I have a feeling that interesting treatment trials for long COVID may become a regular blog topic on Health Rising.
That would be a nice change. Treatment trials have been chronic fatigue syndrome’s Achilles heel. Except for cognitive behavioral therapy (CBT) and graded exercise therapy (GET), which have dominated the clinical trials arena in ME/CFS to an astonishing amount, biological treatment trials have been few and far between. When they have occurred, they’ve been small and follow-up – even when they’ve had positive results – has been rare.
Numerous treatment trials, however, have already been showing up in long COVID. Just last week Health Rising reported on a budding new long-COVID and ME/CFS treatment called Inspiritol, and others, including fecal transplants, oxaloacetate, are already underway.
The NIH’s quick embrace of long-COVID treatment trials demonstrates just how different the situation is. Apparently out of an abundance of caution, the NIH will not fund any ME/CFS treatment trials. It only wants to move on ME/CFS treatment trials after it believes it’s likely to get a good result. Dr. Koroshetz has said he believes bad results could doom the field for years.
Not so with long COVID. Even though the NIH knows far more about ME/CFS than it does about long COVID, and even though it has yet to release its grant rewards for long COVID research, the NIH has already opened up an “urgent” grant award asking for applications for long COVID treatment trials.
The difference is the NIH has a lot of money to spend on long COVID and Congress – which gave the NIH that money- is watching. The NIH isn’t the only institution, though, that’s pumping money into long COVID treatment trials. A consortium of 30 UK researchers, health professionals, patients, and industry partners called STIMULATE-ICP (Symptoms, Trajectory, Inequalities, and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways) plans to run treatment trials in over 4,500 people with long-COVID. Two drugs (rivaroxaban and colchicine) have already been slated for trials.
Axcella’s AXA1125 Long COVID Trial
This week the focus is on a mitochondrial enhancer called AXA1125 LIVRQNac, AXA1125 is composed of 5 amino acids (AAs) and the mitochondrial booster N-acetylcysteine (NAC). NAC, which is currently being trialed in Dikomo Shungu’s trial in ME/CFS. In an early effort, Shungu found that NAC increased the levels of brain glutathione and reduced the levels of a free radical called isoprostane which studies have shown is increased in ME/CFS.
Thus far, AXA1125 has mostly been focused on a disease called nonalcoholic steatohepatitis or NASH which, in its complexity, presents some similarities to ME/CFS. NASH, the most severe form of fatty liver disease, is characterized by numerous dysregulated metabolic, inflammatory, and fibrotic pathways. Its multimodal nature has caused drug companies to back off from trying to treat the disease, but Axcella, the company producing AXA1125, believes the drug can help and is launching a major trial across 70 sites.
Dr. Alison Schecter, President of R&D at Axcella, described the kind of drug one might think would work in ME/CFS.
“In two prior successful clinical studies and in preclinical models, AXA1125 has demonstrated an ability to reverse mitochondrial dysfunction and improve energetic efficiency via increased fatty acid oxidation, restored cellular homeostasis, and reduced inflammation.”
The trial’s focus on patients with “exertional fatigue” suggests it is well aware of the potential for this drug to treat diseases like ME/CFS.
The randomized, double-blind, placebo-controlled 40-person trial of “patients with severe post-Covid fatigue” will use visualizing techniques to see if the drug can improve their exercise tolerance, reduce fatigue and improve mitochondrial metabolism. We should know by the middle of next year how it went.
The Coronavirus and the Mitochondria
It turns out that there’s already evidence that the SARS-CoV-2 virus that causes COVID-19 may be taking a hammer to the mitochondria in immune cells. In fact, some aspects of COVID-19 sound similar to what may be happening in ME/CFS. This statement from a recent paper, for instance, sounds very much like ME/CFS.
“These data suggest that patients with COVID-19 have a compromised mitochondrial function and an energy deficit that is compensated by a metabolic switch to glycolysis.”
In June, a COVID-19 hypothesis paper proposed that it was mitochondrial dysfunction that was causing the long-term consequences seen in both long COVID and ME/CFS. They proposed that the same problems with cellular energy production were happening in both diseases.
One possibility is that the coronavirus, in an attempt to produce more viral particles, has pushed the mitochondria to rely more on glycolysis than aerobic metabolism. Dr. Rathman – the leader of the new trial – in a report that echoed similar findings in ME/CFS, reported that her studies were finding that long-COVID patients were “accumulating lactic acid in their muscles” at faster rates than normal.
