Regulatory Decision Summary for Uceris

Overall, the benefit-risk profile is favorable for Uceris (budesonide) for the induction of remission in adult patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

The safety and efficacy of Uceris was mainly based on two replicate randomized, double-blind, placebo-controlled, clinical studies (BUCF3001 and BUCF3002) in patients with active mild to moderate ulcerative proctitis (UP) or ulcerative proctosigmoiditis (UPS), extending up to 40 cm from the anal verge. In the pivotal trials, patients received Uceris or placebo twice daily for 2 weeks followed by once daily for 4 weeks. The primary efficacy endpoint was the proportion of subjects who were in remission after 6 weeks of treatment. Remission was based on the assessment of the Modified Mayo Disease Activity Index (MMDAI) score, and was defined as a decrease or no change from baseline in the stool frequency subscore, a rectal bleeding subscore of 0, and an endoscopy score of 0 or 1 (normal or mild).

In the pooled clinical trial data, 267 subjects received Uceris rectal foam and 279 received placebo. No significant imbalance in baseline characteristics was reported. The majority of patients had a baseline diagnosis of UPS (71%), and the remaining had UP.

In each study, a significantly higher proportion of patients in the Uceris group were in remission at Week 6 (38.3% in study BUCF3001 and 44% in study BUCF3002) as compared to placebo (25.8% in study BUCF3001 and 22.4 % in study BUCF3002), for a difference of 12.5% in study BUCF3001 (p = 0.003) and 21.6 % in study BUCF3002 (p<0.001). In addition, various sensitivity analyses showed that the results were robust, and there was no significant inconsistency in the effect of Uceris according to various baseline characteristics.

The benefit of Uceris was moderate but present for the three components of the primary composite endpoint, with a preponderance on improvement of rectal bleeding (difference in rate of responders of 20.0%, p<0.001) and endoscopy improvement (difference in rate of responders of 16.0%, p<0.001). The improvement was less salient for stool frequency, with the difference in patients with stool frequency score improved or unchanged at 10.0% in study BUCF3001 (p = 0.073) and 7.1% in study BUCF3002 (p = 0.179). However, in the pooled studies, the difference at 8.4% was statistically significant (p = 0.027). A notable limitation of the studies was the fact that the composite remission endpoint (and related individual bowel frequency component) was defined based on improvement or no change from baseline in stool frequency (i.e., a responder could have no improvement and still be considered a responder). However, an improvement in stool frequency was probably present based on various sensitivity analyses, such as rate of remission when defined as stool score of 0, and also was supported by categorical data suggesting improvement and less worsening in stool frequency with Uceris.

The safety data from the pivotal studies showed that the rate of adverse drug reactions (ADR) was higher with Uceris (20.9%) as compared to placebo (5.8%), mainly due to higher occurrence of decreased blood cortisol (11.2% vs. 0.7%), and adrenal insufficiency (3.7% vs. 0.7%), which were mostly mild or moderate and resolved. However, these effects are known and expected with corticosteroids in general. There were five cases of serious AEs with Uceris, and only one case of acute generalized exanthematous pustulosis that was deemed possibly related to Uceris.

The adrenocorticotropic hormone (ACTH) challenge test were abnormal in 21.6% of patients in the Uceris group as compared to 6.4% of those in the placebo group. In addition, 27.0% of patients treated with Uceris had a low morning plasma cortisol level <5 mcg/dL, as compared to 6.9% with placebo. However, it was noted that the average plasma cortisol level in the Uceris group declined mostly during the twice-dally administration period (Week 1 and 2), and tended to rise thereafter and return to near baseline levels at week 6.

A 26-week safety open-label extension study (BFPS3073) did not raise any unexpected or significant safety issue, but the sample size was small and many patients discontinued use during the study. Reports of Post-Marketing Experience covering almost five years of use in the United States did not reveal any significant or unexpected findings that would change markedly the benefit-risk profile of Uceris at this time.

There were no new safety concerns from the non-clinical information submitted in this NDS that would preclude the approval of Uceris.