An Open Letter to Drs. Anthony Fauci, Deborah Birx and Robert Redfield: On the Potential of Cyclosporine for Blockade of COVID-19 Disease.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), is the public health expert leading the fight against the COVID-19 pandemic in the United States.

Honorable Drs. Fauci, Birx and Redfield,

I write this urgent public letter to you in early Fall of 2020 regarding the high likelihood that the generic immunomodulatory drug, cyclosporine, will be effective in blocking progression of COVID-19 disease to critical illness.

Over 200,000 Americans are now dead due to complications of COVID-19 disease. And as Dr. Redfield has informed the American public, a reasonably safe and widely available vaccine against SARS-CoV-2 is still 6–12 months away. It could be that up to another 1,000,000 Americans will die tragically before an effective vaccine is available to induce iatrogenic “herd immunity”.

Dr. Robert Redfield, director of the Centers for Disease Control and Prevention is a leading member of the US Coronavirus task force.

Since March 2020, when it was becoming clear that COVID-19 disease is a hyperinflammatory disease involving a, likely, dominant role by Macrophage and T-cell populations, I started a focused discourse with the FDA’s Dr. Janet Woodcock, and the Wall Street Journal’s senior leadership — this, regarding the potential of immunosuppressive agents to dampen the inflammatory cascade that seems to be causing the deadly disease triggered by the SARS-CoV-2 virus.

The proposed general concept was that treatment of COVID-19 patients with established and vastly available generic immunodampening agents, prior to the onset of critical illness, would block progression of the disease process in a substantial number of patients.

Some of the clinical similarities between COVID-19 disease and the disease entity rheumatologists know of as Hemophagocytic Lymphohistiocystosis (HLH) are, indeed, striking — pointing to a dysregulated inflammatory response on the part of T-cells and Macrophage. Of course, HLH is quite effectively treated using immunosuppression with a combination of steroids and cyclosporine.

So, when the data emerged, from the United Kingdom, regarding the efficacy of dexamethasone for blockade of COVID-19 disease progression, it was simply proof-of-principle: that immunodampening therapeutics, applied early enough, can effectively protect many lives from SARS-CoV-2’s mortality risk.

Dr. Deborah Birx, a senior member of the White House’s COVID-19 task force, who in partnership with Drs. Fauci and Redfield is leading the US response to the COVID-19 pandemic.

Starting in March 2020, I had started to vocally communicate my strong clinical and scientific opinion, as an immunologist and physician, that the generic immunomodulatory drug cyclosporine has a high likelihood of blocking progression of COVID-19 disease to critical illness. My prognostication about cyclosporine was based on two specific mechanistic facts: 1) cyclosporine, through the Calcineurin pathway, specifically dampens the vigor of T-cell and Macrophage activation and 2) cyclosporine had previously been demonstrated to directly inhibit replication of Coronaviruses. Additionally, based on my knowledge of the immunology literature on this drug, I also recognized that cyclosporine is relatively weak at blocking B-cell and antibody responses, in general. Therefore, one could expect that this drug would have a minimal effect on the neutralizing antibody response elicited by SARS-CoV-2.

Dr. Vas Narasimhan, CEO of Novartis, along with his colleagues were made aware of the potential efficacy of cyclosporine for the treatment of COVID-19 disease in March 2020. Novartis is supporting a clinical trial of cyclosporine at the Baylor College of Medicine.

You likely know that, starting March 2020, I aggressively communicated in writing with Dr. Vas Narasimhan, CEO of Novartis, Dr. Janet Woodcock, chief of FDA’s CDER, and Messrs. Mark Maremont and Matt Murray, senior editors at The Wall Street Journal.

In addition, I communicated my strong opinion that cyclosporine testing for treatment of COVID-19 disease ought to be fast-tracked through federal trial mechanisms, to US Rep. Brian Fitzpatrick. At the time, Fitzpatrick was co-chair of the US House of Representatives’ COVID-19 task-force. Unfortunately, I received no support for this effort from Rep. Fitzpatrick’s office.

My good friend US Rep. Brian Fitzpatrick was informed of the public health effort to fast-track testing of cyclosporine for treatment of COVID-19 disease. He made no response to my many prompts on this issue.

