An Open Letter to the Honorable Dr. Anthony Fauci: On Testing and Use of Cyclosporine to Block Progression of COVID-19 Inflammatory Disease.

Dr. Anthony Fauci, Chief Medical Advisor to the Biden Administration and director of the National Institute of Allergy and Infectious Diseases has been made aware of the potential critical importance of cyclosporine for blockade of COVID-19 disease progression.

Dear Dr. Fauci,

I am writing here to inform you of an effort, since March of 2020, to bring attention to the generic anti-inflammatory drug, cyclosporine, on the COVID-19 therapeutic front. I am certain that Dr. Janet Woodcock has already brought this effort to your attention, as she has been in process since the beginning of this public health campaign.

I ask that you indulge my words here and read this letter, as I hope cyclosporine could become part of your thought process in bringing the pandemic under control with all immediate urgency.

CBS News initially covered the campaign to bring cyclosporine into the forefront of clinical trials in April of 2020. Since then, the resistance to testing this drug against COVID-19 disease has been shocking.

I initially approached FDA, in March 2020, with cyclosporine as a potential block to COVID-19 disease progression, in collaboration with my good friend (and mentor), Professor Carl June at the University of Pennsylvania.

Back in March 2020, our proposition to focus on cyclosporine was a direct result of the basic immunological phenotype emerging from patients with COVID-19 disease, indicating that a hyper-inflammatory state in these patients is tightly correlated with a phenotype of T-cell and macrophage hyper-activation.

Because, cyclosporine selectively inhibits T-cell and Macrophage activation via the Calcineurin pathway, we projected that if applied after 5–7 days of unremitting or worsening COVID-19 disease, the drug would block progression to critical illness — by selectively dampening activation of T-cells and Macrophages.

Additionally, the vast and inexpensive availability of this generic drug in the US and abroad, made it a very attractive candidate for immediate testing. As I argued in a prior writing, “In the COVID-19 Pandemic, A Solution For Some Of Us, Is Not A Solution At All”. Cylcosporine, as you know is immediately and inexpensively available at literally every corner pharmacy in America.

I would be remiss if I do not grumble here, that for the past ten months, two main barriers have blocked progress in efficiently testing cyclosporine against COVID-19: 1) the drug’s “generic” status does not make it sufficiently lucrative to any powerful corporate entity to properly invest in lobbying for adequate clinical trials and 2) the drug’s FDA black-box label designation as an “immunosuppressive” has created an insurmountable intellectual silo for many treating physicians and clinical “trialists” not familiar enough with this specialty drug— simply, many of our colleagues are “gun shy” about using what they view, erroneously and in an exaggerated way, as a “powerful immunosupressive” drug, against what they view as primarily being a viral disease.

But COVID-19 disease is an inflammatory disease driven by T-cells and Macrophages — and cyclosporine selectively dampens the activation of just these cells. Of course, it is an interesting side note to know that cyclosporine has also been shown to inhibit replication of Coronaviruses, including SARS-CoV-2.

Dr. Janet Woodcock, now acting FDA commissioner, has been aware and engaged with the effort to get cyclosporine tested and deployed against COVID-19 disease. Despite her prominent position in the trump administration’s OWS, she too has experienced major stumbling blocks in doing so.

Of note, Dr. Woodcock at FDA is aware of both the above mentioned artifactual challenges to cyclosporine’s urgent testing against COVID-19 in the United States (i.e., being a “generic” “immunosuppressive” agent). And I believe she has done her very best so far to mobilize FDA and NIH resources to stimulate proper clinical trial of this inexpensive and highly accessible generic drug.

To make my point very clear, last week, another striking paper in the journal Nature, demonstrated that the COVID-19 pneumonia, responsible for killing over 400,000 Americans now, is characterized by a dominant accumulation of activated T cells and Macrophages in the lungs of these patients. You may read this paper, HERE.

That cyclosporine is one of the classical staple drugs in our “generic” arsenal capable of selectively dampening activation of these culprit cells, makes it an inevitable choice for being very seriously considered as an inexpensive and scaleable therapy against progression of COVID-19 inflammatory disease. Yet it is simply shocking this has not yet occurred in the United States!

I am sure you are aware that, historically, cyclosporine revolutionized the treatment of an array of T cell and macrophage medicate hyperimmune pathologies, in both the inpatient an outpatient settings: from organ allograft rejection, to the treatment of autoimmune diseases, to the treatment of adult and pediatric hyperinflammatory diseases, like Kawasaki’s disease and HLH. Simply, this drug is a staple agent for dampening diseases that involve T-cell and Macrophage hyperactivity. Moreover, what is striking about cyclosporine is that it does NOT directly inhibit B-cells, Antibody-Secreting Cells, or Plasma Cells — nor does it “ablate” T cells or entirely inhibit their ability to provide T cell help in Germinal Center reactions. So it is very likely that cyclosporine (unlike JAK Inhibitor drugs), when used in patients with unremitting or worsening symptoms , will not inhibit antibody production in response to SARS-CoV-2.

