As the global count of COVID-19 cases continues to climb, researchers, scientists and drug makers are working quickly to find a potential treatment. Several clinical trials are currently underway to find drugs for hospitalized COVID-19 patients, and many companies are working to develop vaccines.
Finding safe and effective treatments for COVID-19 is critical to preventing more deaths, keeping people safe and reopening economies around the world.
One of the researchers who have joined the fight against COVID-19 is Dr. Hooman Noorchashm, a cellular immunologist, thoracic surgeon and patient advocate. Noorchashm has been studying the immune system for years and has received grants for past research from the National Institutes of Health.
He has assembled a team of international experts, including medical professionals from Novartis, Baylor College of Medicine, University of Pennsylvania, Iran and India, in an effort to highlight the potentially important role of the generic immunomodulatory drug cyclosporine in preventing critical illness in COVID-19 patients.
According to Noorchashm, the drug has the potential to block progression of COVID-19 disease and is a well-established, generic drug used successfully to treat other diseases for decades. He has filed a request for an emergency use authorization (EUA) with the U.S. Food and Drug Administration and hopes to start using the drug in trials on noncritical, hospitalized COVID-19 patients.
In this Q&A, Noorchashm explains the process of developing drugs for COVID-19, how COVID-19 leads to fatalities, the research on cyclosporine and what consumers can expect from potential treatment candidates.
Q: Because of the urgency of developing treatments for COVID-19, the FDA has issued emergency use authorizations (EUA) for certain medications and medical devices used to treat the disease. Can you explain what an EUA is and what the process is for obtaining one?
It’s useful to think of an EUA as kind of a temporary FDA label to use a known drug for a new disease indication. Typically, EUA approvals are granted to establish efficacy for a new use in an emergency situation. Of course, for an EUA application to be approved, FDA’s Center for Drug Evaluation and Research (CDER) requires good scientific justification and a reasonable clinical safety justification — either based on phase 1 trial (i.e., safety trial) or based on reasonable precedent in the literature or in clinical experience. In other words, for an EUA to be issued to determine efficacy of a known drug for a new indication, typically FDA needs to first be convinced that there is a real emergency situation and that the drug in question is reasonably safe to use.
Q: The FDA has rigorous testing and clinical trials for drugs that may take years to determine safety and effectiveness. During a pandemic, regulators and researchers have had to alter this process. In this case, you are an advocate for real-world data (RWD) collection. Can you explain what RWD is and how it’s being implemented to develop a COVID-19 treatment?
Well, under normal nonemergency circumstances the gold standard is to perform well-controlled, well-powered, randomize prospective clinical trials. I totally agree with this approach. Such trials are the gold standard in evidence-based medicine because, in theory, they reduce the probability of biased conclusions and give us a best opportunity to establish both safety and efficacy of therapeutics, be they drugs or medical devices. But these kinds of trials are incredibly time and resource intensive, some taking years to complete. Obviously, in the case of the current pandemic, we don’t have the luxury of time with thousands of people dying across the world daily and many economies starting to falter. So, we have to intelligently re-evaluate our approach to triaging treatments. Taking a few lessons from combat medicine may be wise, but I digress.
Even now, in this global health emergency circumstance, it’s important not to abandon science. What’s important now is identifying critical therapeutic targets based on our best scientific understanding of the disease process, assessing our existing arsenal of drugs to match up the best scientific fit to hit the target and then efficiently assessing both safety and efficacy of the drugs.
The 21st Century Cures Act, passed into law in 2016, provided a clear mechanism for rapid and efficient evaluation of drugs (and devices) in the exact public health catastrophe the COVID-19 pandemic is posing. That is the use of real-world data (RWD) and real-world evidence (RWE) to establish safety and efficacy. These mechanisms allow for real-time collection of safety and efficacy data under the exact type of time- and resource-limited circumstance we are in now.
The idea is that if there is a threshold level of scientific and clinical rationale for deploying a drug (or device) against a disease, FDA is well within its legal jurisdiction to provide an EUA approval based on real-world data and evidence. In other words, clinicians can be authorized to use a drug (or device) for an off-label use, while collecting both safety and efficacy data using parameters negotiated with FDA’s CDER. The data collection could be easily streamlined and use simple and novel data collection systems to acquire the necessary information quickly.
Q: In the case of COVID-19, researchers have found that some people become sicker than others. One of the theories is that SARS-CoV-2, the virus that causes COVID-19, causes a hyperimmune response called cytokine storm. What is cytokine storm, and how does it relate to your research with cyclosporine?
It’s become increasingly clear that SARS-CoV-2 has a specific “kill mechanism” that has been causing many thousands of deaths daily across the United States and abroad. Scientific data is pointing to the fact that this kill mechanism is a hyperimmune response the virus triggers. This leads to production of a lot of “inflammatory juices” called cytokines by the cells of the immune system — predominantly, by cells known as T-cells and macrophages.
