Fatigatio meeting Sept 9–livestream from Germany

https://twitter.com/user/status/1701009141198930418


Here is a link to Ron Davis talk at Berlin conference last Saturday. https://icloud.com/attachment/?u=https%3A%2F%2Fcvws.icloud-content.com%2FB%2FAd0Qp2eebsOI0WQu6oLlth0KewrjAYT1_MkdDSETk2o0wwtzpfnTh_7J%2F%24%7Bf%7D%3Fo%3DAjkpnXgukEUs-S_TPgRHJi-BNsbE8e7H2vLhWAbOUkRx%26v%3D1%26x%3D3%26a%3DCAog3Wl38jmiFgZpZ4cIwE_hY2GS_Fq3IAszybLeK0u0b30SdBDTqKHBpTEY07icla8xIgEAKgkC6AMA_wdhPVBSBAp7CuNaBNOH_slqJAerlGYBXyG0SB1WLwjCGhLBo_GgUQEZS4tXueT-CBZlynX1ynIkyQLQlnrZrkQzFsP2buTWCFmyFje7hhj_s44Pth65iUipbm9w%26e%3D1696288152%26fl%3D%26r%3DE3B07A1B-41B0-4453-903F-07080FCF3B5D-1%26k%3D%24%7Buk%7D%26ckc%3Dcom.apple.largeattachment%26ckz%3D8712C54D-0F56-4DC2-842B-AB128D06ABA1%26p%3D164%26s%3DP0h0WnSzF3KJpF0VucmPZZEuXv4&uk=F2YxEu_Cybca3rqpxW2zIw&f=Berlin%20Talk.mp4&sz=39780114
 
Jaybee00 said:
https://twitter.com/user/status/1701009141198930418


Here is a link to Ron Davis talk at Berlin conference last Saturday. https://icloud.com/attachment/?u=https%3A%2F%2Fcvws.icloud-content.com%2FB%2FAd0Qp2eebsOI0WQu6oLlth0KewrjAYT1_MkdDSETk2o0wwtzpfnTh_7J%2F%24%7Bf%7D%3Fo%3DAjkpnXgukEUs-S_TPgRHJi-BNsbE8e7H2vLhWAbOUkRx%26v%3D1%26x%3D3%26a%3DCAog3Wl38jmiFgZpZ4cIwE_hY2GS_Fq3IAszybLeK0u0b30SdBDTqKHBpTEY07icla8xIgEAKgkC6AMA_wdhPVBSBAp7CuNaBNOH_slqJAerlGYBXyG0SB1WLwjCGhLBo_GgUQEZS4tXueT-CBZlynX1ynIkyQLQlnrZrkQzFsP2buTWCFmyFje7hhj_s44Pth65iUipbm9w%26e%3D1696288152%26fl%3D%26r%3DE3B07A1B-41B0-4453-903F-07080FCF3B5D-1%26k%3D%24%7Buk%7D%26ckc%3Dcom.apple.largeattachment%26ckz%3D8712C54D-0F56-4DC2-842B-AB128D06ABA1%26p%3D164%26s%3DP0h0WnSzF3KJpF0VucmPZZEuXv4&uk=F2YxEu_Cybca3rqpxW2zIw&f=Berlin%20Talk.mp4&sz=39780114
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Talks about 2 possible ways to block(?) the Itaconate shunt if I'm correctly. One is blocking CAD for which there currently isn't a known drug, researchers at Utah are working on this apparently. I saw Janet Dafoe post that they found something last week I think, something they now want to trial.

The other way is blocking production of interferon alpha which could be done by JAK-stat inhibitors. Davis shares a story about a patient that said he got cured that way but says it wasn't document by a doctor, others say it didn't help them. One JAK-stat inhibitor I know is currently being tested by De Meirleir is filgotinib, which seems to have a good safety profile. I haven't read any updates on that though.
 
Maybe it inhibits expression of ACOD1….which is different (I think).

ETA
Nope—it’s the same
 
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Solstice said:
The other way is blocking production of interferon alpha which could be done by JAK-stat inhibitors. Davis shares a story about a patient that said he got cured that way but says it wasn't document by a doctor, others say it didn't help them. One JAK-stat inhibitor I know is currently being tested by De Meirleir is filgotinib, which seems to have a good safety profile. I haven't read any updates on that though.
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Wes Ely has applied to study Baricitinib in LC.

[Investigators] asked a computer what the computer thought would be the best drug for Covid. And the computer in this Lancet paper spits out ... five or six hundred drugs ... here's the main drug. That drug was a JAK/STAT inhibitor ... FDA approved for rheumatoid arthritis and lupus ... Baricitinib.
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Baricitinib as the treatment of choice for hospitalised individuals with COVID-19 (2022, Lancet: eClinicalMedicine)

The AI-Assisted Identification and Clinical Efficacy of Baricitinib in the Treatment of COVID-19 (2022, Vaccines)

... designed this very large clinical trial, done in 12 countries, 1500 people. And it became the largest survival advantage of any drug in the Covid era. I'll say it another way. We did a double-blind, placebo-controlled trial of [Baricitinib] vs placebo for acutely ill Covid patients - anybody on oxygen. And we had the largest survival advantage of any drug, including steroids, Tocilizumab, Paxlovid ...
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Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 COV-BARRIER: a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial (2021, The Lancet. Respiratory medicine)

Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial (2022, The Lancet Respiratory Medicine)

See also —

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19 (2020, New England Journal of Medicine)
Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact (2020, Journal of Infection)
 
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Interesting that he mentions 6 months for the trial, then apparently a follow-up at 12 months. I think the idea for filgotinib was also to administer it for 6 months.
 
