Promising drugs

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

Fluvoxamine (multiple CETF trials)

Fluvoxamine is a repurposed antidepressant drug approved by the FDA for the treatment of depression and obsessive-compulsive disorder (OCD). It is also widely used in Europe for treating OCD. It is in the class of drugs called Selective Serotonin-Reuptake Inhibitors (SSRIs). A large multi-center observational study in France showed that SSRIs in general were protective against COVID and the drug with the greatest sigma-1 activation in the study (fluoxetine in that case) had the greatest protection. The hypothesis of the researchers at Washington University is that the protection comes from the activation of Sigma-1. S1R is known to inhibit a cytokine, a chemical in our body that gets activated in certain infections, such as Covid-19.  Excessive inflammatory response, “Cytokine Storm”, was thought to be responsible for some of the complications ("Covid Pneumonia") seen in Covid-19 patients that leads to hospitalization and/or need for ventilator treatment. They chose fluvoxamine because, of all the SSRIs, fluvoxamine had the greatest activation of Sigma-1.

The importance of Sigma-1 has been written about by NIH Director Francis Collins. Collins wrote "COVID-19 patients taking ...drugs ... that target SIGMAR1 were half as likely as those taking other types of ...drugs to require mechanical ventilation." [emphasis ours]

With support from CETF, a randomized, double-blind and fully remote outpatient clinical trial was conducted at the University of Washington in St. Louis, led by Eric Lenze, MD and Angela Reiersen, MD, 152 people participated in this trial, all of whom were 18 years or older, symptomatic, and diagnosed with mild forms of COVID-19. Participants were randomly assigned (1:1) to take either Fluvoxamine or a placebo. In this trial, of the 80 participants who received the drug, no patients hit the endpoint of clinical deterioration (defined as reaching blood oxygen saturation level of less than 92% and shortness of breath requiring supplemental oxygen), versus 6 people out of 72 who got the placebo and did reach the clinical endpoint. In summary, all fluvoxamine-treated patients did not meet the study endpoint. The study appeared as the lead story in JAMA on Nov 12. The Editors noted that they chose this study from over 10,000 COVID submissions received since February 2020. Interest has been high: the study was the third most popular article on JAMA for the month of December.

One week after the study was published, there was a massive COVID outbreak at Golden Gate Fields Racetrack. The track doctor, Dr. David Seftel, had read about the JAMA study the week before and on November 21, started offering it to the employees. At first, only 35% of the employees opted to try the drug. Two weeks later, after the employees saw first-hand what happened with people who took the medication vs. people who refused, there is a 100% acceptance rate of the drug. Employees that previously had rejected the drug changed their minds and requested the drug. In total, 53 employees refused the drug, 6 of them were later hospitalized, an 11.3% hospitalization rate. By contrast, all 62 employees who received the drug (50mg BID for 14 days) had a 0% hospitalization rate (for any reason) and all had very mild symptoms and reported no degradation in pulmonary or cognitive function. These results will be submitted to JAMA soon and the full data will be published. Dr. Seftel characterized the result as "extraordinary" and "a teachable moment." Watch him speak about the results at the 1 hour mark in this video.

Dr. Seftel found that fluvoxamine reliably turned the virus into a mild disease. No patient on fluvoxamine had any symptoms of respiratory distress due to COVID. When patients came to him late in disease when respiratory symptoms were starting to appear, within 3-4 days after starting fluvoxamine, the situation was reversed in each case.  

Between the two studies (total N=267), of the 142 people who took fluvoxamine, there were no hospitalizations for  respiratory distress (one patient in the Lenze study was hospitalized from diarrhea which preceded him taking fluvoxamine). We are not aware of any drug with more promising initial data as a treatment for COVID-infected patients. Fluvoxamine appears to exert a very strong and reliable mitigation effect.

On December 22, the dean of one the top medical schools in the US called for fluvoxamine to be used in clinical practice.

On December 9, FastGrants sent this message to all grantees:

"Given that fluvoxamine is relatively safe, cheap, and widely available, we’ve decided to issue a call for proposals and data pertaining to fluvoxamine. We are interested in funding any fluvoxamine RCTs that can be rapidly initiated or other relevant connected work. (We are already funding one RCT that should start soon.) If you have a related proposal, relevant data (on fluvoxamine, SSRIs, or S1R agonists more broadly), or know of anyone else who does, please also feel free to send them our way. We are eager to see both positive and negative data in this area."

Although most doctors would not hesitate to take Fluvoxamine if they got COVID and couldn't get one of the monoclonal antibodies (which are in very limited supply), because the evidence is limited in the number of patients (N=142 who have received the drug for COVID), a sizable number would be hesitant to proactively suggest this drug to patients (unless the patient asked for the drug explicitly). For this reason, CETF, FastGrants, the Skoll Foundation, and Cures Within Reach are jointly sponsoring a larger Phase 3 trial of fluvoxamine that will begin in December. This is a remote trial that is available to anyone in the US. If you get COVID, we encourage you to enroll in this trial because doing so will increase your chances of having a much better outcome (compared to just staying at home in quarantine) and because it will help us gather the data so we save lives worldwide. Please let anyone who you know that is infected by COVID about this trial.

Fluvoxamine is FDA approved with a 26-year track record of safety in the US so it can be prescribed off-label by physicians today for COVID. For the entire 14-day treatment, fluvoxamine costs $10, even for people without insurance.

Drug timing
The WashU researchers believe that Fluvoxamine could be effective at multiple stages of COVID, including for hospitalized patients when they are first admitted. Fluvoxamine is best given as early as possible. We have one anecdotal report that after a patient is placed on high flow oxygen, standard dosing of fluvoxamine is too little/too late to make a difference. We are interested in funding in-patient trials using fluvoxamine where the drug is administered upon first admission.

