Review of COVID-19 Therapeutics by Mechanism: From Discovery to Approval

Paxlovid (nirmatrelvir/ritonavir)

Paxlovid consists of two molecules. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. A peptidomimetic is a molecule whose structure mimics that of a natural peptide. Inhibition of SARS-CoV-2 Mpro renders the protein incapable of processing polyprotein precursors, thus preventing viral replication. In contrast, ritonavir is a protease inhibitor that boosts the activity of nirmatrelvir by inhibiting cytochrome P450 3A (CYP3A), the enzyme required for metabolizing nirmatrelvir. When administered together with nirmatrelvir, ritonavir increases plasma concentrations of nirmatrelvir. Paxlovid received an EUA from the FDA on December 22, 2021 for treating adults and pediatric patients with mild-to-moderate COVID-19 who are at high risk for progressing to severe COVID-19.7 Paxlovid received final approval from the FDA for treating mild to moderate COVID-19 on March 17, 2023. EU approval was received on January 28, 2022. It is not authorized for initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19, nor is it authorized for use as pre-exposure or as post-exposure prophylaxis.

The recommended Paxlovid dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) taken together orally every 12 hours for 5 days. Paxlovid should be administered as soon as possible after a diagnosis of COVID-19. It should be also be administered within 5 days of symptom onset.8 It cannot be used for over 5 days.9 Paxlovid is not recommended for those with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m²).8 In Korean clinical studies, Paxlovid demonstrated safety and a reduction in viral load against the omicron variant.10 Moreover, it lowered the requirement for supplemental oxygen.11

Lagevrio (molnupiravir)

Molnupiravir is a prodrug with antiviral activity against SARS-CoV-2. It is metabolized to a cytidine nucleoside analog, forming a pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP incorporation into SARS-CoV-2 RNA by viral RNA polymerase (nsp12) introduces copying errors during viral RNA replication. This mechanism of action is known as ‘viral error catastrophe’ and the drug was originally developed at Emory University12 to treat influenza.

Molnupiravir received an EUA from the FDA on December 23, 2021 to treat mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19 and for whom alternative COVID-19 treatment options authorized by FDA are not accessible or clinically appropriate.13 However, EMA did not approve the drug for treating COVID-19 in adults until February 23, 2023, with the main reason being that the clinical benefit of molnupiravir was limited for those with COVID-19 who were not receiving supplemental oxygen.14

The dose for adult patients is 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days. The dug is not authorized for use for longer than five consecutive days. It is not authorized for use in patients who are less than 18 years of age, nor for initiation of treatment in patients who are hospitalized due to COVID-19. Molnupiravir is also not authorized for pre-exposure or post-exposure prophylaxis.15

Azvudine

Azvudine is a thymus-homing nucleoside analogue drug that inhibits viral RNA-dependent RNA polymerase (RdRp).16 It was approved by the National Medical Products Administration (NMPA) of China (the equivalent of the US Food and Drug Administration) on July 25, 2022 for COVID-19 treatment.17 Although there are no specified dosage guidelines for COVID-19, the usual clinical dose of azvudine is 5 mg orally once daily.16

Veklury (remdesivir)

Remdesivir is an adenosine nucleotide prodrug that is metabolized within host cells to form a pharmacologically-active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by SARS-CoV-2 RNA-dependent RNA polymerase. Remdesivir triphosphate also inhibits viral RNA synthesis through incorporation of the complementary natural nucleotide.

Remdesivir received FDA approval for adult and pediatric patients with COVID-19 requiring hospitalization18 on October 22, 2020 as the first approved treatment for COVID-19. FDA expanded its use for treating outpatients with mild-to-moderate COVID-19 on January 21, 2022. Remdesivir received EMA approval on July 3, 2020. According to the EMA, it is indicated for patients with pneumonia requiring supplemental oxygen.

The recommended dose is a 200 mg intravenous infusion on the first day and 100 mg intravenous infusion on the following day. Treatment duration is at least 5 days but not more than 10 days. Treatment duration is 3 days for patients who do not require supplemental oxygen. It must not be given as an intramuscular injection. The recommended dose and treatment duration vary for pediatric patients. Increased liver enzymes (transaminases) and a coagulation tendency are its common adverse effects, affecting more than 1 in 10 patients.19 In the treatment guidelines for mild to moderate COVID-19 patients in South Korea, Remdesivir is widely utilized.20 Additionally, hepatic injury and anemia have been identified as the most common side effects.21

It was reported that remdesivir is superior to placebo in shortening the time to recovery in adults who were hospitalized with SARS-CoV-2 infection and had no effect on all-cause mortality at up to day 28 in hospitalized adults with SARS-CoV-2 infection.22, 23

Mindvy (VV116)

Mindvy is an oral analogue of remdesivir. Mindvy is a nucleoside triphosphate analog drug that binds to the active site of RdRp and inhibits viral replication by creating an error-ridden and therefore defective genome.24, 25, 26 It was conditionally approved by NMPA for treating adult patients with COVID-19.25 It is also approved in Uzbekistan. A dose of 200 mg twice daily is recommended for COVID-19 treatment.26

2-DG (2-deoxy-D-glucose)

2-DG (2-deoxy-D-glucose) is a glucose analogue that competes with it and inhibits metabolism within host cells. It inhibits synthesis of viral molecules and energy production.27 2-DG received approval from the Drugs Controller General of India (DCGI) on May 1, 2021, for adjunctive treatment of moderate-to-severe COVID-19 illness. A clinically tolerable dose is 63 mg/kg. Further studies are underway to determine the optimal dose.28

Kineret (anakinra)

Anakinra is an immunmodulating, interleukin (IL)-1 type I receptor inhibitor that blocks both IL-1α and IL-1β.29 Anakinra has received FDA approved for treatment of three diseases: rheumatoid arthritis (RA), cryopyrin-associated periodic syndromes, and deficiency of IL-1 receptor antagonist.30 Anakinra received an EUA from the FDA on November 8, 2022 to treat hospitalized COVID-19 pneumonia adult patients requiring supplemental oxygen who are at high risk for progressing to severe respiratory failure and likely to have an elevated soluble urokinase plasminogen activator receptor (suPAR).31 EU approval was obtained on December 17, 2021.32 The recommended dose is 100 mg subcutaneous injection once daily for 10 days. Common side effects (occurring more than 10% of patients) are pain and redness at the injection site and increased total cholesterol levels.29

Artlegia (olokizumab)

Olokizumab is a monoclonal antibody targeting IL-6.24 It received approval from the Ministry of Health of the Russian Federation (Minzdrav) for COVID-19 pneumonia.33 The recommended dose is a single subcutaneous injection of 64 mg, administered in the thigh or anterior abdominal wall once every four weeks. It is not recommended for patients aged below 18 years of age.24

Actemra (tocilizumab)

Tocilizumab is an IL-6 receptor (IL-6R) inhibitor that binds membrane-bound IL-6 receptors.34 It has FDA approval for RA, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis (PJIA), systemic juvenile idiopathic arthritis, cytokine release syndrome (CRS), and COVID-19.35

Tocilizumab received an EUA from the FDA on June 24, 2021 for hospitalized COVID-19 patients aged 2 years and older with systemic glucocorticoids who require supplemental oxygen or mechanical ventilation. On December 21, 2022, tocilizumab received Biologics License Application (BLA) 125276 for the same patients.36 EU approval of tocilizumab was obtained on December 7, 2021.37

The recommended dose of tocilizumab is a single 60-minute intravenous infusion at 8 mg/kg (maximum 800 mg). If any clinical improvements are found, one additional infusion can be administered after an interval of at least 8 hours. Patients with abnormal levels of liver enzymes, absolute neutrophil count (ANC), and platelet count are not recommended to receive tocilizumab.34

Ilsira (levilimab)

Levilimab is a monoclonal antibody targeting the IL-6 receptor. Levilimab was developed to prevent cytokine storm caused by COVID-19.38, 39 It received approval from the Ministry of Health of the Russian Federation (Minzdrav) on June 5, 2020 for COVID-19 treatment.38 Subcutaneous injection of Levilimab at 324 mg is generally recommended.40 It apparently has not been approved in the USA.

