Moving from efficacy to effectiveness: budesonide multimatrix in ulcerative colitis

Currently, mesalazine (oral ± topical) is the first-line therapy for the induction and maintenance of remission in active mild-to-moderate ulcerative colitis (UC).^1,2 In cases of intolerance or when symptoms are not adequately controlled with 5-aminosalicylic acid (5-ASA), oral systemic steroids are indicated. ³

Budesonide has greater affinity for the glucocorticoid receptor, greater topical effect than prednisolone, a high first-pass metabolism and minimal systemic absorption.^4,5 Budesonide multimatrix system (budesonide-MMX) is a once-daily oral formulation designed for topical release throughout the colon, overcoming the limited release of other formulations for UC. Three phase III clinical trials evaluated the use of budesonide-MMX in mild-to-moderately active UC. Two pivotal studies, CORE I ⁴ and CORE II, ⁵ assessed the efficacy and safety of budesonide-MMX 9 mg as monotherapy (without mesalazine) for 8 weeks. These studies had the same inclusion and eligibility criteria and assessed the same endpoints. In both, budesonide-MMX was significantly more efficacious than placebo for inducing combined clinical and endoscopic remission, symptom resolution and mucosal healing. However, the placebo effect cannot be neglected: 7.4% and 4.5% of the placebo-treated patients in CORE I and II, respectively, achieved remission using a tight combined endpoint. In CORE I, histological healing was greater in the placebo group (6.6%) than in budesonide-treated patients (4.1%); differently, in CORE II the histological healing was significantly superior in the group receiving budesonide-MMX (16.5% vs. 6.7% placebo). Such a discrepancy may be related to the use, in both trials, of a non-validated histological score (Saverymuttu scale) or may be a red flag for more intense investigation. These trials did not assess inflammatory biomarkers, such as C-reactive protein or fecal calprotectin. In both, adverse events were comparable between the two treatment arms.^6,7

A third clinical trial ⁸ evaluated the role of budesonide-MMX as add-on therapy to oral mesalazine: UC patients inadequately controlled with mesalazine (≥2.4 g/day) were randomly assigned to add once-daily budesonide-MMX 9 mg or placebo for 8 weeks. The percentages of patients achieving endoscopic and histological remission (20.0% vs. 12.3% and 27.0% vs. 17.5%, respectively) were significantly greater in the group receiving mesalazine plus budesonide-MMX versus placebo. Still, no significant differences were observed between treatment arms for clinical remission, combined clinical and endoscopic remission, or inflammatory biomarkers. This alerts to the lack of difference in conventional endpoints between mesalazine in monotherapy and mesalazine plus budesonide-MMX.

In this context, this drug was included in the UC therapeutic armamentarium, ⁹ avoiding or delaying the exposure to systemic steroids and other immunosuppressors. Currently, budesonide-MMX (9 mg, for up to 8 weeks) is approved for the induction of remission in adults with mild-to-moderate active UC, when mesalazine treatment was insufficient.

A network meta-analysis ¹⁰ compared interventions for the induction (48 trials) and maintenance of remission (28 trials) in mild-to-moderate UC. In this study, combined oral and rectal 5-ASA was superior to oral 5-ASA alone, and high-dose mesalazine (>3 g/day) was superior to standard dose. Also, it confirmed the efficacy of budesonide-MMX: odds ratio for failure to induce clinical remission 0.42 (against placebo) or 0.84 (against standard dose mesalazine). However, budesonide-MMX was not more effective than an optimised 5-ASA treatment and its tolerability was inferior. This, together with the inability for long-term use, suggested that budesonide-MMX is not appropriate as first-line therapy. In contrast, budesonide-MMX has superior tolerability to prednisolone, being an appropriate add-on second-line therapy. Another network meta-analysis published in 2019, ¹¹ including 15 clinical trials, reached similar conclusions: the efficacy of budesonide-MMX for the induction of clinical and endoscopic remission is similar to that of high dose mesalazine (>2.4 g/day), yet mesalazine is better tolerated.

Notwithstanding this, randomised trials do not necessarily represent the average population and there may exist an important gap between study-based knowledge and its implementation in daily clinical practice.^12,13 Two studies recently published in the United European Gastroenterology Journal aimed to overcome this limitation by analysing the usefulness of budesonide-MMX in a real-life setting.

Danese and colleagues ¹⁴ performed a prospective, multinational, observational study enrolling 326 patients that aimed to assess clinical benefit and to monitor the safety and tolerability in patients receiving budesonide-MMX in combination with mesalazine (less or more than 14 days after 5-ASA was started) or budesonide-MMX in monotherapy. Significantly higher percentages of clinical improvement, clinical remission, symptom resolution and improvement in the quality of life were obtained for the patients receiving budesonide-MMX as add-on therapy rather than as monotherapy, regardless of the administration timing. Budesonide-MMX was well tolerated, less than one quarter reported an adverse event. ⁷ Globally, this study ¹⁴ suggested that adding budesonide-MMX to 5-ASA is better to induce clinical remission than budesonide-MMX monotherapy.

The other publication, by Maconi and colleagues, ¹⁵ is a retrospective multicentre study of 82 adult patients with mild-to-moderate UC. That study evaluated the use of budesonide-MMX mostly as add-on therapy (91.5% of the patients, 66% of which were concomitantly treated with mesalazine). Clinical remission was achieved in 50% while 10% achieved clinical improvement without remission. These percentages are similar to those reported by Danese et al. ¹⁴ (52% and 8%, respectively) on the population receiving budesonide-MMX, in monotherapy or co-administered with 5-ASA, yet the indexes used for measuring disease activity differed (ulcerative colitis disease activity index ¹⁴ and Mayo score). ¹⁵ In agreement with previous trials, the drug was well tolerated. Due to the observational design, neither of the two later studies had histological data and little information was available on inflammation biomarkers.

Despite the recent advances there are several issues that need further clarification, among which: (a) a direct comparison between budesonide-MMX and conventional steroids; (b) the effect of budesonide-MMX in validated histological scores and its prognostic value; (c) the position of budesonide-MMX in the line of induction agents (should it be first-line therapy in co-administration with mesalazine or just an add-on therapy?; in the case of add-on therapy, how many weeks after mesalazine should budesonide-MMX be given?); (d) the role of budesonide-MMX in maintenance therapy (e.g. as a temporary adjunct therapy to prevent relapsing in an early phase or to overcome loss of efficacy of prolonged treatments (e.g. azathioprine)); (e) the practicality of its long-term use; and (f) the impact of combining budesonide oral and rectal formulations.