Mitodicure GmbH applies for 3 patents for ME/CFS drugs

E

EndME

Senior Member (Voting Rights)
Mitodicure GmbH, the company run by Klaus Wirth, has filed 3 patents for drugs aimed at the treatment of ME/CFS and related conditions. One drug is a THERAPEUTIC AGENT WITH SODIUM-HYDROGEN ANTIPORTER 1 INHIBITORY ACTIVITY, another is THERAPEUTIC AGENT WITH PHOSPHODIESTERASE-7 INHIBITORY ACTIVITY and the third patent is for SUBSTITUTED BENZOXAZOLE AND BENZOFURAN COMPOUNDS. The patents with explicit details can be found here:

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024042160&_cid=P10-LUMW1S-77766-1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024038089&_cid=P10-LUMW1S-77766-1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024038090&_cid=P10-LUMW1S-77766-1
 
I'm not sure if there's much evidence for any of these things ("Lactate blood levels are increased in patients with chronic fatigue. Cellular energetic and mitochondrial dysfunction are present in chronic fatigue, particularly in skeletal muscles"), but it all seems to be built around the Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome study which seemed interesting, but which no one seems to have replicated or is able to interpret meaningfully.

Could be of interest to you @Murph.
 
Jaybee00 said:
TLDR—- what are the compounds?
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I Just looked at one patent.

EndME said:
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024042160&_cid=P10-LUMW1S-77766-1
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It seems very broad scope claiming anything that acts as a NHE1 inhibitory agent. Claim 14 gets a bit more speciific but is still very broad [claims above 7 are not currently numbered but it should be 14]. Here are the key compounds listed in claim 14.
The substance as claimed in one or more of claims 1 to 13, wherein the NHE1 inhibitory agent is a member selected from the group consisting of the compounds Rimeporide, Cariporide, Eniporide, Amiloride, EIPA (5-(N-ethyl-N-isopropyl)amiloride), DMA (5-(N,N-dimethyl)amiloride), MIBA (5-(N-methyl-N-isobutyl)amiloride), HMA (5-(N, N-(hexamethylene)amiloride), 2-aminophenoxazine-3-one, 2-amino-4,4a-dihydro-4a,7-dimethyl-3H-phenoxazine-3-one, Zoniporide, 5-(4-Fluoro-3-methylphenyl)-2-methoxy-4-[4-(5-methyl-l/-/-imidazol-4-yl)piperidin-l-yl]pyrimidine, and 3-[(Cyclopropylcarbonyl)amino]-N-[2-(dimethylamino)ethyl]-4-[4-(4-methyl-l/-/-imidazol-5-yl)-l-piperidinyl] benzamide.
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As it's so broad I'm not going to dig into the coumpounds in the other two patents.
 
A bit more digging on the first patent. NHE1 is also known as SLC9A1. This particular gene was highlighted in the Wirth and Scheibenbogen papers:

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Thread : https://www.s4me.info/threads/patho...ces-in-me-cfs-2021-wirth-scheibenbogen.20256/

Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Thread : https://www.s4me.info/threads/muscl...-2022-petter-scheibenbogen-wirth-et-al.30853/

So the patents seem to be a follow on from their earlier research papers.
 
wigglethemouse said:
A bit more digging on the first patent. NHE1 is also known as SLC9A1. This particular gene was highlighted in the Wirth and Scheibenbogen papers:

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Thread : https://www.s4me.info/threads/patho...ces-in-me-cfs-2021-wirth-scheibenbogen.20256/

Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Thread : https://www.s4me.info/threads/muscl...-2022-petter-scheibenbogen-wirth-et-al.30853/

So the patents seem to be a follow on from their earlier research papers.
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As a note: SLC9A1 expression was measured in the intramural study (without significant differences between ME and HC as far as I can see).
 
The second patent is about PDE7 inhibitors with seemingly the aim of raising cAMP levels in skeletal muscle as well as stimulating Na+/K+-ATPase and NCLX in skeletal muscle. PDE7 is an enzyme encoded by the PDE7A gene (it is not listed in the supplementary data 19 of the intramural study).