Alzumab (itolizumab)

Itolizumab is a monoclonal antibody against CD6, a costimulatory molecule that stimulates T cell proliferation. The drug was developed to prevent CRS or acute respiratory distress syndrome (ARDS) due to COVID-19. It was approved for chronic plaque psoriasis in 2013 in India. Itolizumab also received restricted emergency use approval from the Drugs Controller General of India (DCGI) in July 2020 for treating COVID-19-related CRS or ARDS.41

The recommended dose of itolizumab is 1.6 mg/kg for the first dose, administered as an intravenous infusion. One week later, a second dose 0.8 mg/kg is given.42 Patients with hepatic or renal disease, those with infectious diseases, and pregnant or lactating women are not recommended to receive itolizumab.41

Olumiant (baricitinib)

Olumiant, also known as baricitinib, is a Janus kinase (JAK) inhibitor.43 Baricitinib received FDA approval for RA, alopecia areata, and COVID-19.44 It received an EUA from the FDA on November 19, 2020 for use in combination with remdesivir for COVID-19 patients requiring supplemental oxygen. On May 10, 2022, the FDA approved baricitinib for hospitalized COVID-19 adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).44 On October 27, 2022, FDA expanded the EUA for use of baricitinib in hospitalized adults and pediatric patients aged 2 to 18 years requiring supplemental oxygen.45 However, the EMA did not approve baricitinib for treating hospitalized COVID-19 patients until December 7, 2022.46

The recommended dose of baricitinib for pediatric patients 9 years and older and for adult patients is 4 mg. For pediatric patients aged 2 to 9 years, the recommended dose of baricitinib is 2 mg orally once daily. The recommended treatment duration is 14 days or until hospital discharge.43, 44, 45 In Korea, various immunomodulators, including baricitinib, were administered to patients requiring supplemental oxygen.47 Dosage modifications are recommended for patients with renal or hepatic impairment.43 Olumiant is not recommended for patients with an absolute lymphocyte count less than 200 cells/µL or an ANC less than 500 cells/µL.44 Known adverse events are serious venous thromboses including pulmonary embolism.43

According to the NIH COVID-19 treatment guidelines, non-hospitalized patients at risk of progressing to severe COVID-19 symptoms may be offered Paxlovid, remdesivir, or molnupiravir. For hospitalized patients, those not requiring supplemental oxygen may receive remdesivir, while those requiring supplemental oxygen may receive dexamethasone and remdesivir, and in more severe cases, baricitinib or tocilizumab may be considered.

Evusheld (tixagevimab/ cilgavimab)

Evusheld (previously known as AZD8895 and AZD1061) contains tixagevimab and cilgavimab. Tixagevimab and cilgavimab were designed to attach to the spike protein of SARS-CoV-2 (the virus that causes COVID-19) at two different sites. Evusheld hinders viral entry by attaching to the viral spike protein.49

On December 8, 2021, Evusheld receive Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA) for pre-exposure prophylaxis of COVID-19 in adults and pediatric individuals, and treatment of those with mild to moderate COVID-19 who are at high risk for developing severe disease. However, due to new SARS-CoV-2 variants, EUA of Evusheld is no loonger valid in the U.S..50, 51 Currently, Evusheld approval remains valid throughout the EU.

For pre-exposure prophylaxis of COVID-19, 150 mg of tixagevimab and 150 mg of cilgavimab, administered as two separate sequential intramuscular injections, are recommended. For treatment, 300 mg of tixagevimab and 300 mg of cilgavimab within 7 days of showing symptoms of COVID-19 administered as two separate sequential intramuscular injections are recommended. Tixagevimab and cilgavimab must be given as separate sequential intramuscular injections at different injection sites in two different muscles, preferably in gluteal muscles. These therapies are indicated for treating adults and adolescents aged 12 years or older not requiring supplemental oxygen who are at an increased risk of progressing to severe COVID-19. Systemic hypersensitivity (allergic) reactions and local reactions at the site of injection are the most common side effects.52

Regkirona (regdanvimab)

Regkirona, also known as CT-P59 is a recombinant human IgG1 monoclonal antibody that binds to the receptor binding domain (RBD) of the spike(s) protein of SARS-CoV-2, consequently blocking cellular entry and SARS-CoV-2 infection. Regkirona received approval first from the MFDS (Minister of Food and Drug Safety), of Korea on December 29, 2020. Regkirona received approval from EU on November 12, 2021. It is indicated for treating confirmed COVID-19 in adult patients who do not require supplemental oxygen but are at a high risk of progressing to severe COVID-19.

The recommended dosage of Regkirona is 40 mg/kg via a single dose by intravenous infusion. The maximum dosage is 8000 mg. Adverse allergic responses, including fever, dyspnea, tachycardia, bradycardia, and itching due to Regkirona use are uncommon, occurring in about 1 person per 100.53 With the emergence of the delta variant, Regkirona is no longer recommended.54

Ronapreve (casirivimab/imdevimab)

Ronapreve consists of two recombinant human monoclonal antibodies, casirivimab (IgG1κ) and imdevimab (IgG1λ), that target non-overlapping epitopes of the spike protein RBD of SARS-CoV-2. The drug prevents RBD binding to the human ACE2 receptor and thereby blocks viral entry into cells. Ronapreve received approval throughout the EU on November 12, 2021.

Ronapreve can be used for treating and preventing COVID-19. The recommended dosage for treatment is 600 mg for casirivimab and 600 mg for imdevimab, administered as a single intravenous infusion or subcutaneous injection. They should be given within seven days of the onset of COVID-19 symptoms. The recommended dosage for pre-exposure prophylaxis is 600 mg for casirivimab and 600 mg for imdevimab as an initial dose, administered as a single intravenous infusion or subcutaneous injection. Subsequent doses of 300 mg of casirivimab and 300 mg of imdevimab can be administered as a single intravenous infusion or as subcutaneous injections every four weeks, until prophylaxis is no longer required. There are no data on repeat dosing beyond 24 weeks (6 doses). The recommended dosage for post-exposure prophylaxis is 600 mg for casirivimab and 600 mg for imdevimab, administered as a single intravenous infusion or subcutaneous injection. Casirivimab combined with imdevimab should be given as soon as possible after exposure to persons with COVID-19.55 Ronapreve is not currently authorized for use in any U.S. after emergence of omicron variants.

Xevudy (sotrovimab)

Xevudy, also known as VIR-7831 and GSK4182136, is a human IgG1 monoclonal antibody that binds to a highly conserved epitope on the spike protein RBD of SARS-CoV-2. Xevudy received an EUA from the FDA on May 26, 2021 for treating mild-to-moderate COVID-19 in adults and in children (12 years of age and older weighing at least 40 kg) (+) and those who are at high risk for progression to severe COVID-19, including hospitalization and death. The EUA of Xevudy is not valid for the omicron variant.56, 57 Xevudy received approval throughout the EU on December 17, 2021.

