An $8 million clinical trial of a mitochondrial enhancer, no less, in ME/CFS? I thought I was hearing things but it was so, and, in the end, it even makes sense given how rapidly some parts of this field are moving forward. But first, a little backstory.
A Pulmonologist Takes On ME/CFS
David Systrom is a pulmonologist – a doctor who specializes in lung conditions – not exactly the kind of doctor you might expect to be interested in chronic fatigue syndrome (ME/CFS). In fact, until Systrom came along, I don’t know if we had any pulmonologists interested in ME/CFS.
Systrom, though, is different. The vast majority of pulmonologists focus entirely on the heart and the lungs – which don’t appear to be damaged in ME/CFS – but ignore the other side of the respiratory system that involves the blood vessels and muscles.
At best, most pulmonologists passed their strange exercise-challenged patients off as mysteries. At worst, they sent them off to their local psychologist. Instead of punting on his patients, though, Systrom dug deeper. He was the first to examine in a really detailed way people with exercise intolerance who lacked the heart or lung problems that most pulmonologists concentrated on.
In a recent call, Systrom related the story of a very well-respected exercise physiologist who asked him – after learning that the exercise tests must be done upright to capture what’s going on – something to the effect of: “Do you mean I’ve been wrong to tell my patients they’re deconditioned and crazy?”.
Over time, Systrom’s invasive exercise tests have provided novel insights into the exertion problems people with ME/CFS, POTS, long COVID, and similar disorders face. From mitochondrial issues, to left to right shunts, to hyperventilation to lo-flow and hi-flow subsets, Systrom has been redefining how we understand these diseases.
A Very Low Oxygen Extraction Group
Really good research takes on a life of its own and so it has here. Systrom had his eye on a particular subset of ME/CFS patients who exhibited more difficulty extracting oxygen from their blood at peak exercise. At the very point that their muscles were screaming out for more oxygen, their mitochondria simply weren’t taking it up.
That suggested a mitochondrial problem might be present. In general, mitochondrial disorders are thought to be genetic but Systrom stated that he’d learned long ago that some mitochondria problems are “acquired”; i.e. that they are simply chronic diseases that show up over time.
Suspecting this was happening in some of his patients, Systrom sent 11 ME/CFS patients to Dallas to get a needle muscle biopsy, which was then sent to Baylor for tests of mitochondrial functioning, electron transport chain activity, and mitochondrial enzyme activity.
If my notes are correct, ten of the eleven patients tested positive for a mitochondrial disorder, with most displaying citrate synthase deficiency – which Systrom stated was thought to be a marker of global mitochondrial dysfunction.
ME/CFS Mitochondrial Study Underway
I doubt that even Systrom expected what happened next. Astellas, a multinational pharmaceutical company in Japan, with a branch in the U.S., had apparently been keeping an eye on his work.
Astellas is a large company with dozens of clinical trials underway, many of which are focused on cancer, but it also has a “Mitochondria Biology” section that is funding trials of a PPAR-β/δ receptor modulator called bocidelpar ASP0367/MA-0211. It’s assessing this drug – which is not FDA approved and not available in the U.S. – in a variety of disorders including Duchenne muscular dystrophy, hypoxia, metabolic disorders (aka ME/CFS, renal failure and mitochondrial myopathies.
Bocidelparis is a most intriguing drug for ME/CFS as it appears to be modulating the same peroxisome proliferator-activated receptors pathway (PPAR) that has recently popped up in both chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM). This pathway plays a major regulatory role in energy homeostasis and metabolic function, and has anti-inflammatory properties. The PPAR-β/δ receptor Astellas is interested in metabolizes fatty acids so that they can be used to produce energy.
First, Paul Fisher’s novel cell culture study in 2020 identified a flood of mitochondrial problems in ME/CFS – including problems with beta fatty-acid oxidation.
Next, Ian Lipkin’s metabolomic study, “Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome“, this year put a spotlight on the peroxisomes’ PPAR pathway in ME/CFS.
Plus, a 2020 fibromyalgia (FM) study found fatty acid metabolism problems in a subset of FM patients. Dietary restrictions, MCT oil, and mitochondria enhancing supplements reportedly were helpful.
The PPAR-β/δ receptor drug Astellas is targeting increases in fat burning capacity during exercise, and enhances the development of type I muscle fibers. It’s not clear if a drug targeting that particular receptor would help a little, a lot, or not at all with the Complex V issues Fisher believes are present in ME/CFS.
