Filgotinib (JAK1 inhibitor) future of CFS/ME treatment?

[sam.d]

What happened between the Filgotinib (started Feb 2022) and the comment below you made in Jan. 2019? Did you get worse? Do you think the Filgotinib helped more? Do you think it is going to be more permenant?

I'd say each step was a 10x improvement

So I went from completely bedridden in 2017, say 0.1% of my old self (nearly dead) to 1% of my old self.
Then with filgo I went from 1% to 10%.
Now I can easily do another 10x to be back to 100% my old self. With 100% being equal to top competitive athletic shape.

Each 10x felt life-changing to me, no matter where I was in absolute terms.

I'd say I did regress a bit between 2019 and 2022, simply because of taking antibiotics for so long and just getting more and more emaciated from a super restrictive diet. I weigh 53kg while being 180cm tall (117 lbs - 5' 10'') and I used to weigh about 25 kg or 55 lbs heavier 10 years ago. So I'm really ultra auschwitz level emaciated because of the illness and not being able to eat carbs or work out etc

 

[junkcrap50]

Thanks.

• Do you think the final 10x improvement, from 10% (now) to 100%, will only require yourself?
  • You now now need to rebuild yourself by being healthy & regaining your stregnth - so good diet, sleep, exercise, etc.
  • Like, do you think your CFS/Lyme is cured but now only have left the consequences of CFS from being unable to eat, emancipated, bedbound, and inactive?
• Or do you suspect you need another "miracle" intervention (miracle meaning a CFS treatment that works and leads to a huge improvement)?

(I imagine it's hard to tell or predict with being so weak, and conversely, with how good you feel since it's a big improvement and new, which might wear-off after a new baseline).

 

[sam.d]

Thanks.

• Do you think the final 10x improvement, from 10% (now) to 100%, will only require yourself?
  • You now now need to rebuild yourself by being healthy & regaining your stregnth - so good diet, sleep, exercise, etc.
  • Like, do you think your CFS/Lyme is cured but now only have left the consequences of CFS from being unable to eat, emancipated, bedbound, and inactive?
• Or do you suspect you need another "miracle" intervention (miracle meaning a CFS treatment that works and leads to a huge improvement)?

(I imagine it's hard to tell or predict with being so weak, and conversely, with how good you feel since it's a big improvement and new, which might wear-off after a new baseline).

Yes I believe I can get to 100% on my own. I'm now actively weaning off all my meds as detailed above. I aim to be completely medicine free hopefully this year, else next year. The only consequences left now are neurological. This is well documented and it's the reason why suddenly I'm able to drop so many medications that I absolutely couldn't do without not so long ago. So all the work now is on reconditioning the nervous system to get better and improve my overall physical shape through incremental training. I couldn't do it before because my inflammation was too high. But after the filgo therapy my inflammation has reduced sufficiently that this has become possible.

It comes naturally and you'll clearly feel it when you're ready. During the first month of filgo I skipped one tablet and fell into a black hole that day. A complete drop in energy and back to immense fatigue. But 12 months in I tried it again and surprisingly that day felt a huge boost in energy from skipping a tablet. The complete opposite effect. That was the day I knew I was ready. KDM had always prepared me how to recognize that moment where the immune system gets closer to its natural homeostasis and starts to pick itself up again. That's the moment where you will actually start to feel better than when you're taking immune-suppressants like filgo, because the immune system can stand on its own legs more and does better without interference.

 

[junkcrap50]

That's awesome!

The only consequences left now are neurological. This is well documented and it's the reason why suddenly I'm able to drop so many medications that I absolutely couldn't do without not so long ago. So all the work now is on reconditioning the nervous system to get better and improve my overall physical shape through incremental training.

I don't understand what you mean by the above. Something neurological doesn't seem like it can be fixed on it's own. Nor do I understand how "reconditioning the nervous system" is possible or works. Do you mean psychological (I don't think so) or your sympathetic/parasympathetic nervous system? Also, where and what is it documented as you say? In published papers or documented in your medical history file?

 

[dr. Arf]

Happy for your progress! First thought, Jak1 was required for both signaling and biologic response induction by IFNα and IFNγ, however it is also needed for induction of anti inflammatory IL-10–dependent responses as well as quite a number of others that you are also blocking now ongoing. It seems you are not blocking the IFNa (if stuck on) leading to IFNy and turning it off, instead blocking the response effect of that signaling, but in doing so also blocking the effects of other important cytokine responses below. IFN-a, IFN-,y, and EGF all lead to the phosphorylation of Jakl and Statl, which might suggest a linear pathway with Jakl as the final active kinase after IFN-a activation of Tyk2 and IFN-y activation of Jak2. Not a great place to target it seems but at minimum maybe some day on/day off experimenting rather than every day. https://www.nature.com/articles/s41392-021-00791-1 https://www.cell.com/cell/fulltext/S0092-8674(00)81166-6 https://www.science.org/doi/10.1126/science.8197455 https://pubmed.ncbi.nlm.nih.gov/12686512/

