Janus kinase (JAK) inhibitors show real promise as effective and safe therapeutic agents for the management of inflammatory bowel disease (IBD), Hans Herfarth, MD, PhD, said at the virtual regional meeting of Advances in Inflammatory Bowel Diseases (AIBD) on September 25.

Dr Herfarth is the codirector of the Multidisciplinary Center for IBD Research and Treatment at the University of North Carolina at Chapel Hill.

He reviewed real world data on tofacitinib, the only JAK inhibitor approved for use in IBD. In a  meta-analysis of 17 studies comprising 1162 patients—90% of whom had been exposed to biologic therapy—62% to 64% of patients in 14 studies demonstrated response to tofacitinib during induction periods of 8 to 16 weeks. In 11 studies, 35% of patients achieved remission at 8 weeks, while 47% experienced remission during a longer induction period of 12 to 16 weeks. More than 300 patients achieved steroid-free remission during the 8- to 12-week induction period and 252 showed mucosal healing. All patients received 10 mg twice daily.

“Most importantly, there were no major adverse coronary events or thromboembolic events in any of these studies,” Dr Herfarth stated.

There were 13 reported cases of herpes zoster (3.4%). He explained that all patients with IBD are at increased risk of herpes zoster—approximately twice the risk of the general population. Risk increases with age, with patients aged 50 years and older considered high risk, as are those with a history of shingles or Asian ancestry. In addition, he noted, steroids and thiopurines also increase the risk of patients with IBD developing shingles 2- to 3-fold, while the increased risk with tofacitinib is 2- to 6-fold.

Earlier this year, the US Food and Drug Administration (FDA) approved the Shingrix vaccine for adults 18 and over at increased risk of shingles due to immunodeficiency caused by disease or therapy. It had previously been approved only for people aged 50 years and older.

“ALL IBD patients on tofacitinib, steroids, and/or thiopurines should definitely be vaccinated against shingles,” Dr Herfarth stated.

One study not included in the meta-analysis was the TOUR study, in which Dr Herfarth participated. Using real-time electronic patient-reported outcomes data, his team was able to assess when to discontinue steroids and determine the time to response to tofacitinib. As measured by the simple clinical colitis activity index (SCCAI), patients began to experience significant improvement by day 3 of tofacitinib therapy independent of steroid use.

“This study confirms the OCTAVE results showing rapid onset of action of tofacitinib,” Dr Herfarth noted. “The take-home message is that tofacitinib has a rapid onset of action and overall appears to be very effective in patients who have failed multiple biologics.”

One question that remains is if and when to reduce the dosage of tofacitinib from 10 mg bid to 5 mg bid, Dr Herfarth noted. In the RIVETING trial, conducted in Europe, 140 patients who had been in stable remission for more than 6 months and had taken tofacitinib 10 bid for 2 years were randomized 1:1 to continue at 10 mg bid or reduce to 5 mg bid. At 6 months, 90% of the patients who remained on 10 mg bid of tofacitinib remained in remission compared with 77% of the patients who received the reduced dose.

He added that in the US, tofacitinib is only approved for us with patients who have failed with at least 1 anti-tumor necrosis factor (TNF) biologic and the FDA labeling advises reducing the dosage to 5 mg bid whenever possible.

Comparing modified Mayo scores at 6 months, he explained, among those with a Mayo score of 1, 63% of those who got the reduced dosage remained in remission vs 84% of those who continued the higher dose. “With a difference of 21%, clearly those on 10 mg bid were better off,” he stated.

“From the RIVETING trial, I think what we can take home is that if you have remaining endoscopic inflammation on 10 mg bid or if you have failed a TNF, the reduction from 10 mg to 5 mg bid is risky, and you have a better chance if you stay on 10 mg bid,” Dr Herfarth stated.

In addition, he said, adverse event and serious adverse event rates were similar across both groups, and no deaths were reported.

The possibility of using tofacitinib in combination therapy with a biologic is generating interest, Dr Herfarth reported. He referenced a single-center Australian case series of 7 patients taking 10 mg bid tofacitinib after incomplete response to a biologic—5 patients to infliximab, 1 patient to vedolizumab, and 1 patient to ustekinumab. All patients remained on this combination therapy for 6 months; 5 of 7 patients showed “a significant response in fecal calprotectin as well as endoscopic response.”

A retrospective 2-center study conducted in St Louis among 25 patients with UC and 10 with Crohn disease (CD) combined tofacitinib 10 mg bid with vedolizumab, infliximab, or ustekinumab. Of the 28 patients evaluated at week 8, 50% demonstrated response, with no difference in efficacy seen between the UC and CD groups.

“This is an interesting approach,” Dr Herfarth said. “If you a have a partial response to a biologic you can add tofacitinib either in a synergistic fashion, as with infliximab, or in a complementary fashion as with vedolizumab.”

Another potential for tofacitinib, he said, is in the treatment of patients with acute severe UC (ASUC). “There was a long debate that began after 4 inpatients at the University of Michigan showed relatively good response after starting tofacitinib at 10 mg tid,” he explained. “Of note, this is not an FDA-approved dosing.”

The institution then extended the study to 40 patients with ASUC, with 24 receiving 10 mg tid and 16 receiving 10 mg bid over a mean inpatient duration of 9 days. The investigators performed a retrospective random match of 1:3 tofacitinib to controls, according to admission date and gender. The tofacitinib group was 100% biologic exposed vs 40% in the control group.

The results showed a 15% difference in the rate of colectomy between the group receiving 10 tid tofacitinib vs historic controls. “There was not much difference between the historic control and patients receiving tofacitinib at 5 mg bid,” and there was no difference in safety among the groups, Dr Herfarth reported.

A study conducted in France among a group of patients refractory UC provided similar results, with a colectomy rate of 21% at 3 months among those treated with tofacitinib and steroid. “The conclusion is that tofacitinib may be a novel induction regimen for ASUC at 10 mg tid,” Dr Herfarth said. “Clearly this approach of inpatient application of tofacitinib should be further explored. We should explore  as well whether the higher dose is more effective than the standard approved dose of 10 mg bid.”

Noting that tofacitinib is a “pretty broad” agent that blocks all JAKs, Dr Herfarth explained that new, more selective JAK inhibitors are on the horizon.

In recently published trial results, filgotinib, which selectively blocks only JAK 1, showed a delta of 10.8 between placebo and filgotinib groups among biologic-naïve patients, and 7.3 among biologic-exposed participants. The OCTAVE trial showed an overall delta of 11.4 between placebo and drug groups with no real difference among patients who were biologic-naïve or biologic-exposed.

The results of trials of upadacitinib have been “very impressive” at week 8 of the

U-ACCOMPLISH and U-ACHIEVE trials, Dr Herfarth stated, including a delta of 30% at week 8 per partial adapted Mayo score. “the response rate at week 8 is up to nearly 80%. This is incredibly exciting. This appears to be a very effective drug, and I hope we can test this drug soon in the real world.”

—Rebecca Mashaw

Reference:

Herfarth, H. The optimal use and future use of JAK inhibitors in the management of inflammatory bowel disease. Presented at: Advances in Inflammatory Bowel Diseases regional meeting. September 25, 2021. Virtual.