference noted is that patients with severe disease, now almost universally receive glucocorticoids. Only a minority of patients in the COVACTA trial were treated with glucocorticoids. Fewer in the group that received tocilizumab (19.4%) than in the group that received placebo (28.5%) also received glucocorticoids. In contrast, 93% and 82% of all patients in REMAP-CAP and the RECOVERY trial, respectively, were receiving glucocorticoid therapy. [84]  

Average whole sale price of tocilizumab is approximately $5000 for an 800-mg dose. Preliminary results for sarilumab have also been reported.

Interleukin-1 inhibitors

Endogenous IL-1 levels are elevated in individuals with COVID-19 and other conditions, such as severe CAR-T-cell–mediated cytokine-release syndrome. Anakinra has been used off-label for this indication. As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-1 inhibitors. [85]  

Interleukin-7 inhibitors

The recombinant interleukin-7 inhibitor, CYT107 (RevImmune), increases T-cell production and corrects immune exhaustion. Several phase 2 clinical trials have been completed in France, Belgium, and the UK to assess immune reconstitution in lymphopenic patients with COVID-19. [86, 87, 88] Phase 2 trials were initiated in November 2020 in the US.

JAK and NAK inhibitors

Drugs that target numb-associated kinase (NAK) may mitigate systemic and alveolar inflammation in patients with COVID-19 pneumonia by inhibiting essential cytokine signaling involved in immune-mediated inflammatory response. In particular, NAK inhibition has been shown to reduce viral infection in vitro. ACE2 receptors are a point of cellular entry by COVID-19, which is then expressed in lung AT2 alveolar epithelial cells. A known regulator of endocytosis is the AP2-associated protein kinase-1 (AAK1). The ability to disrupt AAK1 may interrupt intracellular entry of the virus. Baricitinib (Olumiant; Eli Lilly Co), a Janus kinase (JAK) inhibitor, is also identified as a NAK inhibitor with a particularly high affinity for AAK1. [89, 90, 91]  

Baricitinib

Emergency use authorization EUA was issued by the FDA for baricitinib on November 19, 2020. The EUA is for use, in combination with remdesivir, for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized patients aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [11]   

The NIAID Adaptive Covid-19 Treatment Trial (ACTT-2) evaluated the combination of baricitinib (4 mg PO daily up to 14 days) and remdesivir (100 mg IV daily up to 10 days) compared with remdesivir alone. The multinational trial included 1033 patients (515 received baricitinib plus remdesivir and 518 received control [remdesivir plus placebo]). Results demonstrated patients who received baricitinib had a median time to recovery of 7 days compared with 8 days with control (P = 0.03), and a 30% higher odds of improvement in clinical status at day 15. Additionally, those receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Incidence of serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; P = 0.03) There were also fewer new infections in patients who received baricitinib (5.9% vs. 11.2%; P =0 .003). [92]  

Tofacitinib

Tofacitinib (Xeljanz), another JAK inhibitor, was evaluated in 289 hospitalized patients with COVID-19 pneumonia were randomized 1:1 at 15 sites in Brazil. Most patients (89.3%) received glucocorticoids during hospitalization. Cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29% in the placebo group (P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group. [93]  

Corticosteroids

The UK RECOVERY trial assessed the mortality rate at day 28 in hospitalized patients with COVID-19 who received low-dose dexamethasone 6 mg PO or IV daily for 10 days added to usual care. Patients were assigned to receive dexamethasone (n = 2104) plus usual care or usual care alone (n = 4321). Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (P< 0.001). In the dexamethasone group, the incidence of death was lower than the usual care group among patients receiving invasive mechanical ventilation (29.3% vs 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%), but not among those who were receiving no respiratory support at randomization (17.8% vs 14%). [94]

Corticosteroids are not generally recommended for treatment of viral pneumonia. [95] The benefit of corticosteroids in septic shock results from tempering the host immune response to bacterial toxin release. The incidence of shock in patients with COVID-19 is relatively low (5% of cases). It is more likely to produce cardiogenic shock from increased work of the heart need to distribute oxygenated blood supply and thoracic pressure from ventilation. Corticosteroids can induce harm through immunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, such as respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS. [96]

Early guidelines for management of critically ill adults with COVID-19 specified when to use low-dose corticosteroids and when to refrain from using corticosteroids. The recommendations depended on the precise clinical situation (eg, refractory shock, mechanically ventilated patients with ARDS); however, these particular recommendations were based on evidence listed as weak. [97] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial. [94]

Several trials examining use of corticosteroids for COVID-19 were halted following publication of the RECOVERY trial results; however, a prospective meta-analysis from the WHO rapid evidence appraisal for COVID-19 therapies (REACT) pooled data from 7 trials (eg, RECOVERY, REMAP-CAP, CoDEX, CAP COVID) that totaled 1703 patients (678 received corticosteroids and 1025 received usual care or placebo). An association between corticosteroids and reduced mortality was similar for dexamethasone and hydrocortisone, suggesting the benefit is a general class effect of glucocorticoids. The 28-day mortality rate, the primary outcome, was significantly lower among corticosteroid users (32% absolute mortality for corticosteroids vs 40% assumed mortality for controls). [98]  An accompanying editorial addresses the unanswered questions regarding these studies. [99]  

WHO guidelines for use of dexamethasone (6 mg IV or oral) or hydrocortisone (50 mg IV every 8 hours) for 7-10 days in the most seriously ill patients coincides with publication of the meta-analysis. [100]  

Convalescent plasma

The FDA granted emergency use authorization (EUA) on August 23, 2020 for use of convalescent plasma in hospitalized patients with COVID-19. Convalescent plasma contains antibody-rich plasma products collected from eligible donors who have recovered from COVID-19. An expanded access (EA) program for convalescent plasma was initiated in early April 2020. [8, 101]  The Mayo Clinic coordinated the open-access COVID-19 expanded access program, but will discontinued enrollment on August 28, as the FDA authorized emergency use. 

NIH guidelines

The NIH COVID-19 Guidelines Panel further evaluated the Mayo Clinic’s EAP data and further reviewed subgroups. Among patients who were not intubated, 11% of those who received convalescent plasma with high antibody titers died within 7 days of transfusion compared with 14% of those who received convalescent plasma with low antibody titers. Among those who were intubated, there was no difference in 7-day survival. [102]

The NIH halted its trial of convalescent plasma in emergency departments for treatment of patients with mild symptoms as of March 2021. The second planned interim analysis of the trial data determined that while the convalescent plasma intervention caused no harm, it was unlikely to benefit this group of patients.

IDSA guidelines 

IDSA recommends limiting use of high-titer convalescent plasma for hospitalized patients with COVID-19 to the context of a clinical trial. Convalescent plasma transfusion failed to show or to exclude a beneficial or detrimental effect on mortality based on the body of evidence. [16]

Interferons

Laboratory studies suggest normal interferon response is suppressed in some people infected with SARS-CoV-2. In the laboratory, type 1 interferon can inhibit SARS-CoV-2 and two closely related viruses, SARS-CoV and MERS-CoV. [103]

The third iteration of the NIAID’s Adaptive COVID-19 Treatment Trial (ACTT-3) commenced in August 2020 to compare subcutaneous interferon beta-1a (Rebif) plus remdesivir versus remdesivir plus placebo. The ACTT-3 trial anticipates enrolling over 1000 patients in up to 100 sites across the United States. [104]

Miscellaneous Therapies

Nitric oxide

The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19 pneumonia. Instead, they suggest a trial only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies. The cost of iNO is reported as exceeding $100/hour.

Statins

In addition to the cholesterol-lowering abilities of HMG-CoA reductase inhibitors (statins), they also decrease the inflammatory processes of atherosclerosis. [105] Because of this, questions have arisen whether statins may be beneficial to reduce inflammation associated with COVID-19.

RCTs of statins as anti-inflammatory agents for viral infections are limited, and results have been mixed. 

Two meta-analyses have shown opposing conclusions regarding outcomes of patients who were taking statins at the time of COVID-19 diagnosis. [106, 107]  Randomized controlled trials are needed to examine the ability of statins to attenuate inflammation, presumably by inhibiting expression of the MYD88 gene, which is known to trigger inflammatory pathways. [108]  

Adjunctive Nutritional Therapies

NIH guidelines state there are insufficient evidence to recommend either for or against use of vitamins C and D, and zinc for treatment of COVID-19. The guidelines recommend against using zinc supplementation above the recommended dietary allowance.

Vitamin and mineral supplements have been promoted for the treatment and prevention of respiratory viral infections; however, there is insufficient evidence to suggest a therapeutic role in treating COVID-19. [109]

Zinc

A retrospective analysis showed lack of a causal association between zinc and survival in hospitalized patients with COVID-19. [110]

Vitamin D

A study found individuals with untreated vitamin D deficiency were nearly twice as likely to test positive for COVID-19 compared with peers with adequate vitamin D levels. Among 489 individuals, vitamin D status was categorized as likely deficient for 124 participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%). Seventy-one participants (15%) tested positive for COVID-19. In a multivariate analysis, a positive COVID-19 test was significantly more likely in those with likely vitamin D deficiency than in those with likely sufficient vitamin D levels (relative risk [RR], 1.77; 95% CI, 1.12 - 2.81; P = .02). Testing positive for COVID-19 was also associated with increasing age up to age 50 years (RR, 1.06; P = .02) and race other than White (RR, 2.54; P = .009). [111]  It is unknown if vitamin D deficiency is the specific issue, as it is also associated with various conditions that are risk factors for severe COVID-19 conditions (eg, advanced age, cardiovascular disease, diabetes mellitus). [112]  

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Additional Investigational Drugs for ARDS/Cytokine Release

Human Vasoactive Intestinal Polypeptides

Aviptadil (Zyesami; RLF-100; NeuroRx) is a synthetic vasoactive intestinal peptide (VIP) that prevents NMDA-induced caspase-3 activation in lungs and inhibits IL-6 and TNF-alpha production. An EUA was submitted to the FDA on June 1, 2021 to treat critically ill patients with COVID-19 infection and respiratory failure. Results from a phase 2b/3 trial of IV aviptadil for treatment of respiratory failure in critically ill patients with COVID-19 demonstrated meaningful recovery at days 28 (p = 0.014) and 60 (p = 0.013) and survival (P < 0.001). Patients enrolled in the study had respiratory failure despite prior treatment with all approved medicines for COVID-19 including remdesivir. Other therapies administered included steroids, anticoagulants, and various monoclonal antibodies. Although antiviral treatment has shown advantages in treating patients with earlier stages of COVID-19, aviptadil is the first to demonstrate increased recovery and survival in patients who have already progressed to respiratory failure. [113]   

Aviptadil is being studied as part of the NIH’s ACTIV-3 critical care protocol alone and in combination with remdesivir in hospitalized patients with ARDS.