The substance is a member selected from the group consisting of substances containing the structural units
pyrazolopyrimidinone, spirocycle, spirocyclic quinazoline, 8'-chloro-2',3'-dihydro-2'- oxospiro[cyclohexane-l,4'(l'H)-quinazolin]-5'-yl, thiadiazole and oxadiazole, pyridinylpyrazolopyrimidinone, arylindenopyridine, thienopyrazole, 3-methyl-lH-thieno[2,3- c]pyrazole-5-carboxamide, 3-methyl-l-(tetrahydro-2H-pyran-4-yl)-lH-thieno[2,3-c]pyrazole-5- carboxamide, imidazotriazinone, benzenesulfonamide, thiazol-2-yl-imine, (4,2-disubstituted- thiazol-5-yl)amine, amine-substituted thiopheno [2, 3-d] pyrimidine, nitrogen-containing bicycles, 4-substituted fused heteropyrimidine and fused hetero-4-pyrimidone, 2-amine- substituted quinazoline and pyrido[2,3-d]pyrimidine, purine, amine-substituted pyrimidine, amine-substituted purine, fused heterocycles containing a 2-amine-substituted pyrimidine, phthalazinone, 3,4-dihydroisoquinoline and isoquinoline, 1-phenyl-derivative-substituted 3,4- dihydroisoquinoline, sulphonamide, heterobiaryl sulphonamide, naphthalenyl of dihydropurin- 6-one, spirocondensed quinazolin-2-one, spirocyclic and substituted quinazoline, imidazotriazine, spirocondensed 4-amino-butanecarboxylic adic, 4-amine-substituted thieno[2,3-d]pyrimidine-6-carbonitrile, pyrimidin-2-yl sulfide, 5-oxo-pyrrole-3-carboxylate, thieno[2,3-b]thiophen-3-amine, indolo[2,3-b]quinoxaline, methylphenanthrene, spirocyclic and 5,8-substituted (lH,3H)-quinazoline, pyrrolopyrimidine, imidazole, isoxazole, 4-cyano-lH- pyrrole-2-carboxylate, imidazo[4,5-c]pyridine, quinazoline, 3-substituted 2,3-dihydro-2-thioxo- 4(lH)-quinazolinone and 3-substituted 2,3-dihydro-2-oxo-4(lH)-quinazolinone, 3-substituted 2,3-dihydro-2-thioxothieno[3,2-d]pyrimidin-4(lH)-one, 3-substituted 2,3-dihydro-2- thioxo[l]benzothieno[3,2-d]pyrimidin-4(lH)-one, ethyl-substituted purine-2-amine, quinazolinedione, bicyclic nitrogen-containing heterocycles substituted with an amino group, 3,5-substituted l,2,3-triazolo[4,5-d]pyrimidin-7-amine, bicyclic 3-substituted 1,2,4-triazole, 2- pyrimindinone, isochromenone, 5-imino-l,2,4-thiadiazole, 4,5-dihydroisoxazole-substituted pyrazolopyrimidine, imidazopyridine, dihydropurine, pyrrole, benzothiopyranoimidazolone, guanine, arylindenopyrimidine, sulfonylbenzene, trans-aconitic acid, thienopyrimidine/thienopyrimidinone, 2-(isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-one, isothiazole and isoxazole fused pyrimidone, imidazopyridazinone, sulfide, steroids, podocarpanes, fused thiophenes, dihydronaphthyridinedione, furan, S-substituted quinazolines, methylxanthine, and benzothienothiadiazine.
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They don't list specific formulas but simply call them
formula 1A, formula IB, compound 1, compound 2, formula 2A, formula 2B, formula 2C, compound 3, formula 3, compound 4, formula 4A, formula 4B, formula 5, formula 6, formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 7A, formula 7B, formula 8, formula 8A, formula 9, formula 10, formula 11, formula 12, formula 13, formula 14, formula 15A, formula 15B, formula 16, formula 16A, formula 17A, formula 17B, formula 18, formula 19, formula 20, formula 21, formula 22, formula 23, formula 24, formula 25, formula 26, formula 27A, formula 27B, formula 27C, formula 27D, formula 28, formula 29, formula 30, formula 31, formula 32, formula 33, formula 34, formula 35, , formula 35A, formula 36, formula 37, formula 38, formula 39, formula 40, formula 41, formula 42, formula 42A, formula 43A, formula 43B, formula 44, formula 44A, formula 44B, formula 45, formula 46, formula 47, formula 48, formula 49, formula 50, formula 51, formula 52, formula 53, formula 54, formula 55, formula 55A, formula 55B, formula 55C, formula 55D, formula 55E, formula 55F, formula 55G, formula 55H, formula 551, formula 55J, formula 56, formula 56B, formula 56C, formula 56D, formula 56E, formula 56F, formula 56G, formula 56H, formula 57, formula 57A, formula 57B, formula 57C, formula 57D, formula 57E, formula 58, formula 59, formula 60, formula 61, formula 62, formula 63, formula 63A, formula 64, dipyridamole, pentoxifylline, SUN11817, S14, S.14, and IBMX.
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The third patent is also for a PDE7 inhibitor, but made up from different compounds which are all listed in the patent.
 
