‘Don’t shy away’ from JAKs in IBD: Monitor patient outcomes, understand potential risks
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Despite an existing class-wide black box warning, 45% of health care providers felt cardiovascular concerns related to Janus kinase inhibitors “were irrelevant” to patients with inflammatory bowel disease, according to survey results.
Additional data from the prospective, cross-sectional study published in the European Journal of Gastroenterology and Hepatology showed that of 364 surveyed GIs from 48 countries, 31% reported Janus kinase (JAK) inhibitor use outside of market authorization and 62% perceived the long-term safety profile of JAK1-selective drugs to be favorable to tofacitinib.
“Broadly speaking, provided there are no contraindications or cautions, JAK inhibitors are an ideal first-line advanced treatment for patients with IBD,” Sailish Honap, MD, a gastroenterologist and IBD research fellow in the School of Immunology & Microbial Sciences at King’s College London, told Healio Gastroenterology. “They are a highly effective group of drugs with numerous advantages over other therapies, particularly oral delivery, rapid onset of action and no immunogenicity.”
According to a market analysis conducted by Spherix Global Insights in August 2023, in which 200 gastroenterologists completed surveys about their prescribing habits, 31% reported positioning JAKs as first-line treatment for patients with severe ulcerative colitis. The leading reasons were speed of onset of action (56%), favorable efficacy perceptions (55%) and a desire for specific mechanism of action (48%).
Currently, JAK inhibitors in the U.S. are indicated for patients with a history of anti-tumor necrosis factor therapy use. Despite this, Miguel Regueiro, MD, professor of medicine and chief of the Digestive Disease Institute at Cleveland Clinic, reported that JAK efficacy makes it an appealing first-line option that may be available down the road.
“To me, JAK inhibitors have been so effective at treating severe UC that it would be appealing to use them early and not just in the severe category after a patient has failed an anti-TNF,” he said.
Currently, the FDA has only approved two JAK inhibitors: Xeljanz (tofacitinib, Pfizer) for the treatment of patients with moderate to severe UC and Rinvoq (upadacitinib, AbbVie), which has a dual indication for both UC and Crohn’s disease.
In this Healio Gastroenterology exclusive, IBD experts broke down when to prescribe JAK inhibitors, their risk vs. benefit profile and future in the treatment of IBD.
Data derived from Patient Chart Dynamix: Triggers and Drivers in Inflammatory Bowel Disease: New Starts (US) 2023. https://www.spherixglobalinsights.com/gastroenterology/. Published Dec. 23, 2023. Accessed Mar. 28, 2024.
‘Hang Up or Hesitancy’ Around Prescribing JAK Inhibitors
In the past 20 years, the introduction of numerous therapies for IBD, including Remicade (infliximab, Janssen), Stelara (ustekinumab, Janssen) and Entyvio (vedolizumab, Takeda Pharmaceuticals), has improved clinical outcomes among patients. However, primary and secondary nonresponse, loss of response or adverse events often lead to treatment discontinuation. These downstream effects have created a need for new compounds to treat IBD with improved safety and efficacy profiles.
JAK inhibitors were first introduced in 2018 as the first members of the small-molecule family to modulate downstream cytokine signaling in immune-mediated diseases. Currently, the four types of JAK inhibitors that exist include: JAK-1, JAK-2, JAK-3 and tyrosine kinase 2 inhibitors. In IBD, JAK inhibitors that target JAK-1 and JAK-3 have been showed to induce a quick clinical response and, compared with TNF-alpha or anti-alpha-4/beta-7 integrin inhibitors, simultaneously block multiple pro-inflammatory cytokines. These mechanisms of action carry the potential to improve therapeutic response, Claudia Herrera-deGuise, MD, and colleagues reported in Frontiers in Medicine.