Additionally, it is being studied as an inhaled treatment.  [114]

Colony-stimulating factors

Granulocyte-macrophage colony stimulating factor (GM-CSF) has been implicated in the pathogenesis of respiratory failure in patients with severe COVID-19 pneumonia and systemic hyperinflammation. 

Lenzilumab 

Lenzilumab (Humanigen) is a monoclonal antibody directed against GM-CSF. Results from a phase 3 trial (n = 520) found lenzilumab significantly improved survival without ventilation in hospitalized, hypoxic patients with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Those with CRP less than 150 mg/L and age younger than 85 years demonstrated an improvement in survival and had the greatest benefit. [115]   

Additionally, lenzilumab is part of the NIH ACTIV-5/BET trial that is ongoing as of April 2021. 

Sargramostim 

Sargramostim (Leukine, rhuGM-CSF; Partner Therapeutics, Inc) is an inhaled colony-stimulating factor. Results of the phase 2 trial (iLeukPulm) of inhaled sargramostim plus standard of care (SOC) in 122 hospitalized patients with confirmed SARS-CoV-2 infection with acute hypoxemia requiring supplemental oxygen were release in late June 2021. Patients on inhaled sargramostim plus SOC showed an average improvement in oxygenation from baseline, as measured by P(A-a)O2, of 100 mm Hg (31%) compared to 35 mm Hg (5%) on SOC alone (p = 0.033).  Improved oxygenation was observed in 84% of sargramostim-treated patients, compared with 64% in the control arm (p = 0.023). [116]  GM-CSF may reduce the risk of secondary infection, accelerate removal of debris caused by pathogens, and stimulate alveolar epithelial cell healing during lung injury. [117]  

Gimsilumab 

Gimsilumab (Riovant Sciences) is being studied in the phase 2 BREATHE clinical trial at Mt Sinai and Temple University is analyzing this monoclonal antibody that targets granulocyte macrophage-colony stimulating factor (GM-CSF) in patients with ARDS. [118]  

Mavrilimumab 

Mavrilimumab (Kiniksa Pharmaceuticals) is a fully humanized monoclonal antibody that targets granulocyte macrophage colony-stimulating factor (GM-CSF) receptor alpha. Results from an ongoing global phase 2/3 trial showed a significant reduction in need for mechanical ventilation and death in those receiving mavrilimumab. Mortality at day 29 was 21% in the placebo arm but just 8% in the combined mavrilimumab arms (P = .07). [119]  

Otilimab

Otilimab (GlaxoSmithKline) is a humanized monoclonal anti-GM-CSF antibody under development for rheumatoid arthritis. A global, randomized trial (OSCAR; n = 806) compared a single 90-mg infusion of otilimab plus standard of care (SOC) with SOC alone in hospitalized adults with severe COVID-19 respiratory failure and systemic inflammation.  At day 28, 71% of patients who received otilimab were alive and free of respiratory failure compared with 67% of SOC alone. Although this did not reach statistical significance in the entire population, benefit was observed those aged 70 years and older (p = 0.009). This age group also had a reduction of 14.4% in all-cause mortality at Day 60. These findings are being confirmed in a further cohort of patients aged 70 and older. [120]  

Neurokinin-1 (NK-1) receptor antagonists

Tradipitant 

Tradipitant (Vanda Pharmaceuticals) is an NK-1 receptor antagonist. The NK-1 receptor is genetically coded by TACR1 and it is the main receptor for substance P. The substance P NK-1 receptor system is involved in neuroinflammatory processes that lead to serious lung injury following numerous insults, including viral infections. ODYSSEY phase 3 trial in severe or critical COVID-19 infection reported an interim analysis on August 18, 2020.  Patients who received tradipitant recovered earlier than those receiving placebo. [121, 122]  

Aprepitant 

Aprepitant (Cinvanti; Heron Therapeutics) is a substance P/neurokinin-1 (NK1) receptor antagonist. Substance P and its receptor, NK1, are distributed throughout the body in the cells of many tissues and organs, including the lungs. Phase 2 clinical study (GUARDS-1) initiated mid-July 2020 in early-hospitalized patients with COVID-19. Administration to these patients is expected to decrease production and release of inflammatory cytokines mediated by the binding of substance P to NK1 receptors, which could prevent the progression of lung injury to ARDS. [123]

Mesenchymal stem cells

Remestemcel-L 

Remestemcel-L (Ryoncil; Mesoblast Ltd) is an allogeneic mesenchymal stem cell (MSC) product currently pending FDA approval for graft versus host disease (GVHD). On December 1, 2020, the FDA granted Fast Track designation for remestemcel-L in the treatment of ARDS due to COVID-19 infection. Fast Track designation is granted if a therapy demonstrates the potential to address unmet medical needs for a serious or life-threatening disease. [124]  

As of December 2020, the phase 3 trial for COVID-19 ARDS has enrolled about 200 of the goal of 300 ventilator-dependent patients with moderate-to-severe ARDS. The trial’s primary endpoint is overall mortality at Day 30, and the key secondary endpoint is days alive off ventilatory support through Day 60. Two interim analyses by the independent Data Safety Monitoring Board (DSMB) were completed after 90 and 135 patients were enrolled, with recommendations to continue the trial as planned. A third and final interim analysis is planned when 180 patients have completed 30 days of follow-up. A pilot study under emergency compassionate use at New York’s Mt Sinai Hospital in March-April this year showed 9 of 12 ventilator-dependent patients with moderate-to-severe COVID-19 ARDS were successfully discharged from hospital a median of 10 days after receiving 2 intravenous doses of remestemcel-L. Theorized mechanism is down-regulation of proinflammatory cytokines. [125, 124]  

PLX-PAD 

PLX-PAD (Pluristem Therapeutics) contains allogeneic mesenchymal-like cells with immunomodulatory properties that induce the immune system’s natural regulatory T cells and M2 macrophages. Initiating phase 2 study in mechanically ventilated patients with severe COVID-19. [126]  

BM-Allo.MSC 

BM-Allo.MSC (NantKwest, Inc) is a bone marrow-derived allogeneic mesenchymal stem cell product. IND for phase 1b trial initiating Q2 2020 in Los Angeles area hospitals. [127]  

HB-adMSC

Autologous, adipose-derived mesenchymal stem cells (HB-adMSCs; Hope Biosciences) has been shown to attenuate systemic inflammation in phase 1/2 clinical trial for rheumatoid arthritis. Three phase 2 trials are in progress that include patients aged 50 years and older with preexisting health conditions or at high exposure risk, frontline healthcare workers or first responders, and a placebo-controlled study. [128]  

hCT-MSCs 

A multicenter trial using human cord tissue mesenchymal stromal cells (hCT-MSC) for children with multisystem inflammatory syndrome (MIS) was initiated in September 2020. The study will assess if infusion of hCT-MSCs are safe and can suppress the hyperinflammatory response associated with MIS. Duke University is coordinating the study, and is manufacturing the cells at the Robertson GMP cell laboratory. [129]  

ExoFlo

ExoFlo (Direct Biologics) is a paracrine signaling exosome product isolated from human bone marrow MSCs. The EXIT COVID-19 phase 2 study is enrolling patients and was granted expanded access by the FDA to be provided to patients with ARDS. [130]  

Phosphodiesterase inhibitors

Ibudilast 

Ibudilast (MN-166; MediciNova) is a first-in-class, orally bioavailable, small molecule phosphodiesterases (PDE) 4 and 10 inhibitor and a macrophage migration inhibitory factor (MIF) inhibitor that suppresses proinflammatory cytokines and promotes neurotrophic factors. The drug has been approved in Japan and South Korea since 1989 to treat post-stroke complications and bronchial asthma. An IND for a phase 2 trial in the United States to prevent ARDS has been accepted by the FDA. [131]

Apremilast 

Apremilast (Otezla; Amgen Inc) is a small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels, which may indirectly modulate the production of inflammatory mediators. Part of the I-SPY COVID-19 clinical trial.  

Table 2. Investigational Drugs for ARDS/Cytokine Release Associated With COVID-19 (Open Table in a new window)

Drug Description
Ifenprodil (NP-120; Algernon Pharmaceuticals) [132] N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonist. NMDA is linked to inflammation and lung injury. An injectable and long-acting oral product are under production to begin clinical trials for COVID-19 and acute lung injury. The phase 2b part of the 2b/3 study completed enrollment mid-December 2020. Key findings were no mortality at Day 15 in ifenprodil treated patients compared with 3.3% in those in the standard of care (SOC) group. Oxygenation returned to normal at day 4 compared with day 9 in the treated vs SOC groups respectively.
Eculizumab (Soliris; Alexion) [133] Modulates activity of terminal complement to prevent the formation of the membrane attack complex; 10-patient proof of concept completed; if 100-patient single-arm trial in the United States and Europe for 2 weeks shows a positive risk/benefit ratio, a 300-patient randomized controlled trial will proceed.
Ravulizumab (Ultomiris; Alexion) [134] Monoclonal antibody that is a C5 complement inhibitor. Phase 3 randomized controlled trial in hospitalized adults with severe pneumonia or acute ARDS requiring mechanical ventilation was initiated in April 2020, but was paused in January 2021 owing to initial outcomes not showing efficacy. Another phase 3 trial (TACTIC-R) in the UK is studying use of earlier immune modulation in preventing disease progression. 
ATYR1923 (aTyr Pharma, Inc) [135] Phase 2 randomized, double-blind, placebo-controlled trial at up to 10 centers in the United States. In preclinical studies, ATYR1923 (a selective modulator of neuropilin-2) has been shown to down-regulate T-cell responses responsible for cytokine release.
BIO-11006 (Biomark Pharmaceuticals) [136] Results of a phase 2a study for 38 ventilated patients with ARDS showed 43% reduction at day 28 in the all-cause mortality rate. This study was initiated in 2017. The company is in discussion with the FDA to proceed with a phase 3 trial.
Dociparstat sodium (DSTAT; Chimerix) [137] Glycosaminoglycan derivative of heparin with anti-inflammatory properties, including the potential to address underlying causes of coagulation disorders. Phase 2/3 trial starting May 2020.
Opaganib (Yeliva; RedHill Biopharma Ltd) [138, 139] Orally administered sphingosine kinase-2 (SK2) inhibitor that may inhibit viral replication and reduce levels of IL-6 and TNF-alpha. Nonclinical data indicate both antiviral and anti-inflammatory effects. As of December 2020, the phase 2/3 trial has enrolled more than 60% of participants, who are hospitalized patients with severe COVID-19 who have developed pneumonia and require supplemental oxygen. 
Tranexamic acid (LB1148; Leading BioSciences, Inc) [140] Oral/enteral protease inhibitor designed to preserve GI tract integrity and protect organs from proteases leaking from compromised mucosal barrier that can lead to ARDS. Phase 2 study announced May 15, 2020.
DAS181 (Ansun Biopharma) [141] Recombinant sialidase drug is a fusion protein that cleaves sialic receptors. Phase 3 substudy for COVID-19 added to existing study for parainfluenza infection.
AT-001 (Applied Therapeutics) [142] Aldose reductase inhibitor shown to prevent oxidative damage to cardiomyocytes and to decrease oxidative-induced damage.
CM4620-IE (Auxora; CalciMedica, Inc) [143]

Calcium release-activated calcium (CRAC) channel inhibitor that prevents CRAC channel overactivation, which can cause pulmonary endothelial damage and cytokine storm. Results in mid-July 2020 from a small randomized, controlled, open-label study showed CM4620-IE (n = 20) combined with standard of care therapy (n = 10) improved outcomes in patients with severe COVID-19 pneumonia, showing faster recovery (5 days vs 12 days), reduced use of invasive mechanical ventilation (18% vs 50%), and improved mortality rate (10% vs 20%) compared with standard of care alone. Part 2 of this trial will start late summer and will be a placebo-controlled trial, possibly including both remdesivir and dexamethasone.