The recommended dose is a single 500 mg intravenous infusion. Allergic reactions to Xevudy are common, affecting up to 1 in 10 people.58 Xevudy is no longer authorized to treat COVID-19 in any U.S. caused by the Omicron BA.2 sub-variants.

BRII-196/BRII-198 (amubarvimab/romlusevimab)

BRII-196/BRII-198 contains two monoclonal antibodies, amubarvimab (BRII-196) and romlusevimab (BRII-198). Each binds non-overlapping epitopes of the spike protein of SARS-CoV-2 and prevents viral entry into cells. BRII-196/BRII-198 received approval from NMPA of China in December 2021 for treating adult patients (18 years aged and older) with mild COVID-19. The recommended dose is 1,000 mg for amubarvimab and 1,000 mg for romlusevimab, administered as separate sequential intravenous infusions.59 BRII-196/BRII-198 is no longer recommended to use after the emergence of omicron variants.

Jaktinib

Jaktinib is a JAK inhibitor that has been used to prevent and treat cytokine storms in COVID-19 patients. Jaktinib inhibits JAK1, JAK2, JAK3, and TYK2 by blocking the JAK-STAT signaling pathway (suppressing the release of IL-2, IL-4, IL-6, IL-7, and IL-10).73

Jaktinib was developed by Suzhou Zelgen Biopharmaceuticals, Shanghai, China. The drug is being studied for treating myelofibrosis, severe alopecia areata, atopic dermatitis, acute graft versus host disease (GvHD), and COVID-19.74

A phase 2 study to evaluate the safety and efficacy of jaktinib in severe COVID-19 pneumonia patients is planned (NCT05686629) but is not recruiting subjects yet. The treatment group will receive two 50 mg jaktinib doses or placebo tablets twice daily. The primary outcome measures will be the proportion of subjects who show clinical improvement (a score of more than 2) in the NIAID Ordinal Scale (NIAID-OS) for COVID-19, a change in the value of NIAID-OS, the time for subjects to reach 1-3 points, and the time to discharge.

Ilaris (canakinumab)

Ilaris is an IL-1β blocker developed by Novartis, Basel, Switzerland.75 The drug is in development for autoinflammatory periodic fever syndromes and active Still disease. It is now being repurposed to alleviate clinical manifestations in patients with COVID-19.76, 77

Katia and colleagues reported on a single center, single arm study conducted in 20209 in 20 patients with COVID-related severe acute respiratory syndrome. Treatment with canakinumab was associated with reduced requirement for supplemental oxygen.

A phase 3 study to compare the efficacy and safety of canakinumab with standard of care in COVID-19-induced pneumonia and CRS patients has been completed (NCT04362813). The canakinumab group received a single intravenous dose of canakinumab, dosed according to body weight (450 mg for 40 to 60 kg, 600 mg for 60 to 80 kg, and 750 mg for more than 80 kg) in 250 mL of 5% dextrose on day 1. The control group received a single dose of 250 mL of 5% dextrose via intravenous infusion on day 1. All subjects received standard of care. The primary outcome measure was the number of surviving participants who did not need invasive mechanical ventilation from Day 3 to Day 29. Trial results are pending.

Reparixin

Reparixin is a non-competitive allosteric inhibitor of CXCR1 (keratinocyte-derived chemokine receptor) and CXCR2 (macrophage inflammatory protein 2 receptor). Reparaxin was developed by Dompe’ Pharmaceutical, Milan, Italy. By inhibiting CXCR1/2, it suppresses CXCL8 (IL-8)-induced neutrophil activation and reduces lung edema and neutrophil recruitment into the lung.78

Clinical studies evaluating the efficacy and safety of reparixin efficacy and safety in patients with breast cancer or with pancreatic transplantation have been completed.79

Due to its anti-inflammatory properties, reparixin might be a treatment option to prevent or attenuate CRS.80 Clinical trials to test the efficacy of reparixin for treating COVID-19 are currently underway. A phase 3 study is currently recruiting participants to evaluate the efficacy of reparixin in patients with community-acquired pneumonia, including COVID-19 (NCT05254990). Subjects will receive standard of care and two 600 mg reparixin or placebo tablets three times daily with 8 hours intervals (6 tablets daily) for up to 21 days. The primary outcome will be the proportion of subjects who die or need mechanical ventilation or extracorporeal membrane oxygenation within a 28 day period.

Taltz (ixekizumab)

Ixekizumab is a humanized IL-17A antagonist developed by Eli Lilly and Company (Indianapolis, IN, USA).81 In COVID-19 patients, overactivation of T lymphocytes, which is manifested by an increase in Th17 cell numbers, can lead to increased production of IL-17 and IL-22 cytokines. The use of an IL-17 blocking agent could be effective in treating patients with severe COVID-19.82 Ixekizumab was approved by the FDA for treating plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis.81

A phase 3 study aimed at finding an immune modulator of cytokines for subjects with severe COVID-19 was recently completed (NCT04724629). The trial name was Survival RTrial Using CytoKines in COVID-9 (STRUCK). The study drugs included an IL-17 inhibitor (ixekizumab), an IL-2 inhibitor (aldesleukin), and an IL-6 inhibitor (colchicine). The ixekizumab treatment group received 80 mg by subcutaneous injection weekly for four weeks or until hospital discharge. The control group received standard of care including mechanical ventilation or dexamethasone. The primary outcome measure was the proportion of subjects who showed clinical improvement of two points on a seven-category ordinal scale on day 21. Study results are pending.

Remicade (infliximab)

Infliximab blocks tumor necrosis factor (TNF) [formerly named TNF-α) that was developed by Janssen Biotech (Horsham, PA, USA).83 Infliximab received FDA approval for treating Crohn disease, colitis, and RA in 1998.84 Infliximab is now being repurposed to treat COVID-19 patients.

A phase 3 study (ACTIV-1 trial) sponsored by the National Center for Advancing Translational Sciences (NCATS), NIH sought to find an effective immune modulator for patients with COVID-19 and has been completed (NCT04593940). The study consisted of three arms (infliximab, abatacept, and cenicriviroc). Participants in each arm received either drug or placebo, together with standard of care. Participants in the infliximab arm received a single 5 mg/kg dose of infliximab on day 1. The primary outcome measure was the time to recover from COVID-19 up to 29 days. Results are pending.

Orencia (abatacept)

Orencia is a selective T cell co-stimulation modulator that competes with CD28 for binding CD80 and CD86 receptors, thus decreasing T cell proliferation and inhibiting the production of cytokines such as TNF, interferon-γ, and IL-2.85 Neutralizing inflammatory factors in CRS using abatacept could be an effective way to avoid severe inflammation in COVID-19.86

Abatacept was developed by Bristol-Myers Squibb (New York, NY, USA) and was approved by the FDA in 2005 for treating RA, PJIA, and psoriatic arthritis.85 There has been interest in repurposing abatacept to treat patients with COVID-19.

A phase 3 study, the ACTIV-1 IM Trial Immunomodulators for Treating COVID-19 (NCT04593940) was sponsored by National Center for Advancing Translational Sciences (NCATS), NIH and has been complete. This study consisted of three arms. Each arm was provided with a standard of care including remdesivir. The infliximab group received a single 5 mg/kg dose of infliximab via intravenous infusion on day 1. The abatacept arm received a single 10 mg/kg dose of abatacept up to 1,000 mg via intravenous infusion on day 1. The control group received cenicriviroc, a chemokine 2 and 5 receptor antagonist (450 mg on day 1 and 300 mg on days 2 to 29) or a matching placebo. The primary outcome measure was the time to recover from COVID-19 up to day 29. None of the three therapies significantly improved outcomes compared to placebo.

