Review article: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Where Will the Drugs Come From? 2021, Toogood et al

John Mac

John Mac

Senior Member (Voting Rights)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease characterized by severe and disabling fatigue that fails to improve with rest; it is commonly accompanied by multifocal pain, as well as sleep disruption, and cognitive dysfunction.
Even mild exertion can exacerbate symptoms.
The prevalence of ME/CFS in the U.S. is estimated to be 0.5-1.5% and is higher among females.
Viral infection is an established trigger for the onset of ME/CFS symptoms, raising the possibility of an increase in ME/CFS prevalence resulting from the ongoing COVID-19 pandemic.
Current treatments are largely palliative and limited to alleviating symptoms and addressing the psychological sequelae associated with long-term disability.
While ME/CFS is characterized by broad heterogeneity, common features include immune dysregulation and mitochondrial dysfunction.
However, the underlying mechanistic basis of the disease remains poorly understood. Herein, we review the current understanding, diagnosis and treatment of ME/CFS and summarize past clinical studies aimed at identifying effective therapies.
We describe the current status of mechanistic studies, including the identification of multiple targets for potential pharmacological intervention, and ongoing efforts towards the discovery of new medicines for ME/CFS treatment.


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https://www.sciencedirect.com/science/article/pii/S1043661821000487
 
Yes, this feels like quite a step forward.

However, at the current time, interest among pharmaceutical companies and biotech/venture investors appears to be almost non-existent. It is to be hoped that increased awareness of the basis and impact of ME/CFS will stimulate the investment in research that will be necessary for development of effective new therapies.
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A lot of the possibilities were written up rather more positively than I think is warranted though, although I understand that the purpose of attracting interest requires some hopeful statements.


A wide variety of nutrients and nutritional supplements have been explored for their potential benefit in ME/CFS.[91] Very little to no evidence supports the use of these supplements with the possible exception of the mitochondrial modulating combination of NADH and coenzyme-Q10. In a 73 patient RCT, treatment with daily doses of NADH + CoQ10 for 8 weeks produced a small but statistically significant improvement in the Fatigue Impact Scale total score.[115] Further benefit may potentially be achievable with dose optimization.[116,117]
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For example this one for NADH and CoQ10: my conclusion from looking at the study was
"The decrease in the fatigue measure after accounting for the placebo effect was about 3% - hardly clinically significant. And, even if there is a real benefit, we don't know if it was the CoQ10 or the NADH, or some synergy between them. And there are potential conflict of interest issues, with the producer of the supplements supporting the study."​
Other evidence for CoQ10 is not convincing.


The supplementation of low dose methylphenidate with various mitochondrial support nutrients including acetyl-L-carnitine, α-lipoic acid, and N-acetyl-cysteine is called KPAX002, and is being studied for the treatment of ME/CFS.[118,119] KPAX002 provides some benefit in patients with severe symptoms, but appears not to be generally applicable.
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The paper mentions methylphenidate a couple of times as potentially being of benefit. We have a thread on KPAX2 here with these posted comments"
"the results of the "phase 2 randomized, double-blinded, placebo-controlled trial" on KPAX002 published by Jose Montoya and colleagues [1] that, from an intention-to-treat point of view, reported no significant statistical difference in self-reported group scores of fatigue and other measures between active treatment and a placebo."
"I'm a little bit disappointed that the authors weren't more forthright in how the results weren't statistically significant on any and all measures included for study."
"Finally, once again, I note that under the heading 'Disclosure of conflict of interest', the word 'none' appears as per the last research occasion [2]. Personally, and with no malice intended, I would have listed the detail that at least one of the authors is an employee of the manufacturer of KPXA002 given the affiliation details and email address for further correspondence provided on the paper."​
 
As an off-the-wall and circuitous answer to the question "where will the drugs come from?":

Ciguatera poisoning can cause long term sequelae that look a lot like ME/CFS - fatigue, brain fog and pain, with relapses triggered by exercise. The mechanisms are better, although still not well, understood though, with mention of sodium channels being quasi-permanently disabled by a toxin that attaches to them, with downstream impacts on calcium signalling (with issues with TRP channels, which the Griffiths University team have suggested are involved in ME/CFS). Ciguatera is a significant problem and will become more so with warming seas encouraging the growth of the dinoflagellates that cause the toxin to accumulate in the food chain. It's a medical and food supply problem that needs a solution.