Intranasal vazegepant (Biohaven Pharmaceuticals) [144] Calcitonin gene-related peptide (CGRP) receptor antagonist. Received FDA may proceed letter to initiate phase 2 study. Acute lung injury induces up-regulation of transient receptor potential (TRP) channels, activating CGRP release. CGRP contributes to acute lung injury (pulmonary edema with acute-phase cytokine/mediator release, with immunologic milieu shift toward TH17 cytokines). A CGRP receptor antagonist may blunt the severe inflammatory response at the alveolar level, delaying or reversing the path toward oxygen desaturation, ARDS, requirement for supplemental oxygenation, artificial ventilation, or death.
Selinexor (Xpovio; Karyopharma Therapeutics) [145] Selective inhibitor of nuclear export (SINE) that blocks the cellular protein exportin 1 (XPO1), which is involved in both replication of SARS-CoV-2 and the inflammatory response to the virus. An interim analysis indicated that the trial was unlikely to meet its prespecified primary endpoint across the entire patient population studied, and has since been discontinued. However, the results demonstrated encouraging antiviral and anti-inflammatory activity for a subset of treated patients with low baseline LDH or D-dimer.
EDP1815 (Evelo Biosciences; Rutgers University; Robert Wood Johnson University Hospital) [146, 147] Phase 2/3 trials underway in the United States and United Kingdom to determine if early intervention with oral EDP1815 (under development for psoriasis) prevents progression of COVID-19 symptoms and complications in hospitalized patients ≥15 years with COVID-19 who presented at the ER within the preceding 36 hours. The drug showed marked activity on inflammatory markers (eg, IL-6, IL-8, TNF, IL-1b) in a phase 1b study.
VERU-111 (Veru, Inc) [148, 149] Microtubule depolymerization agent that has broad antiviral activity and has strong anti-inflammatory effects. As of August 2020, a phase 2 trial is underway for hospitalized patients with COVID-19 at high risk for ARDS.
Vascular leakage therapy (Q BioMed; Mannin Research) [150] Targets the angiopoietin-Tie2 signaling pathway to reduce endothelial dysfunction.
Trans sodium crocetinate (TSC; Diffusion Pharmaceuticals) [151, 152] TSC increases the diffusion rate of oxygen in aqueous solutions. Guidance has been received from the FDA for a phase 1b/2b clinical trial.
Rayaldee (calcifediol; OPKO Health) [153] Extended-release formulation of calcifediol (25-hydroxyvitamin D3), a prohormone of the active form of vitamin D3. Phase 2 trial (REsCue) objective is to raise and maintain serum total 25-hydroxyvitamin D levels to mitigate COVID-19 severity. Raising serum levels is believed to enable macrophages.
Deupirfenidone (LYT-100; PureTech Bio) [154] Deuterated form of pirfenidone, an approved anti-inflammatory and anti-fibrotic drug. Inhibits TGF-beta and TNF-alpha.  Phase 2 trial initiated in December 2020 for long COVID syndrome to evaluate use for serious respiratory complications, including inflammation and fibrosis, that persist following resolution of SARS-CoV-2 infection.
OP-101 (Ashvattha Therapeutics) [155] Selectively targets reactive macrophages to reduce inflammation and oxidative stress.
Vidofludimus calcium (IMU-838; Immunic Therapeutics) [156, 157] Oral dihydroorotate dehydrogenase (DHODH) inhibitor. DHODH is located on the outer surface of the inner mitochondrial membrane. Inhibitors of this enzyme are used to treat autoimmune diseases. Phase 2 CALVID-1 clinical trial for hospitalized patients with moderate COVID-19. Another phase 2 trial (IONIC) in the UK combines vidofludimus with oseltamivir for moderate-to-severe COVID-19.
Vafidemstat (ORY-2001; Oryzon) [158] Oral CNS lysine-specific histone demethylase 1 (LSD1) inhibitor. Phase 2 trial (ESCAPE) initiated in May 2020 to prevent progression to ARDS in severely ill patients with COVID-19.
Icosapent ethyl (Vascepa; Amarin Co) [159] Randomized, open-label study (CardioLink-9; n = 100) focuses on reduction of circulating proinflammatory biomarkers (eg, high-sensitivity C-reactive protein [hsCRP, D-dimer) in COVID-infected outpatients. Patients in the icosapent ethyl group received a loading dose of 8 g/day for 3 days followed by 4 g/day for 11 days plus usual care. Icosapent ethyl showed a 25% reduction in hsCRP (p = 0.011) and a reduction in D-dimer (p = 0.048). Additionally, icosapent ethyl resulted in a significant 52% reduction of the total FLU-PRO prevalence score (flulike symptoms) compared with 24% reduction in the usual care group (p = 0.003). 
Prazosin (Johns Hopkins) [160, 161] Cytokine storm syndrome is accompanied by increased catecholamine release. This amplifies inflammation by enhancing IL-6 production through a signaling loop that requires the alpha1 adrenergic receptor. A clinical trial at Johns Hopkins University is using prazosin, an alpha1 receptor antagonist, to evaluate its effects to prevent cytokine storm.
Aspartyl-alanyl diketopiperazine (DA-DKP; AmpionTM; Ampio Pharmaceuticals) [162] Low-molecular weight fraction of human serum albumin (developed for inflammation associated with osteoarthritis). Theorized to reduce inflammation by suppressing pro-inflammatory cytokine production in T-cells. Phase 1 trial results of IV Ampion or standard of care (eg, remdesivir and/or convalescent plasma) were evaluated in September 2020. IND granted for phase 1 trial of inhaled Ampion in September 2020.
Losmapimod (Fulcrum Therapeutics) [163] Selective inhibitor of p38alpha/beta mitogen activated protein kinase (MAPK), which is known to mediate acute response to stress, including acute inflammation. FDA authorized a phase 3 trial (LOSVID) for hospitalized patients with COVID-19 at high risk. Losmapimod has been evaluated in phase 2 clinical trials for facioscapulohumeral muscular dystrophy (FSHD).
DUR-928 (Durect Corp) [164] Endogenous epigenetic regulator. Preclinical trials have shown the drug regulates lipid metabolism, inflammation, and cell survival. The FDA accepted the IND application. A phase 2 study is planned for approximately 80 hospitalized patients with COVID-19 who have acute liver or kidney injury.
ATI-450 (Aclaris Therapeutics, Inc) [165] IND approved mid-June 2020 for use in hospitalized patients with COVID-19. ATI-450 is an oral mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, or MK2) inhibitor that targets inflammatory cytokine expression. In a phase 1 clinical trial in healthy volunteers at the University of Kansas Medical Center, researchers used a first-in-human study using an ex vivo lipopolysaccharide (LPS) stimulation model that demonstrated a dose-dependent reduction of TNF-alpha, IL-1-beta, IL-6, and IL-8.
Leronlimab (Vyrologix; CytoDyn) [166, 167] CCR5 antagonist. A phase 2 trial for mild-to-moderate COVID-19 is ongoing. The phase 3 trial in severe-to-critical patients is fully enrolled (n = 390) as of December 2020 and an open-label extension trial has been added to the protocol. Laboratory data following leronlimab administration in 15 patients showed increased CD8 T-lymphocyte percentages by day 3, normalization of CD4/CD8 ratios, and resolving cytokine production, including reduced IL-6 levels correlating with patient improvement. 
Sarconeos (BIO101; Biophytis SA) [168] Activates MAS, a component of the protective arm of the renin angiotensin system. Phase 2/3 trial (COVA) international trial assessing potential treatment for ARDS.
Abivertinib (Sorrento Therapeutics) [169] Tyrosine kinase inhibitor with dual selective targeting of mutant forms of EGFR and BTK. Phase 2 trial starting late July 2020 in hospitalized patients with moderate-to-severe COVID-19 who have developing cytokine storm in the lungs.
Nangibotide (LR12; Inotrem S.A.) [170] Immunotherapy that targets the triggering receptor expressed on myeloid cells-1 (TREM-1) protein pathway, a factor causing unbalanced inflammatory responses. Phase 2a clinical trial (ASTONISH) authorized in the United States, France, and Belgium for mechanically ventilated patients with COVID-19 who have systemic inflammation. Previous clinical studies demonstrated safety and tolerability in patients with septic shock.
Piclidenoson (Can-Fite BioPharma) [171] A3 adenosine receptor (A3AR) agonist that elicits anti-inflammatory effects. Phase 2 trial planned in the United States to start late July 2020 involving hospitalized patients with moderate COVID-19.
LSALT peptide (MetaBlokTM; Arch Biopartners) [172] LSALT peptide that targets dipeptidase-1 (DPEP1), which is a vascular adhesion receptor for neutrophil recruitment in the lungs, liver, and kidney. The first US phase 2 trial will be at Broward Health Medical Center in Florida to treat complications in patients with COVID-19, including prevention of acute lung and/or kidney injury.
RLS-0071 (ReAlta Life Sciences) [173] Animal model shows RLS-0071 decreases inflammatory cytokines IL-1b, IL-6, and TNF-alpha. A phase 1 randomized, double-blind, placebo-controlled trial is planned to begin Q3 2020 in adults with COVID-19 pneumonia and early respiratory failure.
BLD-2660 (Blade Therapeutics) [174] Antifibrotic agent. Targets a specific group of cysteine proteases called dimeric calpains (calpains 1, 2 and 9). Overactivity of dimeric calpains leads to inflammation and fibrosis. Phase 2 trial (CONQUER) in hospitalized patients (n = 120) with COVID pneumonia completed in September 2020. 
EC-18 (Enzychem Lifesciences) [175] Preclinical studies observed EC-18 to control neutrophil infiltration, thereby modulating the inflammatory cytokine and chemokine signaling. A phase 2 multicenter, randomized, double-blind, placebo-controlled study is being initiated in the US to evaluate the safety and efficacy of EC-18 in preventing the progression of COVID-19 infection to severe pneumonia or ARD.
SBI-101 (Sentien Biotechnologies) [176] Biologic/device combination product designed to regulate inflammation and promote repair of injured tissue using allogeneic human mesenchymal stromal cells. The phase 1/2 study integrates SBI-101 into the renal replacement circuit for treatment up to 24 hours in patients with ARDS and acute kidney injury requiring renal replacement therapy (RRT).
Bacille Calmette-Guérin (BCG) vaccine (Baylor, Texas A&M, and Harvard Universities; MD Anderson and Cedars-Sinai Medical Centers) [177] Areas with existing BCG vaccination programs appear to have lower incidence and mortality from COVID19. Study administers BCG vaccine to healthcare workers to see if reduces infection and disease severity during SARS-CoV-2 epidemic.
ARDS-003 (Tetra Bio-Pharma) [178] Cannabinoid that specifically targets CB2 receptor. Phase 1 clinical trial planned to evaluate anti-inflammatory properties and reduce cytokine release to prevent ARDS.
CAP-1002 (Capricor Therapeutics) [179] CAP-1002 consists of allogeneic cardiosphere-derived cells (CDCs), a type of cardiac cell therapy that has been shown in preclinical and clinical studies to exert potent immunomodulatory activity. CDCs releasing exosomes that are taken up largely by macrophages and T-cells and begin a cycle of repair. A phase 2 trial (INSPIRE) in hospitalized patients with severe or critical COVID-19 was initiated in late 2020.
Icatibant (Firazyr; Takeda Pharmaceuticals) [26] Competitive antagonist selective for bradykinin B2 receptor. Bradykinin formation results in vascular leakage and edema. Part of the I-SPY COVID-19 clinical trial.
Razuprotafib (AKB-9778; Aerpio Pharmaceuticals) [26] Tie2 activator that enhances endothelial function and stabilizes blood vessels, including pulmonary and renal vasculature. SC razuprotafib restores Tie2 activation and improves vascular stability in multiple animal models of vascular injury and inflammation, including lipopolysaccharide-induced pulmonary and renal injury, polymicrobial sepsis, and IL-2 induced cytokine storm. Part of the I-SPY COVID-19 clinical trial.
Fenretinide (LAU-7b; Laurent Pharmaceuticals) [180] Synthetic retinoid shown to address the complex links between fatty acids metabolism and inflammatory signaling, which is distinct from the retinoid class MOA. Believed to work by modulating key membrane lipids in conjunction with proinflammatory pathways (eg, ERK1/2, NF-kappa-B, and cPLA2) needed for coronavirus entry, replication, and host defense evasion. It may also have antiviral properties. The phase 2 RESOLUTION trial in Canada has also gained FDA approval in August 2020 for an IND in the US.
Ebselen (SPI-1005; Sound Pharmaceuticals) [181] Anti-inflammatory molecule that mimics and induces glutathione peroxidase. It reduces reactive oxygen and nitrogen species by first binding them to selenocysteine, and then reducing the selenic acid intermediate through a reduction with glutathione. May also inhibit viral replication. Phase 2 studies for moderate and severe COVID-19 infection initiated in Fall 2020.
Fostamatinib (Tavalisse; Rigel Pharmaceuticals) [182] Spleen tyrosine kinase (SYK) inhibitor that reduces signaling by Fc gamma receptor (FcγR) and c-type lectin receptor (CLR), which are drivers of proinflammatory cytokine release. It also reduces mucin-1 protein abundance, which is a biomarker used to predict ARDS development. Clinical trial initiated at the NIH clinical center.
Vadadustat (Akebia Therapeutics) [183] Oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor designed to mimic the physiologic effect of altitude on oxygen availability and increased RBC production. Approved in Japan for anemia owing to chronic kidney disease (in phase 3 trials in US). Phase 2 trial initiated at U of Texas Health Center in Houston for prevention and treatment of ARDS in hospitalized patients with COVID-19. 
Ultramicronized palmitoylethanolamide (PEA; FSD201; FSD Pharma) [184] Fatty acid amide studied for its anti-inflammatory and analgesic actions. Phase 2a trial expected to begin in October 2020 for hospitalized patients with documented COVID-19 disease.
EB05 (Edesa Biotech) [185] Toll-like receptor 4 (TLR4) inhibitor. TLR4 is a key component of the innate immune system which functions to detect molecules generated by pathogens, acting upstream of cytokine storm and IL-6-mediated acute lung injury.
Fluvoxamine (Luvox) [186] Preliminary double, randomized study of nonhospitalized adults with COVID-19 in community living environment showed no clinical deterioration at Day 15 compared with those taking placebo. Limited sample size with short follow-up. Clinical efficacy would require larger randomized trial. Theorized mechanisms include fluvoxamine effects on the S1R agonism (an endoplasmic reticulum chaperone protein), anti-inflammatory actions, and SSRI inhibition of platelet activation. 
Lanadelumab (Takeda) [187] mAb that targets kallikrein. Inhibits kallikrein proteolytic activity to control excess bradykinin. Part of the COVID R&D alliance (Amgen, UCB SA, Takeda) to identify drugs that can reduce severity of COVID-19 in hospitalized patients by moderating the immune system. 
Zilucoplan (UCB SA) [187] Macrocyclic peptide inhibitor of complement C5. Part of the COVID R&D alliance (Amgen, UCB SA, Takeda) to identify drugs that can reduce severity of COVID-19 in hospitalized patients by moderating the immune system.
CRV431 (Hepion) [188] Binds cyclophilin A, which blocks the binding of cyclophilin A to specific receptors on inflammatory cells. This decreases infiltration of the cells into the tissue and production of harmful inflammatory molecules, resulting in reduced lung inflammation. Phase 2 trial starting late 2020. 
Ensifentrine (Verona Pharma) [189] Phosphodiesterase (PDE) 3 and 4 inhibitor. Elicits both bronchodilator and anti-inflammatory activities. Delivered via pressurized metered-dose inhaler. Phase 2 trial in 45 patients completed January 2021. 
TZLS-501 (Tiziana Life Sciences)  [190] Anti-interleukin-6 receptor monoclonal antibody in early development.
Apabetalone (Resverlogix Corp) [191]   Bromodomain and extra-terminal domain (BET) protein function is required for inflammation. BET inhibitors reversibly bind the bromodomains of BET proteins and prevent the protein-protein interaction between BET proteins and acetylated histones and transcription factors. Apabetalone, a BET inhibitor, reduces the expression of both ACE2 and DPP4 at the surface of human lung epithelial cells. Initiating open-label trials mid-2021 for apabetalone plus standard of care.
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Investigational Immunotherapies

