(This blog is based on a post on Phoenix Rising describing Dr. Mella’s Oct. 10th talk in Arendal, Norway and a typically tortured Google translation of part of that talk.)
Another Hypometabolic Signature Found
Naviaux’s paper has clearly sparked a lot of interest. Certainly, antecedents hovered in the background; metabolism has actually been a niche topic in ME/CFS for years. Lemle proposed that a hydrogen sulfide induced state of hibernation or hypometabolism caused the low energy problems in chronic fatigue syndrome in 2011. The Aussies have been doing metabolomics research for quite some time. Their 2014 review paper argued it could be helpful in ME/CFS.
Metabolomics is not a niche topic anymore. The Japanese, who have also done metabolomics research, recently released a metabolomics ME/CFS study (to be covered soon).
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Problems producing energy appear to be fundamental and extend to the immune cells - something Ron Davis has proposed. Fluge and Mella reportedly found reduced levels of phosphate – the P in ATP – in immune cells in ME/CFS. That suggests the reduced killing ability of NK and T-cells could be caused by poor energy production. That makes sense given that some immune cells need to power up to kill pathogens.
Fluge and Mella also have evidence suggesting that metabolic problems may be loading ME/CFS patients with lactic acid – a by-product of anaerobic energy production. (If aerobic energy production is impaired or insufficient, the less-efficient, dirtier and lactic-acid producing anaerobic energy production process kicks in.)
These Norwegian researchers believe ME/CFS patients have two problems with lactic acid; they're producing too much of it, and are having trouble getting rid of it. Mella noted that he produces lactic acid but he can get rid of it quickly - people with ME/CFS cannot. Lactic acid remains a puzzling subject - some researchers find it increased and others do not. That variability may reflect a subset issue.
Rituximab Update
If my calculations are correct, the trial is a bit over halfway done, and we should expect it to end sometime in the summer of next year. At that point, Fluge and Mella will crack the code, and by late 2017 (optimistically) or the first half of 2018, we should know the results.
We've seen some promising Phase III trials go bust recently. Because the larger Phase III trials include more types of patients, they often have less positive results, and Mella warned that this was possible in Rituximab as well. If the results don't apply to ME/CFS overall, then the goal will be to find out which patients it’s effective in and target them. Mella noted that different mechanisms can produce the same symptoms in autoimmune diseases, and he expects this is true in ME/CFS.
According to the translation, Mella stated that they can be "reasonably sure" that a subset of the patients responded. Whether enough people respond to make the trial statistically significant is another matter. Rituximab could be effective in some patients, but not in enough to result in a significant overall response.
(Dr. Patrick in Canada believes he may have found a biomarker that will help identify which patients respond to Rituximab. Dr. Peterson is reportedly testing that biomarker in his patients. )
Mella also cautioned that even if the Norwegian trial is successful, each country will have to put on its own trial. (As it is now, Rituximab would be available off-label to doctors willing to prescribe it, but the drug is very expensive.) The U.S. – the most difficult place to get drug approval – will need its own trial.
According to clinicaltrials.gov. the NIH, one of the biggest clinical trial producers in the world, is currently recruiting for no less than 49 Rituximab trials, mostly in cancer but also in lupus and other autoimmune disorders.
How the NIH, after the IOM and P2P reports, and its statements that ME/CFS constitutes a serious, unmet need, could find a way not to fund a Rituximab trial in the face of a successful Norwegian trial is unclear, but if any group can find a way, surely the NIH can. If the NIH waits for the results of Fluge/Mella’s trial before proceeding, we might be looking at a U.S. Rituximab trial beginning in 2019 with the results in 2020 or 2021.....
It’s remarkable to continue to see the NIH with its 30 plus billion budget continue to sit on its hands while a small country like Norway produces a large Rituximab trial.
Another Drug Possibility…..Cyclophosphamide
Chemotherapy may end up being very good to chronic fatigue syndrome. Fluge and Mella have been giving twenty-five people who didn’t respond to Rituximab or who relapsed after getting it, a shot at another chemotherapeutic drug called cyclophosphamide. Cyclophosphamide is used to treat cancer, autoimmune diseases, and amyloidosis.
A quite toxic drug, Wikipedia reports that it's side effects usually limit it to the beginning phases of treatment in autoimmune diseases. It’s typically used only when first-line treatments such as Rituximab don't work. Like Rituximab it’s an immune suppressant.
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Not all immune suppressants are the same; etanercept (Enbrel) didn’t work for Mella and Fluge. Cyclophosphamide findings have, interestingly, excited some hospitals…
Fluge and Mella are using cyclophosphamide in the lower doses associated with autoimmune disease treatment. They reported that while some people get worse at first, it does appear to work in some ME/CFS patients. Like in autoimmune diseases, the positive effects show up months after taking the drug. Approval for a second trial with severely ill ME/CFS patients has been received.
“Toxic Blood?” (or Another Good Reason Not to Donate Blood)
The idea that something in ME/CFS patient's blood may be turning off the mitochondria or natural killer cells or what have you is not a new one. Although no new studies have come out, reports indicate that the natural killer cell problems in ME/CFS apparently disappear when NK cells from ME/CFS patients are put into a healthy person's blood. Conversely, healthy NK cells poop out when put into ME/CFS patient's blood. Fluge and Mella are finding that healthy muscle cells act strangely when cultured with ME/CFS patient's blood.
Fluge and Mella are also finding that the blood vessels of ME/CFS patients are producing too little nitric oxide. Nitric oxide is a gas produced in the walls of the blood vessels which allows them to enlarge and increase blood flow. If you produce too little nitric oxide, your blood vessels will be so constricted that getting enough blood to the muscles during exercise or other blood requiring activities will be impossible.
Nitroglycerin tests indicate that ME/CFS patient's ability to produce nitric oxide is still present, suggesting presumably that either the signal to produce NO is not being sent or is being ignored, or that the cells that produce NO are being shut down in some way.
(Fluge and Mella filed a patent in 2014 to use a nitric oxide donor in conjunction with Rituximab in ME/CFS. Their understanding of the role that blood flows play may date back to this patient. After checking into a hospital for chest pains, she found that a nitric oxide donor (Imdur) improved her symptoms in much the same way as Rituximab had - except that the results were immediate. They got moderate results in six patients and suggested that using supplements with relatively high doses of L-Arginine 5 g twice daily combined with L-Citrulline 200 mg twice daily might suffice as well.)
Finding some factor in the blood that turns things off could be very helpful. It could a) directly point to a cause, and b) to clear treatment options that block the factor or stop it from being produced.
Fluge and Mella's Journey
Fluge and Mella’s range has become so large, that it’s totally inappropriate at this point to think of them as Rituximab researchers; they're after the source of ME/CFS itself. They're looking at the immune system, blood flows, exercise metabolism, and genetics and have developed a model which incorporates all of it.
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Other researchers – most of whom I would guess were not interested in ME/CFS prior to their work - have clearly been excited by it. Their international partners draw from the Charite University Hospital in Berlin, UCL London, Arizona State University and Institute of Immunology Rikshospitalet and Biomedisn UiB.
Fluge and Mella are going to make their first trip, so far as I can tell, to the U.S. for the IACFS/ME conference where Dr. Fluge's plenary address will focus on how the Rituximab trials have helped him and Mella understand the cause of ME/CFS. At the Patient Day we'll get a trifecta; Fluge, Mella and Dr. Peterson on "Rituximab and Emerging Treatments". It's a rich time for them and for us.
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