What other drugs are being investigated to treat ARDS/cytokine release associated with coronavirus disease 2019 (COVID-19)?

Updated: Jun 25, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Human Vasoactive Intestinal Polypeptides

Aviptadil (Zyesami; RLF-100; NeuroRx) is a synthetic vasoactive intestinal peptide (VIP) that prevents NMDA-induced caspase-3 activation in lungs and inhibits IL-6 and TNF-alpha production. An EUA was submitted to the FDA on June 1, 2021 to treat critically ill patients with COVID-19 infection and respiratory failure. Results from a phase 2b/3 trial of IV aviptadil for treatment of respiratory failure in critically ill patients with COVID-19 demonstrated meaningful recovery at days 28 (p = 0.014) and 60 (p = 0.013) and survival (P < 0.001). Patients enrolled in the study had respiratory failure despite prior treatment with all approved medicines for COVID-19 including remdesivir. Other therapies administered included steroids, anticoagulants, and various monoclonal antibodies. Although antiviral treatment has shown advantages in treating patients with earlier stages of COVID-19, aviptadil is the first to demonstrate increased recovery and survival in patients who have already progressed to respiratory failure. [207]    

Additionally, it is being studied as an inhaled treatment. [208]

Colony-stimulating factors

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

Lenzilumab 

Lenzilumab (Humanigen) is a monoclonal antibody directed against GM-CSF. Results from a phase 3 trial (n = 520) found lenzilumab significantly improved survival without ventilation in hospitalized, hypoxic patients with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Those with CRP less than 150 mg/L and age younger than 85 years demonstrated an improvement in survival and had the greatest benefit. [209]

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

Sargramostim 

Sargramostim (Leukine, rhuGM-CSF; Partner Therapeutics, Inc) is an inhaled colony-stimulating factor. A phase 2 trial (iLeukPulm) in 120  hospitalized patients in the US with COVID-19 was completed and the results are expected mid-2021. 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. [210]

Gimsilumab 

Gimsilumab (Riovant Sciences) is being studied in the phase 2 BREATHE clinical trial at Mt Sinai and Temple University is analyzing this monoclonal antibody that targets granulocyte macrophage-colony stimulating factor (GM-CSF) in patients with ARDS. [211]  

Mavrilimumab 

Mavrilimumab (Kiniksa Pharmaceuticals) is a fully humanized monoclonal antibody that targets granulocyte macrophage colony-stimulating factor (GM-CSF) receptor alpha. Results from an ongoing global phase 2/3 trial showed a significant reduction in need for mechanical ventilation and death in those receiving mavrilimumab. Mortality at day 29 was 21% in the placebo arm but just 8% in the combined mavrilimumab arms (P = .07). [212]   

Otilimab

Otilimab (GlaxoSmithKline) is a humanized monoclonal anti-GM-CSF antibody under development for rheumatoid arthritis. A global, randomized trial (OSCAR; n = 806) compared a single 90-mg infusion of otilimab plus standard of care (SOC) with SOC alone in hospitalized adults with severe COVID-19 respiratory failure and systemic inflammation.  At day 28, 71% of patients who received otilimab were alive and free of respiratory failure compared with 67% of SOC alone. Although this did not reach statistical significance in the entire population, benefit was observed those aged 70 years and older (p = 0.009). This age group also had a reduction of 14.4% in all-cause mortality at Day 60. These findings are being confirmed in a further cohort of patients aged 70 and older. [213]

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. [214, 215]

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. [216]

Mesenchymal stem cells

Remestemcel-L 

Remestemcel-L (Ryoncil; Mesoblast Ltd) is an allogeneic mesenchymal stem cell (MSC) product currently pending FDA approval for graft versus host disease (GVHD). On December 1, 2020, the FDA granted Fast Track designation for remestemcel-L in the treatment of ARDS due to COVID-19 infection. Fast Track designation is granted if a therapy demonstrates the potential to address unmet medical needs for a serious or life-threatening disease. [217]

The trial’s primary endpoint is overall mortality at Day 30, and the key secondary endpoint is days alive off ventilatory support through Day 60. Two interim analyses by the independent Data Safety Monitoring Board (DSMB) were completed after 90 and 135 patients were enrolled, with recommendations to continue the trial as planned. A third and final interim analysis is planned when 180 patients have completed 30 days of follow-up. A pilot study under emergency compassionate use at New York’s Mt Sinai Hospital in March-April this year showed 9 of 12 ventilator-dependent patients with moderate-to-severe COVID-19 ARDS were successfully discharged from hospital a median of 10 days after receiving 2 intravenous doses of remestemcel-L. As of December 2020, the phase 3 trial for COVID-19 ARDS has enrolled about 200 of the goal of 300 ventilator-dependent patients with moderate-to-severe ARDS. Theorized mechanism is down-regulation of proinflammatory cytokines. [217]   [218]

