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Table 1 Emerging anti-viral and immunomodulatory therapies for COVID-19

From: Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents

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