Old Friends Have New Relatives Among IBD Therapies

Promising “relatives” of two current agents, ustekinumab and tofacitinib, with favorable safety profiles were the focus of a presentation by Christina Ha, MD, at the Advances in Inflammatory Bowel Disease (AIBD) 2022 virtual regional meeting March 5.

Dr Ha is a gastroenterologist at the Mayo Clinic in Scottsdale, Arizona.

Risankizumab, guselkumab, and mirikizumab are up-and-coming IL-23 inhibitors that bind to the p19 subunit. While none of these treatments are yet FDA-approved for indications in IBD, all have ongoing phase 3 trials in both ulcerative colitis (UC) and Crohn disease (CD). Risankizumab has an application submitted to the US Food and Drug Administration (FDA) based on promising phase 3 results for CD, while mirikizumab has an application planned for later this year based on phase 3 data in UC.

In the phase 3 ADVANCE study, looking at risankizumab induction therapy in patients with CD, both dosing strategies (600 mg and 1200mg) worked better than placebo to induce clinical remission and endoscopic response which were the primary endpoints of the study. In the Phase 3 FORTIFY study, which looked at risankizumab maintenance therapy in patients with CD, patients with both dosage strategies of risankizumab did better at week 52 than those with placebo for maintenance.

Additionally, in the phase 3 ADVANCE and phase 3 MOTIVATE trials, both looking at risankizumab induction therapy for patients with CD, patients treated with risankizumab overall did better than placebo. However, Dr Ha noted that patients who were biologic-naïve performed better than those who had previously had a biologic agent fail. Similar results with regard to response and remission in biologic-naïve compared to biologic-exposed patients were seen in the Phase 3 FORTIFY trial.

Researchers examining steroid-free outcomes across the ADVANCE, MOTIVATE, and FORTIFY trials found that 50.2% of patients treated with rizankizumab achieved steroid-free clinical remission at week 52, while 37.7% achieved steroid-free endoscopic remission at week 52. Only 11.6% of placebo-treated patients achieved steroid-free endoscopic remission at week 52.

The phase 2 GALAXI trial investigated guselkumab induction therapy for patients with CD. Across various dosing strategies, Dr Ha stated, all patients treated with guselkumab in this trial had “marked changes from baseline to week 12 in their Crohn’s Disease Activity Index score, compared to placebo.” Patients treated with guselkumab had a clinical remission rate of 45.9% to 57.4% at week 12, depending on dosing strategy, compared to 16.4% with placebo. Endoscopic response was 32.8% to 37.7% at week 12 for patients treated with guselkumab, compared to 11.5% for placebo.

Dr Ha stated, “The rates of serious adverse events were pretty low across the board, and especially compared to ustekinumab,” when looking at the safety results from week 48 analyses from the phase 2 GALAXI trial. There were low rates of discontinuation and serious infection, as well.

Data from the phase 2 QUASAR study, testing guselkumab induction therapy for patients with UC, showed around 60.0% clinical response for both dosing strategies compared to 27.6% of placebo. There was a clinical remission rate of about 25.0% for both dosing strategies of guselkumab, with 9.5% for placebo.

Moving to mirikizumab, the Phase 3 LUCENT trial looked at mirikizumab induction therapy for patients with UC and found that all primary and secondary endpoints were met. Clinical remission amongst mirikizumab treated patients was “almost 2-fold greater” than those patients treated with placebo, Dr Ha said.

This study also reported the outcome of rectal urgency. “We know rectal urgency impacts quality of life for many of our patients with ulcerative colitis,” Dr Ha stated. “This is one of the first studies to report an improvement of rectal urgency with treatment.”

Dr Ha mentioned that data from the phase 3 LUCENT trial had recently been “teased,” with the the primary endpoint of clinical remission at 1 year met. All secondary endpoints (clinical measures, endoscopic response and remission, histologic outcomes, and bowel urgency) at 1 year were met, as well.

Speaking to the safety of mirikizumab, Dr Ha stated that “across the board, comparing mirikizumab-treated patients to placebo, the adverse event rates were actually very comparable, with low serious adverse events at week 12 with induction, and week 52 with maintenance.”

Dr Ha then moved to the “family members” of tofacitinib, a nonselective Janus kinase (JAK) inhibitor, looking at selective JAK1-inhibitors filgotinib and upadacitinib. Tofacitinib is currently FDA-approved UC, as well as for a variety of rheumatologic conditions. Upadacitinib has submitted an application to the FDA for approval for UC and has ongoing phase 2 trials for CD. Filgotinib has an application submitted to the European Medical Agencies for UC, with ongoing phase 3 trials for both UC and CD.

Data from the U-ACHIEVE trial, investigating upadacitinib induction therapy for UC, shows that the 45mg daily dose performed best for both clinical remission and clinical response at week 8, with 19.6% and 50.0% respectively. Placebo had a clinical remission rate of 0.0% and a clinical response rate of 13.0% at week 8. Results were similar when looking at endoscopic improvement —35.7% of patients treated with 45mg daily upadacitinib showed endoscopic improvement at week 8, compared to just 2.2% of patients with placebo.

Safety data from the trials showed, at week 8, “lower or comparable adverse event rates across dosing strategies compared to placebo.”

The phase 3 U-ACHIEVE trial investigating upadacitinib maintenance therapy for UC showed that 42.0% of patients treated with upadacitinib at 15 mg and 52.0% of patients treated with upadacitinib at 30mg achieved clinical remission at week 52, compared to 12.0% of patients with placebo. When looking at the patient-reported outcomes of abdominal pain and bowel urgency, upadacitinib “regardless of dosing strategy…performed better than placebo.”

Additionally, patients who had an incomplete response, who did not achieve remission at week 8 with upadacitinib 45mg daily, received an additional 8 weeks of treatment. Close to 50.0% of those patients had a clinical response at week 16 and, continuing to maintenance upadacitinib 30mg daily, 33.3% were able to achieve clinical remission at week 52.

Patients with UC who were treated with upadacitinib did have higher rates of herpes zoster, slight creatine kinase elevation, hepatic disorders, and venous thromboembolism, than those treated with placebo.

Dr Ha stressed the importance of being “cautious when interpreting post-hoc analyses… It’s very unfair to compare data across clinical trials.” She also stated that while the safety profiles of all these agents appear favorable, they are limited by small numbers of adverse events and shorter follow-up periods.

—Allison Casey

Reference:
Ha C. Our old friends’ new relatives. Presented at: Advances in Inflammatory Bowel Disease 2022 Regional Meeting; March 5, 2022; Virtual.