Bucillamine

Bucillamine (Revive Therapeutics) is an antirheumatic agent derived from tiopronin. It has been available in Japan and South Korea for over 30 years. N-acetyl-cysteine (NAC) has been shown to significantly attenuate clinical symptoms in respiratory viral infections in animals and humans, primarily via donation of thiols to increase antioxidant activity of cellular glutathione. Bucillamine has 2 thiol groups and its ability as a thiol donor is estimated to be 16 times that of NAC. A phase 3 confirmatory trial for treatment of outpatients with mild-to-moderate COVID-19 at 10 sites in the US planned for Q1 2021 with enrollment goal of 1000 participants. [192]

MK-7110

MK-7110 (formerly CD24Fc; Merck) is a biological immunomodulator in Phase II/III clinical trial stage. It is a fusion protein comprised of the nonpolymorphic regions of CD24 attached to the Fc region of human IgG1. An interim analysis in September 2020 of data from the Phase 3 trial (SAC-COVID) in 243 participants (full enrollment) indicated that hospitalized patients with COVID-19 treated with a single dose of MK-7110 showed a 60% higher probability of improvement in clinical status compared to placebo, as defined by the protocol. The risk of death or respiratory failure was reduced by more than 50%. [193]

  Table 3. Investigational Immunotherapies for COVID-19 (Open Table in a new window)

Immunotherapy Description
Allogeneic natural killer (NK) cells (CYNK-001; Celularity, Inc) [194] Phase 1/2 clinical trial results assessed by data monitoring committee in December 2020 and confirmed absence of dose-limiting toxicities. Demonstrates a range of biological activities expected of NK cells, including expression of activating receptors (eg, NKG2D, DNAM-1, and the natural cytotoxicity receptors NKp30, NKp44, and NKp46), which bind to stress ligands and viral antigens on infected cells.
ADX-629 (Aldeyra Therapeutics) [195] Oral reactive aldehyde species (RASP) inhibitor. RASP inhibitors have the potential to represent upstream immunological switches that modulate immune systems from pro-inflammatory states to anti-inflammatory states. Phase 2 placebo-controlled trial in hospitalized patients with COVID-19 initiated December 2020.
MultiStem cell therapy (Athersys) [196] Potential to produce therapeutic factors in response to signals of inflammation and tissue damage. A previous phase 1/2 study assessed therapy in ARDS. The first patient has been enrolled in the phase 2/3 trial—MultiStem Administration for COVID-19 Induced Acute Respiratory Distress Syndrome (MACOVIA) at University Hospital’s Cleveland Medical Center.
Foralumab intranasal (Tiziana Life Sciences) [197] Fully human anti-CD3 monoclonal antibody (mAb) found to induce regulatory T-cells, resulting in an IL-10 anti-inflammatory signal. Phase 2 trial planned in Brazil.
Peginterferon lambda (Eiger Biopharmaceuticals; Stanford University) [198] Type Ill interferon (IFN) that stimulates immune responses critical for the development of host protection during viral infections. A phase 2 double-blind, placebo-controlled trial (ILIAD) was conducted between May 18 and September 4 2020 in outpatients with COVID-19. Patients received a single SC injection of either peginterferon lambda 180 mcg (n=30) or placebo (n=30). The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2.42 log copies per mL at day 7 (p = 0.0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p = 0.15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (p = 0.029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with 6 (38%) of 16 in the placebo group (p = 0.012). Among the 60 patients followed in the study, 5 required emergency room visits due to deteriorating respiratory symptoms (4 in the placebo group, 1 in the peg-IFN-lambda group). 
Immune globulin IV (Octagam 10%; Octapharma) [199] Pilot study showed that IVIG plus IV methylprednisolone significantly improved hypoxia and reduced hospital length of stay and progression to mechanical ventilation in coronavirus disease 2019 patients with A-a gradient greater than 200 mm Hg compared with standard of care. A phase 3 multicenter randomized double-blinded clinical trial is under way to validate these findings.
Efineptakin alfa (NT-17; NeoImmuneTech, Inc) [200] A long-acting human interleukin-7 (IL-7), which plays a key role in T-cell development. IL-7 acts through IL-7 receptor (IL-7R), which is expressed on naïve and memory CD4+ and CD8+ T cells and promotes proliferation, maintenance, and functionality of these T-cell subsets that mediate immune responses. A phase 1 trial initiated late 2020 for adults with mild COVID-19 in conjunction with NIAID and the University of Nebraska Medical Center.
Vilobelimab (IFX-1;  InflaRx) [201] First-in-class monoclonal anti-human complement factor C5a antibody. IFX-1 blocks the biological activity of C5a and demonstrates high selectivity toward its target in human blood; therefore, it leaves the formation of the membrane attack complex (C5b-9) intact as an important defense mechanism, which is not the case for molecules blocking C5 cleavage. Phase 3 trial (PANAMO) initiated September 2020 for treatment of COVID-19 related severe pneumonia.  
T-COVID (Altimmune) [202] Intranasal immune modulator in phase 1/2 trial (EPIC) in US for non-hospitalized patients with early COVID-19 infection.  
ALVR109 (AlloVir) [203] Allogeneic virus-specific T-cell therapy that targets SARS-CoV-2. Comprised almost exclusively of CD3+ T cells, with a mixture of cytotoxic (CD8+) and helper (CD4+) T cells. Phase 1 trial in hospitalized patients at high risk for mechanical ventilation started Q4 2020.
Inhaled interferon beta-1a (SNG001; Synairgen Research Ltd) [204] IFN-beta is a naturally occurring protein. Deficiency of IFN-beta increases susceptibility to more severe respiratory symptoms among older and at-risk patients. It is theorized that SNG001 helps restore the lung IFN-beta ability to neutralize the virus. Positive results (fewer days to discharge) from a phase 2 study (101 hospitalized patients with COVID-19) in the UK support continuing clinical trials.
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Investigational Antibody Therapies

Antibodies Granted Emergency Use Authorization

Information, including allocation, for COVID-19 therapies granted emergency use authorization is located at the United States Public Health Emergency webpage. 