Those high accumulations of lactic acid are a possible sign that the aerobic metabolism that we mostly use to power our cells has broken down and that the cells are relying more and more on the anaerobic energy production process that occurs during glycolysis. The excess lactic acid, which has also been found in abundance in fibromyalgia, produces symptoms like fatigue and muscle pain.
Dr. Betty Raman
The lead researcher in the 40-person clinical trial, Dr. Raman is the kind of young researcher we should hope gets into the long-COVID (and ME/CFS) fields. She’s a senior clinical research fellow at Oxford University with a special interest in using advanced cardiovascular magnetic resonance (CMR) imaging to understand cardiovascular diseases.
Her doctorate work in hypertrophic cardiomyopathy (HCM), an inherited condition that’s the number one cause of sudden death in young adults and athletes, won a number of “prestigious and international awards”.
Raman appears to get it about the need for quick action on long COVID:
“Long COVID is having a truly devastating impact on countless people around the world, leaving many with a sense of hopelessness. It is widely recognized that mitochondrial dysfunction may contribute to the profound fatigue associated with this condition. With no approved Long COVID therapies, the need for continued innovation is urgent. I am pleased to be leading an investigation of AXA1125 to understand its potential to restore cellular energetics and address patients’ needs.”
Given long COVID’s complexity, Raman said she would be surprised if the drug was a cure-all but feels it could significantly benefit some patients. It’s encouraging that AXA1125 is the second long-COVID trial, after oxaloacetate, to focus on supplements to enhance mitochondrial activity.
We’ll see what happens with AXA1125 – a supplement-based drug with a short track record. As with Inspiritol, fecal transplants, oxaloacetate, and others, the most important thing about the AXA1125 trial may not be whether it succeeds but that it’s happening and happening quickly, and employing good researchers to boot.
That’s a good sign for the future. It’s possible we’ll have long-COVID clinical trials coming out of our ears before too long.
It’s a protein shake and NAC combo according to the www
Be amazed if it can do miracles.
I don’t think anyone thinks this is the be all and end all of long COVID but fact that this company is funding a 70-site trial in a very serious disease (nonalcoholic steatohepatitis), and has funded a type-11 diabetes trial, and is now funding a 40-person long COVID suggests that they think their product is something more than a “protein shake with NAC”. If it is a “protein shake with NAC hopefully it’s a very powerful one.
Unless there is some hidden potion that’s what it appears to be.
Could make it in 5 mins.
I just don’t buy it. While I admit I don’t know what it is I think there must be something different about the formulation or method of delivery. Why else would a company do the lab studies, do the type II diabetes study, begin a several hundred-person study of the most severe form of fatty liver disease and then start a placebo-controlled study in long COVID? Why would a researcher like Rathman spend her time with it? That doesn’t pass the smell test for me.
I’m going to err on the side of “they’re the ones investing time and money into this” and assume that they know something I don’t and this is a worthwhile trial. Of course, time will tell.
Please, not to be a wet blanket but really? All of this looks like what you see in retail over the counter(I have). Are they just going to make money with a special name put on it.
It is already none a certain combo of amino acids are very helpful(even from info on this site)
I do not have hope for this, sorry, just my opinion.
This supplement combination isn’t going to solve long COVID but look at the larger ramifications of a trial like this. What happens if the trial does succeed and people with long COVID show a small but still significant increase in energy which is linked to an increase in ATP production and improved muscle metabolism. That provides evidence that energy production rather than depression, malingering, or whatever is a problem in long COVID – pointing researchers in that possibly very fruitful direction. Studies like this won’t provide the answer to long COVID but they bend the field in a certain direction – allowing for more resources and money to be put there.
Shungu’s NAC trial in ME/CFS does the same thing. Shungu, who is experimenting with rather large quantities of NAC, found that it did increase brain glutathione and reduce oxidative stress levels in ME/CFS. Is NAC going to solve ME/CFS? No, but a good clinical trial outcome would move the field in a certain way. Neuroinflammation would probably get more attention. Oxidative stress certainly would as well doctors would know that NAC at certain doses can be helpful. That would probably reorient them a bit.
Plus, do we know that there isn’t something different about this formulation. Maybe I’m naive again I ask why a company would devote all these resources to something you can just buy off the shelf?
Interesting. I’m curious to know how exercise intolerance is being measured? Any study, particularly a non-ME/CFS one, that further verifies/explores PEM would be great. Even if they are studying corn syrup. That of course assumes PEM is happening in long-Covid.