Astellas, though, is excited enough to pump $8 million into a clinical trial of a “mitochondrial stoker” in ME/CFS. I almost had to pinch myself when I heard that: a major drug company interested in ME/CFS? Trialing a “mitochondrial stoker” to boot?
In some ways, though, it makes total sense. Systrom, after all, has three things Pharma has been looking for in ME/CFS for quite a while: (1) he has a way to biologically distinguish a subset, (2) he is able to biologically assess treatment effectiveness, and (3) his tests of effectiveness directly impact the magic word “functionality”.
Except for the fact that the invasive or rather the “advanced” exercise test is expensive and well, invasive, Systrom’s testing regimen would be a slam dunk. (Systrom stated that he’s continually looking for less invasive ways to get his results and has some ideas on how to achieve that.)
The 11-week clinical trial consists of 40 ME/CFS patients with some long-COVID patients being added. An initial invasive exercise test determines which participants are eligible for the trial. (Participants need to have peak exercise ([Ca-VO2])/[Hb]) ≤ 0.85 and VO2max < 85% predicted.) The trial is expected to end about this time next year.
The subset of ME/CFS patients that could potentially be helped, if this trial works out, is not small. Systrom stated that the 1,500 invasive CPETS he’s done over the years suggests that 20-25% of ME/CFS patients have enough problems with oxygen uptake to at least meet the criteria for the study.
Systrom noted that getting a mitochondrial disease diagnosis without evidence of family problems; i.e. that a genetic disease is present, is difficult, as getting insurance to pay for the diagnostic procedures needed is near impossible. That could change if Systrom and this study can show that the mitochondrial problems in ME/CFS are not necessarily genetic in nature.
The Mestinon Clinical Trial
Mestinon has been mentioned with respect to ME/CFS for years. Living with Chronic Fatigue Syndrome reported that Dr. Goldstein considered it one of his favorite drugs for ME/CFS and that Dr. Blair Grubb finds it helpful in some of his POTS patients. With the results of Systrom’s proof of concept, the Mestinon clinical trial should soon be published in the Chest journal, and with his years of data on people with ME/CFS, Mestinon may be on its way to becoming a real thing in ME/CFS.
Systrom believes that by triggering the release of norepinephrine, Mestinon is causing the veins to properly narrow, thus propelling blood back up to the heart and giving the muscles more blood. He notes that retrospective studies – studies done after the fact – suggest that pyridostigmine for ME/CFS can improve oxygen uptake, end-tidal carbon dioxide levels, and ventilatory efficiency. Until now, though, no studies have actually directly measured Mestinon’s effect in ME/CFS.
- A Harvard pulmonologist, David Systrom, has found that oxidation extraction problems are common in a substantial subset of people with ME/CFS. The low oxygen extraction rates indicated that their mitochondria were not taking up normal amounts of the fuel they need to produce energy – oxygen – during exercise.
- Suspecting that mitochondrial problems were present, Systrom had muscle biopsies taken of ME/CFS patients who’d displayed very low oxygen extraction rates during peak exercise. Analyses found mitochondria problems, with citrate synthase deficiencies being particularly common.
- Astellas, a multinational Japanese pharmaceutical company, with dozens of clinical trials underway had apparently been keeping an eye on Systrom’s work, and is now funding a (very) rare randomized, placebo-controlled clinical trial in ME/CFS.
- The $8 million trial is assessing the effectiveness of a PPAR-β/δ receptor modulating drug called bocidelpar that is currently being assessed in mitochondrial diseases as well.
- The PPAR receptor modulating capacity of the drug is intriguing as two studies in ME/CFS and one in fibromyalgia have recently turned a spotlight on this particular aspect of mitochondrial function.
- If having a drug company take an interest in ME/CFS is unusual, having a drug company fund a mitochondrial drug trial seems off the charts rare, but Systrom had three things going for him: he’s able to biologically identify a subset, and biologically document progress, and the progress he’s documenting – the ability to exercise in a more normal way – directly impacts functionality.
- The only thing Systrom is missing at this point is an easy way to do this. Invasive exercise tests are expensive and, as their name denotes they’re rather invasive (blood is collected from arteries and veins during the test). Systrom hopes to find a way to gather the data he needs in an easier fashion.
