• Welcome to Crohn's Forum, a support group for people with all forms of IBD. While this community is not a substitute for doctor's advice and we cannot treat or diagnose, we find being able to communicate with others who have IBD is invaluable as we navigate our struggles and celebrate our successes. We invite you to join us.

Tofacitinib Experience

crohnsinct

Well-known member
Has anyone on here used Tofa? Can you share your experience? There wasn't a treatment sub forum so I am posting here. Particularly interested in anyone who used it for predominantly colonic Crohns but would love UC stories as well.

My daughter is out of options and has a total colectomy planned for 12/30 but her GI wants to throw this last Hail Mary pass at this thing.
 

my little penguin

Moderator
Staff member
Inhibition of Janus kinases [JAKs] in Crohn’s disease [CD] patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor, showed efficacy in ulcerative colitis [UC] and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in CD patients were disappointing and the primary end point of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently, phase III programmes in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are being tested in clinical programmes. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity [Tyk2 inhibitors]. In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.
from

 

my little penguin

Moderator
Staff member
As for Xeljanz, its use was recently linked to an increased risk of cancer and serious cardiovascular events. The safety problem raised concerns of pan-class implications for other JAK inhibitors. But in the SVB Leerink survey, 52% of physicians said they would be willing to try a new drug in a given class if it showed better efficacy or safety.

“We believe this bodes well for AbbVie’s Rinvoq in the JAKi class as well as Arena Pharmaceuticals’ etrasimod in the S1P1 class, as both agents have shown superior efficacy and safety than first-in-class agents Pfizer’s Xeljanz and Bristol Myers Squibb’s Zeposia,” the SVB Leerink team wrote in the report.
 

my little penguin

Moderator
Staff member
Due to its rapid onset of action and quick drug clearance, high-intensity tofacitinib has, for instance, been suggested in acute severe colitis as rescue therapy after steroid or infliximab failure.7 However, given the increased infectious risk in patients with lymphopenia and/or high dose concomitant corticosteroids combined with JAK-inhibitors,8more data, ideally randomised, are warranted before considering tofacitinib as standard of care in acute severe UC.

Does tofacitinib still have a role in the treatment algorithm of Crohn’s disease (CD), as drug development was terminated in phase II? Despite not having met the primary and secondary endpoints of the study,9 a modest – although not significant – dose-related reduction in inflammatory biomarkers was observed at week 4, suggesting a mild biological effect. Several explanations for the negative trial could be raised, including the high placebo rates, the lack of central reading and a clinically defined primary endpoint instead of an objective marker of intestinal inflammation. Hence, real-world data in (highly) refractory CD patients treated with off-label tofacitinib have been collected, reporting some effect after 8 weeks of treatment.10 As more selective JAK inhibitors (filgotinib, upadacitinib, TD-1473, PF-06651600, PF-06700841) are currently showing promising results in (late stage) drug development for CD,3 the role of tofacitinib in CD will be limited with only some off-label use in highly refractory patients, without guarantee of therapeutic success.

In conclusion, tofacitinib is a promising, first-in-class treatment option for patients with UC, whereas its added value in CD is very limited. Due to its unique characteristics, including its oral administration and lack of immunogenicity, it offers certain benefits compared with biological agents in UC. However, safety concerns remain an important limitation, especially with high dosing, which needs further study. Because of the rapidly expanding therapeutic armamentarium in UC, head-to-head trials including predictive biomarkers are urgently needed to redefine current treatment algorithms.
From
 

my little penguin

Moderator
Staff member
COMMENT
We currently have one nonselective JAK inhibitor, tofacitinib, approved for ulcerative colitis. Selective JAK inhibition is thought to be an advantage for safety without loss of efficacy. In this study, patients with Crohn disease had higher clinical and endoscopic remission rates on upadacitinib than on placebo but several experienced serious infections. Phase III research in a larger number of patients is needed to determine conclusively whether this agent is superior to what is already available.
From
 

my little penguin

Moderator
Staff member
AbbVie's blockbuster hopeful Rinvoq notched a win in a tricky-to-treat group of Crohn's disease patients, potentially adding another arrow to the company's post-Humira quiver.


The JAK inhibitor helped a "significantly" greater proportion of patients achieve clinical remission and endoscopic response than placebo did, phase 3 data from the company's U-EXCEED study show. The trial studied the AbbVie drug in certain patients with moderate-to-severe Crohn's disease, and the results came after 12 weeks of treatment with the medicine or placebo.

AbbVie expects to submit its Rinvoq application for Crohn's disease in 2022. If Rinvoq passes muster at the FDA, it would become the first JAK inhibitor approved for the disease, opening the door to some $1.3 billion in peak Crohn's disease sales by 2030, Datamonitor Healthcare predicts (PDF).
From

 

my little penguin

Moderator
Staff member
LAS VEGAS, Nevada — An oral Janus kinase 1 (JAK1) inhibitor upadacitinib (Rinvoq, AbbVie) showed high efficacy and good safety as a treatment for ulcerative colitis in a phase 3 trial.


The finding could provide some reassurance after the US Food and Drug Administration (FDA) recently warned of an increased risk of cancer and heart disease associated with medications in the same class as upadacitinib.

"Serious adverse events were numerically lower in patients on upadacitinib, and discontinuations from the study due to adverse events were also lower" than in patients taking a placebo, said Edward Loftus, MD, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota.

