Promising drugs

Existing drugs with the potential to reduce hospitalizations and save lives, when used early to fight COVID-19.

Based on our guiding principles, we’ve identified the following drugs as the most promising to test.

Pegylated interferon lambda (CETF trial)

The promise of this approach, applied early in infection, is that it’s one shot and you’re done. It’s also relatively easy to mass produce at a low cost. It replaces your body’s natural interferon which the virus disables. Pegylated interferon lambda is a well characterized, late-stage, first in class, type III interferon that stimulates cell-mediated immune responses that are critical for the development of host protection during viral infections. Although lambda is not a marketed drug, it has been tested on over 3,000 patients with either Hepatitis B or Hepatitis C virus (many who have been taking it for over a year), so the safety profile is well established. It is currently being developed for use in Hepatitis D (HDV).

Camostat and bicalutamide (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 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.

Fluvoxamine (CETF trial)

Similar in potential impact to Doxazosin, fluvoxamine is a selective serotonin reuptake inhibitor which binds to the sigma-1 receptor to shut down the inflammatory cascade from the endoplasmic reticulum in cells. Prospective randomized placebo controlled clinical studies of early treatment of mild illness are needed.

Favipiravir (CETF planned trial)

There are high hopes for this antiviral from Japan which was first approved to treat influenza. Chinese researchers say that it’s effective, and it has been approved to treat COVID-19 in Russia, China and India. While the safety and efficacy of Favipiravir have not been evaluated in US clinical trials, there is evidence to support the safety and tolerability of Favipiravir in short-term use. The major safety concerns relate to increases in blood uric acid and teratogenic potential. In countries in which the drug is currently approved, there is a strong warning against use in women of reproductive age.

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.

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. These results highlight the need for prospective trials to assess whether prophylactic 𝛼-blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19.

Remdesivir

Remdesivir, a structural analogue of adenosine monophosphate (AMP) that interferes with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), is an investigational. The FDA has issued an Emergency Use Authorization (EUA) for the unapproved product, Remdesivir, for the treatment of COVID-19. The distribution of Remdesivir has been authorized only for the treatment of hospitalized patients with severe COVID-19. As with other antivirals, it is predicted to work best when given early. Remdesivir (an IV medication) is the first antiviral which has been demonstrated to shorten the time to recovery. There is little to no benefit to patients when Remdesivir is given late, which suggests that treatment timing may have important effects on the outcome. This still may be too late in the disease course to have a significant impact on fatality rates. We suspect that it may work better if given early. Gilead has announced development of an inhaled form and projects testing in outpatient trials late this year.

GS-441524

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.

Leronlimab

Leronlimab is an investigational CCR5 antagonist in late stage development to treat triple negative breast cancer. The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation and shows promise for early treatment of COVID-19.

Interferon beta

Interferon beta is being studied for the potential to be delivered through an inhaled route and help restore the body's ability to fight the virus.

Niclosamide

A recent study highlighted niclosamide as one of just two “best drugs” to pursue from an in vitro screen over 50 FDA approved drugs. It was shown 16 years ago to inhibit SARS-CoV replication. The problem is bioavailability: taken as a pill, it just sits in the stomach and doesn’t get absorbed. There are two novel forms that increase bioavailability: micronized and solubilized by OHPP. The OHPP form looks promising — you just drink it and it’s inexpensive. Niclosamide was on everyone’s top screening list, but bioavailability had a been a problem because it isn’t soluble in water. Once it is made bioavailable, side-effects should be analyzed and a longer lead time than the other options since it first must be tested in healthy patients in its new formats to ensure safety.