Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies

Updated: Oct 20, 2020
  • 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]  

No drugs or biologics have been approved by the FDA for the prevention or treatment of COVID-19. Remdesivir gained emergency use authorization (EUA) from the FDA on May 1, 2020, based on preliminary data showing a faster time to recovery of hospitalized patients with severe disease. [5] A new drug application (NDA) for remdesivir was submitted to the FDA in August 2020. An EUA for convalescent plasma was announced on August 23, 2020. [6] 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. [7, 8, 9, 10, 11, 12, 13]

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. [14]

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. [15]  

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. [16, 17]

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. [18]

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. [19]

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. [20]

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. [21]

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. [22]

The 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). As of July 4, 2020, the treatment arms in hospitalized patients that include hydroxychloroquine, chloroquine, or lopinavir/ritonavir have been discontinued because the drugs showed little or no reduction in mortality compared with standard of care. [23]  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). [24]

Additional information for investigational drugs and biologics can be obtained from the following resources:

Next:

Investigational Antiviral Agents

Remdesivir

The broad-spectrum antiviral agent remdesivir (GS-5734; Gilead Sciences, Inc) is a nucleotide analog prodrug. On May 1, 2020, The US FDA issued their EUA (emergency use authorization) of remdesivir to allow prescribing of the agent for severe COVID-19 (confirmed or suspected) in hospitalized adults and children prior to approval. [25, 26] A new drug application (NDA) for remdesivir was submitted to the FDA in August 2020. A phase 1b trial of inhaled nebulized remdesivir was initiated in late June 2020 to determine if remdesivir can be used on an outpatient basis and at earlier stages of disease. [27]  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. [28] 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. [29]

Several phase 3 clinical trials are testing 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. [30] The drug was prescribed under an open-label compassionate use protocol, but the US FDA later moved to allow expanded access to remdesivir, permitting approved sites to prescribe the investigational product for multiple patients under protocol prior to the EUA without requesting permission for each. [31] 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. [32] 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%). [5]

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. [24] 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. [33]

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. [34]

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). [35]

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. [36]

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. [37]

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). [38]

The first published report with a group of patients receiving remdesivir compassionate use described clinical improvement in 36 of 53 hospitalized patients (68%) with severe COVID-19. At baseline, 30 patients (57%) were receiving ventilation and 4 (8%) extracorporeal membrane oxygenation (ECMO). Measurement of efficacy requires randomized, placebo-controlled trials. [39]

Observations during compassionate use follow-up (median of 18 days) included the following: 

  • Oxygen-support class improved in 36 patients (68%), including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated.
  • Twenty-five patients (47%) were discharged.
  • Seven patients (13%) died.
  • The mortality rate was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

Additional data for compassionate use of remdesivir was released on July 10, 2020, and demonstrated that remdesivir treatment was associated with significantly improved clinical recovery and a 62% reduction in the risk of mortality compared with standard of care. Findings from the comparative analysis showed that 74.4% of remdesivir-treated patients recovered by day 14 versus 59% of patients receiving standard of care. The mortality rate in patients treated with remdesivir in the analysis was 7.6% at day 14 compared with 12.5% among patients not taking remdesivir (adjusted OR, 0.38; 95% CI, 0.22-0.68, P = 0.001). The analyses also found that 83% of pediatric patients (n = 77) and 92% of pregnant and postpartum women (n = 86) with a broad spectrum of COVID-19 severity recovered by day 28. [37]

An in vitro study showed that the antiviral activity of remdesivir plus interferon beta (IFNb) for MERS-CoV was superior to that of lopinavir/ritonavir (LPV/RTV; Kaletra, Aluvia; AbbVie Corporation). Prophylactic and therapeutic remdesivir improved pulmonary function and reduced lung viral loads and severe lung pathology in mice, whereas LPV/RTV-IFNb slightly reduced viral loads without affecting other disease parameters. Therapeutic LPV/RTV-IFNb improved pulmonary function but did not reduce virus replication or severe lung pathology in the mice. [40]

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. [41]

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. [42]

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. [43]

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. [44]

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. [26]

Other early-stage investigational antivirals

Favipiravir

Favipiravir (Avigan, Avifavir, Coronavir; Fujifilm Pharmaceuticals; 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). [45]  

In the United States, a phase 2 trial will enroll approximately 50 patients with COVID-19, in collaboration with Brigham and Women's Hospital, Massachusetts General Hospital, and the University of Massachusetts Medical School. Stanford University launched an outpatient trial in July 2020 to test whether the drug can reduce symptoms and viral shedding in people with COVID-19. [46, 47, 48]  Additionally, a phase 2 trial in Canada and the US is planned to evaluate favipiravir as prophylaxis for long-term care facilities experiencing a COVID outbreak. [49]

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. [50, 51]  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. [52]

Ivermectin

Ivermectin, an antiparasitic drug, showed in vitro reduction of viral RNA in Vero-hSLAM cells 2 hours postinfection with SARS-CoV-2 clinical isolate Australia/VIC01/2020. [53] The authors note that this preliminary study does not translate to human use and the effective dose is not established at this early stage of discovery. More research is needed to determine if an antiviral effect would be elicited in humans, as the concentrations tested were much higher than what is achieved from the normal oral dose.

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. [54]

Chaccour et al believe the recent findings regarding ivermectin warrant rapid implementation of controlled clinical trials to assess efficacy against COVID-19. They also raise 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. [55]

The ICON (Ivermectin in COvid Nineteen) retrospective cohort study (n = 280) in hospitalized patients with confirmed SARS-CoV-2 infection at 4 Florida hospitals showed significantly lower mortality rates for ivermectin (n - 173) compared with usual care (n = 107) (15% vs 25.2%; P = 0.03). The mortality rate was also lower among 75 patients with severe pulmonary disease treated with ivermectin (38.8% vs 80.7%; P = 0.001), although the rate of successful extubation did not differ significantly. [56]

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

Antiviral Agent Description
Merimepodib (VicromaxTM; ViralClear Pharmaceuticals, BioSig Technologies) [57, 58]

Oral antiviral in phase 2 trial in combination with remdesivir initiated in June 2020. The mechanism of merimepodib is believed to be inhibition of inosine-5’-monophosphate dehydrogenase (IMPDH), leading to a depletion of guanosine for use by the viral polymerase during replication.

Niclosamide (FW-1002; FirstWave Bio) [59, 60, 61] Anthelmintic agent that has potential use as an antiviral agent. A proprietary formulation that targets the viral reservoir in the gut to decrease prolonged infection and transmission has been developed. Initiation of a phase 2a/2b study is planned for mid-2020.
Rintatolimod (Poly I:Poly C12U; Ampligen; AIM ImmunoTech) [62, 63] 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. It is a broad-spectrum antiviral agent.
Beta-D-N4-hydroxycytidine (NHC, EIDD-2801) [64, 65] Orally bioavailable broad-spectrum antiviral. When administered both prophylactically and therapeutically to mice infected with SARS-CoV, NHC improved pulmonary function and reduced virus titer and body weight loss. It was announced that clinical trials will soon move to humans.
Bemcentinib (BerGenBio ASA) [66] 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.
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. [67] 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. [68] 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. [69] In India, a phase 3 trial combining 2 antiviral agents, favipiravir and umifenovir, started in May 2020. [47]
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. [70]
VIR-2703 (ALN-COV; Vir Biotechnology Inc and Alnylam Pharmaceuticals, Inc) [71] 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.
MK-4482 (previously EIDD-2801; Merck, Ridgeback Bio) [72, 73] Oral nucleoside analogue. Phase 1 trials have been completed. Two phase 2 clinical trials were initiated in June 2020 in both inpatient and outpatient settings. A phase 3 trial is planned for September 2020.
Emetine hydrochloride (Acer Therapeutics) [74] 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) [75] 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) [76] 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. IND for phase 2 randomized, controlled, multicenter trial submitted to FDA.
Stannous protoporphyrin (SnPP; RBT-9; Renibus Therapeutics) [77] 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) [78] 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) [79] 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.
AT-527 (Atea Pharmaceuticals) [80] Orally direct-acting nucleotide antiviral that inhibits viral replication by interfering with viral RNA polymerase. Phase 2 trial multicenter trial initiated.
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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. [81]  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. [82]  

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. [21]   

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. [22]  

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. 