Loftus presented the findings from the U-ACCOMPLISH study here at the American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting.


Although other medications are approved for the treatment of ulcerative colitis, including biologics, many patients do not respond. In 2019, tofacitinib (Xeljanz) became the first JAK inhibitor approved for this condition. It works by blocking the JAK-1 and JAK-3 inflammation pathways, and at high concentrations, it also blocks the tyrosine kinase 2 (TYK2) and JAK-2 pathways.


However, adverse events seen in clinical trials of tofacitinib include pneumonia, herpes zoster, anal abscess, and Clostridioides difficile infections. And, as reported by Medscape Medical News in September, the FDA required its manufacturer, Pfizer, to add a boxed warning that includes information about the risks of stroke, cancer, blood clots, and death.

Upadacitinib may be more selective and reversible because it preferentially blocks JAK-1 or JAK1/3. In August 2019, it received FDA approval at a dose of 15 mg for adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.

But the FDA applied the same warnings to upadacitinib — and to a third related drug, baricitinib (Olumiant) — that it required for tofacitinib, even though they are not as well studied.

The FDA also limited approved uses of these three medications to patients who have not responded well to tumor necrosis factor (TNF) blockers to ensure their benefits outweigh their risks.

A Well-Tolerated Treatment
U-ACCOMPLISH is one of two phase 3 trials induction trials completed on upadacitinib.

Investigators randomized 522 people with moderately to severely active ulcerative colitis, defined as Adapted Mayo Score 5-9 with a centrally read endoscopic score of 2-3. Of those patients, the intent to treat population included 341 in the upadacitinib group (45 mg once daily) and 174 in the placebo group.


The baseline demographics and disease characteristics were similar between groups. More than two thirds of patients in both groups were white, and more than two thirds were men. In the upadacitinib group, 50.7% had responded inadequately to biologic treatments, compared to 51.1% in the placebo group.


After 8 weeks, a significantly higher proportion of patients receiving upadacitinib achieved clinical remission as defined by the adapted Mayo Score (stool frequency subscore ≤1 and not greater than baseline, rectal bleeding subscore of 0, and Mayo endoscopic subscore ≤ 1).

OutcomesUpadacitinib, n = 341Placebo, n = 174Pvalue
Table 1. Efficacy
Clinical remission (by Adapted Mayo Score), %33.54.1< .001
Clinical response (by Adapted Mayo Score), %74.525.4< .001
Endoscopic Improvement, %44.08.3< .001
Histologic-Endoscopic Mucosal Improvement, %36.75.8< .001

"In terms of the efficacy, I think it's very, very promising," said Derrick Eichele, MD, an assistant professor of gastroenterology-hepatology at the University of Nebraska Medical Center in Omaha, who was not involved in the trial.


The efficacy data were similar to those reported for tofacitinib in clinical trials, he said. "But I think again, what we're waiting to see is how is this going to be positioned in relation to tofacitinib in terms of safety profile," he told Medscape Medical News.


More patients in the upadacitinib group reported adverse events, including those deemed related to the drug. However, the proportion that were severe, serious, or led to discontinuation was higher in the placebo group. No one in the study died, and no one in the upadacitinib group had an adjudicated major adverse cardiovascular event, tuberculosis, or malignancy.

EventsPlaceboUpadacitinib
Table 2. Safety
Any Adverse Events, %39.552.9
Adverse Events Possibly Related to Study Drug, %6.823.5
Severe Adverse Events, %4.02.6
Serious Adverse Events, %4.53.2
Adverse Events Leading to Discontinuation, %5.11.7

The most common adverse events were acne, blood creatine phosphokinase elevation, and anemia, which were all more common in the upadacitinib group, and headache and worsening of ulcerative colitis, which were more common in the placebo group.


Among adverse events of special interest, anemia, neutropenia, hepatic disorder, lymphopenia, serious infection, and opportunistic infection were more common in the upadacitinib group than in the placebo group. The four opportunistic infections in the upadacitinib group included two cases of herpes zoster.


In reviewing the poster presented at this meeting, the cases of neutropenia and hepatic disorder in the upadacitinib group stood out for Eichele. But he said it's hard to pass judgment based on this amount of data. He is looking forward to a peer-reviewed publication. "I'll be interested to see what it shows in terms of the details," he said.


Phase 3 trials of upadacitinib are underway in atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, Crohn's disease, giant cell arteritis, and Takayasu arteritis as well as ulcerative colitis.


In a 52-week maintenance trial, according to a press release, malignancies (excluding nonmelanoma skin cancer) included one event among 148 people taking a 15-mg dose of upadacitinib 15, two events among 154 people taking a 30-mg dose of upadacitinib, and one event among 149 people in the placebo group.


Two cases of pulmonary embolism were reported in the 15-mg group and two cases of deep vein thrombosis were reported in the 30-mg group, compared to one event of ovarian vein thrombosis in the placebo group. One adjudicated major cardiovascular event each were reported in the upadacitinib 30-mg group and the placebo group. No one died.


The study was funded by AbbVie. Loftus reported that he is a consultant for AbbVie as well as multiple other gastroenterology drug companies. Eichele has disclosed no relevant financial relationships.


American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting: Abstract P0575. Presented October 24, 2021.


Laird Harrison writes about science, health, and culture. His work has appeared in national magazines, in newspapers, on public radio, and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at www.lairdharrison.com or follow him on Twitter: @LairdH.
 
Top