Table 1.
List of pipeline drugs currently studied/registered in the clinical trial for COVID-19
| Drugs/Drug combinations (Classification) | Stage of development | Targets and possible mechanism of action for use in COVID-19 | Disease indication (Approved/Investigational)* |
|---|---|---|---|
| Remdesivir (antiviral, adenosine nucleotide analog) | Phase 2/3 | Target RdRp and inhibit it, thereby inhibiting viral replication and viral RNA synthesis |
Investigational drug for Ebola virus and variety of RNA viruses; FDA Emergency Use Authorization against COVID-19 |
| Favipiravir (antiviral, purine nucleoside analog) | Phase 2/3/4 | Target RdRp and inhibits viral RNA synthesis | Approved to treat influenza in Japan |
| Ribavirin (antiviral, guanine nucleotide analog) | Phase 1/2 | Target RdRp and inhibits viral RNA synthesis and mRNA capping | Chronic hepatitis C virus (HCV) infection |
| Galidesivir (antiviral, adenosine nucleoside analog) | Phase 1 | Target and bind to viral RNA polymerase, premature termination of the elongating RNA strand | Investigational drug for Ebola, Marburg, Yellow Fever and Zika viruses |
| Lopinavir/Ritonavir (increases oral bioavailability of lopinavir) (antiviral, protease inhibitor) | Phase 2/3 | Target protease enzyme, inhibits protein cleavage and halt virus maturation | Approved for HIV-1 infection |
| Darunavir (antiviral, protease inhibitor) and Cobicistat (Pharmacokinetic enhancer) | Phase 1 | Target protease enzyme, inhibits protein cleavage and halt virus maturation (decrease viral load and increase CD4 cell counts) | Approved as second- generation protease inhibitors for HIV infection |
| Umifenovir or Arbidol (antiviral, fusion inhibitor) | Phase 4 | Inhibits fusion between viral and cellular membrane | Approved in Russia and China for the prophylaxis and treatment of influenza A, B, and other arboviruses |
| Danoprevir (antiviral, protease inhibitor) | Phase 4 | Target protease, Inhibits viral replication | Investigational drug for chronic hepatitis C patients |
| Oseltamivir (antiviral, Neuraminidase inhibitor) | Phase 2/3/4 | Target neuraminidase enzyme, inhibits viral entry, replication and its release | Approved for prophylaxis and treatment of influenza A (including H1N1) and B |
| Camostat Mesylate (serine protease inhibitor) | Phase 2 | Target TMPRSS2, inhibits its action and thereby inhibits viral entry to cells | Approved in Japan for chronic pancreatitis and drug-induced lung injury |
| Clevudine (synthetic pyrimidine analog) | Phase 2 | Target DNA polymerase and reverse transcriptase enzyme, block viral replication and the supply of viral DNA into the nucleus | Investigational drug for hepatitis B |
| Chloroquine and hydroxychloroquine (antimalarial, aminoquinolone derivative, antiviral and immunomodulatory properties) | Phase 2/3/4 | Changes the pH of endosomes and inhibit ACE2 glycosylation, prevent viral entry, transport and, post-entry events | Antimalarial drugs, also used for systemic lupus erythematosus; acute and chronic rheumatoid arthritis |
| Interferon-beta 1a and 1b (antiviral and immunomodulators, protein-based therapy) |
Phase 2/4 (1a) Phase 2 (for 1b) |
Target type 1 interferon receptors, Activate JAK/STAT and stimulate innate antiviral immunity, also changes the expression of cytokine and matrix metalloproteinase | Relapsing remitting multiple sclerosis (RRMS) |
| Peginterferon lambda-1a (antiviral and immunomodulators, protein-based therapy) | Phase 2 | Stimulate innate antiviral immunity | Investigational long acting drug for hepatitis C |
| Convalescent plasma/hyperimmune plasma (passive Immunotherapy) | Phase 1/2/3 | Plasma from persons who have survived COVID-19 might contain antibodies (IgG, IgA, IgM, IgE, and IgD) of human origin as a result of developed humoral immunity to SARS-CoV-2 and can be used to reduce the viral load and disease mortality in other patients | Investigational approach tried for emerging Infectious Diseases like Ebola virus |