Vascepa (icosapent ethyl)

Vascepa is an ethyl ester of eicosapentaenoic acid (EPA) that reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and enhances triglyceride clearance from circulating VLDL particles. The drug was developed by Amarin, Dublin, Ireland.87 Isopent ethyl (Vascepa) received FDA approval as an adjunct to maximally tolerated statin therapy and diet to reduce triglyceride levels.

EPA improves endothelial function, limits vascular inflammation and reactive oxygen species production, and reduces vascular thrombosis. Through these mechanisms, Vascepa might reduce inflammation and improve symptoms of patients with COVID-19.88

A phase 3 study of Vascepa for COVID-19 has been completed (NCT04460651). This study consisted of a prevention group (enrolling subjects at high risk of infection from COVID-19) and a treatment group (COVID-19-positive subjects). Subjects in the prevention group received 8 g oral Vascepa or placebo every 12 hours on days 1 to 3 and 4 g oral Vascepa or placebo every 12 hours for days 4 to 60. Subjects in the treatment group received 8 g oral Vascepa or placebo every 12 hours on days 1 to 3 and 4 g oral Vascepa or placebo every 12 hours for days 4 to 28. Primary outcome measures were COVID-19-positive subjects in the prevention group within 60 days and hospitalized or deceased subjects in the treatment group due to COVID-19 within 28 days. Results are pending.

NuSepin (HY209)

Nusepin is a fibroblast growth factor 19 (FGF-19) analog developed by Shaperon in South Korea. It targets cytokine storm in COVID-19 by suppressing pro-inflammatory cytokine production.89

A phase 2, 3 study to evaluate the safety and efficacy in COVID-19 pneumonia patients is recruiting participants (NCT05352347). Subjects in the treatment group will receive 0.2 mg/kg or 0.4 mg/kg NuSepin, twice daily by intravenous injection. Subjects in the control group will receive 100 mL normal saline twice daily. Primary outcome measures will be the time to improve more than 2 categories of the WHO 8-point ordinal scale and the time to discharge from the first dosing to day 29.

Ruconest (conestat alfa)

Ruconest (conestat alfa) is a C1 esterase inhibitor (C1INH) that promotes activation of complement. Conestat alfa was developed by Pharming Group, Leiden, Netherlands.90 Conestat alfa targets several proteases of the contact and complement systems. Target proteases of conestat alfa are involved in the activation of complement protein C1, kallikrein, factor XIIa, and factor XIa.90

Activation of the complement system plays a central role in the pathogenesis of acute lung injury. The kallikrein-kinin system is also involved in thrombo-inflammation. Targeting multiple inflammatory cascades with conestat alfa could lead to clinical improvement in patients with severe COVID-19.91 Conestat alfa received FDA approval for treating hereditary angioedema in 2014 and is under development for treating COVID-19.

A phase 2 study to evaluate the ability of conestat alfa to prevent severe disease progression in hospitalized COVID-19 patients has been completed (NCT04530136); results are pending. Participants in the conestat alfa to group received an intravenous injection of a dose of 50 U/kg (maximum dose of 4,200 U) every 12 hours for 4 days, for a total 8 injections. The control group received a standard of care. The primary outcome measure was the score of the WHO Ordinal Scale of disease severity on day 7.

MN-166 (ibudilast)

Ibudilast is an allosteric inhibitor developed by Kyorin Pharmaceutical, Tokyo, Japan.92 Ibudilast is a selective inhibitor of phosphodiesterases acts to macrophage function. PDE 3, 4, and 10.93 The use of PDE4 inhibitors has the potential to prevent cytokine storm in COVID-19.94 Additionally, the inhibitor can inhibit production of proinflammatory cytokines such as IL-1β, TNF, and IL-6, while increasing the production of anti-inflammatory cytokines (IL-10, IL-4).93

Ibudilast was approved by Japan in 1989 for treating bronchial asthma and improving dizziness secondary to chronic cerebral circulation impairment associated with sequelae of cerebral infarction.

Currently, ibudilast is being repurposed for use in the treatment of COVID-19. A phase 2 study to evaluate the efficacy and safety of ibudilast in COVID-19 patients is underway (NCT04429555). Participants receive MN-166 or placebo capsules twice daily for 7 days. Primary outcome measures are the proportion of subjects free from respiratory failure, the mean change from baseline in clinical status using the NIAID 8-point ordinal scale, the percentage of patients showing improvement in clinical status, and changes in cytokine levels at day 7.

CAP-1002

CAP-1002 refers to cardiosphere-derived cells (CDCs), which are stromal progenitor cells, derived from heart tissues by Capricor Therapeutics (Beverly Hills, CA, USA).95 Cardiospheres are cell clusters that form invitro when cardiac progenitor cells are cultured. CDCs modulate activity of macrophages and effector T cells, and affect expression pro-inflammatory cytokines, potential o contributing to the pathogenesis of COVID-19. Additionally, CDCs can decrease production of proinflammatory cytokines (IFNγ, TNF, IL-1β, IL-6) and increase plasma levels of IL-10.96

CAP-1002 has been granted orphan drug designation by the FDA for treating Duchenne muscular dystrophy. CAP-1002 is being repurposed to treat COVID-19. A phase 2 study to evaluate the safety and efficacy of CAP-1002 in COVID-19 patients has been completed (NCT04623671). The treatment group received CAP-1002 therapy by infusion of 150 million CDCs in 5% human serum albumin. The control group received a placebo infusion. The primary outcome measure was the number of deaths within 90 days. Results are pending.

GB-0139 (Nafomostat)

GB-0139 is an inhibitor of galectin-3 (Gal-3) developed by Galecto Biotech (Boston, MA, USA). Gal-3 activates signaling pathways, including in particular those involving three molecules: extra-cellular signal regulated kinase (ERK), protein kinase B (Akt), and JAK/signal transducer and activator of transcription (STAT1). Activation of pathways leads to the release of pro-inflammatory cytokines, including IL-6, IL-8, and TNF.

Nafomostat is a synthetic serine protease inhibitor that reduces plasma levels several pro-fibrotic mediators.97 GB-0139 being developed as treatment for idiopathic pulmonary fibrosis and for COVID-19.98 GB-0139 might reduce viral-induced lung injury in patients with COVID-19

A phase 1/2 study to evaluate nafomostat as a therapy for COVID-19 to mitigate lung damage in patients with COVID-19 is currently recruiting participants (NCT04473053). Subjects are randomized into a nafamostat group, a GB-0139 group, and a control group. The nafamostat group will receive nafamostat via continuous intravenous infusion at 0.2 mg/kg/hr for 7 days. The GB-0139 group will receive 10 mg inhaled GB-0139 twice daily for 2 days and then 10 mg once daily for the remaining 12 days. The control group will receive standard of care. Primary outcomes will be changes of vital signs (blood pressure, heart rate, temperature and respiratory rate) up to 16 days following GB-0139 administration.

