First JAK Inhibitor Approved by FDA for Treatment of Crohn's

[Scipio]

Rinvoq:

https://www.medpagetoday.com/gastro...8&utm_term=NL_Daily_DHE_dual-gmail-definition
A new class of drugs for Crohn's and thus new treatment options. Due to increased risk of blood clots and cancer, use of Rinvoq is to restricted those Crohn's patients who have already flunked therapy with anti-TNFs such as Remicade or Humira.

 

[Crohn2357]

This seems to be the most unsafe drug ever to get an approval for the treatment of CD.

I wouldn’t consider using jak inhibitors unless I really had no other choice.

 

[sashaz]

Im newly on Rinvoq, should I ask to change it?

 

[cyberviper]

I remember getting asked to join a trial for it, thankfully i refused

 

[kiny]

I remember getting asked to join a trial for it, thankfully i refused

Good for you. I hope people realize the danger of these drugs and their lack of effectiveness in crohn's disease. There is enormous financial pressure on companies due to anti-TNF patents expiring and cheaper biosimilar replacing them.

I warned multiple times about them:

https://crohnsforum.com/threads/ano...ils-clinical-trials-for-crohns-disease.87050/

 

[NeverBeenEasier]

Good for you. I hope people realize the danger of these drugs and their lack of effectiveness in crohn's disease. There is enormous financial pressure on companies due to anti-TNF patents expiring and cheaper biosimilar replacing them.

I warned multiple times about them:

https://crohnsforum.com/threads/ano...ils-clinical-trials-for-crohns-disease.87050/

Are you able to provide a study that makes you so confidently say they lack effectiveness in Crohn's disease?

Also, Rinvoq is a second-generation JAK inhibitor that targets specifically JAK1 versus first-generation JAKi that tend to inhibit JAKs rather unspecifically.

 

[kiny]

139 patients
Moderate to severe crohn's disease.
No difference from placebo.
1129×1168
346,3 kB



280 subjects.
Moderate to severe crohn's disease.
Efficacy not significantly different from placebo.


78 patients.
Moderate to severe crohn's disease.
No difference from placebo.

 

[Andersen007]

Completely unrelated topic, but the other day I was wondering about how on Earth is it possible that even for really good drugs like anti TNF-s, the difference between “no treatment whatsoever” and “placebo” is often just as big, or even bigger than “placebo” and the “effective drug”. E.g. in many studies I see 0-5% remission rate with no treatment, 25-30% with placebo, 45-50% with an “effective drug”. This tends to be true for many serious organic diseases and their medication. It made me wonder whether if I would be less sceptical, would I have a shitload of treatment options with 25-30% to get into remission with each convincing placebo, like acupuncture, random herbal tablets, etc?

 

[Entchen]

Completely unrelated topic, but the other day I was wondering about how on Earth is it possible that even for really good drugs like anti TNF-s, the difference between “no treatment whatsoever” and “placebo” is often just as big, or even bigger than “placebo” and the “effective drug”. E.g. in many studies I see 0-5% remission rate with no treatment, 25-30% with placebo, 45-50% with an “effective drug”. This tends to be true for many serious organic diseases and their medication. It made me wonder whether if I would be less sceptical, would I have a shitload of treatment options with 25-30% to get into remission with each convincing placebo, like acupuncture, random herbal tablets, etc?

That’s a fair question. The answer from the literature (I’m away from my laptop but I think I have the references somewhere) is that what gets labelled a placebo effect is more likely just one small part genuine placebo effect (belief) and one huge part regression to the mean (passage of time). After a while, most flare ups of any disease will improve at least somewhat. Most Crohn’s flare ups will resolve on their own, given time (um, notwithstanding all the damage it might leave behind!). And so if a trial runs, say, 6 months or 12 months, many participants will see their active disease kind of run its natural course—both in the placebo and in the treatment arms. For those in the treatment arm, this improvement is credited to the drug. For those in the placebo arm, this improvement is attributed to the placebo effect. But it’s not the belief that singly leads to the improvement, it is also the “treatment” of time.