“In 2024, we have many options for treatment of patients with both UC and Crohn’s disease,” Jami A. Kinnucan, MD, senior associate consultant in the section of gastroenterology and hepatology at the Mayo Clinic in Jacksonville, Florida, told Healio Gastroenterology. “In patients with acute severe ulcerative colitis, there are excellent data for the use of JAK inhibitors as rescue therapy and studies showing reduce rates of colectomy. In patients with moderate to severe Crohn’s disease, upadacitinib is the only approved JAK inhibitor.
“There are also emerging data for use in patients with perianal disease,” she added. “This is an area where we have limited effective treatment options.”
While clinical trials and real-world evidence continue to support the use of JAK inhibitors for the treatment of IBD, they also have been linked to serious adverse events when used for other indications. Regueiro noted the “hang up or hesitancy” around prescribing habits has largely come down to safety and the risk vs. benefit profile of these treatment options.
Results from the ORAL Surveillance study published in The New England Journal of Medicine showed incidences of major adverse cardiovascular events (HR = 1.33; 95% CI, 0.91-1.94) and cancer (HR = 1.48; 95% CI, 1.04-2.09) were higher among patients treated with tofacitinib for rheumatoid arthritis compared with a TNF inhibitor.
“For providers who haven’t used JAK inhibitors in their practice there is hesitancy around a new mechanism of action, the black box warning and the dosing variations that exist between induction, extended induction and then maintenance dose variations,” Kinnucan said. “In addition, these therapies require monitoring after initiation. Some practices don’t have the resources to do this, limiting comfort with prescribing these therapies.”
UC-specific survey data from Spherix concur with the provider reluctance both Regueiro and Kinnucan described, as only 17% of those who prescribed JAKs reported doing so for “favorable long-term safety perceptions.”
Approvals for UC, Benefit Profile
Tofacitinib was the first JAK inhibitor approved by the FDA and European Medicines Agency in 2018 for the treatment of patients with moderate to severe UC. Approval was based on two induction trials — OCTAVE 1 and 2 — as well as a 52-week maintenance trial.
“Tofacitinib as the first JAK and small molecule for the treatment of inflammatory bowel disease was a great advancement for the management of UC,” Regueiro said, “The OCTAVE studies provided the important efficacy and safety data that led to FDA registration approval of tofacitinib.”
According to results published in Frontiers in Medicine, OCTAVE 1 and 2 showed 18.5% and 16.6% of those who received twice-daily tofacitinib 10 mg, respectively, achieved remission at week 8 vs. 8.2% and 3.6% in the placebo group. Of those who did not achieve remission during induction, 52.2% went on to achieve a clinical response in the OCTAVE Open long-term extension trial. Results at 12 and 36 months showed 70.3% and 56.1% of delayed responders maintained clinical response, 56.8% and 52% achieved endoscopic improvement and 44.6% achieved endoscopic remission.
A systematic review and meta-analysis published in Inflammatory Bowel Diseases showed that among more than 1,100 patients treated with tofacitinib, 48.3% achieved mucosal healing at week 8 and 47%, 64.2% and 44.3% reached clinical remission, clinical response and corticosteroid-free remission, respectively, at weeks 12 to 16.
Jyseleca (filgotinib, Gilead/Galapagos) is an oral, once-daily JAK1 inhibitor that received approval by the European Medicines Agency in November 2021 for moderate to severe UC following prior treatment failure.
Efficacy of filgotinib in UC was largely demonstrated in the randomized, double-blind, placebo-controlled, phase 2b/3 SELECTION trial, in which patients received 100 mg or 200 mg or placebo in two induction phases and one maintenance phase. Results published in The Lancet showed a greater proportion of patients in the 200 mg group achieved clinical remission at week 10 vs. placebo (first induction study: 26.1% vs. 15.3%; second induction study: 11.5% vs. 4.2%), as well as at week 58 (37.2% vs. 11.2%).
An additional report from Frontline Gastroenterology noted results from the long-term extension study demonstrated that filgotinib maintained symptomatic remission and health-related quality of life, although no real-world outcome studies currently exist to confirm its superiority.
“What we are seeing now reminds me of those early days when Remicade first came out in 1998,” Regueiro said. “We have these very difficult cases of refractory UC and patients being prescribed JAK inhibitors for ulcerative colitis, which just melts away the inflammation.