Owing to the increase in variants of concern (VOC) in the United States, monoclonal antibodies that have gained emergency use authorization have been tested to evaluate activity against VOCs. As of March 24, 2021, U.S. distribution ceased for bamlanivimab alone. On June 25, 2021, U.S. distribution ceased for bamlanivimab plus etesevimab as the P.1/Gamma and B.1.351/Beta variants (first identified in Brazil and South Africa) exceeded 11% of throughout the United States. Consider use of casirivimab plus imdevimab or sotrovimab in outpatients who qualify for monoclonal antibodies. 

Casirivimab plus imdevimab

An EUA was issued for intravenous coadministration of the monoclonal antibodies casirivimab and imdevimab (REGN-COV; Regeneron) on November 21, 2020 for treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years and older who weigh at least 40 kg and are at high risk for progressing to severe COVID-19 and/or hospitalization. [10] The mixture is designed to bind to 2 points on the SARS-CoV-2 spike protein. As with bamlanivimab, administration of casirivimab and imdevimab has not shown benefit in hospitalized patients with severe COVID-19.

Treatment trials

Intravenous casirivimab and imdevimab did show reduced viral levels and improved symptoms in nearly 800 non-hospitalized patients with COVID-19 disease in a phase 2/3 trial. Results showed treatment with the 2 antibodies reduced COVID-19 related medical visits by 57% through day 29 (2.8% combined dose groups; 6.5% placebo; p = 0.024). In high risk patients (1 or more risk factor including age older than 50 years; body mass index greater than 30; cardiovascular, metabolic, lung, liver or kidney disease; or immunocompromised status) COVID-19 related medical visits were reduced by 72% (p = 0.0065). [205, 206]  

A phase 3 trial (n = 4,567) in infected outpatients who were at high risk for hospitalization or severe COVID-19 disease found casirivimab plus imdevimab significantly reduced the risk of hospitalization or death. Risk was decreased by 70% with the 1200 mg IV dose (n = 827) and by 71% with 2400 mg IV (n = 1,849) compared with placebo (n = 1,843). [207]  In June 2021, the EUA was updated with a lower IV dose of casirivimab 600 mg and imdevimab 600 mg. The update also allows administration as a SC injection for when an IV infusion is not feasible. 

An ongoing phase 1/2/3 clinical trial of the IV antibody cocktail in hospitalized patients with COVID-19 disease requiring low-flow oxygen found encouraging results. Patients who had not yet mounted their own immune response to SARS-CoV-2 (ie, seronegative for antibodies at baseline) had a lower risk of death or progression to mechanical ventilation after receiving casirivimab and imdevimab (HR: 0.78; 80% CI: 0.51-1.2). Risk of death or mechanical ventilation decreased by approximately 50% after 1 week following treatment with the antibody cocktail. Seronegative patients (n = 217) had much higher viral loads than those who had already developed their own antibodies (seropositive [n = 270]) to SARS-CoV-2 at the time of randomization. In seronegative patients, the antibody cocktail reduced the time-weighted average daily viral load through day 7 by -0.54 log10 copies/mL, and through day 11 by -0.63 log10 copies/mL (nominal p = 0.002 for combined doses). As expected, the clinical and virologic benefit of the antibody cocktail was limited in seropositive patients. [208, 209]    

The UK-based RECOVERY trial showed reduced 28-day mortality among hospital patients who were seronegative at baseline for antibodies. Between September 18, 2020 and May 22, 2021, 9785 patients were randomly allocated to receive usual care plus casirivimab/imdevimab or usual care alone, including 3153 (32%) seronegative patients, 5272 (54%) seropositive patients, and 1360 (14%) patients with unknown baseline antibody status. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to casirivimab/imdevimab and 451 (30%) of 1520 patients allocated to usual care died within 28 days (p = 0.001). In an analysis involving all randomized patients (regardless of baseline antibody status), 944 (20%) of 4839 patients allocated to casirivimab/imdevimab and 1026 (21%) of 4946 patients allocated to usual care died within 28 days (p = 0.17). The proportional effect of mortality differed significantly between seropositive and seronegative patients for those who received the monoclonal antibody combination (p = 0.001). [210]  

Prevention trials

A phase 3 trial showed an 81% reduced risk of symptomatic SARS-CoV-2 infection of household contacts following exposure through day 29. Participants received either a single 1,200-mg SC dose of casirivimab and imdevimab (n = 753) or placebo (n=752) within 4 days following exposure. Risk of symptomatic infection was decreased by 72% in the first week, and 93% in subsequent weeks. Among individuals who developed symptomatic infections, those who received casirivimab and imdevimab cleared the virus faster and had a shorter duration of symptoms compared with placebo. [211]  

Sotrovimab

Sotrovimab (VIR-7831; VIR Biotechnology; GlaxoSmithKline) is a mAb that binds to conserved epitope of the spiked protein of SARS-CoV-1 and SARS-CoV-2, thereby indicating unlikelihood of mutational escape. This is supported by a preclinical trial showing it retained ability to neutralize SARS-CoV-2 variants (ie, B.1.1.7, B.1.351, P.1). [212]  The FDA granted emergency use authorization on May 26, 2021. 

The EUA submission was based on an interim analysis of the COMET-ICE phase 3 trial.  The trial evaluated VIR-7831 as monotherapy for early treatment of COVID-19 in adults at high risk of hospitalization or death. The interim analysis demonstrated an 85% reduction in hospitalization or death in those who received a single IV dose of VIR-7831 (n = 291) compared with placebo (n = 292) (p = 0.002). [213]   

Results from a phase 2 trial (BLAZE-4) of a single IV dose of VIR-7831 coadministered with bamlanivimab in low-risk adults with mild-to-moderate COVID-19 demonstrated a 70% (p < 0.001) relative reduction in persistently high viral load at day 7 compared with placebo. [214]

Additional trials for VIR-7831 include comparison of IM and IV administration in low-risk adults (COMET-PEAK), IM use in high-risk adults (COMET-TAIL), and IM administration in uninfected adults to prevent symptomatic infection (COMET-STAR). 

Bamlanivimab plus etesevimab (U.S. distribution paused June 25, 2021) 

Bamlanivimab (LY-CoV555; Eli Lilly & Co, AbCellera) is neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially preventing and treating COVID-19. 

Bamlanivimab is no longer recommended as monotherapy owing to viral variants that are resistant to bamlanivimab. The EUA originally issued in November 2020 for use of bamlanivimab as monotherapy. The manufacturer asked the FDA to rescind the EUA for monotherapy on April 16, 2021 owing to decreased efficacy to circulating variants in the United States. 

The FDA issued an EUA for etesevimab (LY-CoV016; Eli Lilly & Co, AbCellera) on February 9, 2021 based on results from the phase 3 BLAZE trial. [215]  The EUA permitted use in combination with bamlanivimab or treatment of mild-to-moderate COVID19 in adults and adolescents who are at high risk for progressing to severe COVID-19 and/or hospitalization. However, even with this combination, the proportion of SARS-CoV-2 VOCs with reduced susceptibility to bamlanivimab plus etesevimab sequenced from U.S. residents continued to grow. 

  Table 4. Investigational Antibody-Directed Therapy Examples for COVID-19 (Open Table in a new window)

Antibody Therapies Description
COVI-SHIELD (Sorrento Therapeutics) [216] mAb Fc cocktail development in conjunction with Mt Sinai Health System in New York City.
AZD7442 (AstraZeneca) [60] Long-acting combination of 2 mAbs (AZD8895 and AZD1061) derived from convalescent patients who recovered from COVID-19 infection. Part of ACTIV-2 NIH master protocol. Study includes assessment of IV and IM administration.  
VH-Fc ab8 (Abound Bio; U of Pittsburgh Medical Center) [217] Small antibody in preclinical trials with potential for treatment and/or prophylaxis against SARS-CoV-2.
ABBV-47D11 (AbbVie) [218]   Neutralizing anti-SARS-CoV-2 monoclonal antibody. Phase 1 study started December 2020. 
AR-711 and AR-713 (Aridis Pharmaceuticals) [219]   Phase 1/2/3 clinical trials for home-administered inhaled mAb cocktail planned for mid-2021.
BRII-196 and BRII-198 (Brii Biosciences) [60] Noncompeting SARS-CoV-2 neutralizing antibodies derived from convalesced patients with COVID-19. Part of phase 2/3 NIH ACTIV-2 protocol.
Camostat mesilate [60]   Orally transmembrane protease serine 2 (TMPRSS2) inhibitor. Activation of the SARS-CoV-2 spike within the ACE2 receptor complex requires TMPRSS2. Part of phase 2/3 NIH ACTIV-2 protocol. 
SAB-185 (SAB Biotherapeutics) [60]   Targeted polyclonal antibodies to subunit of SARS-CoV-2 Wuhan strain. Part of NIH ACTIV-2 protocol. Phase 2/3 trial initiated April 2021 for outpatients with mild-to-moderate COVID-19.
C144-LS and C135-LS (Bristol Myers Squibb)  [60] Phase 1 trial for SC monoclonal antibodies. Part of ACTIV-2 NIH protocol for outpatients with COVID-19.
LY-CoV1404 (Eli Lilly & Co, AbCellera) [220] Preclinical data found this antibody binds to a rarely mutated region of the SARS-CoV-2 spike protein, which neutralizes all currently known variants of the virus, including the UK, Brazil, California, South Africa and New York strains. Will be part of BLAZE-4 clinical trial. 
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Investigational Vaccines

The genetic sequence of SARS-CoV-2 was published on January 11, 2020. A rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers followed. The FDA has granted EUAs for 3 SARS-CoV-2 vaccines since December 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna), whereas the third is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson)

