The blog – taken from presentations at PolyBio’s Fall Long COVID Symposium – is about innovation at the treatment level in long COVID. Long COVID, like chronic fatigue syndrome (ME/CFS), like fibromyalgia, etc., presents a problem – it’s very complex. Neither studying nor treating it is easy, but some researchers are meeting the challenge by upping their game and using different methods to study and treat it in ways that we haven’t seen in ME/CFS before. This blog is about two of them but first a thought about the…

The Tenuousness of Medical Research

The whole thing seems so fragile. Take the LIINC group studying long COVID at the University of California at San Francisco which is “supporting dozens of studies“.  From its small beginnings, LINC has turned into a mammoth and critical factor in long COVID research.

LIINC was launched very early  – in April 2020 and since then has interviewed over 800 participants, banked over 50,000 samples, and shared 20,000 of them with over 50  long COVID projects.

We’re very lucky to have it, but the question arises: why did it show up and why did it do so at UCSF and not at, say, Johns Hopkins, Columbia, UCLA, or other top-rated medical schools? Why don’t we have ten LIINCS?

The same question applies to the Veterans Administration’s work on long COVID. The VA has never done any research that I can tell on ME/CFS, but it has become a big player in the long-COVID world. Ditto with Akiko Iwasaki’s work at Yale and David Putrino’s work at Mt. Sinai Why have places like UCSF (LIINC), the VA, Yale, and Mt Sinai come to play such prominent roles?

It seems quite haphazard. Aside from the RECOVER Initiative – which is funded by Congress – there’s no overall plan to tackle long COVID and that leaves it subject to all sorts of accidents of history.

Take ME/CFS. The Workwell Foundation’s early focus on exercise studies resulted in exercise being commonly nd profitably used as a stressor in ME/CFS studies but the entrance of the Workwell Foundation into the ME/CFS field was not an inevitability. It was more of a lucky break that began when an exercise physiologist named Staci Stevens came down with ME/CFS.

Indeed, judging by the bios of some of the LIINC leaders, the tentative answer as to how these efforts get started is that it’s personal. A researcher with clout simply decides to take long COVID (or any other disease) on and enrolls his colleagues in doing so.

Judging from his bio, Steven Deeks appears to have been the key to the emergence of LIINC. An internationally recognized expert on HIV pathogenesis and treatment, he boasts quite a resume. He’s published over 700 peer-reviewed articles and is the principal investigator of DARE (the Delaney AIDS Research Enterprise), an NIH-funded international collaboration aimed at developing therapeutic interventions to cure HIV infection.

His bio states that in early 2020, he leveraged his HIV research program to construct the “Long-term Impact of Infection with Novel Coronavirus (LIINC)” cohort and there, apparently, you have it. Deeks had the resources needed to start LIINC and it just grew and grew.

His colleagues are almost all HIV guys, many of whom have been trying to find a way to definitively clear the body of HIV. Michael Peluso‘s research is “aimed at understanding the HIV reservoir” and Tim Henrich is working on HIV reservoirs and developing cutting-edge treatments (immunomodulatory, cytoreductive chemotherapeutic and stem cell transplantation) to cure HIV. Priscella Hsue, Matt Durstenfeld, and Jeff Martin are all HIV researchers of one ilk or another. (Dan Martin is Ebola.)

In other words, because they’re already studying “long HIV”, they’re a perfect match for long COVID. While HIV is being kept under control by drugs – which can have significant side effects – the virus is still there – just as the coronavirus is still lingering in the tissues of many people with long COVID.

Stephen Deeks on Doing “Experimental Medicine”

Deeks came to the conference with a problem. He said that he and Michael Peluso have been beating the bushes trying to get pharma involved in long COVID but have been getting rejected left and right. The problem is that pharma wants a mechanism and they can’t give them one yet.

The field is making amazing progress in terms of what’s happening in the laboratory in coming up with these different pathways – and he feels we are moving in the same direction, but the progress, right now, is on the sidelines regarding treatments. They will not get to a cure until they can get pharma involved.