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. [219]

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. [220]

HB-adMSC

Autologous, adipose-derived mesenchymal stem cells (HB-adMSCs; Hope Biosciences) had 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. [221]  

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. [222]  

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. [223]  

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. [224]  

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. [132]  

 

    Table 1. Investigational Drugs for ARDS/Cytokine Release Associated With COVID-19 (Open Table in a new window)

Therapy Description
Ifenprodil (NP-120; Algernon Pharmaceuticals) [225] N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonist. NMDA is linked to inflammation and lung injury. An injectable and long-acting oral product are under production to begin clinical trials for COVID-19 and acute lung injury. The phase 2b part of the 2b/3 study completed enrollment mid-December 2020. Key findings were no mortality at Day 15 in ifenprodil treated patients compared with 3.3% in those in the standard of care (SOC) group. Oxygenation returned to normal at day 4 compared with day 9 in the treated vs SOC groups respectively.  
Eculizumab (Soliris; Alexion) [226] 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) [227] Monoclonal antibody that is a C5 complement inhibitor. Phase 3 randomized controlled trial in hospitalized adults with severe pneumonia or acute ARDS requiring mechanical ventilation was initiated in April 2020, but was paused in January 2021 owing to initial outcomes not showing efficacy. Another phase 3 trial (TACTIC-R) in the UK is studying use of earlier immune modulation in preventing disease progression.
ATYR1923 (aTyr Pharma, Inc){ref227 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) [229] 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) [230] 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) [231, 232] Orally administered sphingosine kinase-2 (SK2) inhibitor that may inhibit viral replication and reduce levels of IL-6 and TNF-alpha. Nonclinical data indicate both antiviral and anti-inflammatory effects. As of December 2020, the phase 2/3 trial has enrolled more than 60% of participants, who are hospitalized patients with severe COVID-19 who have developed pneumonia and require supplemental oxygen. 
Tranexamic acid (LB1148; Leading BioSciences, Inc) [233] 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) [234] 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) [235] Aldose reductase inhibitor shown to prevent oxidative damage to cardiomyocytes and to decrease oxidative-induced damage.
CM4620-IE (Auxora; CalciMedica, Inc) [236] 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) [237] 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) [238] 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) [239]   [240]

Phase 2/3 trials underway in the United States and United Kingdom to determine if early intervention with oral EDP1815 (under development for psoriasis) prevents progression of COVID-19 symptoms and complications in hospitalized patients ≥15 years with COVID-19 who presented at the ER within the preceding 36 hours. The drug showed marked activity on inflammatory markers (eg, IL-6, IL-8, TNF, IL-1b) in a phase 1b study.
VERU-111 (Veru, Inc) [241] 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) [242] Targets the angiopoietin-Tie2 signaling pathway to reduce endothelial dysfunction.
Trans sodium crocetinate (TSC; Diffusion Pharmaceuticals) [243, 244] 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) [245] 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) [246] Deuterated form of pirfenidone, an approved anti-inflammatory and anti-fibrotic drug. Inhibits TGF-beta and TNF-alpha.  Phase 2 trial initiated in December 2020 for long COVID syndrome to evaluate use for serious respiratory complications, including inflammation and fibrosis, that persist following resolution of SARS-CoV-2 infection.
OP-101 (Ashvattha Therapeutics) [247] Selectively targets reactive macrophages to reduce inflammation and oxidative stress.
Vidofludimus calcium (IMU-838; Immunic Therapeutics) [248, 249] 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) [250] 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) [251] Randomized, open-label study (CardioLink-9; n = 100) focuses on reduction of circulating proinflammatory biomarkers (eg, high-sensitivity C-reactive protein [hsCRP, D-dimer) in COVID-infected outpatients. Patients in the icosapent ethyl group received a loading dose of 8 g/day for 3 days followed by 4 g/day for 11 days plus usual care. Icosapent ethyl showed a 25% reduction in hsCRP (p = 0.011) and a reduction in D-dimer (p = 0.048). Additionally, icosapent ethyl resulted in a significant 52% reduction of the total FLU-PRO prevalence score (flulike symptoms) compared with 24% reduction in the usual care group (p = 0.003). 
Prazosin (Johns Hopkins) [252, 253] 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) [254] 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) [255] 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) [256] 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) [257] IND approved mid-June 2020 for use in hospitalized patients with COVID-19. ATI-450 is an oral mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, or MK2) inhibitor that targets inflammatory cytokine expression. In a phase 1 clinical trial in healthy volunteers at the University of Kansas Medical Center, researchers used a first-in-human study using an ex vivo lipopolysaccharide (LPS) stimulation model that demonstrated a dose-dependent reduction of TNF-alpha, IL-1-beta, IL-6, and IL-8.
Leronlimab (Vyrologix [CytoDyn]) [258, 259] CCR5 antagonist. A phase 2 trial for mild-to-moderate COVID-19 is ongoing. The phase 3 trial in severe-to-critical patients is fully enrolled (n = 390) as of December 2020 and an open-label extension trial has been added to the protocol. Laboratory data following leronlimab administration in 15 patients showed increased CD8 T-lymphocyte percentages by day 3, normalization of CD4/CD8 ratios, and resolving cytokine production, including reduced IL-6 levels correlating with patient improvement. 
Sarconeos (BIO101; Biophytis SA) [260] 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) [261] 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.) [262] 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) [263] 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) [264] 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) [265] Animal model shows that 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) [266] 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) [267] 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) [268] 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) [269] 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) [270] 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) [271]