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. [83] As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-6 inhibitors. [84]

On March 16, 2020, Sanofi and Regeneron announced initiation of a phase 2/3 trial of the IL-6 inhibitor sarilumab (Kevzara). The United States–based component of the trial will be initiated in New York. The multicenter, double-blind, phase 2/3 trial has an adaptive design with two parts and is anticipated to enroll up to 400 patients. The first part will recruit patients with severe COVID-19 infection across approximately 16 US sites, and will evaluate the effect of sarilumab on fever and the need for supplemental oxygen. The second, larger, part of the trial will evaluate improvement in longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen, and/or hospitalization. [85]

Based on the phase 2 trial analysis, the ongoing phase 3 design was modified on April 27, 2020, to include only higher-dose sarilumab (400 mg) or placebo in critical patients (ie, requiring mechanical ventilation or high-flow oxygenation or ICU admission). Minor positive trends were observed in the primary prespecified analysis group (n = 194; critical patients on sarilumab 400 mg who were mechanically ventilated at baseline) that did not reach statistical significance, and these were countered by negative trends in a subgroup of critical patients who were not mechanically ventilated at baseline. [86] Based on the results, the US-based trial was stopped, including in a second cohort of patients who received a higher dose (800 mg). [87]

Another IL-6 inhibitor, tocilizumab (Actemra), is part of several randomized, double-blind, placebo-controlled phase 3 clinical trials (REMDACTA, COVACTA, EMPACTA) to evaluate the safety and efficacy of tocilizumab plus standard of care in hospitalized adult patients with severe COVID-19 pneumonia compared to placebo plus standard of care. Preliminary results released September 18, 2020 from the EMPACTA trial found hospitalized patients who received tocilizumab were 44% less likely to progress to mechanical ventilation or death compared with patients who received placebo plus standard of care. The cumulative proportion of patients who progressed to mechanical ventilation or death by day 28 was 12.2% in the tocilizumab group versus 19.3% in the placebo arm. However, the time to hospital discharge and mortality by Day 28 was not statistically significant. [88]  

Results from the COVACTA trial were released in July 2020, announcing that the trial did not meet its primary endpoint of improved clinical status in patients with COVID-19–associated pneumonia or the secondary endpoint of reduced patient mortality. The trial did show a positive trend in time to hospital discharge among patients who received tocilizumab. [89]

An observational study of consecutive patients (n=239) at Yale (New Haven, CT) with severe COVID-19 disease were treated with a standardized algorithm that included tocilizumab to treat cytokine release syndrome. These early observations showed despite a surge of hospitalizations, tocilizumab-treated patients (n = 153) comprised 90% of those with severe disease, but their survival was similar to that of patients with nonsevere disease (83% vs 91%; p = 0.11). For tocilizumab-treated patients requiring mechanical ventilation, survival was 75%. Oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor levels increased significantly. [90] Similarly, a small compassionate use study (n = 27) found a single 400-mg IV dose of tocilizumab reduced inflammation, oxygen requirements, vasopressor support, and mortality. [91]

A study compared outcomes of patients who received tocilizumab (n = 78) with tocilizumab-untreated controls in patients with COVID-19 requiring mechanical ventilation. Tocilizumab was associated with a 45% reduction in hazard of death (hazard ratio 0.55 [95% CI 0.33, 0.90]) and improved status on the ordinal outcome scale (odds ratio per one-level increase: 0.59 [0.36, 0.95]). Tocilizumab was associated with an increased incidence of superinfections (54% vs 26%; P< 0.001); however, there was no difference in 28-day case fatality rate among tocilizumab-treated patients with superinfection versus those without superinfection (22% vs 15%; P = 0.42). [92]

A small case among 29 solid organ transplant (SOT) recipients who received tocilizumab compared outcomes with 88 matched SOT controls who did not received tocilizumab. Mortality at 90 days was significantly higher for those who received tocilizumab (41%) compared with those who did not (20%; p = 0.03). Larger trials are needed to determine if there are subsets of patients who may benefit from tocilizumab. [93]  

An observational study in New Jersey showed an improved survival rate among patients who received tocilizumab. Among 547 ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend toward an improved survival rate of 56% who received tocilizumab compared with 46% who did not receive the therapy and a propensity adjusted hazard ratio of 0.76. [94]

A retrospective, observational cohort study in tertiary care centers in Bologna, Reggio Emilia, and Modena, Italy, between February 21 and March 24, 2020, concluded that tocilizumab may reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia. Of 1351 patients admitted, 544 (40%) had severe COVID-19 pneumonia and were included in the study. Fifty-seven (16%) of 365 patients in the standard care group needed mechanical ventilation compared with 33 (18%) of 179 patients treated with tocilizumab (P = 0.41; 16 [18%] of 88 patients treated IV and 17 [19%] of 91 patients treated SC). Seventy-three (20%) patients in the standard care group died, compared with 13 (7%; P< 0.0001) patients treated with tocilizumab (6 [7%] treated IV and 7 [8%] treated SC). [95]

However, another Italian study was halted after enrolling 126 patients with COVID-19 pneumonia, about one-third of the intended number, because the interim analysis showed it did not reduce severe respiratory symptoms, intensive care, or death compared with standard care. [96]

An open label, non-controlled, non–peer reviewed study was conducted in China in 21 patients with severe respiratory symptoms related to COVID-19. All had a confirmatory diagnosis of SARS-CoV-2 infection. The patients in the trial had a mean age of 56.8 years (18 of 21 were male). Although all patients met enrollment criteria of (1) respiratory rate of 30 breaths/min or more, (2) SpO2 of 93% or less, and (3) PaO2/FiO2 of 300 mm Hg or less, only two of the patients required invasive ventilation. The other 19 patients received various forms of oxygen delivery, including nasal cannula, mask, high-flow oxygen, and noninvasive ventilation. All patients received standard of care, including lopinavir and methylprednisolone. Patients received a single dose of 400 mg tocilizumab via intravenous infusion. In general, the patients improved with lower oxygen requirements, lymphocyte counts returned to normal, and 19 patients were discharged with a mean of 15.5 days after tocilizumab treatment. The authors concluded that tocilizumab was an effective treatment in patients with severe COVID-19. [97]

A retrospective review of 25 patients with confirmed severe COVID-19 who received tocilizumab plus investigational antivirals showed patients who received tocilizumab experienced a decline in inflammatory markers, radiological improvement, and reduced ventilatory support requirements. The authors acknowledged the study’s limitations and the need for adequately powered randomized controlled trials of tocilizumab. [98]

Nonetheless, these conclusions should be viewed with extreme caution. No controls were used in this study, and only one patient was receiving invasive mechanical ventilation. In addition, all patients were receiving standard therapy for at least a week before tocilizumab was started. AWP for 400 mg of tocilizumab is $2765.