| Anakinra (recombinant interleukin, immunotherapy) | Phase 2/3 | Target Interleukin-1 type I receptor (IL-1RI), and acts as an IL-1 receptor antagonist, also block IL-18 production | Rheumatoid arthritis and neonatal-onset multisystem inflammatory disease |
| Tocilizumab (recombinant humanized monoclonal antibody) | Phase 2/3 | IL-6 inhibitor, block cytokine storm | Rheumatoid and giant cell arthritis, polyarticular and systemic juvenile idiopathic arthritis, cytokine release syndrome |
| Sarilumab (monoclonal antibody) | Phase 2/3 | IL-6 inhibitor, blocks cytokine storm | Moderate to severe reactive Rheumatoid Arthritis |
| Natural killer cells (biologicals) | Phase 1/2 | Innate lymphocytes that act via the process of antibody-dependent cellular cytotoxicity, possess antiviral effect | Cancer immunotherapy |
| Stem cell therapy (biologicals) | Phase 2 | Mesenchymal stem cells (MSCs) have high regenerative and immunomodulatory capacities. These modulate the inflammatory response, boost tissue repair, enhance pathogen clearance, and reduce the severity of the injury, pulmonary dysfunction, and apoptosis. | Several carcinomas, inherited metabolic disorders, myelodysplastic syndromes, lymphomas, leukemias, other disorders of blood cell proliferation, inherited disorders affecting the immune system and other organs |
| Fingolimod (immunomodulator; sphingosine-1-phosphate receptor regulators) | Phase 2 | Binds to Sphingosine-1-phosphate receptor and acts as a functional antagonist and reduces lung inflammation | Relapsing remitting multiple sclerosis (RRMS) |
| Bevacizumab (recombinant humanized monoclonal antibody, VEGF inhibitor) | Phase 3 | Target vascular endothelial growth factor (VEGF), inhibit it and prevents acute lung injury (ALI) and ARDS | Metastatic colorectal cancer, metastatic and recurrent non-squamous non-small cell lung cancer, metastatic renal cell carcinoma, recurrent cervical cancer, epithelial ovarian cancer etc. |
| Baricitinib (kinase inhibitor) | Phase 2/3 | Target JAK kinase receptor, inhibit JAK 1/2 selectively and reversibly and inhibits the down-streaming signaling cascades of cytokines and growth factors | Rheumatoid arthritis in adult patients |
| Ruxolitinib (kinase inhibitor) | Phase 1/2/3 | Target JAK kinase receptor, JAK 1/2 inhibition and inhibits the down-streaming signaling cascades of cytokines and growth factors | Intermediate or high-risk myelofibrosis |
| Acalabrutinib (kinase inhibitor) | Phase 2 | A selective inhibitor of Bruton’s tyrosine kinase and inhibits downstream B-cell antigen receptor and cytokine receptor pathways | Chronic lymphocytic leukemia or small lymphocytic lymphoma |
| CD24Fc (biological immunomodulatory, comprises the nonpolymorphic regions of CD24 attached to the Fc region of human IgG1) | Phase 2/3 | Act as innate checkpoints to inflammatory stimuli by identifying danger-associated molecular patterns, inhibit cytokines release and reverse the loss of T lymphocytes | Investigational biologics to inhibit multiple inflammatory cytokines |
| Thymosin (PD1 blocking monoclonal antibody) | Phase 2/3 | Target PD-1 receptor expressed on the surface of T cells and regulate cellular immunity by blocking the activity of PD-1 (immune check pathway), prevent T cell death and regulate cytokine production | Adjuvant for influenza vaccine and hepatitis B vaccines |
| Tradipitant (neurokinin-1 (NK1) receptor antagonist) | Phase 3 | NK1 receptor antagonist; works by blocking substance P, reduces inflammatory lung injury and relieves chronic cough | An investigational drug in trials of eczema, pruritus, gastroparesis, chronic pruritus, atopic dermatitis |
| Eculizumab (monoclonal antibody, terminal complement inhibitor) | Phase 2 | Target complement protein C5, prevents activation of a complement terminal complex and immune-mediated inflammation | Paroxysmal nocturnal hemoglobinuria |
