The Hunt for a COVID-19 Cure

A little refresher: SARS-coV2 is the RNA virus that infects our respiratory tract cells and causes the illness COVID-19. COVID-19 can lead to Acute Respiratory Distress Syndrome (ARDS), a chronic condition often requiring ventilator intervention and resulting in a mortality rate of up to 40%.

So naturally our healthcare teams are doing everything they can to try to prevent patients from getting to that stage. And that means both trying medication regimens typically used for other purposes and exploring novel therapies. 

Source: SMBC

It's really important to note that anecdotes aren't data though and the only way to be sure that a medical intervention actually works is to have a well-designed clinical trial. So what is a clinical trial? How do we get from a chemical compound in the lab to a drug that can be safely and effectively administered to human beings?

Source: NIH.gov

It all begins with preclinical (aka prehuman) research. A drug is discovered and tested in labs on cells in tissue culture and animal models of human disease. If it appears the drug has a positive effect on the disease outcome in these models, then the drug can begin study in a phase 1 clinical trial. (Note that it can take years to get out of the preclinical phase.) Phase 1 trials are small and designed to answer questions of safety and optimal dosage. They typically take a few months to complete. According to the FDA, about 70% of compounds that complete a Phase 1 trial will move onto Phase 2. Phase 2 is designed to test the efficacy of treatment (how many people get better and by how much?) as well as identifying side effects. This stage can last anywhere from a few months to a few years. Assuming the balance of efficacy versus side effects is favorable, the drug proceeds to Phase 3 (about 33% of drugs). Phase 3 trials are the largest and longest (1-4 years) and  focus on collecting more data about efficacy and safety in preparation for approval by the FDA. This is why it is not unusual for it to take a decade or longer for new treatments to come on the market.

I know what you're thinking. HOW CAN WE WAIT 10 YEARS FOR A TREATMENT?!? Quarantine's been less than a month and it already feels like the world's gone mad...

Try not to freak out, take a deep breath and consider this... It probably won't take 10 years to find something effective at combating COVID-19 for a couple of reasons. First and foremost of which is that traditional protocols tend to be broken during an epidemic. We saw this with the frantic and heroic efforts to find an effective Ebola vaccine after the 2014 outbreak. In just about a year, 12 clinical trials from phase 1 to phase 3 were completed. The vaccine was distributed for compassionate use during the 2018 outbreak and the FDA gave their final approval in December 2019. At present, research is already underway to develop a SARS-coV2 vaccine without the typical animal testing phase - at least half a dozen candidates in fact. (For more information about vaccine efforts, click here, here, here, here, here and here.)

Source: The Economist

Second, there are already drugs in the pipeline so to speak. With the emergence of SARS-coV, MERS-coV, and Ebola as real global threats, efforts to find drugs that affect RNA virus replication have been underway for sometime. One such drug that was discovered post 2014 Ebola outbreak is remdesivir. This intravenous drug works by inhibiting the enzyme necessary to replicate virus RNA. Remdesivir showed lackluster results in Ebola trials compared to other candidates so it was dropped. However, subsequent research suggested that it could be effective against coronaviruses. Clinical trials are already underway and results are forthcoming. (For more information about remdesivir, check here, here, here, here and here.) 

And finally - if not the most talked about strategy - is the fact that drugs currently approved for other illnesses are being evaluated for effectiveness in treating COVID-19. The practice of "off label" prescribing is not that unusual in medicine it turns out, though often (about 73% of the time) with little to no scientific evidence to support that use.

Source: Stanford University, 2006

Remember all the hoopla about chloroquine and hydroxychloroquine? These are long-approved anti-malarial drugs known to have anti-inflammatory properties. They are the primary candidates being investigated through off label use for COVID-19. It's unclear that these drugs are really capable of breaking coronavirus replication cycles and the preliminary trial data is tepid at best (or suspect at worst). The French study touted by many only included a small number of patients and treatment categories weren't blinded - meaning the researchers could choose which patients got the treatment, thereby potentially skewing the results. Another alley being investigated is the use of ritonavir/lopinavir, a combination drug used to treat HIV infections - but to date, that seems like a dead end. 

Source: Chemical & Engineering News

Perhaps the most promising drug news is about a compound called EIDD-2801 (discovered at Emory University's Institute for Drug Discovery). Prior to COVID-19, it was being investigated as a therapy for influenza infections - still in the preclinical phase of research. Like remdesivir, EIDD-2801 inhibits viral RNA polymerase - but apparently through a different mechanism so the drugs may turn out to have complementary action. A paper released on April 6th in Science Translational Medicine seems to demonstrate effectiveness at impeding multiple coronaviruses' replication in cell culture, including SARS-coV2. And more excitingly - it appears to reduce lung damage and other symptoms in mice infected with SARS-coV and MERS-coV. It appears that EIDD-2801 (which can be administered in pill form) will begin clinical trials soon.

So what's the take-away from all this? Please don't get suckered by anyone claiming a wonder drug is right around the corner or overselling anecdotes (President Trump and Dr. Oz - I'm looking at you). But also know that a lot of smart, dedicated folks are working their asses off right now to find as many safe preventative and therapeutic treatments as they can. Maybe check out some of their Twitter feeds to stay up to date: Kizzmekia Corbett, Timothy Sheahan, Angela Rasmussen, Amesh Adjala, Tom Inglesby to name just a few. Until next time...

Let's be careful out there.