Another clinical phase 3 trial (COV-AID) with IL-6 inhibitors (ie, tocilizumab, siltuximab), an IL-1 inhibitor (ie, anakinra), or combining an IL-6 inhibitor with anakinra is ongoing. [99]

Another anti-interleukin-6 receptor monoclonal antibody (TZLS-501; Tiziana Life Sciences and Novimmune) is currently under development. [100]

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. [101]

Several studies involving the IL-1 inhibitor anakinra (Kineret) have emerged. A retrospective study in Italy looked at patients with COVID-19 and moderate-to-severe ARDS who were managed with noninvasive ventilation outside of the ICU. The study compared outcomes of patients who received anakinra (5 mg/kg IV BID [high-dose] or 100 mg SC BID [low-dose]) plus standard treatment (ie, hydroxychloroquine 200 mg PO BID and lopinavir/ritonavir 400 mg/100 mg PO BID) with standard of care alone. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein levels and progressive improvements in respiratory function in 21 (72%) of 29 patients; 5 (17%) patients were on mechanical ventilation and 3 (10%) died. In the standard treatment group, 8 (50%) of 16 patients showed respiratory improvement at 21 days; 1 (6%) patient was on mechanical ventilation and 7 (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (P = 0.009). [102]

A study in Paris from March 24 to April 6, 2020, compared outcomes of 52 consecutive patients with COVID-19 who were given anakinra with 44 historical cohort patients. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0.22 [95% CI, 0.11-0.41; P< 0.0001). Similar results were observed for death alone (HR 0.30 [95% CI, 0.12-0.71]; P = 0.0063) and need for invasive mechanical ventilation alone (0.22 [0.09-0.56]; P = 0.0015). [103]

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. [104, 105, 106]

Mehta and colleagues describe the cytokine profile of COVID-19 as being similar to that of hemophagocytic lymphohistiocytosis (sHLH). sHLH is characterized by increased IL-2, IL-7, GCSF, INF-gamma, monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein-1 (MIP-1) alpha, and TNF-alpha. JAK inhibition may be a therapeutic option. [107]

Other selective JAK inhibitors (ie, fedratinib, ruxolitinib) may be effective against consequences of elevated cytokines, although baricitinib has the highest affinity for AAK1. [104]

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. [108]  Another phase 3, placebo-controlled trial (COV-BARRIER) is studying baricitinib in hospitalized patients who have an elevated level of at least one inflammation marker but do not require invasive mechanical ventilation at study entry. [109]

In September 2020, the ACTT-2 study investigators reported an approximately 1-day reduction in median recovery time (ie, well enough for hospital discharge) for the overall population treated with baricitinib plus remdesivir compared with remdesivir. More than 1000 participants were in the trial. Additional analyses are ongoing to understand other clinical outcome data, including mortality and safety data. [108]

A prospective observational study at a single hospital in Spain from March 15 to April 26, 2020 compared addition of baricitinib or baricitinib plus corticosteroids to standard treatment regimens of patients admitted with moderate-to-severe SARS-CoV-2 pneumonia. Patients received lopinavir/ritonavir and hydroxychloroquine as part of their standard therapy during the time of this study. Among 876 patients admitted during the time period, 558 had respiratory insufficiency (SpO2 92% or less breathing room air). Of these, 387 patients were enrolled. After excluding patients with major comorbidities, treatment with other immunomodulators, or nonevaluable cases, a total of 112 patients were analyzed. A greater improvement in SpO2/FiO2 from hospitalization to discharge was observed in the baricitinib plus corticosteroid group (n = 62) compared with the corticosteroid group (n = 50) (p < 0.001). [110]

A small open-labeled study (n = 12) conducted in Italy added baricitinib 4 mg/day to existing therapies (ie, lopinavir/ritonavir 250 mg BID and hydroxychloroquine 400 mg/day). All therapies were given for 2 weeks. Fever, SpO2, PaO2/FiO2, C-reactive protein, and modified early warning scores significantly improved in the baricitinib-treated group compared with controls (P: 0.000; 0.000; 0.017; 0.023; 0.016, respectively). ICU transfer occurred in 33% (4/12) of controls and in none of the baricitinib-treated patients (P = 0.093). Discharge at week 2 occurred in 58% (7/12) of the baricitinib-treated patients compared with 8% (1/12) of controls (P = 0.027). [111]

Ruxolitinib (Jakafi; Incyte) is part of the phase 3 RUXCOVID clinical trial. [112]

Pacritinib (CTI Biopharma) is a JAK2, interleukin-1 receptor-associated kinase-1 (IRAK-1), and colony stimulating factor-1 receptor (CSF-1R) inhibitor that is pending FDA approval for myelofibrosis. The phase 3 PRE-VENT trial has commenced to compare pacritinib with standard of care. Outcomes assessed include progression to mechanical ventilation, ECMO, or death in hospitalized patients with severe COVID-19, including those with cancer. As a JAK2/IRAK-1 inhibitor, pacritinib may ameliorate the effects of cytokine storm via inhibition of IL-6 and IL-1 signaling. Furthermore, as a CSF-1R inhibitor, pacritinib may mitigate effects of macrophage activation syndrome. [113]

A phase 2 trial is underway in the UK for a nebulized JAK inhibitor (TD-0903; Theravance Biopharma) to treat hospitalized patients with acute lung injury caused by COVID-19. Preclinical studies suggest that TD-0903 has a very high lung:plasma ratio and rapid metabolic clearance resulting in low systemic exposure, compatible with its lung selectivity. [114]  

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%). [115]

Corticosteroids are not generally recommended for treatment of viral pneumonia. [116] 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. [117]

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. [118] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial. [115]

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). [119]  An accompanying editorial addresses the unanswered questions regarding these studies. [120]  

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. [121]  

A study describing clinical outcomes of patients diagnosed with COVID-19 was conducted in Wuhan China (N = 201). Eighty-four patients (41.8%) developed ARDS, and of those, 44 (52.4%) died. Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72). [122]

Researchers at Henry Ford Hospital in Detroit implemented a protocol on March 20, 2020, using early, short-course, methylprednisolone 0.5-1 mg/kg/day divided in 2 IV doses for 3 days in patients with moderate-to-severe COVID-19. Outcomes of pre- and post-corticosteroid groups were evaluated. A composite endpoint of escalation of care from ward to ICU, new requirement for mechanical ventilation, or mortality was the primary outcome measure. All patients had at least 14 days of follow-up. They analyzed 213 eligible patients, 81 (38%) and 132 (62%) in pre-and post-corticosteroid groups, respectively. The composite endpoint occurred at a significantly lower rate in the post-corticosteroid group than in the pre-corticosteroid group (34.9% vs 54.3%; P = 0.005). This treatment effect was observed within each individual component of the composite endpoint. A significant reduction in median hospital length of stay was observed in the post-corticosteroid group (8 vs 5 days; P< 0.001). [123]

A study in the Netherlands showed a 5-day course of high-dose corticosteroids accelerated respiratory recovery, lowered hospital mortality rates, and reduced the likelihood of mechanical ventilation in patients with severe COVID-19–associated cytokine storm syndrome compared with historical controls. Forty-three percent of patients also received tocilizumab. [124]

A retrospective study at Montefiore Hospital in the Bronx borough of New York was conducted to evaluate if early glucocorticoid treatment (ie, within 48 hours of admission) reduced mortality rates or the need for mechanical ventilation in hospitalized patients with COVID-19. Of the 1,806 patients included in the study, 140 (7.7%) were treated with glucocorticoids, and 1,666 patients never received glucocorticoids. A key finding of this analysis is the need to verify which patients should receive glucocorticoid treatment. Glucocorticoid use in patients with initial C-reactive protein (CRP) levels of 20 mg/dL or greater was associated with significantly reduced risk of mortality or mechanical ventilation (OR, 0.23; 95% CI, 0.08-0.70), while use in patients with a CRP level of less than 10 mg/dL was associated with significantly increased risk of mortality or mechanical ventilation (OR, 2.64; 95% CI, 1.39-5.03). [125]  For further information regarding administration, see the EUA COVID-19 Convalescent Fact Sheet for Health Care Provider.