In a formula, Outcome = Treatment X + Time, but what happens in drug trials is this can get a bit lazily labelled as Outcome = Treatment X OR Outcome = Placebo.

 

[asadmom]

Completely unrelated topic, but the other day I was wondering about how on Earth is it possible that even for really good drugs like anti TNF-s, the difference between “no treatment whatsoever” and “placebo” is often just as big, or even bigger than “placebo” and the “effective drug”. E.g. in many studies I see 0-5% remission rate with no treatment, 25-30% with placebo, 45-50% with an “effective drug”. This tends to be true for many serious organic diseases and their medication. It made me wonder whether if I would be less sceptical, would I have a shitload of treatment options with 25-30% to get into remission with each convincing placebo, like acupuncture, random herbal tablets, etc?

Patients in clinical trials go through much more thorough testing and receive dedicated and personalized support. Patients are seen way more often and get to talk about anything and everything that's happened to them since all symptoms (including psychological) need to be logged. They get exceptional care and attention and the placebo effect happens when they feel they are better cared for and with this new found hope (although they are in the placebo arm) and way more testing and the specialists they have access to, many just feel better.

 

[Waldo]

The placebo effect tells us there is a psychological component to inflammatory bowel diseases. It seems that traumatic events can lead to physical illness, and that being cared for (by others or oneself) can dampen symptoms.
The field is called psychoneuroimmunilogy (PNI) and is worth following in my opinion.

 

[NeverBeenEasier]

139 patients
Moderate to severe crohn's disease.
No difference from placebo.
1129×1168
346,3 kB
View attachment 4802


280 subjects.
Moderate to severe crohn's disease.
Efficacy not significantly different from placebo.
View attachment 4801

78 patients.
Moderate to severe crohn's disease.
No difference from placebo.
View attachment 4803

Tofacitinib and Filgotinib is literally not approved and most likely will not be approved for Crohn's disease so what is the point of discussing the efficacy of these two drugs when there is Upadacitinib, a JAK-1 selective inhibitor, that has been approved for Crohn's.

Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease | New England Journal of Medicine (nejm.org)

"A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons)."

These are definitely some awesome looking results.

I'll also attach some statistics surrounding the "black box" warning applied on ALL JAKS because of data extrapolation from Tofacitinib (A JAK inhibitor that selectively inhibits Jak 3,1,2):
- Venous Thrombus Embolism: Incidence rates for Tofacitnib (33/10,000) vs TNF inhibitor (20/10,000).
- MACEs: Incidence rates for Tofacitnib (91/10,000) vs TNF inhibitor (73/10,000).


This is a negligible difference. Plus, these risk factors were mostly associated with patients older than 50 and with other comorbidities. Plus, the findings were mostly in those with rheumatoid arthritis, not IBD.

Waiting for JAK inhibitor safety data | RMD Open (bmj.com)
Safety of Janus Kinase Inhibitors in Inflammatory Bowel Diseases - PMC (nih.gov)

 

[NeverBeenEasier]

Completely unrelated topic, but the other day I was wondering about how on Earth is it possible that even for really good drugs like anti TNF-s, the difference between “no treatment whatsoever” and “placebo” is often just as big, or even bigger than “placebo” and the “effective drug”. E.g. in many studies I see 0-5% remission rate with no treatment, 25-30% with placebo, 45-50% with an “effective drug”. This tends to be true for many serious organic diseases and their medication. It made me wonder whether if I would be less sceptical, would I have a shitload of treatment options with 25-30% to get into remission with each convincing placebo, like acupuncture, random herbal tablets, etc?

Take a closer look at the second study posted by Kiny (Panes et al.)
You can see that the placebo group was on corticosteroids during both the induction and maintenance study at which they were receiving a very slow 5 mg taper.

Steroids work like a charm and pushing people into acute-remission. This is a HUGE confounding variable and most likely explains why the control-arm and experimental-arm had such similar response rates.