ABOUT MDC002
MDC002 is a novel oral therapeutic being developed to treat all patients with ME/CFS. It has further potential in diseases where chronic fatigue is associated with Fibromyalgia, Gulf War syndrome, Lyme disease, ANCA vasculitis, Marfan syndrome, and Ehlers-Danlos syndromes. MDC002 could also be effective in curing an undisclosed rare disease (not related to fatigue). MDC002 is ready for GLP toxicity and GLP safety pharmacology studies. It is an orally applicable small molecule stimulating the sodium-potassium pump Na+/K+-ATPase and the mitochondrial sodium-calcium exchanger NCLX in skeletal muscle.
 
Perrier said:
Also learned that they are not initiating at this moment any development of a new drug.
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Oh, that's interesting. So the "novel oral therapeutic being developed" and "ready for GLP toxicity and GLP safety pharmacology studies" might be a new formulation or combination of existing drugs?
 
Kitty said:
Oh, that's interesting. So the "novel oral therapeutic being developed" and "ready for GLP toxicity and GLP safety pharmacology studies" might be a new formulation or combination of existing drugs?
Click to expand...
They said they are looking at approved drugs. Yes,Kitty, that is their plan. No timeline was offered, alas.
 
responding to a deleted post

Klaus Wirth knows about the urgency. I think, that's exaxtly why repurposing is important. It saves so much time in testing. Like Mestinon, it was already out there for Myasthenia Gravis, repurpose it for ME/CFS, and a whole portion of research can be skipped. That's used for POTS in ME/CFS and LC now; saves a lot of time. Patenting it means lower costs too (at least I hope so). When Big Pharma gets the patent it will cost a whole lot more.
Klaus Wirth took about 12 to 18 months to read all the research about ME/CFS and now he works with the Scheibenbogen group. Who else is taking that much time to read it all? I have high hopes for his work.
 
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Here is an AI summary of Klaus Wirth's talk at a conference a couple days ago. (Starts at 5:15, language is German.)


  • Introduction
    • Klaus Wirth presents a comprehensive disease concept for ME/CFS
    • Goal: Develop an effective drug strategy as a pharmacologist and drug researcher
    • Analysis based on corona infection causing severe and complex vascular and circulatory disorder
  • Circulatory Disorder and Sodium Absorption
    • Circulatory disorder leads to reduced blood flow and capillary chemical fusion
    • Muscle cells become loaded with sodium
    • Sodium-potassium ATPase transports sodium out and potassium in, requiring significant energy
    • Beta receptors may become desensitized due to high adrenaline/sympathetic nervous system activity
  • Sodium Levels and Muscle Function
    • MRI studies show increased sodium in calf muscles of patients
    • Higher sodium levels correlate with worse hand strength
    • Increased intracellular sodium leads to worse action potential and excitability
    • Hand strength correlates with prognosis and symptoms
  • Calcium Overload
    • High sodium levels cause sodium-calcium exchanger to reverse, importing calcium
    • Calcium overload may damage mitochondria (hypothesis)
    • Mitochondrial damage leads to less ATP production and increased oxidative stress
  • Vicious Cycle and Chronicity
    • Oxidative stress further inhibits sodium pump function
    • Circulatory disorder and sodium pump dysfunction create a self-perpetuating cycle
    • Repeated damage and regeneration occur with every exertion (PEM)
    • Cumulative mitochondrial damage reinforces the vicious cycle
  • Disease Progression
    • Acute infection leads to post-COVID syndrome with microvascular capillary disorder
    • Some patients (estimated 15%) develop ME/CFS
    • ME/CFS characterized as a dominant mitochondrial disorder with functional vascular damage
  • Skeletal Muscle Findings
    • Clinical signs: fatigue, exhaustion, muscle weakness, pain, and cramps
    • Limited muscle strength, early onset anaerobic metabolism, reduced oxygen uptake
    • Biopsies show muscle damage and regeneration, especially after exertion
    • Biochemical and electron microscopy evidence of mitochondrial dysfunction and damage
  • Proposed Treatment Approach
    • Stimulate sodium-potassium ATPase and mitochondrial sodium-calcium exchanger
    • Improve blood flow in muscles and brain
    • Reduce vascular permeability (anti-inflammatory effect)
    • Address hypervolemia and orthostatic stress
  • Additional Factors
    • Renal hyperexcretion contributes to hypervolemia
    • Renin paradox: lack of expected increase in renin levels
    • Excessive production of vasoactive substances in muscles may explain various symptoms
  • Drug Development
    • Active substance identified based on the proposed mechanism
    • Normal development takes about 7 years, but could potentially be shortened
    • Financing is a current challenge, causing delays in development
    • Routine work needed: safety toxicology, pharmacokinetics, etc.
 