An investigational suprapharmacologic dexamethasone sodium phosphate formulation (AVM0703; Seattle AVM Biotechnology) is starting in phase 1 and 2 trials to determine how it quickly it mobilizes natural killer T- (NKT), cytotoxic T-, and dendritic cells to treat ARDS. [126]

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 program (EAP) for convalescent plasma was initiated in early April 2020. [6, 127]  The Mayo Clinic coordinated the open-access COVID-19 expanded access program, but will discontinue enrollment on August 28, as the FDA authorizes emergency use. 

Additionally, the CoVIg-19 Plasma Alliance is a partnership of numerous pharmaceutical companies who are collecting, developing, producing, and distributing immunoglobulin from patients with confirmed COVID-19 infection who have recovered.

Preliminary data from an open-label, multicenter, expanded access program in hospitalized adults conducted by the Mayo Clinic observed a gradient mortality in relation to IgG antibody levels in transfused ABO-compatible human COVID-19 convalescent plasma. The study analysis is from 2,807 acute care facilities in the US and territories and 5000 participants. The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the ICU and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The 7-day mortality rate in patients who received a high-antibody product was 8.7% in patients transfused within 3 days of COVID-19 diagnosis compared with 11.9% patients transfused 4 or more days after diagnosis (p < 0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p < 0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma – the pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared with to low antibody level plasma units. The authors note this information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma. [128]  The incidence of serious adverse events, including mortality rate (0.3%) within the first 4 hours after transfusion was < 1%. [129]  

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. Based on the available evidence, as of August 27, 2020, the Panel concluded there are insufficient data to recommend either for or against the use of convalescent plasma for the treatment of COVID-19. [130]  Also see NIH Guidelines

Similar observations were published from a study at Houston Methodist Hospital.  Of the 316 transfused patients, 136 met a 28-day outcome and were matched to 251 nontransfused control patients with COVID-19. Matching criteria included age, sex, BMI, comorbidities, and baseline ventilation requirement 48 hours from admission, and in a second matching analysis, ventilation status at Day 0. Variability in the timing of transfusion relative to admission and titer of antibodies of plasma transfused allowed for analysis in specific matched cohorts. The analysis showed a significant reduction (P = 0.047) in mortality within 28 days in patients transfused within 72 hours of admission with plasma that measured an anti-spike protein receptor binding domain titer of 1:1350 or greater. [131]

The use of convalescent plasma has a long history in the treatment of infectious diseases. Writing in the Journal of Clinical Investigation, Casadevall and Pirofski [132]  proposed using it as a treatment for COVID-19, and Bloch et al [133]  laid out a conceptual framework for implementation. Two small case series reported improvement in oxygenation, sequential organ failure assessment (SOFA) scores, and eventual ventilator weaning in some patients. The timelines of improvement varied from days to weeks. Caution is advised, as these were not controlled trials and other pharmacologic methods (antivirals) were used in some patients. [134, 135]  

A Cochrane review of convalescent plasma use in patients with COVID-19 is perpetually being updated as data emerge. As of July 10, 2020, the review included 20 studies with 5443 participants, of whom 5211 received convalescent plasma. Among these studies was one randomized controlled trial with 103 participants (52 received convalescent plasma). At the time of publication, the authors expressed uncertainty as to the benefits of convalescent plasma in terms of affecting mortality at hospital discharge, prolonging time to death, or improving clinical symptoms at 7 or 28 days. [136]

A meta-analysis of 15 controlled studies showed a significantly lower mortality rate in patients with COVID-19 who received convalescent plasma compared with control groups. However, the authors point out that the studies were mostly of low or very low quality with a moderate or high risk of bias. [137]

An open-label study (n = 103) of patients with laboratory-confirmed COVID-19 in Wuhan, China, given convalescent plasma did not result in a statistically significant improvement in time to clinical improvement within 28 days compared with standard of care alone. [138]

A nonrandomized study transfused patients based on supplemental oxygen needs with convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of at least 1:320 dilution. Matched control patients were retrospectively identified within the electronic health record database. Supplemental oxygen requirements and survival were compared between plasma recipients and controls. Results showed convalescent plasma transfusion improved survival in nonintubated patients (P = 0.015), but not in intubated patients (P = 0.752). [139]

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. [140]

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. [141]

Miscellaneous Therapies

Nitric oxide

Published findings from the 2004 SARS-CoV infection suggest the potential role of inhaled nitric oxide (iNO; Mallinckrodt Pharmaceuticals, plc) as a supportive measure for treating infection in patients with pulmonary complications. Treatment with iNO reversed pulmonary hypertension, improved severe hypoxia, and shortened the length of ventilatory support compared with matched control patients with SARS. [142]

A phase 3 study (PULSE-CVD19-001) for iNO (INOpulse; Bellerophon Therapeutics) was accepted by the FDA in mid-March 2020 to evaluate efficacy and safety in patients diagnosed with COVID-19 who require supplemental oxygen before the disease progresses to necessitate mechanical ventilation support. [143] 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. [97] 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. [144] Because of this, questions have arisen whether statins may be beneficial to reduce inflammation associated with COVID-19.

This question has been posed before with studies of patients taking statins who have acute viral infections. Virani [145] provides a brief summary of information regarding observational and randomized controlled trials (RCTs) of statins and viral infections. Some, but not all, observational studies suggest that cardiovascular outcomes were reduced in patients taking statins who were hospitalized with influenza and/or pneumonia. RCTs of statins as anti-inflammatory agents for viral infections are limited, and results have been mixed. An important factor that Virani points out regarding COVID-19 is that no harm was associated with statin therapy in previous trials of statins and viral infections, emphasizing that patients should adhere to their statin regimen.

Two meta-analyses have shown opposing conclusions regarding outcomes of patients who were taking statins at the time of COVID-19 diagnosis. [146, 147]  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. [148]  

Adjunctive Nutritional Therapies

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. [149]

Zinc

A retrospective analysis showed lack of a causal association between zinc and survival in hospitalized patients with COVID-19. [150]

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). [151]

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Additional Investigational Drugs for ARDS/Cytokine Release

 

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. [152, 153]  

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. [154]

Colony-stimulator factors

Sargramostim 

Sargramostim (Leukine, rhuGM-CSF; Partner Therapeutics, Inc) is an inhaled colony-stimulating factor presently in a phase 2 trial in hospitalized patients with COVID-19 (iLeukPulm). 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. [155]  

Gimsilumab 

Gimsilumab (Riovant Sciences) is being studied in the phase 2 BREATHE clinical trial at Mt Sinai and Temple University is analyzing monoclonal antibody that targets granulocyte macrophage-colony stimulating factor (GM-CSF) in patients with ARDS. [156, 157]  