It was the "computer's top pick" for acute Covid. Whether this theoretically translates to utility in the Long Covid scenario is uncertain (it sounds like this RCT will go ahead though so we'll find out). It might be argued that severe acute Covid and Long Covid are at opposite ends of a spectrum or at least quite different mechanistically. Esp as they describe this being directed to the "cytokine storm" of severe acute disease.

From The AI-Assisted Identification and Clinical Efficacy of Baricitinib in the Treatment of COVID-19 (2022, Vaccines) —

In January 2020 [...] scientists at BenevolentAI, a London-based AI-enabled drug discovery company, used their AI-enhanced knowledge graph to piece together the mechanisms behind SARS-CoV-2 and then search for approved drugs capable of treating those mechanisms
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This knowledge graph combines numerous data sources incorporating information on drugs, drug targets, genes, biological mechanisms, and diseases. The knowledge graph contains machine-read literature covering the extensive collection of biomedical knowledge available (more than 30M papers are catalogued in PubMed) and the contents of dozens of structured databases. The interrelationships between biomedical concepts in the knowledge graph are enhanced by AI algorithms, which help describe their confidence, causality, and cover gaps in established knowledge.
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To analyse SARS-CoV-2 mechanisms and identify candidate drugs, BenevolentAI scientists adopted an interactive and iterative approach, combining their expertise and interactive tooling with AI-generated biomedical relationships extracted from recent coronavirus literature. The aim was to find an approved drug which could treat the “cytokine storm” responsible for many of the early deaths from COVID-19. In addition, the drug should also prevent or reduce virus infection, perhaps by inhibiting the infection of cells by the virus which was thought to be via the SARS receptor ACE2.
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After publishing the output of this AI-augmented research, the mechanistic predictions were validated, confirming that baricitinib inhibited signalling by a range of cytokines associated with the COVID-19 hyperinflammation. [...] the signalling of IL-2, IL-6, IL-10, IFNy, and GCSF in monocytes, NK, and T cells was demonstrated. Baricitinib also caused a significant reduction in plasma IL-6 in rheumatoid arthritis patients, these observations together indicating the potential of this drug to inhibit the hyperinflammation associated with COVID-19. In addition, the nM potency of baricitinib on the NAK enzymes was confirmed [...] and baricitinib was shown to reduce SARS-CoV-2 infection of human liver cells through super resolution microscopy
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Perhaps as important was the observation that baricitinib reduced the expression of ISGs associated with platelet activation, suggesting it may reduce the extensive microthrombosis observed in COVID-19.
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Baricitinib has other advantages including an oral once per day formulation, a predominantly renal route of clearance and low plasma protein binding. These properties suggested that baricitinib could be readily dosed with the antivirals being tested at the start of the pandemic, since they were largely cleared through liver metabolism. This enabled the testing of a combination with remdesivir in the ACTT-1 trial as well as with drugs being used as standard care.
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By focusing on anti-inflammatory and viral infection mechanisms [...] the knowledge graph and computational tools revealed approved drugs potentially able to act as both anti-inflammatories and antivirals. The result of this process was the identification of two drugs, baricitinib and fedratinib, approved for inflammatory indications, and ruxolitinib for myeloproliferative diseases. These were predicted inhibitors of JAKs and also of NAKs. Being JAK inhibitors, all three were likely to be effective inhibitors of cytokine signalling and complement activation and neutrophil trapping, thereby reducing the inflammatory consequences of the elevated levels of cytokines typically observed in people with COVID-19.
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baricitinib inhibited signalling by a range of cytokines associated with the COVID-19 hyperinflammation. [...] the signalling of IL-2, IL-6, IL-10, IFNy, and GCSF in monocytes, NK, and T cells was demonstrated. Baricitinib also caused a significant reduction in plasma IL-6 in rheumatoid arthritis patients
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From Epigenetic memory of coronavirus infection in innate immune cells and their progenitors (2023, Cell) —

Our data uncovered activation of the IL-6R signaling pathway as a potential mediator of durably altered hematopoiesis and innate immune memory. IL-6, a pleiotropic cytokine, activates immune cells, promotes cytokine secretion and cell recruitment, and the maintenance and differentiation of HSPC [haematopoietic stem and progenitor cells].
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Surprisingly, IL-6R blockade during acute infection strongly influenced GMP [granulocyte-monocyte progenitors] levels up to 1-year post-infection; untreated individuals featured higher GMP frequencies, whereas IL-6R blockade-treated individuals featured lower GMP levels. We validated these findings by modeling IL-6R blockade in a severe mouse coronavirus infection, recapitulating results from humans. One durable molecular signature of IL-6R signaling during acute infection was sustained chromatin accessibility at STAT3 motifs in both HSPC and monocytes/macrophages.
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Notably, a previous study reported that STAT3, in conjunction with AP-1 TFs [transcription factors], can establish and maintain epigenetic memory of inflammation in epidermal stem cells, highlighting the possibility of an analogous mechanism in post-COVID-19 HSPC. We found that STAT3 motif accessibility corresponds with increased accessibility of motifs for CEBPb (also named nuclear factor IL-6), a prominent myelopoiesis TF. In addition, both STAT3 and CEBPb motif accessibility in convalescence was reduced by IL-6R blockade during acute infection.
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I don't know whether the indicated benefit of targeting IL-6 is only in the acute phase or might show benefits in established LC.
 
@Jonathan Edwards

Could you please give your opinion on the potential use of Baricitinib (as well as fedratinib and ruxolitinib) to treat MECFS. Please see above discussion. As @SNT Gatchaman mentions these drugs might be more appropriate for acute Covid rather than LC MECFS. Thank you.
 
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