If I have it right they are assessing phosphocreatine (?) recovery times. That appears to measure how quickly the mitochondria recover after being stressed.
That’s a v good point?! Is PEM a common diagnostic feature of long Covid? In order to receive a diagnosis of ME CFS one has to have PEM as a symptom according to NICE guidelines. Interesting indeed…
Anecdotally, I always felt a much more improvement to my brain fog from glutatione IVs than ever from taking oral glutathione (even liposomal) or NAC. Unfortunately, even then I would hit a plateau, but I probably wasn’t getting them often enough due to travel and expense. Oral supplements have always come with problematic side effects for me.
It would be interesting to see if there’s a disruption in the pathway somewhere from some of these parent nutrients to some of the components they break down into. That would lend itself to further exploration in the gut microbiome avenue.
I had my DNA sequenced back when Courtagen was looking into these things. I have an interesting mutation that seems to be associated with gut dysbiosis and fatigue, where the recommendation was antioxidant supplementation.
In the end, I have a feeling what we’re going to need is a way to generate personalized profiles that look into individual genetic, gut, and molecular variables to come up with targeted individual therapies.
In the mean time, research like this can help move us forward. It will be interesting to see if the way the Long Covid initiatives are set up for information sharing will be the key to unraveling a problem that requires multidisciplinary communication in a world where medicine has cleaved us into individual organ systems and body parts, with few systemic incentives to be more scientifically holistic.
Unfortunately I don’t see what you’re suggesting ever being accessible to most of the people who need it. I think medicine is a long way off from being individualized and customized. DNA testing has been around for awhile yet most drs will never order. naturopathic doctors and functional medicine practitioners are likely rolling their eyes right now as they were suggesting glutathione and NAC from the very beginning. I do wonder the quantity and frequency though. It would be interesting but unfortunate if there was a plateau that was quickly reached only leading to partial recovery.
Not protein. Specific amino acids. Individual amino acids can in some cases have specific effects not seen with complex proteins. Dietary proteins are lots of different amino acids, but often little of key aminos that could support some function in larger amounts. For example, taking large amounts of tryptophan can boost serotonin in cases where ordinary proteins (which contain rather little tryptophan) don’t have much effect.
Agree that it would be unrealistic to consider it a miracle – long covid is a complex thing, not holding my breath for a miracle. But
I’m thanking for the researchers that are studying long covid. I suffer from cfs/me and hope someday a cure will be found.
I know from my own experience that NAC, BCAAs, Arginine, Glutamine abd Glycine have improved my condition a little so I anticipate there will be some positive effect for some people. But given a lot of people have tried this sort of thing quite a bit its unlikely to be a big impact.
I don’t know. I have to question, though, why a company would put this kind of money (or be able to raise this kind of money) for a product that consists of simply packaging some supplements together. I think there must be more to it than that.
Nothing was said about symptoms but a placebo-controlled trial in NASH found clinically relevant reductions in several markers( ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions) after 16 weeks. https://pubmed.ncbi.nlm.nih.gov/34382947/
Long covid is a hot market and will be for next decade at least.
Capitalists will back anything that has a long shot even its a mutton dressed as a lamb.
Does anyone know the full reason why the FDA in recent months banned NAC for sale as a supplement in the US by retailers and online stores like ‘iHerb‘
I heard the FDA said it was being used by people as a therapeutic instead of as a supplement. (i.e. not for any safety reasons but for it’s intended use reasons).
Yet, now all of a sudden we see it’s in a therapeutic, no doubt to be prescribed to patients.
That could be just coincidence, but the FDA never banned the retail sale of ‘Creatine‘ which is clearly used way beyond its boundaries as a supplement by bodybuilders, athletes and fitness fanatics
I used NAC safely for years, now can’t get it. And have weakened as a result
I have no idea what is going on. The FDA says they’ve banned it, Amazon is not selling it, but you can actually easily find other retailers that are. I could actually find it on iHERB. Maybe they backed off at first but decided it’s OK to sell it now.
Basically, with the 12 x 150 mg of NAC / day that is (purportedly) in their formulation they are down the same alley as Dr. Shungu who is currently recruiting for a ME/CFS study of 3 x 600 mg NAC:
NAC may be a plausible candidate because it may influence excitotoxicity/neuroinflammation
Thanks. I added Shungu’s data to the blog. Am I right in that is quite a bit of NAC?