Use in other diseases
Fluvoxamine, through S1R activation, may prove in the near future be effective in treating other diseases such as influenza, sepsis, future viruses, pneumonia, and Alzheimer's. Together, these diseases require hospitalization and kill millions of people every year.

Use in vaccine challenge trials
‍Because fluvoxamine reliably turns the virus into a mild disease, once it is proven in the upcoming phase 3 trial, it could be considered as a salvage therapy for individuals who volunteer for vaccine challenge trials and are not protected. This has the potential to accelerate the speed of vaccine trials by several months.

Other possible mechanisms of action
Fluvoxamine increases melatonin levels through inhibition of CYP1A2, whether the melatonin is endogenously produced or taken as a supplement. The SARS-CoV-2 virus may activate the NLRP3 inflammasome, which may contribute to cytokine storm. Melatonin may reduce inflammation through its inhibition of the NLRP3 pathway

Longer-term benefits
While fluvoxamine is clearly effective in mitigating the immediate respiratory distress and other symptoms, it is not yet known if it is superior to placebo with respect to any long-term impacts of COVID. Successful treatment of COVID may involve the use of multiple drugs to address both short and long-term effects of the virus.

To enroll in the Phase 3 fluvoxamine trial
There is no cost to enroll and you can enroll and participate from home. Either:
1. Visit https://stopcovidtrial.wustl.edu/
2. Send your email and phone number to: stopcovidtrial@wustl.edu

Other articles about fluvoxamine
Psychiatric Drugs Could Be the Key to Treating Covid-19 (Medium)
SSRI Antidepressants May Be Effective Early Treatments for COVID-19 (BioSpace)
These drugs might prevent severe COVID (Scientific American)

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 (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.

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. This drug can be justified on the basis of treating hypertension or enlarged prostrate alone.

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.

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.

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Ivermectin (IVM)

While many of CETF's scientific advisory board members are skeptical of Ivermectin due to the abundance of low-quality studies and lack of "gold standard" RCT studies, as of Jan 1, 2021, it is rapidly becoming increasingly clear that this was a mistake as more and more data shows it is extremely effective in all stages of the disease and it is highly likely to emerge as the preferred drug for prevention (if you haven't yet been vaccinated) and treatment.

In this video of testimony at the US Senate by Dr. Pierre Kory, he cites the Carvallo study from Argentina where Ivermectin protected 788 healthcare workers from infection by 100% (taking it just once per month), whereas of the 400 that didn't get the drug, 58% got sick (that is not a typo... 237 of the 407 got sick).

The dose recommended by Dr. Pierre Kory for prevention is .1mg/kg taken once per week. The recommended dose for treatment (i.e., once you are COVID positive) is much higher and more frequent: .2mg/kg taken once a day for 5 days.

The first high quality randomized trial result on ivermectin (Podder et al.) showed that it was not effective in shortening the duration of a COVID infection. As a result, many researchers focused their efforts elsewhere. However, there were several problems with that RCT study: 1) it was a small study with only 32 patients in the intervention arm 2) all the patients were relatively healthy and able to defeat the virus without help, and 3) the dose given, a single dose of .2mg/kg was not the dose recommended by today's researchers.

Today, many doctors only believe what is in well controlled double-blind randomized clinical trials; everything else, no matter how compelling, is heavily discounted. This is why fluvoxamine is more likely to get mainstream traction before Ivermectin, but that preference may reverse over time.

Fenofibrate (Tricor)

Fenofibrate is a commonly prescribed medication for the treatment of high cholesterol with lipid-modifying effects. COVID-19 progression in the lungs often relies upon lipid proliferation in bronchial cells. In recent human studies, early use of fenofibrate markedly inhibited SARS-CoV-2 viral replication. Fenofibrate also has immunomodulatory effects that may be beneficial in the setting of COVID-19.

Multiple Fenofibrate trials are currently recruiting participants in order to assess the clinical impact of in patients with COVID-19. You can learn more about the ongoing Fenofibrate clinical trials here.

Metformin

Metformin has a very low side effect profile. John Buse, former president of the American Diabetes Association jokes that Metformin is healthier than orange juice. He's absolutely correct. So if you have a drug with almost no downsides where there is evidence of a 25% to 50% impact on the virus at all stages of the disease (pre-, post-exposure, post-infection, post-hospitalization), we should pay very close attention and support that work. CETF has invited the team at the University of Minnesota lead by Carolyn Bramante, Christopher Tignanelli, and Michael Puskarich to apply for a grant so that we can study this drug in an RCT.

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.

Interferon beta

One of the most promising drugs on our list, Interferon Beta is being studied for the potential to restore the body's ability to fight the virus early.  We are most interested in inhaled route of delivery. In June, results from a European Phase II trial of Synarigen's inhaled formulation of interferon beta, dubbed SNG001, were released and showed a 79% reduction in hospitalizations in COVID-19 patients.

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.

MK-4482/EIDD-2801

This antiviral was originally created to fight the flu and has shown promise treating COVID-19 in animal studies. Merck is planning to launch a Phase III trial of this drug in September.

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.

Hydroxychloroquine

We are not looking at Hydroxychloroquine (HCQ) actively because it doesn't meet our threshold of 75% or more reduction in the hospitalization rate. The Boulware study showed HCQ did reduce the hospitalization rate, but it was not statistically significant (because the study size was too small relative to the effect). A non-peer-reviewed meta-analysis of hydroxychloroquine studies concludes that it has a 24% reduction in the infection, hospitalization, and death rate but there were several problems with this study. Newer studies show no effect.

Nafamostat

Similar to Camostat, this drug has shown promise in several studies.

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Other Drugs: The New York Times maintains a broad tracker of COVID-19 treatments under development.