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.

 

[Vlad83]

Yes I believe I can get to 100% on my own.

Hi Sam, how are you doing? Still seeing benefits from filgotinib?

 

[junkcrap50]

@sam.d hi, I'm also interested in an update. Anything else you may have learned along the way related to it too? Have you heard of any other patients' experience on filgotinib?

 

[datadragon]

In response to:

Robert Phair
Is to ask the question, whether the pathways that are supposed to turn off the interferon-alpha positive
feedback loop are actually doing that. And so we're going to measure the messenger RNAs for not only
SOCS3, which is thought to be the major pathway by which the interferon signaling via JAK-STAT
pathway is turned off. So we need to know whether it's SOCS3, and there's another SOCS protein
called SOCS1, stands for Suppressor of Cytokine Signaling. And that's what it does, normally. But
we're hypothesizing that the positive feedback loop is present in ME/CFS cells, and not in normal
healthy controls who get an infection. So the pathway waits long enough for the adaptive immune
system to get going. And then is turned off by one or more of these suppressor pathways, is sometimes
referred to as checkpoints.

In this study, we show that the HDAC inhibitor sodium butyrate (SB) inhibited JAK2/STAT signaling and increased the expression of suppressors of cytokine signaling. SB inhibits JAK2/STAT signaling through HDAC8-mediated upregulation of SOCS1 and SOCS3 https://pubmed.ncbi.nlm.nih.gov/23111066/

Many HDACs are zinc-dependent enzymes which require the zinc ion for the catalytic reaction, yet another reason I keep mentioning zinc in tandem. Class I (HDAC1, 2, 3, and 8), II (HDAC4–7, 9, and 10), and IV (HDAC11) all require zinc. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009916/

Further to simplify, inflammation/infection is lowering zinc availability and uptake, and the zinc unavailability happens to have huge numbers of downstream effects. Interferon-y (intensive exercise also is ifn-y), Interferon-α (IFN-a) and inflammatory cytokines IL-1β, IL-6 and TNF-a, have all been shown to induce metallothioneins in the research, which can all reduce zinc availability and uptake. Low butyrate levels, confirmed by the NIH, are also shown to occur as another downstream effect from zinc deficiency. So you see that even using a drug or butyrate may not work without the zinc even for this one area in someone with excessive pro inflammatory cytokines present, while still leaving all the other areas that are also affected by the zinc deficiency. This is more of a problem with a systemwide chronic condition rather than an acute illness where fixing the single pathway would be enough to relieve the acute symptom. Drugs also can be improved by adding nutrients such as zinc in this case.

Butyrate is a strong HDAC inhibitor, as is 4-phenylbutyric acid. https://www.nature.com/articles/s41598-018-36941-9 and https://onlinelibrary.wiley.com/doi/full/10.1002/kjm2.12376

 

[sam.d]

@junkcrap50 @Vlad83 yep, progress remain very stable and keeps improving. Took a long time of withdrawal from Telfast though. I read it was about histamine receptors having to grow back. Took about 4/5 months!
Now I've completely stopped the whole KDM treatment and feel a bunch better than before I started taking it.
The only things I still take on my own are probiotics, vitamin D, vitamin C, zinc, copper, vitamin K2.
The very last crutch I'm trying to wean off of is Movicol. I still take 3 bags a day to be able to have bowel movement. This is next up on my focus list

But it all started with Filgotinib for me. That was the missing piece that got me to jump the unbridgeable gap. Now I clearly feel for the first time since 1987 that my immune system is on my side and moving with me towards full health and not away from me further and further away from homeostasis like it used to.

 

[dr. Arf]

I’m going to copy paste text I’ve written somewhere else, as I trialed it for 4 months (and might do it again)

My experience / experiment Filgotinib:

- Aug 2023: 6 weeks 200 mg/day
No noticeable effect (very minor side effects)

Followed by a pulse protocol:
- 3 consecutive days higher dosage
- 1 week stop
- 3 consecutive days higher dosage
- 1 week stop

Repeated 5 times.
DO NOT DO THIS without consulting with your doctor.

might repeat

I did have a bit improvement but I do not know if I can subscribe this to Filgo or another factor

 

[dr. Arf]

Before I started I did a little survey n=10
- thru Direct first-hand online contact
- Almost all are Meirleir patients

experience: chances better when moderate + mild (as always…)
- Most did get some improvement, a minority a substantial improvement
- You need to take for at least 4-6 months
- Expensive : minimum 850€/month (or more)
- Most stopped: a) side-effect or b) plateaued or c) expensive