| Sargramostim (recombinant humanized granulocyte-macrophage colony stimulating factor (rhuGM-CSF)) | Phase 4 | Target GMCSF, a pleiotropic cytokine and stimulates JAK2 STAT1/STAT3 signal transduction pathway, pivotal function in hematopoiesis and cell-mediated immunity. | Cancer and bone marrow transplant |
| Aviptadil (vasoactive intestinal polypeptide) | Phase 2/3 | Prevents NMDA-induced caspase-3 activation in the lung, inhibits IL-6 and TNFα production and restores barrier function at the endothelial/alveolar interface | Approved in Europe for, erectile dysfunction, FDA orphan drug designation for treating ARDS |
| Telmisartan, Losartan (angiotensin II receptor blocker) | Phase 2/3/4 (one phase 1 study for losartan) | Target angiotensin II type 1 (AT1) receptors, degrade angiotensin II to angiotensin 1–7, reduces inflammation and release of proinflammatory cytokines thereby reduces chances of ARDS | Hypertension; diabetic nephropathy in hypertensive patients with type 2 diabetes mellitus; congestive heart failure |
| Isotretinoin (retinoid derivative of vitamin A) | Phase 1/3 | Strongest down-regulation of ACE 2 receptors also inhibit potential papain-like protease (PLpro), which is a protein encoded by SARS-CoV-2 genes | Severe recalcitrant nodular acne |
| Naproxen (anti-inflammatory) (studied in combination with antiviral) | Phase 3 | Inhibit cyclo-oxygenase 2 (COX-2) and Influenza A virus nucleoprotein (NP), reduces inflammation | Osteoarthritis, rheumatoid arthritis, acute gouty arthritis, primary dysmenorrhea, for inflammation and pain in musculoskeletal |
| Azithromycin (broad-spectrum macrolide antibiotic (studied alone or in combination with hydroxychloroquine or amoxicillin/clavulanic acid)) | Phase 2/3/4 | Target bacterial ribosomes, inhibits transpeptidation and stops protein synthesis, also have immunomodulatory effects, which might decrease respiratory inflammation | Respiratory, enteric and genitourinary infections; some sexually transmitted and enteric infections, infections caused by susceptible strains of the microorganisms listed by FDA; |
| Nitazoxanide (antiviral and antiprotozoal, studied in combination with hydroxychloroquine, or other drugs) | Phase 2/3 | Targets viral hemagglutinin and the viral transcription factor, inhibits viral replication, possess anti-cytokine and autophagy properties | diarrhea in adults and children |
| Colchicine (alkaloids, anti-inflammatory drug) | Phase 2/3 | Targets inflammasome complex, inhibits microtubules polymerization and production of IL-1β and IL-6, prevents cytokine storm | Gout and familial Mediterranean fever |
| Deferoxamine (iron chelator) | Phase 1/2/3 | Manages excess iron levels in the blood, prevents iron toxicity and hence prevents severe respiratory manifestations and inflammation in the alveoli | Acute iron or aluminum toxicity; anemia in patients who must receive many blood transfusions |
| Heparin (enoxaparin), Tinzaparin or unfractionated heparin (anticoagulant) | Phase 2/3/4 | Inhibit coagulation factor Xa and thrombin by binding to the plasma protease inhibitor, prevents venous thromboembolism in COVID-19 patients | Prevention of postoperative venous thromboembolism; deep vein thrombosis and/or pulmonary embolism; prevention of clot formation in indwelling intravenous lines for hemodialysis |
| Inhaled nitric oxide (INO) (pulmonary vasodilator) | Phase 1/2 | Targets heme molecule of cytosolic guanylate cyclase and results in pulmonary vasodilation, early administration might prevent cases of respiratory failure in COVID-19, also act as anti-thrombotic in lung | Hypoxic respiratory failure in neonates |
| Ascorbic acid (nutraceutical, antioxidant) | Phase 1/2/3 | Targets the dysregulated immune response, increase the activity of lymphocytes, reduce the risk of development of inflammatory markers, ARDS and respiratory failure |
Approved for scurvy, delayed wound and bone healing, urine acidification. Investigational drug for sepsis, acute lung injury (ALI) |
*All drugs mentioned here are investigational drugs for COVID-19; however, they might be approved for some other disease indications