There are currently no FDA approved drugs to prevent or treat COVID-19. Clinical management includes supportive care like supplemental oxygen and mechanical ventilation; that’s slim pickings as we face off against a virus that launched a global pandemic after emerging just several months ago. As cases continue to quickly tick upward surpassing 6 million worldwide, scientists are scrambling to generate vaccines and treatments. But they’re not just looking to engineer new medications that can disable the coronavirus, SARS-CoV2, they’re also sifting through already established drugs from a panoply of uses. Repurposing already approved drugs allows for rapid clinical trials and regulatory reviews. As researchers identify the ways SARS-CoV2 breaks into and hijacks human cells, they also find targetable processes, vulnerabilities they’re hoping a current drug has the ability to exploit.
Hydroxychloroquine, a drug used to treat malaria and rheumatoid conditions, is one such repurposed medication; it made headlines around the world when President Trump touted its efficacy and even admitted to taking it prophylactically despite known dangerous side-effects. While it has recognized antiviral activity and can inhibit SARS-CoV-2 replication in cellular models, data from a large-scale observational study and a randomized control trial (RCT) found that the drug did not result in clinical improvement in hospitalized patients. The NIH is currently recruiting for its own RCT in symptomatic patients. As for its potential role as a preventative when taken by those with known exposure to the virus, mostly healthcare workers, on June 3, The New England Journal of Medicine published that hydroxychloroquine does not appear to offer protection against COVID-19 infection, although it did not address whether the drug might prevent infection if taken prior to exposure (that is being studied in other clinical trials).
Blocking coronavirus entry
SARS-CoV-2 uses its Spike protein to enter human cells by binding to angiotensin-converting enzyme 2 (ACE2)-receptors across myriad tissue types. Endocytic entry into host cells is one part of the viral life cycle that can be targeted; in fact, several vaccines in development focus on this ACE2-SARS-CoV-2-Spike interaction. Recombinant human ACE2 (rhACE2, or APN01) is currently in development for acute lung injury and arterial hypertension. The protein has undergone a phase 1 clinical trial in healthy individuals and phase 2 testing in some patients with acute respiratory distress syndrome (ARDS). In vitro experiments in blood vessel and kidney organoids derived from human cells also showed that the protein can block early stages of SARS-Cov-2 infection, probably by acting as decoy for virus binding, therefore diluting the amount of virus that reaches actual ACE2 receptors. As expected, blocking SARS-CoV-2 from human ACE2 receptors is not complete and is dose-dependent.
The ability of the coronavirus to successfully enter the human cell through ACE2 receptors requires cleavage and activation of the Spike protein by proteases; this can be carried out by transmembrane protease serine 2 (TMPRSS2). Camostat is a TMPRSS2 inhibitor approved in Japan for the treatment of chronic pancreatitis and postoperative gastric reflux. The authors of a recent Cell paper showing that Camostat can inhibit SARS-CoV-2 infection in human lung cells, urged consideration of this drug and similar ones for off-label-treatment of coronavirus. Camostat’s suitability for COVID-19 treatment is currently being tested in clinical trials in Denmark and the U.K. Nafamostat is another TMPRSS2 inhibitor approved by the FDA for the treatment of acute pancreatitis. This drug also blocked SARS-CoV-2 infection of human lung cells, and with markedly higher efficiency than Camostat. This compound is now also the subject of a clinical trial to determine efficacy against COVID-19. The hope is that this class of compounds could be used to reduce the severity of the infection giving the immune system a better chance at overpowering it.
Mitigating the inflammatory response
Antivirals and anti-inflammatory drugs are also advancing in COVID-19 clinical trials. Remdesivir was originally developed for the treatment of flaviviruses that cause Ebola and Marburg diseases. The antiviral has since proven to be effective against both MERS and SARS in animal models (SARS or SARS-CoV-1 shares significant genetic overlap with SARS-CoV-2). In those hospitalized for COVID-19, remsdesivir decreases time to recovery. Now newer clinical studies are pairing the drug with other potential therapeutic agents, such as barictinib, an ant-inflammatory approved in the U.S. and many other countries for the treatment of rheumatoid arthritis. When taken orally, barictinib inhibits cytokine signaling that produces inflammatory responses. Some COVID-19 patients develop ARDS caused by inflammation of the lungs. The RCT will compare recovery times and mortality outcomes in patients that receive both drugs compared to remsdesivir alone. Another rheumatoid arthritis drug, Roche’s Actemra, will be assessed in combination with remsdevir in a phase 3 clinical trial, to determine efficacy in COVID-19 patients with severe pneumonia.