I'm kind of getting the feeling Mitodicure is the new BC 007. People keep sharing posts about it in my group. There is also this new book that builds a lot of hype around it:

Understanding ME/CFS & Strategies for Healing by Patrick Ussher

https://www.patrickussher.com/#my-new-book

"About the book:

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) might - at last - have been explained and demystified.

Recent research has mapped out the central, interlinking mechanisms which can create an illness of exercise intolerance and post-exertional malaise. Those mechanisms include low blood volume, vascular and cardiac autoimmunity, dysfunctions in the cells and mitochondria, microclots and, in general, a reduction in blood perfusion throughout the body.

In particular, research from Germany has mapped out a convincing model for how all of these dysfunctions inter-relate and how they are likely part of one big vicious cycle. For the first time, this provides a ‘unifying model’ of what ME/CFS probably is. Aimed at a patient audience, this book offers accessible explanations of this crucial, breakthrough research by Prof. Klaus Wirth and Prof. Carmen Scheibenbogen.

This book also focusses on healing strategies and solutions. This includes discussion of various conventional medical procedures and treatments as well as of:

- the Buteyko method (to improve bodily oxygenation)
- ancestral approaches to nutrition and diet (to improve gut health and energy production)
- the Perrin technique
- treatments for microclots
- the potential strengths - and limitations - of neuroplasticity interventions.

Possible future medications are also discussed, including the ‘Mitodicure’ pill. Based on the research of Wirth, this pill could become the world’s first ME/CFS-specific medication and one which could be capable of profoundly reducing the suffering of millions worldwide. It could even be a medicine which leads to recovery.

Patrick Ussher, an ME/CFS patient, weaves together the personal and theoretical in this book, unravelling the most exciting research ‘in plain English’ but also talking about his own personal experience with various treatments to improve quality of life. He also shares advice on how to construct a life of hope and meaning, despite having a chronic illness.

This is primarily intended to be a guide and handbook for ME/CFS and Long Covid patients (although it will also likely be of interest to patients with the closely related Fibromyalgia and Postural Orthostatic Tachycardia Syndrome (POTS)). It will help many sufferers understand the true physical nature of their illness and provide them with a range of healing strategies.

But most importantly, this is a book which inspires hope for a future in which ME/CFS patients are at last treated with the dignity they deserve and in ways which truly do diminish their suffering.

The book has a foreword written by Prof. Klaus Wirth in which he describes his encounter with ME/CFS, subsequent research and initial work on developing the ‘Mitodicure’ drug."
 
Curious what is the opinion of the science savvy folks on S4me about Dr. Wirth's thesis. For a layman like myself it does look very rational and seems to explain all the symptoms that appear. Would be grateful to hear what others think. Thank you
 
Perrier said:
Curious what is the opinion of the science savvy folks on S4me about Dr. Wirth's thesis. For a layman like myself it does look very rational and seems to explain all the symptoms that appear. Would be grateful to hear what others think. Thank you
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My drive-by assessment is that it is overall a very vague theory. Perhaps a few points might be plausible, but as a unifying theory of ME/CFS, it has a lot of weaknesses. It fails to explain other hallmark ME/CFS symptoms like brain fog or other semi-consistent findings in the literature (especially thinking of metabolomics findings here). I don't think there's been any convincing evidence of high sympathetic activity which would result in desensitization. At most, I vaguely recall some studies showing that there might be a hypersensitive short term response to some stimuli, and that was in patients that had ME/CFS for a while.

Studies that have found differences in ME/CFS mitochondrial capacity have been largely been performed in isolated immune cells--meaning that they're receiving plenty of oxygen. So if there is a difference in mitochondrial function, it is unlikely to be due to oxygen availability. And as far as I know, there have been a couple studies assessing mitochondrial morphology and none of them showed strong signs of "damage"--though I don't know what exactly is meant by "damage" here.

Overall, I see a lack of evidence to confirm the vast majority of these points. Happy to be proven wrong if that evidence comes out in the future. I know that Maureen Hanson's group is planning spatial transcriptomics of muscle biopsies. If muscle hypoxia is a key player, we'd likely see a very strong HIF-1 mediated gene signature.
 
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