Mavrilimumab 

Mavrilimumab (Kiniksa Pharmaceuticals) is a fully humanized monoclonal antibody that targets granulocyte macrophage colony-stimulating factor (GM-CSF) receptor alpha. An open-label study of mavrilimumab in Italy treated patients with severe COVID-19 pneumonia and hyperinflammation. Over the 14-day follow-up period, mavrilimumab-treated patients experienced greater and earlier clinical improvements than control-group patients, including earlier weaning from supplemental oxygen, shorter hospitalizations, and no deaths. Phase 2 trials are ongoing in the US. [158, 159]

Otilimab

Otilimab (GlaxoSmithKline) is a humanized monoclonal anti-GM-CSF antibody under development for rheumatoid arthritis. Clinical trial initiating May 2020 for severe pulmonary COVID-19. [160]  

Lenzilumab 

Lenzilumab (Humanigen) is a monoclonal antibody directed against GM-CSF. A phase 3 trial of hospitalized patients at 15 US sites is about halfway through the 300-patient enrollment mark as of early August 2020. [161]  

TJM2 

TJM2 (I-MAB Biopharma) is a neutralizing antibody against human granulocyte-macrophage colony stimulating factor (GM-CSF), an important cytokine that plays a critical role in acute and chronic inflammation. [162]

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). As of October 2020, the phase 3 trial for COVID-19 ARDS has enrolled 50% of the goal of 300 ventilator-dependent patients with moderate-to-severe ARDS. Theorized mechanism is down-regulation of proinflammatory cytokines. [163]  

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. [164]  

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. [165]  

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. [166]  

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. [167]  

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. [168]  

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. [169]

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) [170, 171] 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. As of October 2020, the phase 2b/3 multinational study has enrolled about 75% of participants.
Eculizumab (Soliris; Alexion) [172] 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) [173] Phase 3 randomized controlled trial planned in hospitalized adults with severe pneumonia or acute ARDS to evaluate complement (C5) inhibition for treatment. Trial commencement based on preclinical data of animal models suggesting inhibition of terminal complement may lower cytokine levels and reduce lung inflammation, as well as preliminary evidence from another C5 inhibitor (ie, eculizumab) compassionate use program.
Aviptadil (RLF-100; NeuroRx and Relief Therapeutics) [174, 175, 176, 177] Synthetic vasoactive intestinal peptide that prevents NMDA-induced caspase-3 activation in lungs and inhibits IL-6 and TNF-alpha production. Phase 2b/3 clinical trial for IV treatment of ARDS in all patients with severe COVID-19 and respiratory failure was initiated June 2020. Expanded access for hospitals not participating in the ongoing phase 2/3 clinical trials was approved by the FDA in late July 2020. IND for inhaled treatment approved by FDA in August 2020.
ATYR1923 (aTyr Pharma, Inc) [178] 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) [179] 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) [180] 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) [181, 182] 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. Phase 2/3 trial has been initiated for hospitalized patients with severe COVID-19 who have developed pneumonia and require supplemental oxygen.
Tranexamic acid (LB1148; Leading BioSciences, Inc) [183] 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) [184] 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) [185] Aldose reductase inhibitor shown to prevent oxidative damage to cardiomyocytes and to decrease oxidative-induced damage.
CM4620-IE (Auxora; CalciMedica, Inc) [186]

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) [187] 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) [188] 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) [189, 190] 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.
Acalabrutinib (Calquence; AstraZeneca; NCT04380688) [191, 192] Findings from an exploratory research project of this Bruton tyrosine kinase inhibitor showed encouraging improvement of excessive inflammation associated with COVID-19. Two phase 2 trials compared with best supportive care in hospitalized patients are underway.
VERU-111 (Veru, Inc) [193, 194] 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) [195] Targets the angiopoietin-Tie2 signaling pathway to reduce endothelial dysfunction.
Trans sodium crocetinate (TSC; Diffusion Pharmaceuticals) [196, 197] 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) [198] 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) [199] Deuterated form of pirfenidone, an approved anti-inflammatory and anti-fibrotic drug. Inhibits TGF-beta and TNF-alpha. Clinical trial starting in summer 2020 to evaluate use for serious respiratory complications, including inflammation and fibrosis, that persist following resolution of SARS-CoV-2 infection.
OP-101 (Ashvattha Therapeutics) [200] Selectively targets reactive macrophages to reduce inflammation and oxidative stress.
Vidofludimus calcium (IMU-838; Immunic Therapeutics) [201, 202] 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) [203] 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) [204] Study focuses on reduction of circulating proinflammatory biomarkers (eg, C-reactive protein).
Prazosin (Johns Hopkins) [205, 206] 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) [207] 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) [208] 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) [209] 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) [210] 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 (CytoDyn) [211, 212] CCR5 antagonist. A phase 2 trial for mild-to-moderate COVID-19 and a phase 2b/3 trial for severe COVID-19 are ongoing. 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) [213] 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) [214] 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.) [215] 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) [216] 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) [217] 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) [218] 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) [219] 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) [220] 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) [221] 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) [222] 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) [223] 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) [224] 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) initiated in August 2020.
Icatibant (Firazyr; Takeda Pharmaceuticals) [22] 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) [22] 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) [225] 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) [226] 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) [227] 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) [228] 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) [229] 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.
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Investigational Immunotherapies

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

Immunotherapy Description
CEL-SCI Corporation [230] Preferentially directed immunotherapy using ligand antigen epitope presentation system (LEAPS) peptide technology to reduce COVID-19 viral load and consequent lung damage.
Brilacidin (Innovation Pharmaceuticals) [231] Defensin-mimetic that mimics the immune system and disrupts the pathogen membrane, leading to cell death. It is undergoing clinical-stage testing at a US regional biocontainment laboratory. Also see Table 5 for potential use as a vaccine adjuvant.
Allogeneic natural killer (NK) cells (CYNK-001; Celularity, Inc) [232] FDA-approved investigational new drug for phase 1/2 clinical trial; demonstrates a range of biological activities expected of NK cells, including expression of activating receptors such as 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) [233] 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. A phase 2 placebo-controlled trial planned to begin Fall 2020 in hospitalized patients with COVID-19.
MultiStem cell therapy (Athersys) [234] 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.
CD24Fc (OncoImmune) [235] Biologic that fortifies an innate immune checkpoint against excessive inflammation caused by tissue injuries. Phase 3 testing was initiated April 20, 2020, at the University of Maryland. As of mid-June 2020, 70 patients have been enrolled.
LY3127804 (Eli Lilly Co) [109] Selective monoclonal antibody against angiopoietin 2 (Ang2), which is known to be elevated in patients with ARDS. Trial initiated at several US medical centers to determine if it reduces progression to ARDS or mechanical ventilation.
Bucillamine (N-mercapto-2-methylpropionyl-L-cysteine; Revive Therapeutics) [236] Bucillamine, an N-acetylcysteine derivative, has been shown to significantly attenuate clinical symptoms in respiratory viral infections in humans, primarily via donation of thiols to restore antioxidant and to reduce the activity of cellular glutathione. A phase 3 trial for treatment of mild-to-moderate COVID-19 was approved by the FDA in late April 2020 with initiation planned for September 2020.
Peginterferon lambda (Eiger Biopharmaceuticals; Stanford University) [237] Phase 2 trial initiated in outpatients with mild COVID-19 to evaluate efficacy of reducing viral shedding. Patients receive a single SC dose and are monitored for 28 days. Interferon lambda is thought to target innate immune response against viral pathogens.
Immune globulin IV (Octagam 10%; Octapharma) [238] IND for phase 3 randomized trial accepted by FDA to assess efficacy and safety in patients with severe COVID-19 disease.
Efineptakin alfa (NT-17; NeoImmuneTech, Inc) [239] 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 was announced in mid-July 2020 for adults with mild COVID-19 in conjunction with NIAID and the University of Nebraska Medical Center.
IFX-1 (InflaRx) [240] 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. Plans for phase 3 trial in patients with severe COVID-19–induced pneumonia who are mechanically ventilated.
T-COVID (Altimmune) [241] Intranasal immunostimulant starting phase 1/2 trials in US for non-hospitalized patients with early COVID-19 infection.  
ALVR109 (AlloVir) [242] Allogeneic virus-specific T-cell therapy that targets SARS-CoV-2. Initial dose-ranging trial followed by a pilot study in hospitalized patients at high risk for mechanical ventilation starting Q4 2020.
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Investigational Antibody Therapies