Remestemcel-L

Remestemcel-L refers to mesenchymal stromal cells (MSCs) derived from the bone marrow of healthy donors. Cells are prepared by Mesoblast (Melbourne, Australia). MSCs prevent T lymphocytes from entering the cell cycle, thus inhibiting clonal expansion. Additionally, MSCs promote the secretion of IL-4, impeding the secretion of IFN-γ and enhancing the development of regulatory T lymphocytes.99 Remestemcel-L is currently under development as a drug for treating acute (GVHD), inflammatory bowel disease, and ARDS caused by COVID-19 infection.100

A pilot study showed that remestemcel-L improved clinical outcomes of COVID-19-associated multisystem inflammatory syndrome in children (MIS-C).101 The primary aim is to achieve 43% reduction in mortality at 30 days in patients with moderate-to-severe acute respiratory distress (ARDS). An expanded access study to evaluate the safety and efficacy of remestemcel-L cells for MIS-C is currently enrolling subjects (NCT04456439), including children and adolescents from 2 months to 17 years of age. Subjects will receive a total of 2 × 10⁶ remestemcel-L over 5 days. Participants will receive an intravenous infusion of diphenhydramine 0.5–1 mg/kg (up to 50 mg) prior to infusion of remestemcel-L. Subjects who are not receiving glucocorticoids for other indications will receive an intravenous infusion of 0.5–1 mg/kg hydrocortisone (up to 50 mg) prior to infusion of remestemcel-L.

IMM-101

IMM-101 is an immunotherapeutic agent containing heat-killed Mycobacterium obuense that was developed by Immodulon Therapeutics in Uxbridge, UK. IMM-101 is very effective at inducing cytokines expressed by innate immune cells. Recognition of IMM-101 by dendritic cells can enhance antigen processing and presentation capacity, increase expression of co-stimulatory molecules, and promote secretion of anti-viral interferon-γ, perforin, and granzyme B.102 IMM-101 is currently being developed as a drug for treating pancreatic cancer, colorectal cancer and advanced melanoma, and colorectal cancer.103 Additionally, clinical trials are underway to investigate potential use in the treatment of COVID-19. A phase 3 study to evaluate the safety and efficacy of IMM-101 in cancer patients with severe respiratory and COVID-19 infections is enrolling subjects (NCT04442048). The treatment group will receive 1.0 mg IMM-101 on day 0 and 0.5 mg on day 14 and day 45. Subjects in the control group will not receive any active treatment. The primary endpoint is the rate of flu-like illness or confirmed viral/bacterial respiratory infection after treatment.

Sarconeos (BIO101)

The small molecule sarconeos (Ruvembri, BIO101) activates the Mas receptor and triggers the P13K/AKT/mTOR pathway and the AMPK/ACC pathway.104 The drug was developed by Biophytis (Paris, France). It is being developed as a drug for treating sarcopenia.104

Stimulating the Mas receptor may have beneficial effects on respiratory function, arterial oxygenation, and lung tissues in patients with severe COVID-19.105 Investigation is underway to explore the potential use of sarconeos in the treatment of COVID-19. A phase 2, 3 study to evaluate the efficacy and safety of sarconeos for preventing respiratory deterioration in hospitalized COVID-19 patients was terminated due to the lack of eligible patients (NCT04472728). However, Biophytis continues developing sarconeos for COVID-19.106

Leukine (sargramostim)

Sargramostim is a GM-CSF manufactured by Partner Therapeutics (Lynnwood, WA, USA).110 It stimulates the division and differentiation of partially committed progenitor cells in granulocyte-macrophage pathways.110 Sargramostim is thought to offer benefits in the early phase of SARS-CoV-2 infection by preserving the function of alveolar macrophages.111

Sargramostim was approved by the FDA for treating acute myeloid leukemia and delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation. Investigations are being conducted to repurpose sargramostim for treating COVID-19.

A phase 4 study to evaluate the safety and efficacy of sargramostim in patients with COVID-19 and acute hypoxic respiratory failure has been completed (NCT04326920). The treatment group received 125 mcg inhaled sargramostim twice daily for 5 days in addition to the standard of care. If subjects in the treatment group require mechanical ventilation within 5 days, inhaled Leukine could be replaced by intravenous infusion of 125 mcg/m² until day 5. After day 6, clinicians could choose to administer Leukine intravenously for an additional 5 days. The control group received standard of care for 5 days. If subjects in the control group required mechanical ventilation, the clinician could decide to administer an intravenous infusion of sargramostim 125 mcg/m² once daily for 5 days from day 6 onwards. The primary outcome measure was mean improvement in oxygenation on day 6 or hospital discharge. Results are pending.

Plonmarlimab (TJ003234)

Plonmarlimab directly binds GM-CSF, blocking intracellular signaling. Downstream signaling from the GM-CSF receptor involves JAK2/signal transducer and activator of transcription 5 (STAT5), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ERK, and the phosphoinositide 3-kinase (PI3K)-Akt (protein kinase B) pathway. Therefore, inhibiting GM-CSF might represent a viable treatment option for preventing the CRS.112

Plonmarlimab is under development for treating CRS and COVID-19. It is manufactured by I-Mab Biopharma based in China.113

Phase 2 and 3 studies to evaluate the safety and efficacy of plonmarlimab (also known as TJ003234) in severe COVID-19 patients have been completed (NCT04341116). In those studies, subjects were randomized to receive an infusions of placebo or plonmarlimab at low, medium or high dose. The primary outcome measure was the proportion of subjects who were alive and free from mechanical ventilation among subjects who were free of mechanical ventilation at baseline for 30 days. Plonmarlimab reduced mortality in the phase 2/3 trial.

Lenzilumab

Lenzilumab is a GM-CSF monoclonal antibody developed by Humanigen based in Burlingame, CA, USA. By binding to GM-CSF, lenzilumab prevent binding to the GM-CSF receptor, thereby alleviating CRS. This GM-CSF neutralization can reduce IL-6, MCP-1, macrophage inflammatory protein 1 alpha (MIP-1α), IP-10, VEGF, and TNFα levels. Consequently, lenzilumab exhibits potential immunomodulatory activity.114 It is indicated for treating refractory chronic myelomonocytic leukemia, acute GvHD, COVID-19, among other indications.115

A phase 2 study, which is the ACTIV-5 Big Effect Trial (BET), sponsored by NIAID, NIH for COVID-19 patients, has been completed (NCT04583969). The experimental group received 200-mg intravenous remdesivir on Day 1, followed by a 100-mg once-daily intravenous maintenance dose up to a 10-day course while hospitalized; this group also received 600-mg intravenous lenzilumab infusion every 8 hours starting on Day 1, for a total of 3 doses. The control group received 200 mg of intravenous remdesivir on Day 1, followed by a 100 mg once-daily intravenous maintenance dose and 600-mg intravenous placebo infusion every 8 hours starting on Day 1. The primary outcome measures were the number of surviving participants and ventilation-free subjects at 29 days.

Avastin (bevacizumab)

Bevacizumab was developed by Roche in Basel, Switzerland.140 This monoclonal antibody recognizes vascular endothelial growth factor-A (VEGF-A) and prevents the interaction of VEGF-A with the VEGF receptor. Consequentially, bevacizumab inhibits the activation of the VEGF signaling pathways and represses angiogenesis.141 In patients with COVID-19, ARDS induces tissue hypoxia, which leads to increased VEGF expression through activation of the HIF PHD-1 pathway. In these patients, VEGF contributes to plasma extravasation and pulmonary edema, further exacerbating tissue hypoxia and lung inflammation. Therefore, blocking VEGF with Avastin (bevacizumab) can improve oxygen perfusion and elicit anti-inflammatory response in patients with COVID-19.142

Avastin (bevacizumab) received FDA approval in 2004 for treating metastatic colorectal cancer. Currently, it is being repurposed for treating COVID-19. A phase 3 study to evaluate the efficacy and safety of bevacizumab for patients with COVID-19 is recruiting participants (NCT04305106). The bevacizumab group will receive a single 7.5 mg/kg dose of bevacizumab via intravenous infusion with a standard of care if necessary. The control group will receive a single dose of placebo (inactive excipient) at 7.5 mg/kg via intravenous infusion, together with a standard of care. The primary outcome measures are the time to achieve a clinical improvement of two points on a seven-category ordinal scale and discharge from the hospital within 28 days.

