Table 1 Emerging anti-viral and immunomodulatory therapies for COVID-19
Drug | Mechanism of action | Adverse effects | Current and planned clinical trials |
|---|---|---|---|
REMDESIVIR (GS-5734) | Nucleotide/adenosine analog which incorporates into viral RNA causing premature termination of replication Active substrate shown to prevent SARS- and MERS-CoV replication in human airway epithelial cells | Transaminitis Nausea Diarrhea | NCT04257656, NCT04302766, NCT04252664, NCT04292899, NCT04292730 |
FAVIPIRAVIR (T705) | Synthetic nucleoside analog selectively and potently inhibit the RNA-dependent RNA polymerase (RdRp) of RNA viruses | Nausea and Diarrhea Headache Embryotoxicity | ChiCTR2000030894—Tocilizumab and Faripavir |
UMIFENOVIR | Membrane fusion inhibitor developed as a treatment for influenza | Nausea and diarrhea | NCT04260594: monotherapy trial NCT04306497: comparison of various Western medications vs traditional Chinese medications NCT04252885, NCT04273763, NCT04261907, NCT04286503: various combinations |
CHLOROQUINE (CQ) and HYDROXYCHLOROQUINE (HCQ) | Endosomal inhibitors: alkalinizes the normally acidic endosomal pH required for virus/cell fusion Decreases glycosylation of receptors which limits viral fusion Presumed to interfere with SARS-CoV binding to hemoglobin Immunomodulatory | Dilated cardiomyopathy Photosensitivity Retinal damage Steven Johnson’s syndrome Should avoid in patients with G-6-PD deficiency or porphyrias | Monotherapy or combination trials: NCT04308668, ChiCTR2000029939, ChiCTR2000029935, ChiCTR2000029899, ChiCTR2000029898, ChiCTR2000029868, ChiCTR2000029837, ChiCTR2000029826, ChiCTR2000029803, ChiCTR2000029762, ChiCTR2000029761, ChiCTR2000029760, ChiCTR2000029741, ChiCTR2000029740, ChiCTR2000029609, ChiCTR2000029559, ChiCTR2000029542 |
HCQ + AZITHROMYCIN | Azithromycin prevents bacterial superinfection | Prolonged QTC Arrythmias (concern given cardiomyopathy associated with COVID-19) | NCT04322123, EU Clinical trials register number 2020-000890-25 |
GELDANAMYCIN | Heat shock protein inhibitor; degrades endosomal activity, thereby interferes with viral replication in host cells | Hepatotoxicity Anemia | No registered trials on clinicaltrials.gov yet Has antitumor activity by inducing cell apoptosis |
LOPINAVIR (LPV) AND RITONAVIR (RTV) ± RIBAVIRIN | Lopinavir: Protease inhibitor; inhibits assembly of mature virions Ritonavir: CYP3A4 inhibitor; slows the metabolism of lopinavir Ribavirin: inhibits IMP dehydrogenase. Some evidence that Ribavarin targets a protein that SARS-Co-V-2 directly binds to | Due to CYP3A4 interaction, can cause significant drug-drug interaction GI disturbances (diarrhea, nausea, and vomiting) Lipid abnormalities | NCT04307693, NCT04255017, NCT04261907, NCT04276688, NCT04303299, NCT04303299 MIRACLE trial, NCT02845843 Initial studies from China showing no change in survival or recovery speed, although high mortality rate suggests patient population was only severely ill |
COMBINATION ANTIVIRAL THERAPY | Remdesivir Lopinavir/Ritonavir (Kaletra/Aluvia) Chloroquine Lopinavir/Ritonavir & IFN beta | Due to CYP3A4 interaction, can cause significant drug-drug interaction GI disturbances (diarrhea, nausea, and vomiting) Lipid abnormalities | - NCT04321616: SOLIDARITY trial currently in Argentina, Bahrain, Canada, France, Iran, Norway, South Africa, Spain, Switzerland, and Thailand). Endpoints: mortality rate, length of hospitalization, utilization of ICU and ventilators |
DARUNAVIR AND COBICISTAT | HIV Protease Inhibitors | Diarrhea Nausea Vomiting Headache | NCT04252274, NCT04303299 ChiCTR2000029541: Prezcobix vs. lopinavir-ritonavir combination combined with thymosin a1 |
OSELTAMIVIR | viral neuraminidase inhibitor (enzyme found on the surface of the influenza virus) | Transaminitis Nausea Diarrhea | NCT04261270: Monotherapy: NCT04303299: Combination therapy |
DANOPREVIR (RG7227/ITMN-191) & RITONAVIR & INTERFERON | Danoprevir: Non-covalent macrocyclic inhibitor of HCV NS3/4A protease Ritonavir: CYP3A4 inhibitor; slows the metabolism of lopinavir Interferon: cytokine | Nausea Anorexia Transaminitis | NCT04291729 |