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

Antibody Therapies Description
REGN-COV2 Anti-Viral Antibody Cocktail (Regeneron) [243, 244, 245] Dual antibody combination (REGN10933 plus REGN109887). The 2 antibodies bind noncompetitively to the critical receptor binding domain (RBD) of the virus' spike protein, which diminishes the ability of mutant viruses to escape treatment. The clinical program consists of 4 separate study populations: hospitalized patients, nonhospitalized symptomatic patients, uninfected people in groups that are at high-risk of exposure (eg, healthcare workers, first responders), and uninfected people with close exposure to a patient with COVID-19 (eg, patient's housemate). Results released in late September 2020 showed a single infusion of REGN-COV2 reduced viral levels and improved symptoms in 275 nonhospitalized patients with COVID-19.  
VIR-7831 & VIR-7832 (Vir Biotechnology collaborating with Biogen and Generations Bio) [246]

VIR-7831 and VIR-7832 are mAbs that bind to an epitope on SARS-CoV-2. The epitope is also on SARS-CoV-1, indicating the epitope is highly conserved and more difficult to mutate. Each of the monoclonal antibodies are engineered to have an extended half-life and enhanced lung bioavailability. A phase 2/3 study (COMET-ICE) for VIR-7831 began in August 2020 for early treatment of COVID-19 in patients who are at high risk of hospitalization. Phase 1b/2a trial for VIR-7832 expected to start in late 2020.

LY-Cov555 (Eli Lilly and AbCellera) [247, 248, 21, 249]

Antibody treatment from more than 500 unique antibodies isolated from one of the first US patients to recover from COVID-19. Phase 1 study in hospitalized patients initiated in June 2020. An interim analysis of the phase 2 study (BLAZE-1) in people recently diagnosed with COVID-19 in the ambulatory setting showed a reduced rate of hospitalization or ER visits compared with placebo (1.7% [5/302] vs 6% [9/150]). A phase 3 trial (BLAZE-2) announced in August 2020 by NIAID is planned for prevention of SARS-CoV-2 infection in residents and staff at long-term care facilities in the United States.

JS-016 (Junshi Bioschiences and Eli Lilly) [250] Neutralizing antibody that binds a different epitope on the COVID spike protein than Lilly’s other antibody (LY-CoV555). The phase 1 trial in China completed in 40 healthy participants in mid-July 2020. A phase 1b trial planned for non-severe COVID-19 infection and a phase 2/3 trial planned for severe and critically ill patients.
COVI-SHIELD (Sorrento Therapeutics) [251] mAb Fc cocktail development in conjunction with Mt Sinai Health System in New York City.
STI-1499 (Sorrento Therapeutics) [252] COVID-19 targeting mAb. Phase 1 dose-ranging trial (COVI-GUARD) in hospitalized patients.
AZD7442 (AstraZeneca) [253] Long-acting combination of 2 mAbs derived from convalescent patients who recovered from COVID-19 infection. Two phase 3 trials starting in October 2020 will measure efficacy of preventing infection for up to 12 months.
Foralumab intranasal (Tiziana Life Sciences) [254]   Fully human anti-CD3 monoclonal antibody (mAb) found to induce regulatory T-cells, resulting in an IL-10 anti-inflammatory signal. As of September 2020, it is in a phase 2 trial in Brazil.
Ab8 (Abound Bio; U of Pittsburgh Medical Center) [255] Small antibody in preclinical trials with potential for treatment and/or prophylaxis against SARS-CoV-2.
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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. As of late August 2020, The New York Times Coronavirus Vaccine Tracker lists more than 165 vaccines against coronavirus are in development, and 32 vaccines are in human trials. [256]  

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.

Thanh Le et al describe platforms based on DNA or mRNA that offer flexibility regarding antigen manipulation and speed of development. Recombinant protein-based development may be beneficial owing to existing large-scale production capabilities. Use of an adjuvant can be of particular importance in a pandemic situation. Adjuvants are compounds that potentiate that antigen in the vaccine, thereby reducing the amount of antigen protein required per dose. This method allows more people to be vaccinated and conserves antigen resources. [257]

Vaccines in phase 3 clinical testing in the United States  

mRNA-1273

Overview

  • Once vial opened, must use within 6 hours
  • Dose: 2 injections 28-days apart

mRNA-1273 (Moderna Inc) encodes the S-2P antigen. The phase 1 study, a dose-escalation trial, was initiated in 45 healthy volunteers aged 18-55 years on March 16, 2020 at Kaiser Permanente Washington Health Research Instituted in Seattle and at the Emory University School of Medicine in Atlanta. Three doses—25, 100, and 250 mcg—were administered on a 2-dose schedule given 28 days apart. After the second vaccination, serum-neutralizing activity was detected via 2 methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. [258]  This trial was expanded to include 40 adults older than 55 years (20 adults aged 56-70 years and 20 adults aged 71 years and older). Safety results describe mild-to-moderate adverse effects. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. [259]

Phase 2 testing of placebo, 50-mcg, or 100-mcg given as 2 doses 28 days apart in adults aged 18-55 years (n=300) and in adults aged 55 years or older (n=50) was completed in June. US phase 3 trial (COVE) launched July 27, 2020, in cooperation with NIAID and will include about 30,000 participants who will receive two 100-mcg doses on days 1 and 29 or matched placebo. It is also stratified to include 25-40% of participants aged 65 years and older or be younger, but with comorbidities that increase severity of COVID-19 disease. [260]

In mid-October 2020, Moderna received confirmation from the European Medicine Agency (EMA) that their vaccine is eligible for submission of an application for European Union marketing authorization.

BNT-162b2

Overview

  • Storage and shipping requirements: Frozen
  • Requires reconstitution
  • Once thawed, stable refrigerated for up to 5 days
  • Dose: 2 injections 21-days apart

Nucleoside-modified messenger RNA (modRNA) vaccine (BioNTech and Pfizer) that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen. Human testing was initiated in early May 2020. Preliminary results from the phase 1/2 trial showed the vaccine (BNT162b1) could be administered in a 2-dose series that was well tolerated and that generated dose-dependent immunogenicity as measured by RBD-binding IgG concentrations and SARS-CoV-2 neutralizing antibody titers. All subjects in the prime-boost cohorts, except for 2 at the lowest dose level, had CD4+ T-cell responses. [261]  BNT162b2 vaccine (one of four mRNA constructs under clinically evaluation) emerged as the candidate with fewer adverse effects (eg, local reactions, fevers, fatigue) and it elicited T-cell responses against the RBD, which may generate more a consistent response across diverse populations, including older individuals. [262]  

The phase 2b/3 trial launched in late July 2020 with BNT162b2 vaccine. As of early October 2020, the phase 3 trial has enrolled nearly 38,000 participants with more than 31,000 having received their second vaccination. A rolling submission has been initiated with the European Medicines Agency. In mid-October 2020, the FDA allowed Pfizer to expand phase 3 trials to include adolescents aged 12 years and older. Additionally, the trial has strived to include diverse participants. About 43% of overall and 29% of US participants in its trial have diverse backgrounds: in the US, 5% are Asian, 10% Black, 13% Hispanic/Latinx, 0.8% Native American, and 47% are between the ages of 56 and 85 years.