In addition to the complexity of finding the most effective vaccine candidates, the production process is also important for manufacturing the vaccine to the scale needed globally. Other variable that increase complexity of distribution include storage requirements (eg, frozen vs refrigerated) and if more than a single injection is required for optimal immunity. Several technological methods (eg, DNA, RNA, inactivated, viral vector, protein subunit) are available for vaccine development. Vaccine attributes (eg, number of doses, speed of development, scalability) depends on the type of technological method employed. For example, the mRNA vaccine platforms allow for rapid development. [221, 222]   

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Antithrombotics

 

COVID-19 is a systemic illness that adversely affects various organ systems. A review of COVID-19 hypercoagulopathy aptly describes both microangiopathy and local thrombus formation, and a systemic coagulation defect leading to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism, in critically ill patients. [223]  While sepsis is recognized to activate the coagulation system, the precise mechanism by which COVID-19 inflammation affects coagulopathy is not fully understood. [224]   

Several retrospective cohort studies have described use of therapeutic and prophylactic anticoagulant doses in critically ill hospitalized patients with COVID-19. No difference in 28-day mortality was observed for 46 patients empirically treated with therapeutic anticoagulant doses compared with 95 patients who received standard DVT prophylaxis doses, including those with D-dimer levels greater than 2 mcg/mL. In this study, day 0 was the day of intubation, therefore, they did not evaluate all patients who received empiric therapeutic anticoagulation at the time of diagnosis to see if progression to intubation was improved. [225]  

In contrast to the above findings, a retrospective cohort study showed a median 21 day survival for patients requiring mechanical ventilation who received therapeutic anticoagulation compared with 9 days for those who received DVT prophylaxis. [226]   

NIH trial

Current guidelines include thrombosis prophylaxis (typically with low-molecular-weight heparin [LMWH]) for hospitalized patients. As of September 2020, the NIH ACTIV trial includes an arm (ACTIV-4) for use of antithrombotics in the outpatient (trial closed as of June 2021), inpatient, and convalescent settings. 

The 3 adaptive clinical trials within ACTIV-4 include preventing, treating, and addressing COVID-19-associated coagulopathy (CAC). Additionally, a goal to understand the effects of CAC across patient populations – inpatient, outpatient, and convalescent. 

Purpose and initial drugs included in ACTIV-4 are: 

Outpatient trial 

For nonhospitalized patients with COVID-19, anticoagulants and antiplatelet therapy should not be initiated for the prevention of VTE or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial.

The ACTIV-4B was initiated mid-2020 to investigate whether anticoagulants or antithrombotic therapy can reduce life-threatening cardiovascular or pulmonary complications in newly diagnosed patients with COVID-19 who do not require hospital admission. Participants were randomized to take either a placebo, aspirin, or a low or therapeutic dose of apixaban. The outpatient thrombosis prevention study was halted as the researchers concluded that among mildly symptomatic but clinically stable COVID-19 outpatients a week or more since the time of diagnosis, rates of major cardio-pulmonary complications are very low and do not justify preventive anticoagulant or antiplatelet therapy unless otherwise clinically indicated. [227]   

Inpatient trial 

Investigates an approach aimed at preventing clotting events and improving outcomes in hospitalized patients with COVID-19. Varying doses of unfractionated heparin or LMWH will be evaluated on ability to prevent or reduce blood clot formation.

Convalescent trial

Investigates safety and efficacy anticoagulants and/or antiplatelets administered to patients who have been discharged from the hospital or are convalescing in reducing thrombotic complications (eg, MI, stroke, DVT, PE, death). Patients will be assessed for these complications within 45 days of being hospitalized for moderate and severe COVID-19.

Investigational antithrombotics

AB201

AB201 (ARCA Biopharma) is a recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits tissue factor (TF)/factor VIIa complex and has anticoagulant, anti-inflammatory, and potential antiviral properties. TF plays a central role in inflammatory response to viral infections. Phase 2b/3 clinical trial (ASPEN-COVID-19) started in December 2020 in hospitalized patients with COVID-19 at the University of Colorado. The phase 2b trial randomizes 2 AB201 dosage regimens compared with heparin. The primary endpoint is change in D-dimer level from baseline to Day 8. The phase 3 trial design is contingent upon phase 2b results. [228]

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Renin Angiotensin System Blockade and COVID-19

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. [229] Data are limited concerning whether to continue or discontinue drugs that inhibit the renin-angiotensin-aldosterone system (RAAS), namely angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).

The first randomized study to compare continuing vs stopping (ACEIs) or ARBs receptor for patients with COVID-19 has shown no difference in key outcomes between the 2 approaches. A similar 30-day mortality rate was observed for patients who continued and those who suspended ACE inhibitor/ARB therapy, at 2.8% and 2.7%, respectively (hazard ratio, 0.97). [230]  

The BRACE Corona trial design further explains the 2 hypotheses. [230]  

  • One hypothesis suggests that use of these drugs could be harmful by increasing the expression of ACE2 receptors (which the SARS-CoV-2 virus uses to gain entry into cells), thus potentially enhancing viral binding and viral entry.
  • The other suggests that ACE inhibitors and ARBs could be protective by reducing production of angiotensin II and enhancing the generation of angiotensin 1-7, which attenuates inflammation and fibrosis and therefore could attenuate lung injury.

Concern arose regarding appropriateness of continuation of ACEIs and ARBs in patients with COVID-19 after early reports noted an association between disease severity and comorbidities such as hypertension, cardiovascular disease, and diabetes, which are often treated with ACEIs and ARBs. The reason for this association remains unclear. [231, 232]

The speculated mechanism for detrimental effect of ACEIs and ARBs is related to ACE2. It was therefore hypothesized that any agent that increases expression of ACE2 could potentially increase susceptibility to severe COVID-19 by improving viral cellular entry; [231] however, physiologically, ACE2 also converts angiotensin 2 to angiotensin 1-7, which leads to vasodilation and may protect against lung injury by lowering angiotensin 2 receptor binding. [232, 233] It is therefore uncertain whether an increased expression of ACE2 receptors would worsen or mitigate the effects of SARS-CoV-2 in human lungs.

Vaduganathan et al note that data in humans are limited, so it is difficult to support or negate the opposing theories regarding RAAS inhibitors. They offer an alternate hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury. As mentioned, ACE2 acts as a counterregulatory enzyme that degrades angiotensin 2 to angiotensin 1-7. SARS-CoV-2 not only appears to gain initial entry through ACE2 but also down-regulates ACE2 expression, possibly mitigating the counterregulatory effects of ACE2. [234]

There are also conflicting data regarding whether ACEIs and ARBs increase ACE2 levels. Some studies in animals have suggested that ACEIs and ARBs increase expression of ACE2, [235, 236, 237] while other studies have not shown this effect. [238, 239]

As uncertainty controversy remains regarding whether ACEIs and/or ARBs increase ACE2 expression and how this effect may influence outcomes in patients with COVID-19, cardiology societies have largely recommended against initiating or discontinuing these medications based solely on active SARS-CoV-2 infection. [240, 241]

A systematic review and meta-analysis found use of ACEIs or ARBs was not associated with a higher risk of mortality among patients with COVID-19 with hypertension or multiple comorbidities, supporting recommendations of medical societies to continue use of these agents to control underlying conditions. [242]

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Diabetes and COVID-19

High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia. [243, 244] Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following: [245]

  • Higher-affinity cellular binding and efficient virus entry
  • Decreased viral clearance
  • Diminished T-cell function
  • Increased susceptibility to hyperinflammation and cytokine storm syndrome
  • Presence of cardiovascular disease

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors [229] for entry into target cells. Insulin administration attenuates ACE2 expression, while hypoglycemic agents (eg, glucagonlike peptide 1 [GLP-1] agonists, thiazolidinediones) up-regulate ACE2. [245] Dipeptidyl peptidase 4 (DPP-4) is highly involved in glucose and insulin metabolism, as well as in immune regulation. This protein was shown to be a functional receptor for Middle East respiratory syndrome coronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2, the virus responsible for COVID-19. [246]

The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. Important clinical conclusions of the review include the following: [244]

  • Hospitalization is more common for acute COVID-19 among patients with diabetes and obesity.
  • Diabetic medications need to be reevaluated upon admission.
  • Insulin is the glucose-lowering therapy of choice, not DPP-4 inhibitors or GLP-1 receptor agonists, in patients with diabetes who are hospitalized with acute COVID-19.
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Therapies Determined Ineffective

Hydroxychloroquine and chloroquine

On June 15, 2020, the FDA revoked the emergency use authorization (EUA) for hydroxychloroquine and chloroquine donated to the Strategic National Stockpile to be used for treating certain hospitalized patients with COVID-19 when a clinical trial was unavailable or participation in a clinical trial was not feasible. [247]

Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that hydroxychloroquine is unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other potential serious adverse effects, the known and potential benefits of hydroxychloroquine no longer outweigh the known and potential risks for the EUA.

While additional clinical trials may continue to evaluate potential benefit, the FDA determined the EUA was no longer appropriate.

Additionally, the NIH halted the Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease (ORCHID) study on June 20, 2020. After the fourth analysis that included more than 470 participants, the NIH data and safety monitoring board determined that while, there was no harm, the study drug was very unlikely to be beneficial to hospitalized patients with COVID-19. [248]

Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of heme polymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro. [249] The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug. Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days. [97]

Published reports stemming from the worldwide outbreak of COVID-19 have evaluated the potential usefulness of these drugs in controlling cytokine release syndrome in critically ill patients. Owing to widely varying dosage regimens, disease severity, measured outcomes, and lack of control groups, efficacy data have been largely inconclusive.