Vadadustat (AKB-6548)

Vadadustat is a structural analog of α-ketoglutarate, a Krebs cycle intermediate that inhibits HIF-PHD. Vladadustat was developed by Akebia Therapeutics (Cambridge, MA, USA).143 The drug inhibits PHD catalysis and stabilizes HIF-2α to a greater extent than does HIF-1α. Vadadustat increases hemoglobin levels, increases total iron binding capacity, and lowers plasma ferritin and hepcidin levels. Vadadustat was developed for treating anemia due to chronic kidney disease.143 Currently, it is being studied for its potential application in the treatment of COVID-19-associated hypoxemia.139

A phase 2 study of vadadustat for preventing ARDS in COVID-19 patients is currently active but recruitment has not begun (NCT04478071). Subjects will be randomized to receive 900 mg vadadustat or placebo, taken orally once daily for 14 days. The primary outcome measure will be the number of subjects who are classified as 8 (deceased), 7 (hospitalized, on invasive mechanical ventilation or ECMO), or 6 (hospitalized, on non-invasive ventilation or high flow oxygen devices) by the NIAID ordinal scale on day 14.144

Trimodulin (BT588)

Trimodulin is an immunoglobulin concentrate containing IgG (~56%), IgA (~21%), and IgM (~23%). It was developed by Biotest, Germany. Initially, trimodulin was developed to treat patients with severe community-acquired pneumonia (sCAP). Trimodulint is currently under clinical development for treating patients with either sCAP or severe COVID-19.145

As immunoglobulin preparations have long been used as therapy for inflammatory diseases, the anti-inflammatory effects of trimodulin might be beneficial for patients with severe COVID-19.146

A phase 3 study to evaluate the efficacy and safety of trimodulin as an adjunctive treatment together with standard of care for patients with COVID-19 is recruiting participants (NCT05531149). Subjects will receive trimodulin or human albumin 1% (placebo) via intravenous infusion for five consecutive days. Primary outcome measures will be percentage of clinical deterioration rate and the percentage of mortality rate between days 6 to 29.

Octagam

Octagam is an intravenous human immune globulin preparation that supplies both opsonic and neutralizing IgG antibodies. It was developed by Octapharma in Lachen, Switzerland. The name derives from the company’s expertise in developing factor 8 preparations to treat hemophilia).147 Intravenous immunoglobulin (IVIG) enhances pro-inflammatory cell activation and suppresses T cell and B cell proliferation. As severe cytokine storm is associated with high death rates in severe COVID-19, use of IVIG might be effective.148 Octagam received FDA approval for treating primary humoral immunodeficiency in 2004.147 It is currently being repurposed for use in the treatment of COVID-19.

A phase 2 study to evaluate the safety and efficacy of Octagam to reduce all-cause mortality in COVID-19 has been completed (NCT04480424). The treatment groups received intravenous infusions of Octagam (500 mg/kg for 4 days or 400 mg/kg for 5 days), together with standard of care. The control group received a standard of care. The primary outcome measure was all-cause mortality rate up to 29 days. Octagam treatment was associated with improved functional status,

Opaganib

Opaganib is an oral sphingosine kinase 2 (SK2) inhibitor developed by RedHill Biopharma (Tel Aviv, Israel). Opaganib inhibits host SK2 but not viral SK2. Thus, it is less affected by viral mutations.149 This drug is being studied for treating cancer and infectious diseases including COVID-19. Its mechanism of action is through inhibiting production of sphingosine 1-phosphate (S1P). S1P promotes TNF signaling, which promotes cytokine production. Opaganib also inhibits dihydroceramide desaturase (DES1) and glucosylceramide (GCS). DES1 inhibition promotes autophagy to inhibit viral replication, while GCS inhibition can also reduce the viral entry into cells. Hence, opaganib might be effective for treating COVID-19 through multiple mechanisms.150

A phase 2/3 study to evaluate the efficacy and safety of opaganib in hospitalized patients with severe COVID-19 has been completed (NCT04467840). The opaganib group received 500 mg opaganib orally every 12 hours with the standard of care. The medication can be administered as a liquid suspension via nasogastric tube. The control group received a placebo orally every 12 hours, together with standard of care. All participants received drug or placebo for 14 days. The primary outcome measure was comparing the proportion of patients no longer requiring supplemental oxygen for at least 24 hours in a time frame of 14 days. In a phase 2/3 study of 475 patients, treatment with opaganib was associated with a 62% decrease mortality in patients with moderate to severe COVID-19.

ARADKOA (Tafenoquine)

Tafenoquine is a potential TMPRSS2 and Mpro inhibitor developed by 60 Degrees Pharmaceuticals (Washington, D.C., USA). It received FDA approval for prophylaxis of malaria. It inhibits hematin polymerization and induce parasite death.151 It has potential to inhibit TMPRSS2 and Mpro. Inhibiting TMPRSS2 can reduce virus entry. Mpro is involved in the correct cleavage of viral polyproteins translated from the viral genome. Inhibiting Mpro can reduce viral replication.152 Therefore, tafenoquine may be effective in the treatment of COVID-19.

A phase 2 study of tafenoquine treatment in patients with mild to moderate COVID-19 been completed (NCT04533347). Subjects took two 100 mg tafenoquine tablets or two placebo tablets orally for 10 days. The primary outcome measure was the proportion of patients with clinical recovery of COVID-19 symptoms on Day 14. Results are pending.

Luvox (fluvoxamine)

Fluvoxamine is an inhalant selective serotonin reuptake inhibitor developed by Solvay in Houston, TX. It received FDA approval for treating obsessive-compulsive disorders in 1994.153 Its mechanisms of action are diverse and include reducing histamine release from mast cells, showing lysosomotrophic effects (i.e., increasing lysosomal pH) by interfering with viral trafficking, interfering with lysosomal membrane binding of acid sphingomyelinase, affecting inositol-requiring enzyme 1α-mediated inflammation, and increasing melatonin levels.154 Due to these anti-inflammatory and antiviral properties, Fluvoxamine might be effective for treating COVID-19.

A phase 3, ACTIV-6 trial to evaluate the effectiveness of repurposed medications in COVID-19 patients is recruiting participants (NCT04885530). This study consists of six subgroups (fluvoxamine and ivermectin will each have two subgroups with different doses, together with two placebo group. Each subgroup participant will receive either a study drug (fluvoxamine, ivermectin, fluticasone, montelukast) or placebo. Fluvoxamine subgroups are ‘arm B’ and ‘arm E’. Arm B participants will self-administer 50 mg fluvoxamine or placebo orally twice a day for 10 days. Arm E participants will orally self-administer 50 mg fluvoxamine or placebo twice on day 1, and 100 mg fluvoxamine or placebo twice a day for 12 days. Primary outcome measures are number of hospitalizations, deaths and symptoms reported by subjects, all within a time frame of up to 28 days.