AZD-1222

Overview

  • As of October 7, 2020: Phase 3 trial remains on hold in U.S. since September 6, 2020 pending further FDA review of data from a study participant in the U.K. diagnosed with transverse myelitis. Phase 3 trial has resumed in U.K., Brazil, and South Africa.
  • Dose: 2 injections 28-days apart
  • Storage requirements: Ultra-cold storage

Following immunization with AZD1222 (ChAdOx1 nCoV-19; AstraZeneca, University of Oxford), production of the surface spiked protein ensues. This primes the immune system to attack the SARS-CoV-2 virus if it later infects the body. Because of testing of a different coronavirus vaccine last year, development for this vaccine has accelerated. Phase 1/2 testing enrolled 1077 participants and showed neutralizing antibody responses in 91% after a single dose and 100% after a booster dose in those tested. T-cell response peaked at Day 14 and were boosted by the second dose. [263] As of late August 2020, the vaccine is in Phase 2/3 clinical trials in England and India, and phase 3 trials in Brazil, South Africa, and the US. 

Ad26.COV2.S

Overview

  • Storage: Refrigeration only
  • Dose: 1 injection

The phase 3 trial (ENSEMBLE) for adenovirus serotype 26 (Ad26) recombinant vector-based vaccine (JNJ-78436735; Johnson & Johnson [Janssen]) was launched in September 2020 with a goal of 60,000 participants in the US, South Africa, and South America. Antibodies to COVID-19 were observed following a single injection in 99% of participants aged 18-55 years in an interim analysis of phase 1/2a clinical trials. Additionally, 98% of participants were positive for neutralizing antibodies against SARS-CoV-2 at day 29, as well as strong T cell responses and a Th1 response. [264]  The vaccine uses Janssen’s AdVac technology, the vaccine, which assists vaccine stability (ie, 2 years at -20 degrees Celsius and at least 3 months at 2-8 degrees Celsius). This makes the vaccine candidate compatible with standard vaccine distribution channels and would not require new infrastructure to get it to the people who need it. [265]

Other examples of vaccines under development are included in Tables 5 and 6.

Table 5. Investigational Vaccines for COVID-19 (Open Table in a new window)

Vaccine Comments
Saponin-based Matrix-M adjuvant vaccine (NVX-CoV2373; Novavax and Emergent BioSolutions) [266, 267]

Contains an adjuvant that stimulates the entry of antigen-presenting cells into the injection site and enhances antigen presentation in local lymph nodes to boost the immune response. Phase 1/2 trials initiated in May 2020. Phase 1 data in healthy adults showed the vaccine with adjuvant induced neutralization titers exceeded responses in convalescent serum from mostly symptomatic patients with COVID-19. The phase 2 trial will assess 2 dose sizes (5 and 25 mcg), each with 50 mcg of Matrix‑M. Enrollment is planned for up to 1,500 healthy volunteers, with approximately 50 percent of participants aged 60 years and older, at up to 40 sites in the US and Australia. Phase 3 trials expected to start in October 2020.

INO-4800 (Inovio Pharmaceuticals) [268, 269]

The phase 1 human clinical trial enrolled 40 healthy volunteers was complete late April 2020. Favorable interim results of safety and immunogenicity were reported in June. The phase 1 trial was expanded to include older participants and Phase 2/3 efficacy trials are planned to commence by the end of summer 2020. Inovio has received a grant from the Bill and Melinda Gates Foundation to accelerate testing and scale up a smart device (Cellectra 3PSP) for large-scale intradermal vaccine delivery.

mRNA vaccine (CureVac) [270] Vaccine is in phase 1 testing as of August 24, 2020. Expects to enter phase 2b/3 in Q4 2020. 
Two vaccine candidates (Merck) [271] Developing 2 separate single-dose vaccines. After purchasing Themis Bioscience (Austrian vaccine maker), one vaccine (V591) will be based on a modified measles virus that delivers portions of SARS-CoV-2 virus. A phase 1 trial of V591 was launched in August 2020. The second vaccine in collaboration with IAVI uses Merck’s Ebola vaccine technology. This vaccine is expected to start human trials in 2020.
COVID-19 S-Trimer (GlaxoSmithKline [GSK] and Clover Biopharmaceuticals) [272] Preclinical development is underway using GSK’s adjuvants (compounds that enhance vaccine efficacy) and Clover’s proprietary proteins, which stimulate an immune response.
XWG-03 (GlaxoSmithKline and Xiamen Innovax collaboration) [273] GSK will provide Innovax with its adjuvant system for preclinical vaccine evaluation.
CpG 1018 adjuvant (Dynavax) and Sinovac’s inactivated coronavirus vaccine candidate [274] Collaboration for adjuvanted vaccine development.
Vaccine with CpG 1018 adjuvant (Dynavax and Clover Biopharmaceuticals) [275] Dynavax is providing Clover with adjuvant for its protein-based coronavirus vaccine candidate.
VLA2001 plus CpG 1018 adjuvant (Valneva and Dynavax) [276] Dynavax is providing technical expertise and the toll-like receptor 9 (TLR9) agonist adjuvant CpG 1018. Valneva is leveraging their platform for Japanese encephalitis vaccine, which operates on a highly purified Vero-cell–based, inactivated, whole-virus strategy for vaccine development.
Adjuvanted vaccine (GlaxoSmithKline and Sanofi) [277]

Adjuvanted vaccine under development with Sanofi’s S-protein COVID-19 antigen and GSK’s adjuvant technology that stimulates the immune system. Phase 1/2 trial expected to begin September 2020.