CAP-1002 consists of allogeneic cardiosphere-derived cells (CDCs), a type of cardiac cell therapy that has been shown in preclinical and clinical studies to exert potent immunomodulatory activity. CDCs releasing exosomes that are taken up largely by macrophages and T-cells and begin a cycle of repair. A phase 2 trial (INSPIRE) in hospitalized patients with severe or critical COVID-19 was initiated in late 2020.

Icatibant (Firazyr; Takeda Pharmaceuticals) [132] 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) [132]   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) [272]   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) [273] 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) [274] 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) [275] 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) [276] Fatty acid amide studied for its anti-inflammatory and analgesic actions. Phase 2a trial expected to begin in October 2020 for hospitalized patients with documented COVID-19 disease.
EB05 (Edesa Biotech) [277] Toll-like receptor 4 (TLR4) inhibitor. TLR4 is a key component of the innate immune system which functions to detect molecules generated by pathogens, acting upstream of cytokine storm and IL-6-mediated acute lung injury.
Fluvoxamine (Luvox) [278]   Preliminary double, randomized study of nonhospitalized adults with COVID-19 in community living environment showed no clinical deterioration at Day 15 compared with those taking placebo. Limited sample size with short follow-up. Clinical efficacy would require larger randomized trial. Theorized mechanisms include fluvoxamine effects on the S1R agonism (an endoplasmic reticulum chaperone protein), anti-inflammatory actions, and SSRI inhibition of platelet activation.
Lanadelumab (Takeda) [279]   mAb that targets kallikrein. Inhibits kallikrein proteolytic activity to control excess bradykinin. Part of the COVID R&D alliance (Amgen, UCB SA, Takeda) to identify drugs that can reduce severity of COVID-19 in hospitalized patients by moderating the immune system. 
Zilucoplan (UCB SA) [279]   Macrocyclic peptide inhibitor of complement C5. Part of the COVID R&D alliance (Amgen, UCB SA, Takeda) to identify drugs that can reduce severity of COVID-19 in hospitalized patients by moderating the immune system. 
CRV431 (Hepion) [280]   Binds cyclophilin A, which blocks the binding of cyclophilin A to specific receptors on inflammatory cells. This decreases infiltration of the cells into the tissue and production of harmful inflammatory molecules, resulting in reduced lung inflammation. Phase 2 trial starting late 2020.
Ensifentrine (Verona Pharma) [281]   Phosphodiesterase (PDE) 3 and 4 inhibitor. Elicits both bronchodilator and anti-inflammatory activities. Delivered via pressurized metered-dose inhaler. Phase 2 trial in 45 patients completed January 2021. 
TZLS-501 (Tiziana Life Sciences) [282]   Anti-interleukin-6 receptor monoclonal antibody in early development. 
Apabetalone (Resverlogix Corp) [283] Bromodomain and extra-terminal domain (BET) protein function is required for inflammation. BET inhibitors reversibly bind the bromodomains of BET proteins and prevent the protein-protein interaction between BET proteins and acetylated histones and transcription factors. Apabetalone, a BET inhibitor, reduces the expression of both ACE2 and DPP4 at the surface of human lung epithelial cells. Initiating open-label trials mid-2021 for apabetalone plus standard of care.

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