The Yin and Yang of COVID-19 Clinical Trials
Well, it looks like we are flattening the curve! Unfortunately, it’s the wrong curve which is the exponential increase in COVID-19 clinical trials. By our assessment, as of this past weekend, there are a mere 2,653 trials on COVID-19 registered on www.clinincaltrials.gov, a figure not palpably different from a few weeks ago. As we have reflected in a past COVID-19 Corner, it is still the Wild West out there in the scope and bravura of design and ingenuity of many of these trials and with this push, our excitement and expectations are justifiably high but today we want to focus on potential harms.
Given that, as of this moment, there are over 35,000 COVID-19 articles that have been put into the public domain we clearly recognize that we are seeing only the surface of a stormy sea and our eyes are merely catching an occasional white cap to focus on. So here are some things to think about this week:
In Ancient Chinese philosophy, yin and yang is a concept of dualism, describing how seemingly opposite or contrary forces may actually be complementary, interconnected, and interdependent in the natural world, and how they may give rise to each other as they interrelate to one another. This principle is timeless and we think aptly applies to COVID-19 trials. We will share with you several examples that we hope you keep in mind as you filter the flood of information about new and current trials you will be hearing abut in the months ahead.
When you mess with the immune system, we must remember that there are no free lunches. As we re-examine the idealized course of COVID-19 below we continue to focus on Act 3, the phase where it is believed that most of the end organ damage is mediated by unbridled inflammation from cytokine release and a space we are experimentally treating with a myriad of immunomodulatory agents. We must now recognize more than ever that there are risks with each and every therapy on the drawing board. We as rheumatologists are acutely aware that all of our targeted therapies come at a cost of increased serious infections and that has been clearly documented in the IL-6 experience in rheumatic diseases (1) and not surprisingly already observed in COVID-19 trials (2). Accordingly, we strongly believe we should expect a similar adverse infectious signal with other targeted therapies now in clinical trials including TNF inhibitors, JAK inhibitors, glucocorticoids and beyond. On the bright side it has been postulated that IL-1 inhibitors may be a safer space in this regard, especially in the case of anakinra (3) which has an extremely broad therapeutic window. We shall see.
Host Antiviral Response
If we re-examine the idealized course of COVID19 just focus on Act 1 (Figure below) for a moment which is the essential phase of the infection where individuals generate an effective innate immune response which is mediated in part by a brisk interferon response via TLRs and other PAMP recognition response units (i.e. RIG, NOD, c-GAS/STING, others). We have already commented in earlier reflections that COVID-19 appears to usurp this system at the molecular basis and thus it is already compromised. Now consider the 15 plus clinical trials exploring JAK inhibitors as well as other kinase inhibitors (BTK, PI3K and others). Our concern relates in particular to JAK inhibitors which theoretically may be particularly risky given their capacity to inhibit canonical and non-canonical IFN activation pathways via JAK1, JAK2 and TYK2. Many others have also echoed concerns that JAKi given too early in an evolving infection may further compromise an already flailing anti-viral response. Safety studies focusing on the off-target effects of JAKi via monitoring IFN levels and gene transcription as well as measuring quantitative viral loads are critically needed and yet none have thus far been reported to our knowledge.
“Non-Immunologic” off-target effects
Finally, Puja Mehta and her UK colleagues have just this week written an opinion piece (4) calling on a need for vigilance regarding increased thrombotic risks in clinical trials employing the JAKi class of drugs. We as rheumatologists are all too familiar with this concern though we are as of yet still uncertain of the mechanism of this putative risk. Currently unanswered is the question whether the palpable increase in VTEs in our RA trials are an off-target effect of the class or are the observed increases an effect from confounding by indication in which we are observing clotting in our inflammatory diseases which may merely be enriched substrates for such complications. Regardless, in COVID-19, the incidence of pulmonary emboli alone has been estimated to be as high as 1 in 4 in overall and as high as 1 in 2 in the ICU. Vigilance is clearly needed.
So as we start to look at maybe the 4th inning of COVID-19 it may be time to think defense as well as offense. This is our take this week. Give us yours.
Leonard H. Calabrese, DO, is the head of the RJ Fasenmyer Center for Clinical Immunology and Vice-Chair of the Department of Rheumatic and Immunologic Diseases at Cleveland Clinic Dr. Calabrese has lectured nationally and internationally on the subjects of immunology, rheumatology, and viral diseases. He is the author of more than 400 published peer-reviewed articles, book chapters, and reviews. @LCalabreseDO
Cassandra Calabrese, DO, is a staff physician in the Department of Rheumatic and Immunologic Diseases and the Department of Infectious Diseases at Cleveland Clinic and directs the combined Rheumatology-Infectious Disease training program. She also directs the Clinic for immune-related adverse events form cancer immunotherapy within the department of Rheumatic and Immunologic Diseases. @CCalabreseDO
1. Stefan Rose-John, Kevin Winthrop & Leonard Calabrese The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nature Reviews Rheumatology volume 13, pages399–409(2017)
2. Lucas M Kimmig et al., IL6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections https://www.medrxiv.org/content/10.1101/2020.05.15.20103531v2
3. Leonard H. Calabrese, Cassandra Calabrese, Cytokine release syndrome and the prospects for immunotherapy with COVID-19. Part 2: The role of interleukin 1 Clev Clin J Med (online) https://www.ccjm.org/content/early/2020/07/01/ccjm.87a.ccc044
4. Mehta P, et. Al JAK inhibitors in COVID-19: need for vigilance regarding increased inherent thrombotic risk European Resp Jorn July 2020 (on line ) https://erj.ersjournals.com/content/early/2020/07/02/13993003.01919-2020