Dear Mr. Cort Johnson,
Your analysis of this topic is interesting., However,, I take issue with your statement; “That provides evidence that energy production rather than depression, malingering, or whatever is a problem in long COVID – pointing researchers in that possibly very fruitful direction.”. Your statement shows a dinosaur level of knowledge about the causes, and true and real symptoms of long Covid. Perhaps you should have a dose for awhile to see for yourself how much depression, malingering or whatever is a problem in long COVID. You are welcome to my world for the last four months of extreme exhaustion, deep headaches and brain fog, not to miss the exertion intolerance. Besides these effects there are also the lost lifetime, loss of time with families, grandchildren, friends, hobbies and being able to enjoy life and nature.
I do agree with the potential for amino acids, and have myself seen improvement with NACO ( sorry it’s not NACHO). I hop these thoughts are helpful.
Yes, depression is a real problem for people with long COVID – as it is for anyone with a serious chronic illness. I actually know your world pretty well as I’ve lived in it for four decades with ME/CFS. As impactful as depression can be, sudy after study, has failed to show that depression is anything other than an add-on – a natural consequence of being so functionally deprived. Studies suggest, on the other hand, that reduction in the ability to produce energy is a core element of both long COVID and ME/CFS.
Having taken NAC for about 5 years for Lyme/TBD and then CFS, it alone doesn’t seem to do much at least at 600mg/day. I did have some success in putting PEM to rest with Solgar amino acid complex but I also started large doses of Vit B1&2 at the same time. (NAC as well). I don’t take the AA now except if I know I’m going to be doing more exercise than normal (raking leaves) and it does seem to help. One red flag though. I’ve learned that NAC is contraindicated if you have histamine/MCAS issues. So the question in my mind is, did long term use of NAC exacerbate my histamine issues?
You should try NACO at 600 mg twice a day
Amino acids and precusors
AXA1125 consists of a combination of:
Does anyone know if Arginine supplements are bad if you suffer from Epstein Barr virus reactivations? I have read conflicting reports
Thank you for the writeup, Cort.
This had caught my attention because the description of the UK trial mentioned that it could reverse the tendency for too much glycolysis and not enough fatty acid oxidation, something my tests have shown to be a problem. Do you know what the mechanism behind this is supposed to be?
And, Axcella is based in Cambridge, MA. Is there any way US patients could try it via an IND their doctor submits?
AXA1125 is reportedly a “mitochondrial normalizer” but I don’t know its specific mode or modes of action. Since the compound is composed of safe apparently well-studied ingredients I wonder if the company might let your doctor give it a try (?)
Or you could try it yourself 600mg NAC 3 x a day is a lot but check for side effects on anything first before you take it and Solgar amino acid complex is readily available. If it’s going to work you should know within a couple of weeks. I knew in 3 days. 🙂
Do you follow Ron A Davis of Stanford – a leading biochemist in the field of M.E. Research? He
Makes the point that research into Long COVID is just duplicating what has already been done…? My interest is that I have a daughter with Severe M.E.
Closely! We’ve done quite a few blogs on Ron – you can find them using search. I think he’s largely right! Almost all the big long COVID findings (exercise, gut, cortisol, persistent viruses, autonomic nervous system) thus far are duplicating what’s been found in ME/CFS.
Professor Julia Newton, Newcastle University UK, also recognised the similarities in symptoms between NASH (her original research area) and M.E., prompting her to expand her research to dysautonomia, syncope (POTS) and M.E. I wonder if she has any involvement with the AXA1125 trials?
Ha! Didn’t know that. I had never heard of NASH before.
There is a precedent for taking something which is sold as a supplement, patented and then it becomes ‘medicine’ i.e sold under prescription only. And all the companies selling it as a supplement are no longer able to do so.
Something like this was a foot with intramuscular ascorbic acid
and something exactly like this happened with a B6 vitamer – pyridoxamine.
With the very sad part that the years later, it is still not available as a medicine. A lot of people got screwed when it went off the market in the States. It tends to have less of a problem than the other B6 supplements have.
The other two medications being trailed for ‘long Covid’ are 1- an anti-coagulant and 2 – an anti-inflammatory.
Aspirin does both and dirt cheap in comparison…
I’m doing the study and yes they are measuring Phospocreatine (PCr) via MRI – this in itself is a step forward for Long Covid as it’s an objective measure that the mitochondria/ATP isn’t functioning properly. There’s also other diagnostics, ECG, bloods, urine & lactate. As someone who’s been post viral 3 times it feels a miracle to actually have any type of test.
Congratulations for being in the study and thanks so much for letting us know. Crossing fingers!