“Having that as a once-a-day pill that is easy to take with a short half-life and rapid onset of action, where you can stop and start without worrying about immunogenicity, is very appealing.”
Dual Indication: The Approval of Upadacitinib
Upadacitinib was approved by the FDA in March 2022 for the treatment of adults with moderately to severely active UC, followed by approval by the European Commission in July 2022 for patients who had an inadequate response, lost response or were intolerant to conventional therapy. Data from U-ACHIEVE and U-ACCOMPLISH induction studies, as well as U-ACHIEVE maintenance studies, supported its approval.
“These pivotal studies showed efficacy of upadacitinib as an induction and maintenance therapy and showed upadacitinib had a favorable safety profile,” Kinnucan said. “These ulcerative colitis studies confirmed benefit of what we had seen in tofacitinib.”
Final results published in The Lancet Gastroenterology & Hepatology from the phase 3 U-ACHIEVE maintenance study, which included 681 patients with a clinical response to once-daily upadacitinib 45 mg from the U-ACHIEVE induction (n = 319), U-ACCOMPLISH (n = 341) and phase 2b induction (n = 21) trials, showed a significantly greater proportion of patients achieved clinical remission at week 52 with upadacitinib 15 mg (40.4%) and 30 mg (53.6%) vs. placebo (10.8%).
Similarly, more patients in the 15 mg and 30 mg groups achieved endoscopic (48.5% and 63.3%, respectively, vs. 14.1%) and histologic-endoscopic improvement (40.5% and 56% vs. 12.3%), in addition to maintaining endoscopic improvement (61.2% and 71% vs. 18.4%).
“These results are very encouraging,” Honap said. “It shows that the drugs are rapidly acting with much higher efficacy rates not seen by prior advanced therapies.”
In May 2023, upadacitinib became the first FDA-approved oral product to treat moderate to severe CD based on two induction studies, U-EXCEED and U-EXCEL, and the U-ENDURE maintenance study. Results from the induction studies showed 34% and 46% of patients, respectively, achieved endoscopic response with upadacitinib 45 mg at 12 weeks vs. 3% and 13% with placebo and 36% and 46% vs. 18% and 23% achieved clinical remission.
In the lower dosage groups — 15 mg and 30 mg — 28% and 41% achieved endoscopic response at week 52 in the maintenance study vs. 7% on placebo. Results from U-ENDURE showed 42% and 55% achieved clinical remission vs. 14%.
“Upadacitinib approval in Crohn’s disease has expanded our treatment options in the advanced therapy space, offering the first oral advanced therapy shown to be effective in moderate to severe Crohn’s disease,” Kinnucan said. “Having the dual indication has made it easier to use this therapy in our patients with inflammatory bowel disease.”
Positioning, Common Contraindications
In the current U.S. label, JAK inhibitors cannot be positioned as first-line therapy and are instead indicated for patients who have previously been exposed to anti-TNF.
“There are different parts of the world where there is not that labeled step-through recommendation and JAK inhibitors can be used in first-line,” Regueiro said. “I would consider using JAK inhibitors for first-line therapy among patients who are on more of the severe end of moderate to severe UC, also the patients with extraintestinal manifestations of joint inflammation.”
According to Honap, additional indications for JAK therapy include younger age, no history of “major medical problems,” those with concomitant immune-mediated inflammatory diseases as well as those with a preference for an oral treatment option. Conversely, common contraindications include hypersensitivity to the active substance, active tuberculosis or serious infections and severe hepatic impairment as well as pregnancy and breastfeeding.
“Though not contraindicated, for safety reasons, JAK inhibitors should be used at the lowest dose possible and avoided in individuals with risk factors if alternatives are available,” Honap said. “These include age 65 years or older, cigarette smokers or significant smoking history, risk factors for cancer or risk factors for major adverse cardiovascular events.”