 

[eduard]

I was invited to participate in the Upadacitinib trial, and I agreed. Initially, I began to feel excellent and noticed weight gain (+15 kg).

However, after a year and a half, my calprotectin levels soared to over 800, and then over 1000. Despite experiencing poor stool quality, I still felt good. Suddenly, I developed a fever and chills, leading to the discontinuation of my participation in the trial.

They never told me that I had developed fistulas in my descending colon (splenic flexure).
Additionally, I experienced Penile Mondor's disease, which resolved after one month.

Be careful!

 

[Andersen007]

Damn, sorry to hear that! I am a bit confused tho - I thought that you cannot really become "resistant" to JAK inhibitors like anti-TNF-s due to the different mechanism of action - I guess naive on my part!

 

[NeverBeenEasier]

Biologics (e.g. TNF-alpha inhibitors like Humira, IL-23 inhibitors like Skyrizi, etc.) all fall under the category of monoclonal antibodies. The immune system is able to recognize these antibodies and may "destroy" them resulting in medication failure.

Upadacitinib (Rinvoq) is NOT a biologic, so, it is not a monoclonal antibody. However, that doesn't mean you can't fail these medications.

Sometimes, medications just stop working. You can fail biologics due to medication non-response despite normal drug levels and no antibody formation. If Upadacitinib worked for some time but eventually fails, it's most likely due to the medication not working well for you anymore. No rhyme. No reason*.

*There's always a reason. But it's probably some complex mechanism.

 

[eduard]

Among all the participants in the hospital study, I was the sole individual who lasted the longest (1 year and a half).
The medication remains effective until it isn't.

 

[Andersen007]

Among all the participants in the hospital study, I was the sole individual who lasted the longest (1 year and a half).
The medication remains effective until it isn't.

so everyone else lasted less than that? damn, thats not encouraging.

have you been able to find something that works for you since?

 

[eduard]

Remicade - 1 year
Upadacitinib - 1 year and a half

I'm currently on Stelara, but it appears to be less effective compared to Remicade and Upadacitinib.
However, it works 7 weeks out of 8. They need to adjust the dose...
Occasionally, during the first week following the dose, I experience symptoms of diverticulitis. Therefore, I need to take paraffin oil to empty my bowels and prevent obstructions.

 

[my little penguin]

@eduard
My adult child has been on Stelara for over 6 years (since he was a teenager )
He has needed the dose frequency to be every 4 weeks for all of that time.
Some folks just need a higher frequency for it to work .
Hope the increase helps you

 

[J100]

I came across the below link. Not sure if it is of some use or not?

https://ir.organovo.com/news-releas...data-presented-digestive-disease-week-ddw2024

 

[Crohn2357]

Tofacitinib and Filgotinib is literally not approved and most likely will not be approved for Crohn's disease so what is the point of discussing the efficacy of these two drugs when there is Upadacitinib, a JAK-1 selective inhibitor, that has been approved for Crohn's.

Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease | New England Journal of Medicine (nejm.org)

"A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons)."

These are definitely some awesome looking results.

I'll also attach some statistics surrounding the "black box" warning applied on ALL JAKS because of data extrapolation from Tofacitinib (A JAK inhibitor that selectively inhibits Jak 3,1,2):
- Venous Thrombus Embolism: Incidence rates for Tofacitnib (33/10,000) vs TNF inhibitor (20/10,000).
- MACEs: Incidence rates for Tofacitnib (91/10,000) vs TNF inhibitor (73/10,000).


This is a negligible difference. Plus, these risk factors were mostly associated with patients older than 50 and with other comorbidities. Plus, the findings were mostly in those with rheumatoid arthritis, not IBD.

Waiting for JAK inhibitor safety data | RMD Open (bmj.com)
Safety of Janus Kinase Inhibitors in Inflammatory Bowel Diseases - PMC (nih.gov)

https://pmc.ncbi.nlm.nih.gov/articles/PMC11532615/

https://pmc.ncbi.nlm.nih.gov/articles/PMC10838816/