Live-attenuated vaccine (Codagenix) [278] Codagenix, a clinical-stage biotechnology company, is collaborating with the Serum Institute of India to co-develop a live-attenuated vaccine.
PCR-based DNA vaccine (Applied DNA Sciences and Takis Biotech) [279] The collaboration has designed four COVID-19 vaccine candidates utilizing PCR-based DNA manufacturing systems for preclinical testing in animals.
UB-612 multitope peptide-based vaccine (COVAXX [division of United Biomedical, Inc]) [280] Comprised of SARS-CoV-2 amino acid sequences of the Receptor Binding Domain (RBD). Further formulated with designer Th and CTL epitope peptides derived from the S2 subunit, membrane and nucleoprotein regions of SARS-CoV-2 structural proteins for induction of memory recall, T-cell activation and effector functions against SARS-CoV-2. COVAXX is partnering with University of Nebraska Medical Center for a phase1/2 trial beginning Fall 2020.
Brilacidin adjuvant vaccine (Innovation Pharmaceuticals) [281] Material Transfer Agreement (MTA) signed with a leading public health-focused US university and top coronavirus expert to evaluate the potential antiviral properties as a defensing adjuvant. Also see Table 1.
HaloVax (Hoth Therapeutics; Voltron Therapeutics) [282] Collaboration with the Vaccine and Immunotherapy Center of the Massachusetts General Hospital. Use of VaxCelerate self-assembling vaccine platform offers one fixed immune adjuvant and one variable immune targeting to allow rapid development.
PittCoVax (U of Pittsburgh School of Medicine) [283] Vaccine candidate using microneedle transdermal for COVID-19. Testing in mice produced antibodies over a 2-week period. Microneedles are made of sugar, making it easy to mass-produce and store without refrigeration.
Nanoparticle SARS-CoV-2 vaccine (Ufovax) [284] Vaccine prototype development utilizing self-assembling protein nanoparticle (1c-SapNP) vaccine platform technology.
Vaccine candidate (PDS Biotechnology Corp) [285] Utilizes Versamune T-cell activating platform for vaccine development.
TNX-1800 (Tonix Pharmaceuticals and Fujifilm Diosynth Biotechnologies) [286] Modified horsepox virus that is designed to express a protein from the SARS-CoV-2 virus.
Virus-like protein (VLP) based vaccine (Catalent; Spicona) [287] Catalent will use its proprietary GPEx cell line development technology to develop a cell line expressing the recombinant VLP.
Recombinant coronavirus Virus-Like Particles (CoVLP; Medicago and GlaxoSmithKline) [288] Combines Medicago’s rCoVLP with GSK’s adjuvant system. Phase 1 trial initiation planned for mid-July 2020.
Recombinant adenovirus type-5-vectored vaccine (Ad5-vectored vaccine; CanSino Biologics Inc [China]) [289, 290] Approved in June 2020 for Chinese military. Phase 2 trial (n = 508) completed. The vaccine induced seroconversion of neutralizing antibodies in 59% and 47% of participants in the 1x 1011 and 5x 1010 viral particles dose groups, respectively, and seroconversion of binding antibody in 96% and 97% of participants, respectively. Positive specific T-cell responses were found in 90% and 88%, respectively. Phase 3 trial in Saudi Arabia planned.
rAd26 (frozen) and rAd5 vector-based (lyophilized) formulations (Sputnik V; Moscow Gamaleya Institute) [291] Phase 1/2 trial completed followed by approval in early August 2020 by Russian government. Both vaccines were safe and well tolerated with mostly mild adverse events, and no serious adverse events were reported. All trial participants produced anti-spike protein and neutralizing antibodies after the second dose, as well as generated CD4+ and CD8+ responses.
hAd5-COVID-19 (ImmunityBio) [292] Phase I trial of second-generation human adenovirus serotype 5 vaccine initiated October 2020. The vaccine is designed to target inner nucleocapsid (N) and outer spike (S) protein, which have been engineered to activate T cells and antibodies against SARS-CoV-2, respectively. These dual constructs offer the possibility for the vaccine candidate to provide durable, long-term cell-mediated immunity with potent antibody stimulation to patients against both the S and N proteins. 
MRT5500 (Sanofi and Translate Bio) [293] mRNA-based vaccine candidate. Preclinical evaluation demonstrated favorable ability to elicit neutralizing antibodies using a 2-dose schedule administered 3 weeks apart. Phase I/II trial anticipated to start Q4 2020.
AG0302-COVID19 (AnGes and Brickell Biotech) [294] Adjuvanted DNA vaccine in phase 1/2 study in Japan. Data readouts expected Q1 2021. Intent to follow with phase 3 trials in US and South America.

 

Table 6. Investigational Noninjectable Vaccines for COVID-19 (Open Table in a new window)

Noninjectable Vaccine Comments
Intranasal COVID-19 vaccine (AdCOVID; Altimmune, Inc) [295] Single-dose vaccine. Preclinical results completed a University of Alabama Birmingham showed stimulation of antigen-specific CD4+ and CD8+ T cell in mild lungs as early as 10 days. Phase 1 safety and immunogenicity study expected to begin in Q4 2020.
ChAdOx1 nCov-19 inhaled (University of Oxford) [296] Dose-ranging trial for orally inhaled vaccine beginning phase 1 trials in 30 volunteers in Fall 2020.
saRNA inhaled (Imperial College of London) [296] Dose-ranging trial for orally inhaled vaccine beginning phase 1 trials in 30 volunteers in Fall 2020.
Recombinant Ad5 oral vaccine (Vaxart) [297] Adenovirus vector type 5 (Ad5) expressing coronavirus antigen and a toll-like receptor 3 (TLR3) agonist as an adjuvant. Theorized to confer superior protection compared with injection owing to activation of mucosal immunity. Room temperature stable vaccine tablet entering phase 1 trial September 2020. 

 

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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. [298]  While sepsis is recognized to activate the coagulation system, the precise mechanism by which COVID-19 inflammation affects coagulopathy is not fully understood. [299]   

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. [300]  

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. [301]   

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, inpatient, and convalescent settings. [21]  

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. [21]  

Purpose and initial drugs included in ACTIV-4 are: 

Outpatient trial 

Investigates 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 will be randomized to take either a placebo, aspirin, or a low or therapeutic dose of apixaban. 

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

AB021 (ARCA Biopharma) is a recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits tissue factor (TF)/factor VIIa complex and elicits novel antithrombotic activity. TF plays a central role in inflammatory response to viral infections. Phase 2b/3 clinical trials planned for late 2020. [302]

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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. [303] 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). [304]  

The BRACE Corona trial design further explains the 2 hypotheses. [305]  

  • 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. [306, 307]

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; [306] 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. [307, 308] 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. [309]

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, [310, 311, 312] while other studies have not shown this effect. [313, 314]

As 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. [315, 316]

Two clinical trials are currently in development at the University of Minnesota evaluating the use of losartan in patients with COVID-19 in inpatient and outpatient settings. [317, 318] Results from these trials will provide insight into the potential role of ARBs in the treatment of COVID-19.

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Diabetes and COVID-19

High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia. [319, 320] Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following: [321]

  • 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 [303] for entry into target cells. Insulin administration attenuates ACE2 expression, while hypoglycemic agents (eg, glucagonlike peptide 1 [GLP-1] agonists, thiazolidinediones) up-regulate ACE2. [321] 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. [322]

The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. Important clinical conclusions of the review include the following: [320]

  • 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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Hydroxychloroquine, Chloroquine, and Lopinavir/Ritonavir

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. [323]

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. [324]

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. [325] 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. [118]

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). [326]

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. [327]

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. [94]

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. [23] 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). [24]  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. [323, 328]

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. [329]

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. [330]  

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. [331, 332]

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. [333]

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. [334]

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. [335] 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. [336] 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. [337]

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. [338]

Hydroxychloroquine plus azithromycin

Opposing conclusions by French researchers regarding viral clearance and clinical benefit with the regimen of hydroxychloroquine plus azithromycin have been published. [339, 340, 341]

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. [341]

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]). [339] 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). [339]

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. [340] 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). [342]

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. [343, 344, 345, 346, 347, 348]

Results from the PATCH trial (n=125) did not show any benefit of hydroxychloroquine to reduce infection among healthcare workers compared with placebo. [345]

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). [349]

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. [350] 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. [351]

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. [352]

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. [353]

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. [354]

The Infectious Diseases Society of America (IDSA) guidelines recommend use of lopinavir/ritonavir only in the context of a randomized clinical trial. The guidelines also mention the risk for severe cutaneous reactions, QT prolongation, and the potential for drug interactions owing to CYP3A inhibition. [11]

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. [355]

The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020. [23]  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). [24]  

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. [356] 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. [357]

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. [69]

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. [358]

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

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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. [350] 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. [351, 359]

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. [360]

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. [361]

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. [362]

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. [352]

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. [353]

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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. [363]

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. [364, 365]

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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. [366]

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. [367]

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