As part of the effort to bring cyclosporine to the forefront of testing, since March of 2020, my colleagues and I submitted two separate formal Emergency Use Authorization (EUA) applications for its use in COVID-19 disease to FDA. Unfortunately, and I believe unreasonably given the well-established safety and efficacy profile of cyclosporine and the compelling scientific and clinical rationale present in these applications, both were rejected by FDA. These EUA rejections by FDA occurred despite Dr. Janet Woodcock’s stated opinion to me in an email that, it is “highly desirable” to test the efficacy of cyclosporine as a COVID-19 therapy.

Dr. Janet Woodcock, Chief of the Center for Devices and Radiological Health at the FDA. She was personally informed of the potential efficacy of cyclosporine for treatment of COVID-19 disease. She stated that it is “very desirable that cyclosporine be quickly tested for any impact in COVID-19 disease.”

Additionally, my vocal attempt to convince the Wall Street Journal’s leadership to break out of their “rear-view-mirror”, pre-COVID approach to journalism, also failed. My hope had been that given the compelling scientific rationale for immunosuppression to block COVID-19 disease progression, The Journal’s editors might be willing to take a chance on stimulating a broad nationwide discourse about this vastly available immunosuppressive drug for treatment of COVID-19 disease: a hyper-inflammatory, HLH-like disease, that was starting to ravage our nation. My hope vis-a-vis the investigative journalists at WSJ was that given the FDA leadership’s, Novartis’ and some very high level academic scientists’ recognition that cyclosporine holds great therapeutic potential, the editors might find justification to tell a story that would provide national academic traction. Unfortunately, they did not. Instead, a few good WSJ editors and reporters engaged me in a petulant war of words on email. It was truly shocking to see this level of astigmatism— especially from the high-level and respected journalistic outlet I know the WSJ to be. But also, particularly, because the past work I had done with these journalists should have given them a reasonable assurance that I was not just engaged in wishful thinking or presenting another far-fetched “hypothesis” — as WSJ reporter, Mr. Joseph Walker, stated to me in an email.

Notwithstanding, while attempting to get EUA approvals from FDA and doing my best to stimulate the WSJ to tell the story of this drug’s potential utility for treatment of COVID-19 disease, I started a conversation with my good friends and mentors at two major academic medical centers in the US: Drs. Carl June and Bryan Burt, at the University of Pennsylvania and Baylor College of Medicine, respectively.

Professor Carl June of the University of Pennsylvania is the lead investigator on a clinical trial of cyclosporine for treatment of COVID-19 disease.

Professors Burt and June both agreed that the similarities between COVID-19’s clinical features and that of HLH were, indeed, striking. They also agreed that the rationale for applying immunosuppression to block progression of COVID-19 disease to critical illness was compelling. They saw clearly that a combination of cyclosporine and steroids could be highly effective at blocking progression of COVID-19 disease — as it does in blocking progression of HLH.

After frustrating and lengthy administrative processes that took nearly all of Spring and Summer of 2020, Drs. June and Burt’s teams were able to independently secure IND approvals from FDA and initiated clinical trials of cyclosporine at Penn and Baylor. Still, despite being active, these trials have been extremely slow to accrue patients — in part because of obstructionist internal politics, and in part because these centers missed the COVID-19 surges in both Philadelphia and Houston.

Professor Bryan Burt, chief of the division of Thoracic Surgery at the Baylor College of Medicine is the lead investigator on a Phase 2/3 clinical trial of cyclosporine for treatment of COVID-19 disease in Houston, TX.

To summarize, the main idea driving these clinical trials is that adding a transient 7–14 day course of cyclosporine to the existing standard of care (i.e., Remdesivir and dexamethasone) in hospital patients with moderate COVID-19 disease (i.e., pre-ICU), would effectively block progression to critical illness and death in a majority of treated patients.

The Penn and Baylor clinical trials are now ongoing and can very certainly use strong support from your offices at HHS in order to progress more efficiently. At this late hour, I urge you to engage these groups and support them aggressively.

Additionally, I was fortunate to be in communication with physician colleagues in critical care medicine in Iran, at two distinct and large scale medical centers where COVID-19 was surging — one located in Tehran and one in the northern Iranian province of Hamedan.