LERONLIMAB (PRO 140) | Humanized IgG4 monoclonal antibody CCR5 antagonist | Diarrhea Headache Lymphadenopathy Hypertension | No registered trial on clinicaltrials.gov yet Phase 2 clinical trial planned Currently being studied as combination therapy with HAART for HIV-infected patients, and for metastatic triple-negative breast cancer |
APN01 (RHACE2) | Recombinant human angiotensin-converting enzyme 2 | Awaiting study results | NCT04287686: Pilot trial |
LOSARTAN | Angiotensin receptor blocker; blocks viral entry | Kidney injury Hypotension | NCT04312009, NCT04311177 |
CORTICOSTEROIDS | Presumed to decrease inflammation and hence pulmonary fibrosis Was recommended only if alternative indication exists, e.g. refractory ARDS, sepsis or septic shock Dexamethasone recently recommended for disease requiring oxygen supplementation | Hyperglycemia Psychosis Secondary infection Avascular necrosis | NCT0424459, ChiCTR2000029656, ChiCTR2000029386, NCT04323592, NCT04244591 Used in severe disease Different preparations, doses and schedules being studied |
THALIDOMIDE | Blocks NF- ƙB binding to gene promotors, reducing the production of IL-6, TNF-α and chemokines | Well known teratogen | NCT04273529, NCT04273581 |
TOCILIZUMAB | IL-6 receptor antibody | Neutropenia Transaminitis Immunosuppression | NCT04317092: TOCIVID-19 with use in COVID pneumonia ChiCTR2000030894—Tocilizumab and Faripavir ChiCTR2000029765)—Tocilizumab alone |
SARILUMAB (REGN88) | IL-6 receptor antagonist | Neutropenia Transaminitis Nasal congestion | NCT04315298, NCT04327388 and NCT04324073: CORIMUNO-19-SARI trial A trial planned with combination with remdesivir |
SILTUXIMAB | Chimeric anti-IL-6 monoclonal antibody Binds to soluble and membrane-bound forms of IL-6 | Cytopenias Edema Hypotension Increased risk of secondary infections Hyperuricemia | No registered trials on clincialtrials.gov |
ANAKINRA | IL 1 inhibitor | Hypersensitivity Neutropenia Immunosuppression | Currently being evaluated for neurotoxicity in CAR-T neurotoxicity: NCT04150913 and active rheumatoid arthritis: NCT00117091 Planned but no registered trial for COVID-19 yet on clinicaltrials.gov |
RUXOLITINIB | JAK-STAT inhibitor | Pancytopenia Orthostatic dizziness Vertigo Hyperlipidemia | ChiCTR 2000029580: MSC + ruxolitinib versus ruxolitinib alone |
FEDRATINIB (SAR302503, TG101348) | Selective JAK2 inhibitor Decreases the IL-17 production and IL-22 production by Th17 cells Inhibits GM-CSF communication via the JAK pathway | Pancytopenia Hyperlipidemia | Preclinical data by Wu et al. Journal of Microbiology, Immunology and Infection. Online March 11, 2020 No registered trials on clincialtrials.gov |
BARICITINIB | JAK inhibitor | Drowsiness Visual problems | NCT04320277: BARI-COVID study of baricitinib in symptomatic patients |
RECOMBINANT INTERFERON THERAPY | Stimulates immune response to inhibit viral replication | Hypersensitivity reactions Immunosuppression | NCT04320238: Inhaled recombinant human interferon alpha-1b NCT04315948, NCT04276688: IFN infusion in combination with LPV/RTV |
CAMRELIZUMAB | Anti-PD-1 antibody | Hypersensitivity Neutropenia Immunosuppression | NCT04268537: Camrelizumab and Thymosin combination |
ECULIZUMAB | Distal complement inhibitor | Risk of severe meningococcal and pneumococcus infections, requiring vaccinations before initiating therapy | NCT04288713: SOLID-C19 study |
NATURAL KILLER (NK) CELL THERAPY | Cytotoxic to virally infected cells Non-MHC dependent cytotoxicity Secrete cytokines to generate a potent anti-viral immune response | Infusion reactions | NCT04280224: NK cell therapy in COVID-19 associated pneumonia |
MESENCHYMAL STEM CELL (MSC) THERAPY | Cell therapy with regenerative properties potentially can prevention of lung fibrosis in COVID-19 associated lung injury | Infusions may cause microcirculatory blockage, aerosolized MSC-exosome does not carry this risk | ChiCTR 2000029580: phase 1 clinical trial in combination with ruxolitinib versus ruxolitinib alone NCT04252118, NCT04288102, NCT04273646, NCT04269525: Uses umbilical cord derived MSC NCT04276987: Uses MSC exosomes in COVID-19 Different sources, preparations, doses and schedules of MSC in different studies |
CONVALESCENT PLASMA THERAPY | Treatment aimed at isolating and transfusing protective antibodies from plasma of recovered patients | Transfusion reactions | NCT04321421: COV-19-PLASMA study in critically ill patients NCT04325672 |