Pyramax (artesunate/pyronaridine)

Pyramax is an oral antimalarial drug repurposed for COVID-19 by Shin Poong Pharmaceutical, Seoul, South Korea. Pyronaridine inhibits hematin formation to protect the heme group that is toxic to malaria. Artesunate produces free radicals with antimalarial activity.155, 156 In treating COVID-19, artesunate can act as a viral infection inhibitor at the cellular post-entry level.157 Pyronaridine modulates appropriate levels of antiviral interferons, including interferon-1β. Moreover, pyronaridine can lower high levels of CXCL1 and CCL3 involved in inflammation responses.158 Therefore, Pyramax has potential as an effective COVID-19 treatment. A phase 3 study to evaluate the efficacy and safety of Pyramax in COVID-19 patients is currently recruiting participants (NCT05084911). The Pyramax group will receive a pyronaridine-artesunate (180/60 mg) tablet for three days and the control group will receive a placebo. The primary outcome measure will be the proportion of patients who require hospitalization or have died due to COVID-19 infection up to 29 days.

RVX-208 (Apabetalone)

Apabetalone is an inhibitor of bromodomain and extra-terminal (BET) proteins. It specifically targets bromodomain 2 (BD2). It was shown by Resverlogix (Calgary, Aberta, Canada)159 to be a potential treatment for cardiovascular disease, pulmonary arterial hypertension, chronic kidney disease, and COVID-19. It was developed with a cardiovascular indication and was granted a Breakthrough Therapy Designation by the FDA.160

The mechanism of action is to prevent interactions between acetylated lysine on histone tails and transcription factors. In particular, apabetalone can suppress gene expression of vascular inflammation mediators whose genes are dependent for transcription on BET domain and extra terminal domain protein (BET) proteins. Apabetalone prevents BRD4 associations with key transcriptional enhancers and promoters.159

In addition, ACE2 expression is regulated by BET proteins. Inhibitors of BET proteins downregulate ACE2 expression and limit SARS-CoV-2 replication in vitro.160 Due to its antiviral and anti-inflammatory effects, apabetalone is a promising candidate for treating COVID-19.161

A phase 2, 3 study to evaluate the safety and efficacy of apabetalone in COVID-19 patients is recruiting participants (NCT04894266). The treatment group will receive 100 mg apabetalone orally twice daily together with standard of care, and the control group will receive standard of care only. The primary outcome measure is the WHO Ordinal Scale for Clinical Improvement change on day 14.

ANA001 (Niclosamide)

Niclosamide is an inhaled preparation of salicylanilide, a derivative of salicylic acid belonging to a large group of lipophilic compounds. Niclosamide was developed by NeuroBo Pharmaceuticals, Cambridge, MA, USA.162, 163 Plausible mechanisms of action of niclosamide against COVID-19 involve four cellular processes: 1) endosomal pH neutralization to prevent viral replication, 2) promotion of autophagy through inhibition of S-phase kinase-associated protein 2 (SKP2), 3) decreased mucus plugging through inhibition of TMEM16A (calcium activated chloride channel, CaCC), and 4) prevention of syncytia formation by ion channel inhibition.163

Additionally, niclosamide has anti-inflammatory effects by inhibiting pro-inflammatory cytokines, mainly TNF. Furthermore, it can inhibit the progression of inflammatory airway diseases by suppressing the release of IL-8 and intracellular Ca⁺² signaling.164 Due to these anti-inflammatory and antiviral effects, it may be effective for treating patients with COVID-19.

A phase 4 study of niclosamide to treat patients with COVID-19 has been completed (NCT05087381) in Thailand. One treatment group received 500 mg niclosamide orally by tablet twice daily for 14 days. A second treatment group received the same dose for 14 days but in combination with one 8 mg tablet of bromhexine twice daily for 10 days. The control group received supportive care. Primary outcome measures were hospital admission or mortality related to COVID-19 within 28 days, the time taken to self-report recovery until the final day of participation, and the progression to severe COVID-19 disease until the final study day. Study results are not available.

(pamapimod/pioglitazone)

KIN001 is a combination of pamapimod, a selective inhibitor of p38 mitogen-activated protein kinase alpha (p38 MAPKα), and pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist. The drug was developed by Kinarus Therapeutics in Switzerland for treating wet age-related macular degeneration (Wet-AMD) and idiopathic pulmonary fibrosis. The route of administration is oral inhalation.165

The p38 MAPK pathway plays a crucial role in viral infection. Viral p38 MAPK activation can promote endocytosis of viral receptors, including ACE2. Downstream effectors of this pathway include transcription factors and RNA binding proteins that regulate cytokine production, cell proliferation, cell differentiation, and apoptosis, as well as development. PPARs are transcription factors involved in insulin responses. Studies have suggested that pioglitazone, a glucose-lowering medication, can improve manifestations of COVID-19 patients with type 2 diabetes. Therefore, KIN001, the combination of a p38 MAPK inhibitor with pioglitazone, might have synergistic antiviral activity against SARS-CoV-2 with anti-inflammatory effects.166

A phase 2 study to evaluate the efficacy and safety of KIN001 (pamapimod/pioglitazone) in non-hospitalized COVID-19 patients is recruiting participants (NCT05659459). The treatment group will receive 75 mg pamapimod and 5 mg pioglitazone orally twice daily for 14 days. The control group will receive matching tablets of KIN001 orally twice daily for 14 days. The primary outcome measure is the evaluation of COVID-19 symptoms within 28 days.

Xpovio (selinexor)

Selinexor is an oral exportin 1 (XPO1) blocker developed by Karyopharm Therapeutics, Newton, MA. In 2019, selinexor received FDA approval for treating multiple myeloma and diffuse large B-cell lymphoma.167 In COVID-19, XPO1 inhibitors can transiently inhibit expression of ACE2 and its interaction with SARS-CoV-2. Selinexor also inhibits transport of the tumor suppressor protein p53. This results in nuclear accumulation of p53, and induction of apoptosis and cell-cycle arrest. Therefore, inhibition of the p53 pathway might induce apoptosis of SARS-CoV-2. Moreover, selinexor prevents release of pro-inflammatory cytokines and reduce oxidative and inflammatory disorders by activating nuclear factor erythroid 2-related factor-2 (Nrf2) and peroxisome proliferator-activated receptor (PPAR)-γ.168

A phase 2 study to evaluate the efficacy and safety of selinexor (KPT-330) in patients with severe COVID-19 has been completed (NCT04349098). In that study, subjects received standard of care together with 20 mg of oral selinexor or a matching placebo on Days 1, 3, and 5 of each week for up to two weeks. If subjects could tolerate the therapy and experienced clinical benefit, dosing could continue for an additional 2 weeks (28 days). The primary outcome measure was the proportion of subjects showing clinical improvement of at least two points on the 8-point ordinal scale within 14 days. Selinexor did not reduce mortality, reduce ICU admission rate or recovery time, compared to placebo.

Alinia (Nitazoxanide)

Nitazoxanide is an oral medication consisting of a nitrothiazole moiety and salicylamide moiety. It was developed by Romark Laboratories (Tampa, FL, USA).169 Upon administration, the drug is rapidly deacetylated to tizoxanide (TIZ), its active metabolite.170 Alinia received FDA approval in 2002 for treating diarrhea caused by Giardia lamblia or Cryptosporidium parvum as an anti-parasitic drug with potent antiviral activity.

Nitazoxanide’s mechanism of action is to inhibit viral entry and viral replication, and to suppress pro-inflammatory responses. Nitazoxanide inhibits ACE2 receptor/TMPRSS2 interactions by inhibiting protein disulfide isomerase. It also inhibits SARS-CoV-2 fusion and entry by suppressing intracellular signaling, including via MAPK/ERK, PI3K/Akt/mTOR, and Wnt/β-catenin.