The UK RECOVERY Trial randomized 1561 patients to hydroxychloroquine and 3155 patients to usual care alone. Results found no significant difference in the primary endpoint of 28-day mortality (27% hydroxychloroquine vs 25% usual care; hazard ratio 1.09 [95% CI, 0.97-1.23]; P = 0.15). Secondary outcomes showed patients in the hydroxychloroquine group had a longer duration of hospitalization than those in the usual-care group (median, 16 days vs. 13 days) and a lower probability of discharge alive within 28 days (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). [250]

A multicenter, randomized, open-label trial in Brazil found no improvement in 504 hospitalized patients with mild-to-moderate COVID-19. Use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days compared with standard care. Prolonged QTc interval and elevated liver-enzyme levels were more common in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. [251]

An observational study of 2512 hospitalized patients in New Jersey with confirmed COVID-19 was conducted between March 1, 2020 and April 22, 2020, with follow-up through May 5, 2020. Outcomes included 547 deaths (22%) and 1539 (61%) discharges; 426 (17%) remained hospitalized. Patients who received at least one dose of hydroxychloroquine totaled 1914 (76%), and those who received hydroxychloroquine plus azithromycin totaled 1473 (59%). No significant differences were observed in associated mortality among patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality rate in patients receiving hydroxychloroquine alone, azithromycin alone, the combination, or neither drug was 25%, 20%, 18%, and 20%, respectively. [252]

Because of findings from the aforementioned studies, the WHO halted the hydroxychloroquine arm of the Solidarity Trial and then removed its use entirely as of July 4, 2020. [27] Interim results released mid-October 2020 found hydroxychloroquine and chloroquine appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. Death rate ratio for hydroxychloroquine was 1.19 (0.89-1.59, p = 0.23; 104/947 vs 84/906). [28]  The FDA issued a safety alert for hydroxychloroquine or chloroquine use in COVID-19 on April 24, 2020, and revoked the EUA on June 15, 2020. [247, 253]  

A multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US showed hydroxychloroquine did not significantly improved clinical status at day 14 in adults who were hospitalized with COVID-19 respiratory illness. Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). [254]

An observational study of consecutively hospitalized patients (n = 1446) at a large medical center in the New York City area showed hydroxychloroquine was not associated with either a greatly lowered or an increased risk of the composite endpoint of intubation or death. [255]

A nationwide, observational cohort study in The Netherlands showed early treatment with hydroxychloroquine (but not chloroquine) on the first day of hospital admission was associated with a 53% reduced risk of transfer to the ICU for mechanical ventilation. Hospitals were given the opportunity to decide independently on the use of 3 different treatment strategies: hydroxychloroquine (n = 189), chloroquine (n = 377), or no treatment (n =498). The authors concluded that additional prospective data on early hydroxychloroquine use is still needed. [256]  

A retrospective observational study of 2,541 consecutive patients hospitalized with COVID at Henry Ford Health System from March 10, 2020, to May 2, 2020, showed a decreased mortality rate in patients treated with hydroxychloroquine alone or in combination with azithromycin. Overall in-hospital mortality was 18.1%; by treatment: hydroxychloroquine plus azithromycin, 157/783 (20.1%), hydroxychloroquine alone, 162/1202 (13.5%), azithromycin alone, 33/147 (22.4%), and neither drug, 108/409 (26.4%). Therapy with corticosteroids (methylprednisolone and/or prednisone) was administered in 68% of all patients. Corticosteroids were administered to 78.9% of patients who received hydroxychloroquine alone. In addition to adjunctive use of corticosteroids, an accompanying editorial discusses time bias, missing prognostic indicators, and other confounding factors of this observational study. [257, 258]

A retrospective analysis of data from patients hospitalized with confirmed COVID-19 infection in all US Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020, has been published. Patients who had received hydroxychloroquine (HC) alone or with azithromycin (HC + AZ) as treatment in addition to standard supportive care were identified. A total of 368 patients were evaluated (HC n=97; HC + AZ n=113; no HC n=158). Death rates in the HC, HC + AZ, and no-HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC + AZ, and no-HC groups were 13.3%, 6.9%, 14.1%, respectively. The authors concluded that they found no evidence that hydroxychloroquine, with or without azithromycin, reduced the risk of mechanical ventilation and that the overall mortality rate was increased with hydroxychloroquine treatment. Furthermore, they stressed the importance of waiting for results of ongoing, prospective, randomized controlled trials before wide adoption of these drugs. [259]

A retrospective study assessed effects of hydroxychloroquine according to its plasma concentration in patient hospitalized in the ICU. The researchers compared 17 patients with hydroxychloroquine plasma concentrations within the therapeutic target and 12 patients with plasma concentrations below the target. At 15 days of follow-up, no association was found between hydroxychloroquine plasma concentration and viral load evolution (p = 0.77). Additionally, there was no significant difference between the 2 groups for duration of mechanical ventilation, length of ICU stays, in-hospital mortality, and 15-days mortality. [260]

According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500 mg (300 mg base) twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia. [261] While no peer-reviewed treatment outcomes are available, Gao and colleagues report that 100 patients have demonstrated significant improvement with this regimen without documented toxicity. [262] It should be noted this is 14 times the typical dose of chloroquine used per week for malaria prophylaxis and 4 times that used for treatment. Cardiac toxicity should temper enthusiasm for this as a widespread cure for COVID-19. It should also be noted that chloroquine was previously found to be active in vitro against multiple other viruses but has not proven fruitful in clinical trials, even resulting in worse clinical outcomes in human studies of Chikungunya virus infection (a virus unrelated to SARS-CoV-2).

A randomized controlled trial in Wuhan, China, enrolled 62 hospitalized patients (average age, 44.7 years) with confirmed COVID-19. Additional inclusion criteria included age 18 years or older, chest CT scans showing pneumonia, and SaO2/SPOs ratio of more than 93% (or PaOs/FIOs ratio >300 mm Hg). Patients with severe or critical illness were excluded. All patients enrolled in the study received standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or without corticosteroids). Thirty-one patients were randomized to receive hydroxychloroquine sulfate (200 mg PO BID for 5 days) in addition to standardized treatment. Changes in time to clinical recovery (TTCR) was evaluated and defined as return of normal body temperature and cough relief, maintained for more than 72 hours. Compared with the control group, TTCR for body temperature and cough were significantly shortened in the hydroxychloroquine group. Four of the 62 patients progressed to severe illness, all of whom were in the control group. [263]

An open-label multicenter study using high-dose hydroxychloroquine or standard of care did not show a difference at 28 days for seronegative conversion or the rate of symptom alleviation between the two treatment arms. The trial was conducted in 150 patients in China with mild-to-moderate disease. [264]

Hydroxychloroquine plus azithromycin

Opposing conclusions by French researchers regarding viral clearance and clinical benefit with the regimen of hydroxychloroquine plus azithromycin have been published. [265, 266, 267]

A small prospective study found no evidence of a strong antiviral activity or clinical benefit from use of hydroxychloroquine plus azithromycin. Molina et al assessed virologic and clinical outcomes of 11 consecutive patients hospitalized who received hydroxychloroquine (600 mg per day x10 days) and azithromycin (500 mg Day 1, then 250 mg days 2-5). Patient demographics were as follows: 7 men and 4 women; mean age 58.7 years (range: 20-77); 8 had significant comorbidities associated with poor outcomes (ie, obesity 2; solid cancer 3; hematological cancer 2; HIV-infection 1). Ten of the eleven patients had fever and received oxygen via nasal cannula. Within 5 days, 1 patient died, 2 were transferred to the ICU. Hydroxychloroquine and azithromycin were discontinued in 1 patient owing to prolonged QT interval. Nasopharyngeal swabs remained positive for SARS-CoV-2 RNA in 8/10 patients (80%, 95% confidence interval: 49-94) at days 5-6 after treatment initiation. [267]

In direct contrast to aforementioned results, another study in France evaluated patients treated with hydroxychloroquine (N=26) against a control group (n=16) who received standard of care. After dropping 6 patients who received treatment from the analysis for having incomplete data, the 20 remaining patients receiving hydroxychloroquine (200 mg PO q8h) had improved nasopharyngeal clearance of the virus on day 6 (70% [14/20] vs 12.5% [2/16]). [265] This is an unusual approach to reporting results because the clinical correlation with nasopharyngeal clearance on day 6 is unknown and several patients changed status within a few days of that endpoint (converting from negative back to positive). The choice of that particular endpoint was also not explained by the authors, yet 4 of the 6 excluded patients had adverse outcomes (admission to ICU or death) at that time but were not counted in the analysis. Furthermore, patients who refused to consent to the study group were included in the control arm, indicating unorthodox study enrollment.

This small open-label study of hydroxychloroquine in France included azithromycin in 6 patients for potential bacterial superinfection (500 mg once, then 250 mg PO daily for 4 days). These patients were reported to have 100% clearance of SARS-CoV-2. While intriguing, these results warrant further analysis. The patients receiving combination therapy had initially lower viral loads, and, when compared with patients receiving hydroxychloroquine alone with similar viral burden, the results are fairly similar (6/6 vs 7/9). [265]

The French researchers continued their practice of using hydroxychloroquine plus azithromycin and accumulated data in 80 patients with at least 6 days of follow-up. They note that the 6 patients on combination therapy enrolled in their first analysis were also included in the present case series, with a longer follow-up. However, it was not clear from the description in their posted methods when patients were assessed. A favorable outcome was defined as not requiring aggressive oxygen therapy or transfer to the ICU after 3 days of treatment. Sixty-five of the 80 patients (81.3%) met this outcome. One patient aged 86 years died, and a 74-year-old patient remained in the ICU. Two others were transferred to the ICU and then back to the infection ward. Results showed a decrease in nasopharyngeal viral load tested via qPCR, with 83% negative at day 7 and 93% at day 8. Virus culture results from patient respiratory samples were negative in 97.5% patients at day 5. [266] This is described as a promising method of reducing spread of SARS-CoV-2, but, unfortunately, the study lacked a control group and did not compare treatment with hydroxychloroquine plus azithromycin to a similar group of patients receiving no drug therapy or hydroxychloroquine alone. Overall, the acuity of these patients was low, and 92% had a low score on the national Early Warning System used to assess risk of clinical deterioration. Only 15% were febrile, a common criterion for testing in the United States, and 4 individuals were considered asymptomatic carriers. In addition, the results did not delineate between asymptomatic carriers and those with high viral load or low viral load.

Nonhospitalized patients with early COVID-19

Hydroxychloroquine did not improve outcomes when administered to outpatient adults (n = 423) with early COVID-19. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine compared with 22% (46 of 211) receiving placebo (P< 0.001). Among patients receiving placebo, 10 were hospitalized (two cases unrelated to COVID-19), one of whom died. Among patients receiving hydroxychloroquine, four were hospitalized and one nonhospitalized patient died (P = 0.29). [268]

Clinical trials evaluating prevention

Various clinical trials in the United States were initiated to determine if hydroxychloroquine reduces the rate of infection when used by individuals at high risk for exposure, such as high-risk healthcare workers, first responders, and individuals who share a home with a COVID-19–positive individual. [269, 270, 271, 272, 273, 274]

Results from the PATCH trial (n=125) did not show any benefit of hydroxychloroquine to reduce infection among healthcare workers compared with placebo. [271]

Another study rerolled 1483 healthcare workers, of which 79% performed aerosol-generating procedures did not show a difference in preventing infection with once or twice weekly hydroxychloroquine compared with placebo. The incidence of SARS-CoV-2 laboratory-confirmed or symptomatic compatible illness was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo (p = 0.18 and 0.22 respectively). [275]

Results from a double-blind randomized trial (n = 821) from the University of Minnesota found no benefit of hydroxychloroquine (n = 414) in preventing illness due to COVID-19 compared with placebo (n = 407) when used as postexposure prophylaxis in asymptomatic participants within 4 days following high-risk or moderate-risk exposure. Overall, 87.6% of participants had high-risk exposures without eye shields and surgical masks or respirators. New COVID-19 (either PCR-confirmed or symptomatically compatible) developed in 107 participants (13%) during the 14-day follow-up. Incidence of new illness compatible with COVID-19 did not differ significantly between those receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]) (P = 0.35). [276]

QT prolongation with hydroxychloroquine and azithromycin

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. [277] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion of the arrhythmogenicity of hydroxychloroquine and azithromycin that includes a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. [278]

A Brazilian study comparing chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days) observed QT prolongation in 25% of patients in the high-dose group. All patients received other drugs (ie, azithromycin, oseltamivir) that may contribute to prolonged QT. [279]

An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine from an analysis of pooled data from Japan, Europe, and the United States. The analysis compared use of hydroxychloroquine, sulfamethoxazole, or the combinations of hydroxychloroquine plus amoxicillin or hydroxychloroquine plus azithromycin. [280]

For more information, see QT Prolongation with Potential COVID-19 Pharmacotherapies

Doxycycline

A few case reports and small case series have speculated on a use for doxycycline in COVID-19. Most seem to have been searching for an antibacterial to replace azithromycin for use in combination with hydroxychloroquine. In general, the use of HCQ has been abandoned. The anti-inflammatory effects of doxycycline were also postulated to moderate the cytokine surge of COVID-19 and provide some benefits. However, the data on corticosteroid use has returned, and is convincing and strongly suggests their use. It is unclear that doxycycline would provide further benefits. Finally, concomitant bacterial infection during acute COVID-19 is proving to be rare decreasing the utility of antibacterial drugs. Overall, there does not appear to be a routine role for doxycycline.