When patients offer clues
The mechanism by which SARS-CoV-2 successfully infects cells highlights potential targetable pathways. But sometimes the patients themselves can offer clues into otherwise unknown ways the virus functions in the body. For example, doctors in Wuhan noticed that COVID-19 patients that happened to be taking the popular histamine receptor H2 antagonist heartburn medication, famotidine (or Pepcid), seemed to have lower mortality rates. These observations were published in a non-peer-reviewed preprint. This led scientists to question the role of histamine in COVID-19 pathogenesis and posit that the disease may be partially driven by dysfunctional mast cell degranulation (in which case, drugs being used to treat mast cell disorders may also help to reduce the severity of COVID-19 symptoms). A controlled trial is currently underway.
Similarly doctors noticed that men seemed worse off compared to women when infected with the coronavirus. And indeed epidemiological data from around the world has confirmed this, with men making up more than 80% of patients admitted to intensive care units in Italy and male mortality exceeding women in every adult age group in a study of 5,700 New York City patients. This male bias is thought to be driven by androgens, and its link to COVID-19 via TMPRSS2, which primes the SARS-CoV-2 Spike protein and plays a vital role in its cell entry via ACE2 receptors. It turns out that, at least in the prostate, TMPRSS2 is made when male hormones bind to the androgen receptor. When researchers looked at patients on androgen-deprivation therapy, drugs that drastically reduce levels of testosterone (commonly used in prostate cancer), they found patients were only one quarter as likely to contract COVID-19. The androgen suppressing drug degarelix is currently being tested in an RCT across several U.S. cities; it reduces prostate expression of the TMPRSS2 gene to nearly nothing. Biculatamide, another androgen blocker, is also being studied. It is thought that these drugs may decrease the viral load in patients. Finasteride and dutasteride, two FDA-approved drugs that block the conversion of testosterone to dihydrotestosterone (DHT), were also recently flagged in a screen to find drugs that reduce ACE2 receptor (required for SARS-CoV-2 infection) levels in heart cells.
The worldwide effort to mine already approved drugs with potential COVID-19 therapeutic capabilities has resulted in the creation of Covid19 Registry of Off-label and New Agents or, CORONA, a central repository of information about repurposed drugs. Currently, the database consists of 14 therapeutic categories, containing 115 reported treatments. A systematic literature review revealed that the drugs most frequently given include antivirals, antibiotics, and corticosteroids (this does not mean that these drugs work the best). The goal of the project is to identify which drugs require more rigorous study. COVID-19 is not expected to disappear and life is unlikely to return to normal until herd immunity emerges. In the meantime, the challenge will be finding safe and effective treatments and ensuring availability on a very abbreviated timeline.
Dexamethasone and Its Potential as a COVID-19 Treatment
Throughout June, there has been growing excitement that a cheap, commonly used steroid drug called dexamethasone could be used as a COVID-19 treatment for those seriously ill with the disease. In a large trial conducted by Oxford University, dexamethasone cut deaths of COVID-19 patients on ventilators by about one-third.
According to the investigators, dexamethasone is the first treatment that has been shown to reduce the mortality rate of COVID-19 patients. Many physicians have enthusiastically run with these findings and are already incorporating dexamethasone into their treatment regimes. Other physicians, however, are wary of how quickly dexamethasone is being adopted. After all, we jumped on board with hydroxychloroquine earlier this year after optimistic early reports, only to find that the treatment actually does no good and could potentially harm COVID-19 patients.
Either way, there are growing concerns about whether our supply of dexamethasone will be enough to meet our needs. Dexamethasone is an established drug that is readily available, but with the increased demand, it could potentially run out. Additionally, people are already exhibiting hoarding and speculative procurement behavior, and if this continues, physicians may not be able to access the drug for patients who really need it.
Overall, dexamethasone is a promising treatment that well may reduce the COVID-19 death toll. We just have to rein in our hoarding tendencies, keep an eye on the statistics to make sure the effects continue to be positive, and amp up production so that we can have dexamethasone available for any patients who need it.