Feedback: n=10
1. ++ (moderate-severe - effect 30% after 15 months - stopped)
2. -/+ (moderate/severe - 5% - stopped after 3 months due to side effects)
3. -/+ (mild - 5% - stopped after 3 months due to infection)
4. + (mild - 25-30% - then plateau reached - stopped)
5. -/+ (mild-moderate effect 20-30% over 7 months - Stopped - too expensive, relapse?)
6. + (moderate - 20-25% - 1.5 years - Difficulty quitting / withdrawal causes relapse)
7. -/+ (10% - stopped due to side effects (intestines)
8. -/+ (moderate 25% +/- 1 year (- 100 mg p/d), more energy, cognitive + gut better - but LC setback)
9. ++ (severe - 25-50% - 'my daughter improved on Filgotinib, it saved her life' - Euthanasia was cancelled)
10. - (LongCovid - no success - Short course of treatment, just a few weeks)

 

[Vlad83]

@junkcrap50 @Vlad83 yep, progress remain very stable and keeps improving. Took a long time of withdrawal from Telfast though. I read it was about histamine receptors having to grow back. Took about 4/5 months!
Now I've completely stopped the whole KDM treatment and feel a bunch better than before I started taking it.
The only things I still take on my own are probiotics, vitamin D, vitamin C, zinc, copper, vitamin K2.
The very last crutch I'm trying to wean off of is Movicol. I still take 3 bags a day to be able to have bowel movement. This is next up on my focus list

But it all started with Filgotinib for me. That was the missing piece that got me to jump the unbridgeable gap. Now I clearly feel for the first time since 1987 that my immune system is on my side and moving with me towards full health and not away from me further and further away from homeostasis like it used to.

Thank you for the update, Sam. I am glad you are doing better and keep improving!

Are you off filgo now? How long were you (or have you been) on it? How much did you improve while on filgo? (Sorry if you already answered this, but I can't seem to find it after reading the thread again.)

 

[sam.d]

Thank you for the update, Sam. I am glad you are doing better and keep improving!

Are you off filgo now? How long were you (or have you been) on it? How much did you improve while on filgo? (Sorry if you already answered this, but I can't seem to find it after reading the thread again.)

Cheers, Vlad! Please see my posts here for the answers to all your questions: https://forums.phoenixrising.me/members/sam-d.32724/#recent-content

 

[sam.d]

Before I started I did a little survey n=10
- thru Direct first-hand online contact
- Almost all are Meirleir patients

experience: chances better when moderate + mild (as always…)
- Most did get some improvement, a minority a substantial improvement
- You need to take for at least 4-6 months
- Expensive : minimum 850€/month (or more)
- Most stopped: a) side-effect or b) plateaued or c) expensive

Feedback: n=10
1. ++ (moderate-severe - effect 30% after 15 months - stopped)
2. -/+ (moderate/severe - 5% - stopped after 3 months due to side effects)
3. -/+ (mild - 5% - stopped after 3 months due to infection)
4. + (mild - 25-30% - then plateau reached - stopped)
5. -/+ (mild-moderate effect 20-30% over 7 months - Stopped - too expensive, relapse?)
6. + (moderate - 20-25% - 1.5 years - Difficulty quitting / withdrawal causes relapse)
7. -/+ (10% - stopped due to side effects (intestines)
8. -/+ (moderate 25% +/- 1 year (- 100 mg p/d), more energy, cognitive + gut better - but LC setback)
9. ++ (severe - 25-50% - 'my daughter improved on Filgotinib, it saved her life' - Euthanasia was cancelled)
10. - (LongCovid - no success - Short course of treatment, just a few weeks)

my experience with Filgo:
- my condition was moderate to severe
- 10x improvement (my subjective feeling of course, but I am a completely different person, totally life-changing, see my earlier posts for more detailed descriptions)
- took filgo 12 months. Did not feel anything for the first 6 months. Progress started super slowly from 6 months onwards.
- stopped because I tried skipping one tablet and suddenly felt better. KDM had always told me to be on the lookout for this effect. It means the immune system has regained the capacity to move to homeostasis on its own and you will feel better without medication than with medication. With Jyseleca being hyper-expensive and me being more than 60.000€ in debt, I didn't need any other reasons to stop (ps took me about 6 weeks of weaning off I think, just kept halving my dose until I was fully off)
- now stopped with all the KDM medications, I only take a bifidobacterium probiotic and still on movicol but these are not prescribed by KDM, I take these myself over-the-counter. Now working on dropping those last two things. For the rest I just take some vitamin C, D, K2, zinc and copper. Just regular humans stuff

ps from my last conversation with KDM, it would appear that I'm the patient that has made the most progress on Jyseleca of anyone he knows. So definitely consider that I might be an outlier here, although I do think that many people have missed the chance at recovery because they stopped taking it too soon. I did have to dig deep to get through the periods of sometimes rough side-effects and the long plateau where seemingly nothing happens.