A report from the European Journal of Gastroenterology & Hepatology noted that international recommendations advocate for a higher JAK dosage for a shorter period of time to address safety concerns. This is applicable to both tofacitinib and upadacitinib but not filgotinib, as it is licensed at a fixed dose through both induction and maintenance therapy.
“Moving forward, I think the efficacy will lead,” Regueiro added. “I’m starting to see this trend where there may be still concern about safety, but the efficacy is starting to take off and people are saying this really works well and it’s a once-a-day pill. That to me is probably catching on now more than anything.”
Contextualizing the Black Box Warning
Despite provider acknowledgement that risk data for the use of JAK inhibitors among patients with IBD are generally positive, patients may be aware of the black box warning that is still in effect. Kinnucan said this is an important topic to bring up as a part of patient education.
“Highlight that this was not seen in IBD clinical trials or post-marketing studies for tofacitinib or upadacitinib,” she said.
Regueiro tackles this topic with his patients by first discussing the risks detailed on the label while also highlighting what he has seen in other clinical research and post-marketing experience.
“As with any class of immunosuppressive therapy, there is a higher risk for infections,” he said. “Shingles is the one we are seeing with JAK inhibitors in my own practice and in clinical trials. However, I also explain that we see certain risk around venous thromboembolism and major adverse cardiovascular events.”
Although available evidence suggests this risk is low overall, experts from an international Delphi consensus panel recommended screening for cardiovascular risk factors and stratification before JAK initiation to prevent these outcomes in at-risk patients. The panel noted in Digestive and Liver Disease that “it becomes crucial” to weigh the potential cardiovascular risk against the risks associated with uncontrolled inflammation.
“This is a class of medicine that works very well, and I think the future is bright for JAK inhibitors,” Regueiro said. “We can use these safely, monitor our patients and still have that understanding of those potential risks, but what is important is that we don’t shy away from these very effective therapies.”
- References:
- Feagan BG, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)00666-8.
- Herrera-deGuise C, et al. Front Med. 2023;doi:10.3389/fmed.2023.1089099.
- Honap S, et al. Euro J Gastroenterol Hepatol. 2023;doi:10.1097/MEG.0000000000002650.
- Honap S, et al. Frontline Gastroenterol. 2023;doi:10.1136/flgastro-2023-102400.
- Nunez P, et al. Drugs. 2023;doi:10.1007/s40265-023-01840-5.
- Olivera PA, et al. Dig Liver Dis. 2024;doi:10.1016/j.dld.2024.03.010.
- Patient Chart Dynamix: Triggers and Drivers in Inflammatory Bowel Disease: New Starts (US) 2023. https://www.spherixglobalinsights.com/gastroenterology/. Published Dec. 23, 2023. Accessed Mar. 28, 2024.
- Taxonera C, et al. Inflamm Bowel Dis. 2022;doi:10.1093/ibd/izab011.
- U.S. FDA approves Rinvoq (upadacitinib) as a once-daily pill for moderately to severely active Crohn’s disease in adults. https://news.abbvie.com/2023-05-18-U-S-FDA-Approves-RINVOQ-R-upadacitinib-as-a-Once-Daily-Pill-for-Moderately-to-Severely-Active-Crohns-Disease-in-Adults. Published May 18, 2023. Accessed July 25, 2023.
- Vermeire S, et al. Lancet Gastroenterol Hepatol. 2023;doi:10.1016/S2468-1253(23)00208-X.
- Ytterberg SR, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2109927.
- For more information:
- Sailish Honap, MD, is a gastroenterologist and IBD research fellow in the School of Immunology & Microbial Sciences at King’s College London; he can be reached at shonap@nhs.net.
- Jami A. Kinnucan, MD, is a senior associate consultant in the section of gastroenterology and hepatology at the Mayo Clinic in Jacksonville, Florida; she can be reached at kinnucan.jami@mayo.edu.
- Miguel Regueiro, MD, is professor of medicine and chief of the Digestive Disease Institute at Cleveland Clinic; he can be reached at regueim@ccf.org.
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