Further, nitazoxanide inhibits viral replication by inhibiting enzymatic activity of the 3-chymotrypsin-like protease (3cLpro) and (papain-like proteae (pLpro). Nitazoxanide also stimulates immune responses of host cells by activating Type-I interferon secretion and curbing proinflammatory responses. Due to these mechanisms, nitazoxanide offers potential for repurposing as therapy for COVID-19.170

A phase 3 study to evaluate the efficacy and safety of nitazoxanide in patients with non-critical COVID-19 illness is recruiting participants (NCT04423861). The treatment group will receive a 600 mg tablet of nitazoxanide twice daily for 7 days and the control group will receive placebo twice daily for 7 days. The primary outcome measure will be the need for mechanical ventilation by evaluation of change in acute respiratory syndrome up to 14 days.

VirX/enovid (Nitric oxide nasal spray)

Nitric oxide nasal spray of SaNOtize is approved as a medical device in Thailand, Singapore, Hong Kong, Nepal, South Africa, Germany (branded as VirX), Israel, Indonesia and Bahrain (branded as Enovid). The drug releases nitric oxide.171 Tandon et al.172 have reported that NO has immediate virucidal action against SARS-CoV-2 and other respiratory pathogens. Mechanistically, NO can quickly alter structural integrity of viral proteins, including spike protein and viral protease, through reduced palmitoylation and reduced nitrosylation. In addition, NO is a systemic vasodilator endogenously produced in the endothelium. Inhaled NO induces bronchodilation, thereby improving oxygen delivery to the alveoli. Studies have indicated that NO as a therapeutic agent improves ventilation perfusion in patients with severe ARDS associated with COVID-19.172, 173

A phase 3 study to evaluate the efficacy and safety of nitric oxide nasal spray (NONS) for preventing COVID-19 infection is ongoing (NCT05109611). The treatment group will receive a nasal spray with nitric oxide-releasing solution up to 3 times daily for 28 days. The control group will receive a nasal spray with isotonic saline up to 3 times daily for 28 days. The primary outcome measure is assessing whether subjects were infected with SARS-CoV-2 through a COVID-19 test within 28 days.

Hesperco (hesperidin)

Hesperidin is a bioflavonoid formulation with antioxidant properties that was developed by Valeo Pharma in Kirkland, Quebec, Canada.174 The drug received a Natural Product License approval from Health Canada, authorizing its sale in Canada. Hesperidin is a potential medicine against COVID-19. Some studies have suggested that hesperidin may disrupt the interaction of ACE2 with the viral RBD. Hesperidin also has potent antioxidant properties that make it serve as an effective agent against superoxide and hydroxyl radicals. It also inhibits nitric oxide production. Therefore, Hesperidin might contribute to strategies for the prevention of COVID-19.175

A phase 2 study to evaluate the efficacy and safety of hesperidin in COVID-19 patients has been completed. Subjects were randomized to receive 1,000 mg hesperidin or matching placebo capsules once daily for 14 days. The primary outcome measure was the number of subjects with COVID-19 symptoms (fever, cough, shortness of breath, or anosmia) on days 3, 7, 10, and 14. Results are pending.

Lipitor (atorvastatin calcium)

Atorvostatin is an oral, selective, competitor inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase developed by Viatris in Canonsburg, PA. It received FDA approval as an adjunct to reduce low-density lipoprotein.176 HMG-CoA reductase inhibitors (statins) and have anti-inflammatory and antithrombotic effects. Statins reduce inflammation by inhibiting the NF-kB pathway and reduce the risk of thrombotic events through its profibrinolytic activities. Therefore, statin treatment might alleviate inflammation and improve respiratory status in patients with COVID-19.177

A phase 3 study to evaluate the effects of atorvastatin in Long COVID-19 neurological symptoms patients is recruiting participants (NCT04904536). The treatment group will receive six months of daily oral atorvastatin (40 mg), together with standard of care for 18 months. The control group will receive standard of care for 18 months. The primary outcome measure will be subject speed on the oral Symbol Digit Modalities Test after 18 months.

RA 101495 (Zilucoplan)

Zilucoplan is a macrocyclic peptide that binds complement factor C5 and allosterically inhibits cleavage of C5 into C5a and C5b. It was developed by Union Chemique Belgium (UCB)178 for treating generalized myasthenia gravis and paroxysmal nocturnal hemoglobinurias.179 Its mechanism of action is by suppressing inflammation and coagulation. The anaphylatoxin C5a attracts inflammatory cells into tissues. C5b can induce further drive the complement cascade reaction by promoting assembly of the membrane attack complex, which kills damaged cells and opsonized pathogens. C5b can also trigger the formation of microthrombi on endothelial cells.

De Leeuw et al.180 have shown that increased complement system activation is related to a worse clinical outcomes in COVID-19 patients. As a result, complement blockade has emerged as a potential therapy for COVID-19. Zilucoplan may benefit COVID-19 patients with respiratory failure and signs of systemic inflammation.180

A phase 3 study to evaluate the efficacy and safety of three candidate COVID-19 drugs (Apremilast, Lanadelumab, Zilucoplan) in COVID-19 patients has been completed (NCT04590586). In that study, subjects were randomized between candidate drug or placebo with standard of care. The zilucoplan treatment group received standard of care and a subcutaneous injection of 32.4 mg zilucoplan once daily until discharge or up to 14 days. The zilucoplan control group received standard of care and a subcutaneous injection of zilucoplan matching placebo once daily until discharge or up to 14 days. The primary outcome measure was the time to discharge without re-hospitalization before day 29. This study was terminated without statistical analysis.

Vilobelimab

Vilobelimab is a chimeric monoclonal IgG4 antibody that binds human complement split product, factor C5a. The drug was developed by InflaRx in Jena Germany181 for treating pyoderma gangrenosum, cutaneous squamous cell carcinoma, and critical COVID-19.182 The antibody acts by suppressing inflammation and coagulation. The potent anaphylatoxin C5a recruits monocytes and neutrophils to infection sites and activates these cells, causing tissue damage by enzyme release and free radical formation. C5a also induces the release of tissue factor from endothelial cells and neutrophils, which can activate the coagulation system. Therefore, C5a inhibition can inhibit organ damage induced by neutrophils and improve microangiopathy and microthrombosis.181

A phase 2, 3 study of vilobelimab (IFX-1) to treat severe COVID-19 pneumonia has been completed (NCT04333420). Subjects received 800 mg vilobelimab or placebo via intravenous infusion for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) with standard of care.183 The primary outcome measure was mortality within 28 days. Results are pending.

Lyfaquin (centhaquine)

Centhaquine is an α-2B adrenergic receptor agonist developed by Pharmazz (Willobroodk, IL, USA). Additionally, centhaquine enhances tissue blood perfusion by stimulating central α-2A adrenergic receptors.184 As a result, centhaquine improves tissue perfusion and oxygenation in patients with ARDS.185

The drug is approved in India and indicated as a resuscitative agent for treating patients with hypovolemic shock.184 Currently, research is being conducted to repurpose centhaquine as a treatment for COVID-19 patients.

A phase 2 study to evaluate the safety and efficacy of centhaquine in COVID-19 patients with ARDS is on-going (NCT05241067). In that study, subjects are randomized to a treatment group and a control group. The treatment group will receive an intravenous infusion of 0.01 mg/kg centhaquine with standard of care. An additional dose of centhaquine is administered if oxygenation is required or SBP remains or falls below or becomes equal to, 90 mmHg; but not until 24 hours after the previous dose. The control group receives an intravenous infusion of normal saline with standard of care. The primary outcome measure is clinical improvement of moderate to severe ARDS in subjects within 28 days. Phase 3 trials have been approved by the FDA and are in the planning stage.