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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.

Axcella believes its new drug can help complex diseases that affect the mitochondria, such as long COVID.

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.

Mitochondrial Enhancers for ME/CFS and Fibromyalgia Pt IV: N-Acetyl Cysteine (NAC)

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.

Norwegian 2-Day ME/CFS Exercise Study Adds Crucial Factor to Exercise Intolerance Findings

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.

Lactate – Is it Everywhere in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)?

Dr. Betty Raman

Betty Raman

Two years ago, Dr. Raman won a young investigator award. (From Oxford University)

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.

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