JAK1 is widely expressed in tissues and can phosphorylate all STATs. JAK1 is phosphorylated by four cytokine-receptor families: (1) Cytokine receptors with the γc receptor subunit, IL-2 receptor, IL-4 receptor, IL-7 receptor, IL-9 receptor, and IL-15 receptor; (2) class II cytokine receptors include the IFNα/β receptor, IFN-γ receptor, and IL-10 family cytokine receptors; and (3) receptors with a gp130 subunit, including the IL-6 receptor, IL-11 receptor, ciliary neurotrophic factor (CNTF) receptor, oncostatin M (OSM) receptor, leukemia inhibitory factor (LIF) receptor, and cardiotrophin-1 (CT-1) receptor.34 JAK1 can promote body haematopoietic function after being activated by IL-3, IL-5, IL-7, granulocyte–macrophage colony-stimulating factor (GM-CSF), or granulocyte colony-stimulating factor (G-CSF).35 JAK1−/− mice are perinatal dead and exhibit neurological disease and severe lymphocyte damage caused by deficient of LIF and IL-7 signal, JAK2-knockout mice exhibit specific defects in IFN-γ-related biological responses, but they do not respond to IFN-α or IFN-β. It also has numerous other effects mentiioned and appears not good to constantly inhibit without breaks.

@datadragon can you try explain the gist of your post in more layman terms?

Not a great place to target it seems but at minimum maybe some day on/day off experimenting rather than every day.

Especially this one?

Do you mean that if you follow the Robert Phair model, This seems does not seem the ideal drug, but it could work ?

Day on/off experimenting, because you expect immediate effect?
BTW “mean terminal half-lives of filgotinib and GS-829845 were approximately 7 and 19 hours, respectively”

 

[datadragon]

Do you mean that if you follow the Robert Phair model, This seems does not seem the ideal drug, but it could work ?

Day on/off experimenting, because you expect immediate effect?

First thought is restoring butyrate levels, perhaps sodium butyrate, seems to be the first target to look at as in later stages your body lacks acetyl-coa to make butyrate which is found low in ME/CFS, and without acetyl-coa you end up unable to make energy properly in the krebs cycle (Dr Phairs itaconate shunt info). Butyrate is metabolized to acetyl-coa which should help fix the low acetyl-coa leading to the itaconate shunt. The immune system is also stuck in a TH2 mode and Butyrate as a HDAC inhibitor mentions it can restore TH1 also as I was thinking here https://forums.phoenixrising.me/thr...ed-abnormalities-in-me-cfs.90173/post-2437768

Targeting the IL-1a or better interleukin-1 receptor antagonist (IL-1ra) that blocks the action of interleukin-1may be helpful in earlier stages as it could prevent further lowering of orexin and putting you further into TH2. https://forums.phoenixrising.me/threads/could-oral-topical-minoxidil-help-cfs.90310/post-2437242 Just some early thoughts from my scattered research among posts here and there.

can you try explain the gist of your post in more layman terms?

Jak1 is needed for IFNa and iFNy but its also needed for anti inflammatory IL-10 response and others so you are essentially blocking everything and not just a specific single target like IL-10 or IFNa. Doing so ongoing may cause unintended effects due to blocking everything and therefore just thought on/off like sam said is using now might work better was my thought there.

 

[dr. Arf]

Doing so ongoing may cause unintended effects due to blocking everything and therefore just thought on/off like sam said is using now might work better was my thought the

So if half-lives of filgotinib and GS-829845 are approximately 7 and 19 hours, respective original states can be restored within a day?
Or are the effects of the changed signaling further along the chain longer lasting?

Another thing you might have an opinion about:
R. Phair has mentioned somewhere that a Jak Stat inhibitor dose might really matter, as you have to reach "escape velocity" with a high enough dose or it's not going to do anything.

And - now I am really struggling with memory - than for 3 consequent I’ve days, followed by interval?

Does this make sense to you?

 

[annaloecher]

Another thing you might have an opinion about:
R. Phair has mentioned somewhere that a Jak Stat inhibitor dose might really matter, as you have to reach "escape velocity" with a high enough dose or it's not going to do anything.

i’m wondering if phair is right and it‘s all about a high enough dose but then it only takes 3 days to flip the switch. would taking a high dose filgotinib (e.g. 500 mg/day) for 3 days only maybe have the same effect as long term standard dosing? pls contact me if anyone has tried or will try this.

 

[dr. Arf]

Instructive JAK STAT overview

 

[Anish04]

Is tofacitinib a bad idea? Although it's not selective to JAK1 but itd a inhibitorof JAKSTAT 1 and 3 and upto a extent for 2.

 

[hmnr asg]

Is tofacitinib a bad idea? Although it's not selective to JAK1 but itd a inhibitorof JAKSTAT 1 and 3 and upto a extent for 2.

might have more side effects (not really sure) but i would give it a try myself if i could get a hold of it.