Promising drugs

Based on our guiding principles, we’ve identified the following early treatments with the potential to significantly reduce hospitalization and fatality rates and worthy of further testing.

Promising drug trials supported by CETF

Fluvoxamine

Fluvoxamine is a repurposed SSRI antidepressant drug approved by the FDA for the treatment of depression and obsessive-compulsive disorder (OCD). It is also highly effective at activating the Sigma-1 Receptor (S1R). The S1R is known to inhibit a cytokine, the chemical responsible for “Cytokine Storms”, which can lead to hospitalization and/or death in COVID-19 patients. Recent studies, including a CETF-sponsored clinical trial, showed that patients treated early with fluvoxamine had a dramatically reduced rate of hospitalization, compared to the control. The results of the trial were featured as the lead story in JAMA on November 12, 2020. CETF is now sponsoring a larger, Phase 3 trial to validate the results of the original study. This is the drug we are the most excited about. To learn more, visit our Fluvoxamine page dedicated to providing the most up to date information about the use of this drug for the early treatment of COVID-19.

Camostat (CETF trial)

Camostat mesylate is a drug approved in Japan for treatment of pancreatitis. Bicalutamide is an antiandrogen medication that is primarily used to treat prostate cancer. These drugs work in combination to fully inhibit TMPRSS2 activation which is required for the virus to infect and spread to other cells. The two ways to inhibit TMPRSS2 are: to inhibit proteolytic activity and to downregulate expression of the protein. Camostat is used for proteolytic inhibition. Since TMPRSS2 is androgen regulated, downregulation of expression can be achieved using antiandrogens such as the generic drug bicalutamide. As promising as this approach appears, inhibition of TMPRSS2 may not completely prevent SARS-CoV-2 infection, since the virus can also be endocytosed and could therefore still be activated to fuse by cathepsins. Therefore, it will also be important to evaluate this approach in combination with other agents (such as the cathepsin inhibitor Selva SLV213) to identify a potent combination. The dose of camostat mesylate being evaluated in the clinic is higher than the dose used for pancreatitis, with the aim of achieving sufficient concentration to be effective in the lungs.

Selva SLV213 (CETF trial)

This is a cathepsin inhibitor (see Camostat above). If camostat is successful, pairing it with a cathepsin inhibitor would create very potent combination antiviral therapy that would leave no avenue for the virus to replicate.

Monoclonal antibodies (CETF planned trial)

Antibodies are proteins the immune system naturally makes in response to a virus. Historically, passive immunization strategies have been used to combat infectious disease epidemics. Currently convalescent plasma is being studied in clinical trials and under compassionate use to provide neutralizing antibodies to hospitalized patients with COVID-19, with over 30,000 units given to date. Many groups have worked to identify which antibodies had the strongest anti-viral effects and then produced them from clones of the parent cell that produced the desired antibody. Desired attributes include potent neutralizing activity which fully blocks the receptor-binding domain of S (SRBD) from interacting with human ACE2 (hACE2). These have therapeutic potential for both preventive and early treatment. Current formulations in investigational use require infusion over 60 minutes, but if refined could be given as an injection. Some of these studies are funded by drug companies, but many are not. Monoclonal antibodies may be combined in a cocktail for maximum effect.

GS-441524 (CETF supported trial)

A Gilead compound that is similar to Remdesivir, GS-441524 is a small-molecule antiviral that targets specific proteins involved in RNA virus replication. It has been used combat different coronaviruses in cats and is currently being explored by the NIH. More info.

Doxazosin (CETF planned trial) ‍‍

It has been shown that cytokine storm syndrome (CSS), observed with bacterial infections, CAR-T cells, and other T cell-activating therapies, is accompanied by a surge in catecholamines. These catecholamines, in turn, enhance inflammatory injury by augmenting the production of IL-6 and other cytokines through a self-amplifying feed-forward loop in immune cells that requires 𝛼-1 adrenergic receptor (𝛼1-AR) signaling. Preliminary results from a recent retrospective clinical study revealed that, for hospitalized patients diagnosed with pneumonia or acute respiratory distress, the likelihood of requiring mechanical ventilation and dying was significantly lower (by 56% and 20%, respectively) if patients were taking 𝛼1-AR antagonists during the year preceding hospitalization. However, an unpublished retrospective study showed even stronger protection: 75% or more. In a study at a very large hospital network, the number of deaths from COVID from people taking doxazosin was just one person. These results highlight the need for prospective trials to prove beyond a reasonable doubt whether prophylactic 𝛼-blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19. In the interim, until those results are available, informed patients can ask their doctor about taking doxazosin if they are diagnosed with COVID.

Other Promising Drugs

The New York Times maintains a broad tracker of COVID-19 treatments under development, as does the Milken Institute on their treatment and vaccine tracker.