Conquering COVID Part 1.2:
“Drug Repurposing” clinical studies are happening right now!
(aka Hydroxychloroquine, Tocilizumab … & even Viagra Versus COVID-19?)
March 23, 2020
by Mark A. Moyad, MD, MPH
“I am concerned, of course, but I am also incredibly optimistic.”
Howdy! Did you miss me? I missed you very much, and even though it has only been 5 days since the last update there is a lot happening and I want to share things with you, so let us get right down to business. One of my favorite unsung topics in cancer research and general medical research itself is known as
“drug repurposing.”
We should advocate for more drug repurposing research throughout medicine, including within cancer treatment.
Drug repurposing is exactly what it sounds like - a drug with a specific well-known purpose, say aspirin, may have another less recognized purpose or benefit in doing something else quite wonderful after further clinical research. For example, aspirin was known to help with aches and pains and now we know it has the potential to reduce the risk of cardiovascular events, such as heart attacks and strokes, and it also appears to reduce the risk of colorectal cancer (for those who qualify). Thus, aspirin represents a repurposed drug that has already helped many people. Additionally, aspirin is being studied in the U.K., Ireland, and India in a fabulous large phase-3 clinical trial known as “ADD-ASPIRIN” (for more information see
addaspirintrial.org
). Women and men treated with conventional curative therapy for a variety of earlier stage cancers (including breast, colon/rectum, stomach or esophagus, and prostate cancer - up to 11,000 being recruited) are then placed on aspirin (100 mg or 300 mg) or placebo to be taken for at least 5-years to determine if it can reduce the risk of cancer recurrence (coming back after the conventional treatment). How exciting is that!
Other generic drugs including statin drugs, and metformin are also being tested in numerous clinical studies to prevent many diseases from coming back or progressing, including several cancers. The good news is that statins and/or metformin have already long ago proven themselves to reduce the risk of cardiovascular events (in the case of statins) and type 2 diabetes (metformin). Even some blood pressure drugs are being utilized in clinical trials including beta-blockers to determine if they can slow the growth of some cancers based on recent evidence (De Giorgi V, et al.
JAMA Oncol
February 8, 2018).
The beauty of some of these aforementioned drugs is that they are cheap and generally heart healthy in the right people (they reduce the risk of cardiovascular events - heart attack and strokes, even if they do not work against cancer). This is the dream - cheap, safe, or even heart-healthy, or generally healthy drugs/medications that can help prevent or fight a disease that currently has no perfect solution. This is the game of win-win. I think you get my belabored point. Yet, this does not imply whatsoever that drug repurposing is without some side effects, which is why just guinea pigging these drugs is dangerous. Ergo (I love that S.A.T. word), with
what I just discussed as background let us move on as to why this topic of drug repurposing is so critical in the battle against COVID-19.
When I wrote about the 100 or so clinical studies being initiated in the last COVID issue (part 1.1) there was not enough space to write about all the research going on right now with potential drug repurposing against COVID-19. The first shot of drug repurposing against COVID-19 was a slight miss, a well-known HIV treatment drug (lopinavir/ritonavir) did NOT appear to work. It had no significant impact on clinical outcomes and basically did not reduce viral RNA levels among patients with serious cases of COVID-19. The HIV drug appeared to be as safe, in general, as the standard-of-care group (comparison control group), but just not more or less effective. This does not suggest this drug has no role with COVID-19 since the possibility of combining it with other anti-viral drugs (aka drug cocktail) is still being considered in other studies. This latest research paper was just published in the
New England Journal of Medicine
(Cao B, et al., March 18, 2020). Still, the ability to almost immediately construct, coordinate, and report the results of such a high-quality clinical trial in such a short time under such stressful conditions helps current research teams with a beautiful blueprint of how to do things now and in the near future.
Next up, one malaria drug used for as long as I have been alive known as “hydroxychloroquine” (also known as “plaquenil”). Wow! Arguably, there has been more talk about repurposing this drug (with or without azithromycin) compared to any other drug. The good news is that this malaria drug has a long track record of success and general safety in the people that need it, and azithromycin even has some interesting preliminary research in other conditions that it could enhance the immune system’s anti-viral responses (Schogler A, et al.
Eur Resp J
2015;45:428-439) despite being an antibiotic, but the bad news is that there are no rigorous studies suggesting these drugs work against COVID-19.
However, there are several initiated clinical trials already underway, including one starting in New York tomorrow!
Yes, tomorrow! There are two issues with taking it right now without evidence, and the first is that there needs to be a large enough supply for people who are very sick with COVID-19, if the drug ends up working. In other words, this is not like toilet paper folks! You buy up all the toilet paper in the store and I am not happy because other people cannot access it. Still, I will be okay because I have plenty of smooth leaves around my house. On the other hand, you start reducing the drug supply from the people that need them now (for example some patients with Lupus or Rheumatoid Arthritis use it for their condition) or will need them first and foremost in the near future (COVID-19), if these drugs work at all, then there are greater issues here! It is also for this reason that many experts did not want masks or tests to be utilized by people that did not need them. I call this
public health triaging
, which is trying to do the most good for the most people with the greatest immediate need. The second issue with hydroxychloroquine
(and even azithromycin)
are the potential side effects in healthier people could turn out to be problematic, even if there is a “low rate” of them from other studies. There are cardiovascular, as well as other side effects, including drug interactions, that I do not want to elaborate on to scare you, but rather to understand that the pros and cons need to be weighed and this is assuming it gets some objective positive news. Still, this would be a great story if it shows some efficacy because mass production would be easy with these pills, and it is inexpensive.