These Iranian colleagues also quickly recognized the therapeutic potential of cyclosporine — and they agreed to initiate clinical trials of the drug at their centers for treatment of COVID-19 patients. These trials are also currently underway in Iran — having to deal with that country’s own administrative red-tape and inefficiencies, not so different from our own in the US.

Mr. Mark Maremont, senior editor at the Wall Street Journal, was informed of the potential efficacy of cyclosporine for treatment of COVID-19 disease in March 2020.

Nearly 7 months after the pandemic hit the United States and 7 months after my colleagues and I initiated our public advocacy for testing of cyclosporine as a COVID-19 therapeutic, we still have no answer.

Is cyclosporine reasonably effective, in combination with low dose dexamethasone, at blocking progression of COVID-19 disease to critical illness in a substantial proportion of hospitalized patients?

Over 200,000 Americans are dead as of this writing in September 2020. And the question I have for you, with the large numbers of our countrymen and women affected and many dead, is the following: Is it truly that difficult to more efficiently test promising therapeutics, like cyclosporine, with adequate federal support to promote efficient testing?

I know that the federal effort to create a vaccine is where a massive focus is being exerted by your group — and justifiably so. But you all know, as Dr. Redfield has stated in his testimony to the US Senate, that even assuming a reasonably safe vaccine is created soon, it will not be available to the general public for another 6–12 months. It is, therefore, critical that you quickly open the door to efficient testing of reasonable and scalable drugs that are highly likely to block COVID-19 disease progression — especially, those that are inexpensive and vastly available generic drugs, like cyclosporine.

Mr. Matt Murray is chief editor of the WSJ. He and his colleagues were made aware of the potential efficacy of cyclosporine for treatment of COVID-19 disease — as well as, the public health campaign to drive clinical trials and obtain EUA approval for use of this generic immunomodulatory agent as a therapy. The WSJ leadership’s refusal to give this effort any air-time to initiate a serious discourse, in early Spring 2020, despite a compelling scientific and clinical rationale in the face of devastating evolving pandemic was shocking.

Here, I write to ask that you please immediately consider the potential therapeutic benefit of cyclosporine plus dexamethasone in blocking progression of COVID-19 disease to critical illness — specifically in hospital patients, pre-ICU. As the Fall and Winter of 2020 place millions more Americans at risk of COVID-19 disease and death, we do not have a vaccine. But we must do everything humanly possible to test and utilize all scientifically and clinically cogent therapeutic agents — especially those that are generic, scientifically cogent and vastly available and inexpensive.

I strongly believe that in patients with moderate COVID-19 disease, pre-ICU, initiation of an immunomodulatory regime including dexamethasone and cyclosporine will save many lives. And I can only pray that you all will consider this possibility with care, as the leading clinician-scientists in charge of our federal response to COVID-19.

I predicted to my friend, Mr. Mark Maremont of the WSJ in a parting exchange, that it may be only after over 250,000 Americans are dead that our nation’s public health experts (and the press), will fully recognize that more aggressive and generically available immunosuppressive approaches, deployed early enough in the course of disease, will hold the key to blocking progression of COVID-19 disease to critical illness.

As we surpass the 200,000 dead mark, I cannot help but remember….that we are almost there.

Drs. Fauci, Birx and Redfield, with this public letter I ask for your focused consideration of cyclosporine’s potential therapeutic efficacy for treatment of COVID-19 disease — and I specifically request that you immediately and urgently engage Drs. June and Burt at Penn and Baylor, respectively, to help them execute their trials with all possible speed — and with all the federal level public health support (and publicity) possible. I suspect that Dr. Janet Woodcock will be able to brief you on the last 7 months’ effort to bring cyclosporine to the attention of our nation’s public health agencies and our academic medical leaders.

I am not arrogant enough to assume that cyclosporine will be the “silver bullet” against COVID-19 disease. But I have sufficient understanding of immunology and hyper-inflammatory diseases to know, with reasonable certainty, that a combination of cyclosporine and low dose dexamethasone, will save many American lives, before an effective vaccine emerges in the next year.

I ask for your careful eyes on cyclosporine and I pray for your continued resolve and success in defending America’s health.

Yours with respect, in friendship, and in defense of the United States,

Hooman Noorchashm MD, PhD.