Lopinavir/ritonavir

The NIH Panel for COVID-19 Treatment Guidelines recommend against the use of lopinavir/ritonavir or other HIV protease inhibitors, owing to unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit in patients with COVID-19. [281]

The Infectious Diseases Society of America (IDSA) guidelines recommend against use of lopinavir/ritonavir. The guidelines also mention the risk for severe cutaneous reactions, QT prolongation, and the potential for drug interactions owing to CYP3A inhibition. [16]

The RECOVERY trial concluded no beneficial effect was observed in hospitalized patients with COVID-19 who were randomized to receive lopinavir/ritonavir (n = 1616) compared with those who received standard care (n = 3424). No significant difference for 28-day mortality was shown. Overall, 374 (23%) patients allocated to lopinavir/ritonavir and 767 (22%) patients allocated to usual care died within 28 days (p = 0.60). No evidence was found for beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. [282]

The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020. [27]  Interim results released mid-October 2020 found lopinavir/ritonavir (with or without interferon) appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. Death rate ratios were: lopinavir RR = 1.00 (0.79-1.25, p = 0.97; 148/1399 vs 146/1372) and lopinavir plus interferon RR=1.16 (0.96-1.39, p = 0.11; 243/2050 vs 216/2050). [28]  

In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruited patients had an oxygen saturation of 94% or less on ambient air or PaO2 of less than 300 mm Hg and were receiving a range of ventilatory support modes (eg, no support, mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). These patients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) or standard care alone (n=100). Results showed that time to clinical improvement did not differ between the two groups (median, 16 days). The mortality rate at 28 days was numerically lower for lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach statistical significance. [283] An editorial accompanies this study that is informative in regard to the extraordinary circumstances of conducting such a study in the midst of the outbreak. [284]

Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group. [285]

A multicenter study in Hong Kong compared 14 days of triple therapy (n = 86) (lopinavir/ritonavir [400 mg/100 mg q12h], ribavirin [400 mg q12h], interferon beta1b [8 million IU x 3 doses q48h]) with lopinavir/ritonavir alone (n = 41). Results showed that triple therapy significantly shortened the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19. [286]

Average wholesale price (AWP) for a course of lopinavir/ritonavir at this dose is $575. 

Ivermectin

NIH COVID-19 guidelines for ivermectin provide analysis of several randomized trials and retrospective cohort studies of ivermectin use in patients with COVID-19. The guidelines concluded most of these studies had incomplete information and significant methodological limitations, which make it difficult to exclude common causes of bias.  Ivermectin has been shown to inhibit SAR-COV-2 in cell cultures; however, available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans. [287]

Chaccour and colleagues raised concerns regarding ivermectin-associated neurotoxicity, particularly in patients with a hyperinflammatory state possible with COVID-19. In addition, drug interactions with potent CYP3A4 inhibitors (eg, ritonavir) warrant careful consideration of coadministered drugs. Finally, evidence suggests that ivermectin plasma levels with meaningful activity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans. More data are needed to assess pulmonary tissue levels in humans. [288]

A prospective study (n = 400) of adults with mild COVID-19 were randomized 1:1 to receive ivermectin 300 mcg/kg/day for 5 days or placebo. Use of ivermectin did not show a significantly shorten duration of symptoms compared with placebo (p = 0.53). [289]

Table 5. Other therapies determined ineffective (Open Table in a new window)

Therapy Comment
Merimepodib (antiviral; BioSig Technologies) [290]   Phase 2 trial in combination with remdesivir in advanced disease (NCT04410354).
Acalabrutinib (Calquence; AstraZeneca) [291] Phase 2 trial (CALAVI US) of Bruton kinase inhibitor in hospitalized patients to ameliorate excessive inflammation (NCT04380688).
Ruxolitinib (Jakafi) [292] Data from the RUXCOVID study (n = 432) showed treatment with ruxolitinib plus standard-of-care did not prevent complications in patients with COVID-19 associated cytokine storm. 
Umifenovir (Arbidol) Antiviral drug that binds to hemagglutinin protein; it is used in China and Russia to treat influenza. In a structural and molecular dynamics study, Vankadari corroborated that the drug target for umifenovir is the spike glycoproteins of SARS-CoV-2, similar to that of H3N2. [293] A retrospective study of non-ICU hospitalized patients (n = 81) with COVID-19 conducted in China did not show an improved prognosis or accelerated viral clearance. [294] Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group. [285]  
Colchicine UK RECOVERY trial stopped the colchicine arm upon advice from its independent data monitoring committee for lack of efficacy in hospitalized patients with COVID-19.

 

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QT Prolongation with Potential COVID-19 Pharmacotherapies

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. [277] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion on the arrhythmogenicity of hydroxychloroquine and azithromycin, including a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. [278, 295]

Giudicessi et al have published guidance for evaluating the torsadogenic potential of chloroquine, hydroxychloroquine, lopinavir/ritonavir, and azithromycin. Chloroquine and hydroxychloroquine block the potassium channel, specifically KCNH2-encoded HERG/Kv11.1. Additional modifiable risk factors (eg, treatment duration, other QT-prolonging drugs, hypocalcemia, hypokalemia, hypomagnesemia) and nonmodifiable risk factors (eg, acute coronary syndrome, renal failure, congenital long QT syndrome, hypoglycemia, female sex, age ≥65 years) for QT prolongation may further increase the risk. Some of the modifiable and nonmodifiable risk factors may be caused by or exacerbated by severe illness. [296]

A retrospective study was performed by reviewing 84 consecutive adult patients who were hospitalized at NYU Langone Medical Center with COVID-19 and treated with hydroxychloroquine plus azithromycin. QTc increased by greater than 40 ms in 30% of patients. In 11% of patients, QTc increased to more than 500 ms, which is considered a high risk for arrhythmia. The researcher noted that development of acute renal failure, but not baseline QTc, was a strong predictor of extreme QTc prolongation. [297]

A cohort study was performed from March 1 through April 7, 2020, at an academic tertiary care center in Boston to characterize the risk and degree of QT prolongation in patients with COVID-19 who received hydroxychloroquine, with or without azithromycin. Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin. Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more, and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. Clinicians should carefully monitor QTc and concomitant medication usage if considering using hydroxychloroquine. [298]

A Brazilian study (n=81) compared chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days). A positive COVID-19 infection was confirmed by RT-PCR in 40 of 81 patients. In addition, all patients received ceftriaxone and azithromycin. Oseltamivir was also prescribed in 89% of patients. Prolonged QT interval (> 500 msec) was observed in 25% of the high-dose group, along with a trend toward higher lethality (17%) compared with lower dose. The high incidence of QT prolongation prompted the investigators to prematurely halt use of the high-dose treatment arm, noting that azithromycin and oseltamivir can also contribute to prolonged QT interval. The fatality rate was 13.5%. In 14 patients with paired samples, respiratory secretions at day 4 showed negative results in only one patient. [279]

Although not specific to patients with COVID-19, an increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine in a large study of administrative claims. Pooled data from 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, United Kingdom, and the United states were analyzed for adverse effects of hydroxychloroquine, sulfasalazine, or the combinations of hydroxychloroquine plus azithromycin or amoxicillin. Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, respectively, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin, respectively, were included in the analysis. [280]

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Investigational Agents for Postexposure Prophylaxis

PUL-042

PUL-042 (Pulmotech, MD Anderson Cancer Center, and Texas A&M) is a solution for nebulization with potential immunostimulating activity. It consists of two toll-like receptor (TLR) ligands: Pam2CSK4 acetate (Pam2), a TLR2/6 agonist, and the TLR9 agonist oligodeoxynucleotide M362.

PUL-042 binds to and activates TLRs on lung epithelial cells. This induces the epithelial cells to produce peptides and reactive oxygen species (ROS) against pathogens in the lungs, including bacteria, fungi, and viruses. M362, through binding of the CpG motifs to TLR9 and subsequent TLR9-mediated signaling, initiates the innate immune system and activates macrophages, natural killer (NK) cells, B cells, and plasmacytoid dendritic cells; stimulates interferon-alpha production; and induces a T-helper 1 cells–mediated immune response. Pam2CSK4, through TLR2/6, activates the production of T-helper 2 cells, leading to the production of specific cytokines. [299]

In May 2020, the FDA approved initiation of two COVID-19 phase 2 clinical trials of PUL-042 at up to 20 US sites. The trials are for the prevention of infection with SARS-CoV-2 and the prevention of disease progression in patients with early COVID-19. In the first study, up to 4 doses of PUL-042 or placebo will be administered to 200 participants via inhalation over a 10-day period to evaluate the prevention of infection and reduction in severity of COVID-19. In the second study, 100 patients with early symptoms of COVID-19 will receive PUL-042 up to 3 times over 6 days. Each trial will monitor participants for 28 days to assess effectiveness and tolerability. [300, 301]

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Investigational Devices

Blood purification devices

Several extracorporeal blood purification filters (eg, CytoSorb, oXiris, Seraph 100 Microbind, Spectra Optia Apheresis) have received emergency use authorization from the FDA for the treatment of severe COVID-19 pneumonia in patients with respiratory failure. The devices have various purposes, including use in continuous renal replacement therapy or in reduction of proinflammatory cytokines levels. [302]

Nanosponges

Cellular nanosponges made from plasma membranes derived from human lung epithelial type II cells or human macrophages have been evaluated in vitro. The nanosponges display the same protein receptors required by SARS-CoV-2 for cellular entry and act as decoys to bind the virus. In addition, acute toxicity was evaluated in vivo in mice by intratracheal administration. [303]

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