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Depending on the dose, maintenance upadacitinib (Rinvoq) either doubled or tripled clinical remissions at 1 year in patients with moderately to severely active Crohn's disease, the phase III trial showed.

In an intention-to-treat analysis involving over 500 patients who had initially responded to induction therapy with the Janus kinase (JAK) inhibitor, clinical remission was observed in 47.6% of the 30-mg upadacitinib group and 37.3% of the 15-mg group, as compared with 15.1% of placebo patients (P<0.0001 for both comparisons), reported Edward Loftus Jr., MD, of the Mayo Clinic in Rochester, Minnesota.

In line with FDA requirements, clinical remission was defined as a Crohn's Disease Activity Index (CDAI) score below 150.

And for the study's co-primary endpoint, far more patients on the 30-mg and 15-mg upadacitinib doses had endoscopic response compared with placebo patients (40.1% and 27.6% vs 7.3%; P<0.0001 for both), he said in a late-breaking presentation at the American College of Gastroenterology annual meeting.

Furthermore, corticosteroid-free clinical remissions based on CDAI scores were higher with upadacitinib both in all patients (37-46% vs 14.5% in the placebo group) and in those on steroids at baseline (40% vs 4.9%, respectively), Loftus highlighted.

Reached for comment, Russell Cohen, MD, of the University of Chicago Medicine, told MedPage Today that upadacitinib's safety was "excellent" overall, and said the findings indicate that the higher dosage may be best for sicker patients.

"Those with more refractory disease, more extensive disease, or failures of other therapies should ideally be maintained on the 30-mg maintenance dose, while others may be able to use the 15-mg dose," said Cohen, who was not involved in the study.

Due to safety concerns -- ranging from cancer, blood clots, and death observed in prior trials -- current FDA rules stipulate that JAK inhibitors be reserved for patients who fail on biologics. In the current study, no cardiovascular events or deaths were deemed related to treatment.

The double-blind U-ENDURE study enrolled 502 patients with moderate to severe Crohn's disease who had achieved a clinical response -- based on average daily soft or liquid stool frequency (SF) and abdominal pain score (APS) -- to induction treatment with upadacitinib in the and trials.

These phase III studies involved patients who largely did not adequately respond to or were intolerant of biologics. Responders were then randomized 1:1:1 to receive either upadacitinib maintenance (30 mg or 15 mg) or placebo.

Clinical remission rates were largely the same when analyzed under EU requirements (SF/APS). Endoscopic response was defined as more than a 50% decrease in Simple Endoscopic Score for Crohn's Disease from baseline, or at least a 2-point reduction from baseline.

Mean patient age in the study was 37-38 years, 53-60% were men, and mean CDAI scores ranged from 301-312 at baseline (out of 600). Average disease duration was 7-8 years, and 37% of participants were on concomitant corticosteroids.

Three-quarters of the study group had previously failed biologics, "and there were a significant number of patients who failed three or more biologics," said Loftus, noting that the vast majority of these failures involved tumor necrosis factor (TNF) inhibitors.

Multiple secondary endpoints assessed with CDAI scores also favored upadacitinib at the 30-mg and 15-mg doses, respectively, versus placebo:

• Clinical response: 51.2% and 41.4% vs 15.2%
• Endoscopic remission: 28.6% and 19.1% vs 5.5%
• Maintenance of clinical remission: 65.2% and 49.5% vs 21.2%
• Clinical and endoscopic remission: 23.2% and 14.8% vs 3.7%

And these secondary endpoints were largely consistent when measured by SF/APS.

Both doses of the JAK inhibitor were well tolerated, said Loftus. Serious adverse events (AEs) occurred 35 times in the 30-mg arm, 37 times in the 15-mg arm, and 40 times in the placebo group. Treatment discontinuation rates due to AEs were similar across groups, he noted.

Among AEs of special interest, serious infections were similar across groups, except for herpes zoster infection rates, which were highest in the 30-mg group.

Each group experienced a gastrointestinal perforation, while one hepatic vein thrombosis event occurred in the 30-mg upadacitinib group; no cases of tuberculosis occurred. Within 9 months of initial upadacitinib exposure, one patient in the 15-mg group developed ovarian cancer, while two malignancies occurred in the 30-mg group (colon and breast cancer).

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