The most important thing, he asserted, that the long-COVID field needs to do is to come up with a therapeutically actionable mechanism that can encourage big pharma. One way to do that is using “experimental medicine” – an exploratory approach that both reveals the mechanisms involved in the disease and provides data on how to treat it.

In this case, it means using small studies of already available drugs that study the heck out of the patients that take them to learn what is going on in the body.

As other people at the conference did, Deeks emphasized how complex these infection-associated illnesses are. He said it’s probably not that “A” causes long COVID but it is more like A leads to B which leads to C and long COVID; in other words, a kind of perfect storm of dysregulation happens. Something like a virus causes inflammation, which damages the endothelial cells, which results in autoantibody production, etc. Note that all these pathways are actionable now using existing drugs.

That brought me back to Dr. Klimas’s supercomputer modeling work which suggested that people with ME/CFS get pushed and embedded in a new kind of dysfunctional normal that will require multiple treatments – done in the right order – to push them back to normality.

Then it was onto viral persistence, where we learned that viral persistence is probably not going to be “it”. The evidence shows that the spike protein is persisting for a year in some individuals – and in a subset of patients – spike protein in the blood is associated with symptoms (but not everybody). Viral persistence sparks an immune reaction in some people, for instance, but not in others.

Deeks noted that the viral persistence hypothesis has resulted in at least three antiviral (Paxlovid) long-COVID trials (RECOVER, Stanford, Yale) that are seeking to eradicate the virus, but then delivered a shocker – at least to me.

These drugs are not going to be able to clear the virus from the body. Antiviral drugs, it turns out, don’t do that – instead, they halt the replication of the virus. Those “persistent reservoirs” of virus – they’re going to stick around. The viruses that remain, but are not replicating, could still be causing problems.

We in the ME/CFS world know this from Williams and Ariza’s work at Ohio State which found that smoldering EBV infections that are not replicating but are pumping out toxic proteins can evoke a nasty immune reaction.

An ME/CFS researcher at Nancy Klimas’s lab also agrees. Travis Craddock’s models indicate that one antiviral is not going to do the trick with the Epstein-Barr virus. Yes, the virus can be temporarily suppressed but unless you can get at those viral reservoirs, once it sees an opening, it’s going to come roaring back.  Craddock’s models indicate though, that a B-cell suppressor like Rituximab to the mix completely flatlined the virus – it was no longer able to reactivate. The model suggested the approach could theoretically produce a long-term reduction – not a forever reduction, but a long-term reduction of viral load.

As Deeks said, interventions are readily available. For the time being it may be more a matter of putting them together in the right way.

Monoclonal Antibody Study

Deeks and his team will be using a monoclonal antibody called AER002 in a small trial that is effective against all COVID variants through late 2022 and has the potential to get at a viral reservoir. Besides the usual inflammatory/coagulation markers, they’re going to do a deep dive into their patients’ physiology. They’ll be looking at the gut, the spinal fluid, the lymph nodes (biopsy), bone marrow, blood vessels, and their ability to exercise.

The results will be fascinating given the case reports we recently saw which featured complete and rapid recoveries from long COVID using an earlier monoclonal antibody (which doesn’t work against the current variants).

Anti-Inflammatory Study

Deeks cited his 20 years studying and treating inflammation in HIV concerning a trial of baricitinib (Olumiant) in long COVID that is underway. Olumiant is a Janus kinase (JAK) inhibitor used in rheumatoid arthritis and some other diseases. The elevated cytokines (IL-6, IL-1B, TNF-a), Deek said, suggest microglial activation. This is probably the kind of anti-inflammatory drug that Dr. Klimas has been wanting to test in ME/CFS for at least a decade.

Disruptive Innovation at the Clinical Level – David Putrino

When David Putrino, PhD, at Mount Sinai was interviewed for a job at Mt. Sinai, he was told Mt. Sinai needed to innovate and that if he could come up with something innovative, he would have the job. He did not disappoint. He said he wanted to run a lab that would never use NIH grants.