Interestingly, the rheumatoid arthritis drug “sarilumab” (also known as “Kevzara” from Regeneron & Sanofi) is now entering a clinical trial for patients hospitalized with severe COVID-19 infection. This drug is a human antibody that blocks the interleukin-6 (IL-6) pathway via inhibiting the IL-6 receptor. What does that mean? IL-6 is a compound produced during inflammation and some patients with COVID-19 who are in critical condition appear to have an overactive inflammatory response, especially in the lungs
. It is not that the body cannot react to COVID-19 but, in some cases, it is the overreaction that is the issue
. Perhaps reducing this excessive immune system response could improve the health of patients and save lives. A recent single observational study from China (Xiaolong Xu MD, et al. from the First Affiliated Hospital of the University of Science and Technology) suggested impacting this IL-6 pathway could potentially improve oxygenation and other clinical outcomes in COVID-19 patients.
There is also a drug known as “tocilizumab” (also known as “Actemra” from Roche/Genentech) approved in the United States for moderate-to-severe forms of active rheumatoid arthritis, and in children ages two and above with other specific severe forms of arthritis. It also blocks IL-6 (mentioned in the last paragraph), which assists in reducing joint pain and swelling and other symptoms caused by inflammation. It was given to 21 patients with severe COVID-19 in February and the researchers observed reductions in fever to normal and improved symptoms within several days along with a reduced need for oxygen intake. A total of 19 of the patients were allowed to go home after an average of 13.5 days of treatment. This is a preliminary observation and needs to get published in a peer-review journal. Interestingly, this intravenous drug was also approved on August 30, 2017 to reduce some severe side effects of immune therapy treatments in some cancer patients. The more recent or pertinent good news is that tocilizumab is now entering into a phase-3 clinical trial in the U.S. and around the globe, and this clinical trial is officially known as “COVACTA”. Other studies of this drug and COVID-19 have already started in Italy.
Ever heard of Viagra (sildenafil)? Okay, that was slight sarcasm. However, have you ever heard of Revatio? This is also the same active ingredient (sildenafil) that was later approved for Pulmonary Arterial Hypertension (PAH) many years after Viagra was FDA approved. It was given a different name because it is for a different clinical indication (see
revatio.com
). PAH is a situation where the blood pressure in the lungs becomes too high, and then your heart has to work much harder to get blood to the lungs. There is some old and new basic science research to suggest nitric oxide, a compound which sildenafil helps improve the action of, in different tissues of the body (including the lungs), could have some anti-viral activity (Akerstrom S, et. al.
J Virol
2005;79:1966-1969 &
Virology
2009;395:1-9). Boston researchers are also testing an inhaled nitric oxide device (not a pill) to see if it protects healthcare workers in terms of COVID-19. Still, this is a theory right now and a clinical trial has apparently already been launched in China to test this theory in just a small number of patients using sildenafil tablets.
Whether sildenafil (“Viagra”) or any of these related drugs help, or not, or even make things worse is not known right now.
This is why, again, you do not want to be a clinical trial of 1 and wait until we get more information soon.
The real take home point is that when dealing with a pandemic that currently does not have a definitive treatment option, then drug repurposing research becomes critical. We have thousands of drugs capable of doing thousands of things sitting on the sidelines, and basic science, in some cases, or even observational studies suggest some may have additional benefits. Again, until you have a cure for any disease then drug repurposing should always be considered. This is what is immediately happening for COVID-19, which is fabulous, and it is my hope this will also be the case for countless other diseases now and in the future.
In fact, another drug everyone seems to be talking about (as I am about to submit this column), is known as “remdesivir”, which is, in reality, another repurposed drug. It was tested for Ebola and was not effective and now it is in clinical trials for COVID-19 and will be reporting initial results potentially in the next few weeks!
Finally, I cannot overstate the importance of practicing social distancing! The so-called “curve” that we want to flatten is moving toward a crucial juncture, especially when comparing it to other countries having already dealt with and/or continuing to deal with COVID-19. This is our time to step up to help control/flatten the curve! For more immediate information on protective measures please go to the websites for the
CDC
or
WHO
. These sites also do a good job of also covering myths and misconceptions with this virus (aka what is B.S. or not).
Thank you for reading my latest installment and I wish you and your family the best of health.
I am concerned, of course, but I am also incredibly optimistic!
I look forward to modern day science and you of course, kicking COVID-19 and cancer in the gluteus maximus!
All of my best always,
Mark A. Moyad MD, MPH
Read my previous COVID-19 articles at:
