Spherix Global Insights

April 17, 2024

‘Efficacy will lead’ as first-line JAK inhibitor use picks up in moderate to severe UC

Despite a class-wide black box warning for prescribing in the early setting, 31% of providers reported positioning Janus kinase inhibitors as first-line treatment among patients with severe ulcerative colitis, according to survey results.

“Where it is positioned in the label today is after an anti-TNF, meaning that patients had to have been on some form of TNF inhibitor prior to a JAK inhibitor,” Miguel Regueiro, MD, professor of medicine and chief of the Digestive Disease Institute at Cleveland Clinic, told Healio. “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.”

He continued: “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.”

According to a Spherix Global Insights market analysis conducted in August 2023, in which 200 gastroenterologists who manage patients with inflammatory bowel disease were surveyed about their prescribing habits, the leading reason for positioning a Janus kinase (JAK) inhibitor as first-line treatment was speed of onset of action (56%), followed by favorable efficacy perceptions (55%) and desire for specific mechanism of action (48%).

At present, the FDA has only approved two JAK inhibitors, Xeljanz (tofacitinib, Pfizer) and Rinvoq (upadacitinib, AbbVie), for the treatment of patients with moderate to severe UC, but other contenders in the JAK pipeline – brepocitinib (Priovant) and ritlecitinib (Pfizer) –have shown promise in phase 2 trials.

What is a JAK inhibitor?

In the past 20 years, the introduction of traditional biologic therapies, including Remicade (infliximab, Janssen), Stelara (ustekinumab, Janssen) and Entyvio (vedolizumab, Takeda Pharmaceuticals), has improved clinical outcomes among patients with UC. However, primary and secondary non-response, loss of response or adverse events often lead to treatment discontinuation.

Introduced in 2018, JAK inhibitors modulate downstream cytokine signaling in immune-mediated diseases. They can induce a quick clinical response and, compared with tumor necrosis factor-alpha or anti-alpha 4 beta 7 integrin inhibitors, can simultaneously block multiple cytokines from inflammatory pathways, rather than a few specific molecules at a time, which has the potential to improve therapeutic response.

“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 as a first-line option 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.”

While clinical trials and real-world evidence continue to support the use of JAK inhibitors for the treatment of UC, 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 with tofacitinib compared with a TNF inhibitor.

Survey data from Spherix coincide with the provider reluctance Regueiro describes, as only 17% of those who prescribed JAKs reported doing so for “favorable long-term safety perceptions.”

Approvals, 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 — and a 52-week maintenance trial.

According to results published in Frontiers in Medicine, OCTAVE 1 and 2 showed 18.5% and 16.6% of those who received tofacitinib 10 mg, respectively, achieved remission at week 8 vs. 8.2% and 3.6% of those 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 arm. 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 while 47%, 64.2% and 44.3% reached clinical remission, clinical response and corticosteroid-free remission, respectively, at weeks 12 to 16.

“These real-world effectiveness and safety results were consistent with clinical trials and provide a broader perspective that can be used to aid treatment decisions in a more heterogeneous clinical setting,” Carlos Taxonera, MD, PhD, and colleagues wrote.

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 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.

Final results 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%).

Breaking down the black box warning

Despite the acknowledgement that efficacy data for use of JAK inhibitors is generally positive, patients may be aware of the black box warning, which is still in effect. 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’s 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.”

Contraindications include individuals older than 65 years with significant cardiovascular risk, smokers, those with a history of blood clots and women who are actively trying to conceive or are pregnant.

On the flip side, Regueiro recommended first-line JAK use among patients on the “more severe end” of the moderate to severe UC spectrum, as well as among those with extraintestinal manifestations such as joint inflammation.

“Moving forward, I think the efficacy will lead,” he said. “I’m starting to see this trend where there’s maybe 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.”

References:

Source: Healio: https://www.healio.com/news/gastroenterology/20240416/efficacy-will-lead-as-firstline-jak-inhibitor-use-picks-up-in-moderate-to-severe-uc