When asked to explain, he said the average time to take a treatment from the bench (lab) to the bedside (patient) is 17 years. The reason for this is a focus on incremental science. While incremental science is important, Putrino explained that this hyper-siloization (new word!) works well in less complex illnesses, it doesn’t work well in infection-associated complex diseases like long COVID (and ME/CFS).

He’s called for a model of disruptive innovation that includes a focus on interventions that are cheap and available, which physicians can quickly adopt and translate the results of evidence-based clinical trials into treatment protocols.

Putrino got the job and instead of going to the NIH, he went to industry and told them if they had a product they thought would work, Mt. Sinai would put on a clinical trial using its hospital network. If the product worked, Mt. Sinai – which is a huge clinical center – will immediately adopt it.

Not surprisingly, he got some pushback. The tech transfer guys at Mt. Sinai wanted to know how Mt. Sinai was going to make money off something like that. Other researchers were leery because his team wasn’t being specialized enough; i.e. they didn’t demonstrate a “core competency”. The idea that they were simply trying to figure out what helps patients was not enough for them. They had other concerns as well – keeping the research centers and labs going, for instance.

Never Running Dry…

Putrino’s guiding principle, though, was different. His goal was to never run dry when it came to treatments. If something didn’t work, he would always have two or three other things to try. There would always be something innovative and novel to try.

The new approach worked at first. Putrino said they had companies coming out of the woodwork willing to fund clinical trials, but the doctors were the problem!  They said they didn’t have enough time to learn about the treatment, said patients wouldn’t want it (?), the evidence base wasn’t good enough, they were afraid that technology is going to replace them (?), etc. In short, the perhaps overworked doctors balked at doing this.

Putrino shifted gears and opened the Center for Recovery From Complex Diseases at Mt. Sinai which is doing the testing. When something works he’s disseminating it nto the larger hospital system.

The Mt. Sinai Center recently received a $6.2 million grant from the Steven & Alexandra Cohen Foundation to study “long Lyme” and other infection-associated complex illnesses such as ME/CFS.  Because everyone visiting the Center will go through the same testing protocol, they’ll be able to compare and contrast these diseases in “unprecedented detail”. (And so the field of post-infectious illnesses takes another step).

Plus, because they understand that single treatments probably aren’t going to do, they’re going to do “adaptive clinical trials”: clinical trials that involve combination trials.

Note that this is the second such Center to open this year (Metrodora was the first) that will focus entirely on this group of diseases – a good sign.

 

Calling the grant a “logical and important extension of our Center’s work”, Putrino said:

“For decades, people with long Lyme disease have struggled to find centers that can provide knowledgeable and compassionate care for their serious and debilitating symptoms. We are proud that our Center will be one of the few places in the world that is embedded in a major clinical institution to provide this care—this is a patient population that has been without access to adequate care for too long,”

 

“Millions of patients all over the world experience infection-associated complex chronic illnesses, and there are very few clinical centers of excellence that engage in both outstanding clinical care and world-leading research focused on biological discovery,” Dr. Putrino

Putrino, who has helped to treat over 3000 long COVID patients, has identified three sets of patients. No matter what he throws at them he can’t move the needle on about 10% of them. He can produce some improvement in about 70% and about 15-20% recover – at least temporarily. (If they catch COVID again, Putrino said some will get ill again.)

• Find Putrino’s presentation here – 4:00:46

Health Rising BIG (little) Drive Update

Thanks to the many, many people who have contributed to Health Rising thus far in our end-of-the-year drive! (I am behind in my tallies!)

It’s in our logo – Health Rising is about “finding answers to diseases like ME/CFS, fibromyalgia and long COVID”. It’s going to take innovative work to break down what’s happening in these complex illnesses and effectively treat them.

That’s why we look to the conferences for the latest news on these diseases and delight in reporting innovative efforts like Stephen Deeks and David Putrino are doing. If that focus supports you, please support us in a way that works for you.