When this kind of hyperimmunity leads to enough cytokines being produced in a COVID-19 patient, a syndrome known as cytokine release syndrome (CRS) or “cytokine storm” is caused. Cytokine storm is a life-threatening illness that can lead to respiratory failure and multi-organ system failure. If the hyperimmunity isn’t cooled-off, the cytokine storm can kill the patient — as it does in somewhere around 1 to 5 percent of COVID-19 patients.
Cyclosporine is a generic and vastly available drug that’s traditionally been used to dampen a spectrum of different hyperimmunity diseases. In fact, it does so by blocking a central pathway in T-cell and macrophage activation, known as the calcineurin pathway. Most importantly, as it relates to the cytokine storm syndrome caused by SARS-CoV-2, cyclosporine is one of the main drugs that has been used for many years to treat other types of cytokine storm syndromes.
When it comes to blocking the T-cells and macrophages that cause cytokine storm, cyclosporine is mechanistically and clinically very specific. We should already be testing or using it to block COVID-19 hyperimmunity.
Q: How did you come to identify cyclosporine as a potential treatment candidate for COVID-19?
As a cellular immunologist and prior heart and lung transplant surgeon, I am very familiar with cyclosporine. I’ve prescribed it and its sister compound tacrolimus to many patients over the years. This drug is a generic drug that can be delivered in both intravenous and oral forms. It is used to prevent organ transplant rejection and really transformed that field of transplantation in the 1970s by cooling off the immune response to the transplanted organs.
It is also used in several other common disease processes where the immune system flares, including ulcerative colitis, lupus and rheumatoid arthritis. In all these cases, it does so by dampening T-cell and macrophage responses. Of course, as I mentioned before, cyclosporine is also an effective drug against two specific cytokine storm syndromes caused by macrophages and T-cells: hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). These latter two are rare diseases that are providing a window of insight into this drug’s potential use for COVID-19 cytokine storm. So really, as soon as it became clear that SARS-CoV-2 is causing critical illness by inducing a T-cell and macrophage mediated cytokine storm, cyclosporine should be front and center in the minds of every reasonable clinician as a defensive drug to dampen the deadly disease.
Cyclosporine has a widely established safety profile. It’s been around for nearly 40 years now and is a generic drug used for the indication I described before. In fact, probably millions of people are currently taking this drug across the world daily in oral form for one reason or another. Its main side effects with long-term use (i.e., on the order of months to years) are kidney failure and uncontrolled hypertension. With very long-term use it’s also been associated with development of certain skin and blood cancers, but we’re talking with many years of use for these adverse events to be seen. Really this drug has an excellent safety profile for long-term use as an immune dampening drug targeting T-cells and macrophages. For the type of short-term use we could anticipate using to treat COVID-19 disease, the safety profile is expected to be even better.
In terms of scalability, not only is cyclosporine a generic drug, it’s not a biologic. It’s one of the most abundant and easy to produce drugs in the global arsenal, which can be used in intravenous and oral forms. From the cost and scalability perspectives, this drug can easily be scaled to a global level in developed and developing nations. Unlike some biologic alternatives like anti-IL6 which are very expensive, unavailable on a mass scale and time consuming to produce en masse, cyclosporine is readily available and can be distributed rapidly and distributed globally — including to developing nations.
Q: In recent media, we’ve heard a lot about hydroxychloroquine, a malaria and lupus drug that was an early potential treatment for COVID-19. How does cyclosporine compare to hydroxychloroquine?
Hydroxychloroquine was basically chosen as a candidate drug by FDA and others based on studies that originally came from China. The recent data indicating that this drug may be harmful to critically ill patients is very concerning, but since FDA has gone down this path of testing this drug’s efficacy, I think we’ll find out. My prediction is that hydroxychloroquine will be proven ineffective or even harmful in the treatment of COVID-19 disease, but we will see.
What it comes down to is that the original choice of hydroxychloroquine was not based on verifiable science, mechanistic clarity or even reasonable clinical precedent. On the other hand, in all those categories, cyclosporine is a seriously logical choice to be assessing.
Q: There are bound to be a lot of stories coming out about potential treatments for COVID-19, and it can be overwhelming for a consumer. What should consumers keep in mind when they hear about potential treatments?
Unfortunately, patients are in between a rock and a hard place with COVID-19. There is some good news, though. The truth is that the majority of people don’t get sick from SARS-CoV-2. So that should be reassuring. Of the folks who do get sick, most recover. That’s good too.
But because the number of people susceptible to this virus is so large, even a 1 to 5 percent mortality risk from critical illness means that our hospitals and our society can take a catastrophic blow. So it’s critical for people to understand that the immediate target of treatment should be keeping patients out of getting critically ill and ending up in the ICU.
As of right now, there are no known effective treatments to keep people from getting critically ill. But any patient with COVID-19 illness who is not improving or is worsening ought to consider any clinical trials being offered to them. Really, the Achilles heel of this pandemic is going to be blocking patients from getting into a cytokine storm situation and becoming critically ill. The body can take care of the rest very well.
Disclaimer: Views, thoughts and opinions expressed in the Q&A belong solely to the interviewee and not necessarily to the author, editor or Drugwatch.com.
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