- If ultimately successful the subset of patients this drug – which is not FDA-approved for any diseases – could help could be substantial as approximately a quarter of Systrom’s patients probably meet the criteria to be in this study.
- Systrom is also conducting a proof-of-concept biologically based Mestinon trial that is having patients exercise – take Mestinon – and then exercise again to determine if Mestinon improved their ability to produce energy during exercise.
- Several other studies are digging deeper into the breakdown that occurs when people with ME/CFS exercise. Two are assessing cytokine production and proteomics during exercise, and Systrom is working with Peter Novak to determine if the small fiber neuropathy found in the skin of many people with ME/CFS and/or fibromyalgia and/or long COVID extends deeper and is producing autonomic nervous system problems across the body.
- Finally, the NIH long-COVID RECOVER Initiative has formed a commonalities task force to explore the intersection between long COVID and ME/CFS and other post-infectious diseases. Systrom co-chairs the exercise subcommittee and has reported to the NIH on his findings in ME/CFS and long COVID.
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Since we know that Mestinon helps some but certainly not all people with ME/CFS or POTS, it was good to see a Congressionally Directed Medical Research Program grant to Dr. Rosa Maria Pari Ñaña will help her identify patients that are likely to benefit.
A positive Mestinon result could pave the way for a larger clinical trial. That trial wouldn’t likely be funded by a drug company, though, as Mestinon is a generic drug, and drug companies aren’t interested in funding trials on generic drugs.
That would leave the National Institutes of Health (NIH) as one of the sole potential sponsors. This drug, in fact, seems perfect for the NIH. It’s a generic drug with a long safety record. If Systrom’s trial provides solid biological evidence of benefit for a disease like ME/CFS – which has no FDA-approved drugs – one wonders what excuse, if any, the NIH could come up with to explain turning down an opportunity to fund a trial.
Another ME/CFS researcher, Dikomo Shungu has paved the way here. The NIH’s ME/CFS program announcement still will not allow funding for clinical trials (something that has galled Nancy Klimas, in particular, for years), but Shungu took another route and succeeded. It was his biological data that undoubtedly turned the tide.
After Shungu produced preliminary evidence that high-dose NAC could help in ME/CFS, the NIH funded his expanded ME/CFS clinical trial.
Charting the Exercise Breakdown in ME/CFS
Really good studies open more doors and Systrom has been stepping through quite a few lately. Several studies underway are building on his iCPET studies to further uncover the biological effects exercise has on ME/CFS. A hopefully soon-to-be-published paper, for instance, assessed whether exercise triggers a burst of inflammatory cytokines.
Another study the Open Medicine Foundation helped fund is doing proteomic analysis of samples taken during the exercise.
Systrom is also in the midst of a Department of Defense grant that is funding the interaction between blood vessel dysregulation and small fiber neuropathy. Systrom was the first to document damaged small nerve fibers in the skin of about 45% of people with ME/CFS. He believes the real action, though, may be happening deeper. He’s proposed that the small fiber neuropathy found in the skin and eyes of people with ME/CFS and fibromyalgia extends deeper than the skin and is affecting blood flows to the muscles.
He’s working with Peter Novak to do deeper biopsies that capture sweat glands in the thigh in an attempt to get at the autonomic nervous system regulating fibers. The possible implications of a finding that the autonomic nervous system-regulating nerve fibers have been damaged system-wide in ME/CFS are staggering.
RECOVER Initiative IS Getting the Goods on ME/CFS
Lastly, there was (finally) some very good news from the long-COVID RECOVER Initiative. I’ve been regularly blasting the NIH for its inattention to ME/CFS, but it appears that the NIH is actually quite engaged in the ME/CFS long-COVID connection. (It would be nice for them and for us if they would get out of their ivory tower and communicate this stuff to the patient communities they make such a big deal about engaging with.)
It turns out that the NIH is interested enough in other post-infectious diseases that it established a Commonalities Taskforce to explore the links between ME/CFS and other post-viral illnesses and long COVID. Systrom is co-chair of the Exercise subcommittee of that task force and recently gave a talk to the RECOVER Initiative about his invasive exercise findings in ME/CFS and long COVID.
It was a great relief, at least for me, to learn that the NIH’s RECOVER initiative is actually well-informed about the really exciting invasive and other exercise study results. That’s good for long COVID and it’s certainly good for ME/CFS.
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