There are communities, such as those in the Pacific Islands, that have been coping with ciguatera poisoning for a long time. They depend on reef fish for protein, the fish that can contain the toxin. While they have traditional knowledge that helps them reduce the risk of poisoning (e.g. 'don't take fish from certain sides of an island in certain seasons'), they have had to regularly deal with it, because there is no way to identify a contaminated fish from its smell or appearance. Papers on ciguatera mention that these communities use specific indigenous plants to treat poisonings. Those plants could be analysed to identify compounds that might be of use.

It might be possible to trial those compounds on cells treated with the ciguatera toxin. Or, if the mechanism is better understood, existing drugs might be able to be repurposed.

Coming up with a treatment that reduces the impact of the acute ciguatera illness, and prevents and treats subsequent chronic illness is a useful thing to do. And, it's probably something that can be achieved, as the molecule causing the problem, and something of the mechanism, is already known. Furthermore, the process of doing that might just possibly also help with the understanding and treatment of ME/CFS. So a drug company that develops a ciguatera drug treatment might have an advantage in developing an ME/CFS/Long Covid drug treatment.

I know it's a highly speculative and, very likely, stupid idea. But we've seen published papers where 'animal models of CFS' have consisted of rats put in buckets and forced to swim until exhaustion. It's not as stupid as that.
 
What drugs are being developed for the treatment of ME/CFS?
Commentary by Dr Charles Shepherd,
Hon Medical Adviser, ME Association
An interesting review of the latest research into new drug therapies that might be able to tackle the underlying disease process in ME/CFS, rather than just being used to treat symptoms, has been published by the American journal ‘Pharmacological Research‘.

Special attention has been paid as to how new treatments might impact on the immune systems of people with ME/CFS as well as any detected metabolic and mitochondrial dysfunction.


It is encouraging to note that one of the authors has links to the major pharmaceutical company Pfizer. However, as noted in their conclusion:

“interest among pharmaceutical companies and biotech/venture investors appears to be almost non-existent”.

This is clearly something that needs to be addressed on both sides of the Atlantic. In the UK, the CFS/ME Research Collaborative is showing a clear signs of interest,

Given the clinical and pathological overlaps between ME/CFS and Long Covid, and the research initiatives looking at the treatment of Long Covid, this review should also be of interest to the Long Covid patient and medical community.
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https://meassociation.org.uk/2021/02/what-drugs-are-being-developed-for-the-treatment-of-me-cfs/
 
Global Chronic Fatigue Syndrome Market to Witness Huge Growth by Worldwide| Global Current Trade Size And Future Prospective

Few of the major competitors currently working in the global chronic fatigue syndrome market are Hemispherx Biopharma, Inc.; Torrent Pharmaceuticals Ltd.; Fortis Healthcare; London School of Hygiene L& Tropical Medicine – CureME; Dr Batra’s; F. Hoffmann-La Roche Ltd; K-PAX Pharmaceuticals among others.
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Market Definition: Global Chronic Fatigue Syndrome Market

Chronic fatigue syndrome, also known as myalgic encephalomyelitis is a chronic disorder associated with long term fatigue and tiredness in patients. These symptoms cannot be defined by any particular condition and even with continued rest the condition of the patient is not improved. This disorder is not very well known and no solidified information is available for its cause.

Market Drivers

  • Continued research and government support regarding the development and awareness regarding the chronic fatigue syndrome is expected to drive the growth of the market
  • Various different market players and pharmaceutical companies are focusing on the development of diagnostics tests and treatment for the disorder; this factor is expected to boost the growth of the market
Market Restraints

  • Lack of awareness regarding the disease is expected to restrict the growth of the market
  • Absence of information regarding the treatments and drug combination available for the treatment of symptoms of the disease is also expected to restrict the growth of the market
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https://www.pharmiweb.com/press-rel...-growth-by-worldwide-global-current-trade-siz
 
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