Table 1.
immunomodulatory drugs in clinical development to treat SARS-CoV-2. This table lists agents under investigation and/or theoretically being considered for patient management. At this time, no recommendation can be made for any of these agents and some of them are off-label use.
| Drug or cocktail | Status and mechanisms | NETs | DAMPs | Autophagy | Clinical trials (trial posting date) |
|---|---|---|---|---|---|
| Adalimumab | Anti-TNF-α humanized mAb able to suppress the physiologic response to TNF-α, which is part of the inflammatory response in autoimmune and immune-mediated disorders | No data | No data | In autoimmune disease, it inhibits autophagy, enhancing regulation | One clinical trial enrolled in China (ChiCTR2000030089) in combination with standard treatment in severe disease |
| Anakinra | IL-1 receptor antagonist hypothesized to quell cytokine storming. No data available as adjunctive therapy for SARS-CoV-2 | Possible role in blocking NET formation | Anti-IL1R may have a role in blocking DAMP release | Anti-IL1R may have a role in restoring a regulatory function | 12 clinical trials as single drug or in combination are enrolling patients in Europe |
| Bevacizumab | Recombinant humanized mAb that prevents vascular endothelial growth factor (VEGF) association with endothelial receptors Flt-1 and KDR approved for multiple cancers in the US | No data | No activity | Autophagy promotes resistance to Bevacizumab | Being evaluated in two clinical trials in China for COVID-19 (NCT04305106 and NCT04275414) and one international trial (NCT04344782), no data are currently available to support its use |
| Chloroquine or hydroxychloroquine | Endosomal acidification fusion inhibitor | Inhibition of NETosis as a consequence of autophagy blockade | Inhibition of HMGB1 activity in a septic in vivo model | Blocks autophagosome fusion and degradation | At least 300 trials, alone and in combination, for mild symptoms and prophylaxis, have been registered with the FDA and Chinese clinical trials |
| Convalescent plasma | Plasma from convalescent patients who have recovered from the SARS-CoV-2 infection has been used with success much in the same way as for SARS-CoV-1, MERS, Ebola, and H1N1 influenza | Possible role overlapping IVIg | Possible role overlapping IVIg | Possible role overlapping IVIg | Up to 250 clinical trials enrolled patients with severe SARS-CoV-2 disease in the US, China, Italy, and Mexico registered with the FDA and Chinese clinical trials |
| Diflunisal | Diflunisal, a nonsteroid anti-inflammatory drug (NSAID) included in the salicylate class, has a specific indication to prevent flogosis and pain control in joint disease | No data | Blocks immune cell recruitment inhibiting HMGB1/CXCL12 activation | No data | No clinical trial for SARS-CoV-2 |
| Disulfiram | Thiuram derivative that blocks alcohol oxidation, demonstrating ability to competitively inhibit the papain-like proteases of SARS but no clinical data. No in vitro or clinical data available for SARS-CoV-2 | No data | Reduces the release of DAMPs in apoptotic cells | Dual role in Disulfiram mechanism studied in cancer | None |
| Eculizumab | Humanized IgG mAb that binds to complement protein C5 and prevents formation of membrane attack complex (MAC) | Blocking NET formation via complement activation | No data | No data | Being evaluated in a clinical trial (NCT04288713) for SARS-CoV-2 to quell immune response. New clinical trial (NCT04346797) is recruited as a single agent |
| Heparin/low molecular weight heparin | Heparin binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in activation and consequent inactivation of thrombin, factor Xa, and other proteases. Possible role in immune modulation | Reduction of NETosis due to a reduction of autophagy | Inhibition of activity via blockade of HMGB1 binding to immune cell surface | Reduction of neutrophil activation autophagy | At least 40 clinical trials planned to evaluate its efficacy in the prevention of SARS-CoV-2 complications |
| Hyperbaric oxygen | Hyperbaric oxygen therapy is a medical use of oxygen at an ambient pressure higher than atmospheric pressure. It reduces inflammation, modulating cytokine release, and increases ROS production, reduces apoptosis, and modulates leukocyte activation and adhesion | Reduction of ROS-dependentNET release | Reduced activation of HMGB1 pathways | Inhibits autophagy activation reducing ROS | 8 clinical trials are ongoing to evaluate its efficacy in ARDS and pneumonia |
| Interferon alpha-2b alone or in combination with other drugs | Interferon α-2b is a recombinant cytokine with antiviral properties; ribavirin is a guanine derivative; as above | Type I IFN enhance NETosis | HMGB1 is related to IFNα in sustaining inflammation | Possible role in enhancing antiviral autophagy | 60 clinical trials registered as a single agent or in combination for SARS-CoV-2 |
| Intravenous immunoglobulin (IVIg) | IVIg remain on critical national shortage in the US. The benefit in patients with SARS-CoV-2 is unclear | IVIg reduce NET formation | Protection against HMGB1-induced cell death modulating TLR and RAGE expressions | IVIg may have a role in modulating a regulatory function | More than 250 clinical trials are planned all over the world to evaluate efficacy in SARS-CoV-2 pneumonia |
| Methylprednisolone | Synthetic corticosteroid that binds to nuclear receptors to dampen proinflammatory cytokines | Reduction of NET formation in in vitro and in vivo model | Reduces the release of HMGB1 and its interaction with TLR4 | Modulation of regulatory autophagy | 25 clinical trials in COVID-19 disease as a single agent or in combination with standard care or mAb in US and China |
| Remdesivir | Adenosine analogue that leads to premature or delayed termination of the viral RNA chains | No data | No data | No data | First approved specifically to treat COVID-19 |
| Sarilumab | IL-6 receptor antagonist FDA-approved for rheumatoid arthritis | Possible role in blocking NET formation | No data | Role in blocking regulatory autophagy | 15 clinical trials in SARS-CoV-2 disease as a single agent or in combination |
| Sirolimus | Commercial drug form of rapamycin blocks mTOR and subsequent pathways, reducing cytokine (such as IL-6 and TNF-α) expression | Enhances NETosis also without external stimuli | Reduces the expression of HMGB1 | Stimulation of autophagy as a direct effect of mTOR blockade | 4 clinical trials as a single agent, enrolling patients affected by SARS-CoV-2 disease |
| Tocilizumab | Humanized mAb targeting IL-6 | Possible role in blocking NET formation | No data | Role in blocking hypoxia-induced autophagy | Up to 60 clinical trials in different countries |
Last search run on June 06 using https://clinicaltrials.gov and http://www.chictr.org.cn. This table lists agents being investigated and/or theoretically considered for the management of SARS-CoV-2-infected patients. At this time, no recommendation can be made for any of these agents. In general, they should be avoided without additional supporting evidence.