Professor Carl June has been leading a Phase 1 clinical trial of cyclosporine at Penn since June 2020. This trial aimed to enroll 20 patients and has been progressing too slowly. Despite Dr. June’s concerted efforts at Penn, as of this writing the trial is on hold at 10 patients enrolled, for an internal audit by that institution’s administrators— in a setting where over 400,000 Americans are dead.

I’d like you to know that two studies published in Lancet and the Journal of Internal Medicine from Spain and Central America, respectively, have shown a very strong survival signal in COVID-19 patients treated with cyclosporine.

Dr. Janet Woodcock (FDA), Dr. Peter Kim (NIH)and Dr. Stacey Adam (NIH) have all been made aware of these studies, and others indicating a strong rationale for immediate testing and deployment of cyclosporine against COVID-19 disease.

Additionally, a Phase 1 clinical trial of cyclosporine at Penn under professor Carl June’s guidance has been very slow to enroll patients, because of inadequate motivation and high level support from administrators, government and the press. Amazingly, the trial’s goal since coming on line in June 2020 has been to enroll 20 patients! As of this writing the trial has enrolled only 10, all of whom were successfully discharged home without need for ICU care or any major adverse reactions. The trial is now on hold for an internal audit at Penn!

Professor Bryan Burt, chief of Thoracic Surgery at Baylor College of Medicine is leading a randomized Phase 2/3 clinical trial of cyclosporine for treatment of COVID-19 disease. The trial aims to enroll 75 patients and is currently underway.

A Phase 2/3 trial of cyclosporine is also underway by my good friend and colleague professor Bryan Burt at Baylor College of Medicine. This small trial aims to enroll 75 patients into a randomized trial and is funded by Novartis. The trial is currently underway in Houston.

In addition to collaborating with Drs. June and Burt, I’ve also focused on stimulating FDA and NIH to quickly engage in testing cyclosporine. So far, this effort to stimulate large scale testing of cyclosporine under the trump administration was unsuccessful — despite the direct involvement of Dr. Janet Woodcock in the discussions surrounding this therapeutic option. I do believe that under the Biden administration, reason, logic and scientific cogency will finally prevail in fully highlighting the potential critical utility of cyclosporine.

Generic Drug Could Be 'Overlooked Therapy' For Coronavirus

I’ve been privileged by my friendship to a few prominent members of the press over the years — and, in particular, because journalists at CBS News, The Philadelphia Inquirer, The New York Times and The Wall Street Journal have been listening and looking at the campaign to initiate testing and use of cyclosporine.

Both CBS News and the Inquirer have already covered the effort directed at testing and use of cyclosporine. And I know that others at the WSJ and the NYTimes are looking at this drug with keen eyes.

Here, on this new day for our nation, I am writing to directly inform you that based on the immunological fingerprint of the hyper-inflammatory disease caused by SARS-CoV-2, which involves T-cell and Macrophage hyper-activation, it is nearly certain that cyclosporine is a lock-and-key therapeutic agent for COVID-19 hyperinflammation. I suspect that when used to treat patients with 5–7 days of unremitting or worsening COVID-19 symptoms, this drug will block progression of disease to critical illness, in a substantial proportion of the ill.

Dr. Fauci, the fact that we’ve had so much difficulty rapidly and urgently testing cyclosporine is a testament to two critical problems in our national approach to COVID-19: 1) the trump administration’s haphazard and financially/politically charged and non-scientific orientation towards identifying and testing therapeutic agents (e.g., HCQ, etc), and 2) a severe market failure in ignoring the existing “generic” drugs in our arsenal in favor of “trademarked” and “monied”, but entirely non-scaleable and at time irrational, options.

As I have shared with my my good friend, Dr. Janet Woodcock, I strongly suspect, as an immunologist with good experience in the science behind cyclosporine and its clinical use, that ignoring this drug will turn out to have been a major strategic national health security blunder in this pandemic.

We all know that “silver bullets” are rare in medicine. But there are also very profound examples of drugs that very effectively treat or interrupt progression of various disease processes. I want you to know that from an immunological perspective, it is highly likely that cyclosporine is just such a drug to COVID-19 disease.

I write you here for the record, in friendship as a colleague and one whose career as a clinician-scientist, motivated my own in the 1990s while I was an undergraduate intern at the LTCB with Dr. Bob Gallo’s group — and I write in hopes that as this pandemic continues to surge and as the virus flirts with dangerous mutations, you might now be able to very seriously focus on the potential of cyclosporine to block progression of COVID-19 disease.

America continues to lack an inexpensive, scaleable and effective therapy against the T-cell and macrophage hyper-immunity triggered by SARS-CoV-2….I suspect you, Dr. Fauci, will not be sorry when you and your colleagues drive cyclosporine into the mainstream of testing and use.

With respect, in friendship, and in defense of the United States,

Hooman Noorchashm MD, PhD.