Budesonide multi-matrix system formulation for treating ulcerative colitis

Abstract

Budesonide is a corticosteroid characterized by high topical activity and low systemic effect associated with fewer glucocorticoid-related adverse events than conventional steroids. Differently from Crohn's disease, no evidence suggests that oral budesonide is effective for the induction of remission of ulcerative colitis (UC). Budesonide multi-matrix (MMX) system is a new oral preparation that, by employing a MMX, provides the release of the drug throughout the entire colon. Its efficacy in inducing UC remission, at a dose of 9 mg, is based on some recent trials. However, in two studies the absolute differences between budesonide MMX and placebo were much lower than the rate of success reported in previous trials with mesalazines. In addition, the therapeutic advantage of budesonide MMX 9 mg over 5-aminosalicylic acid (5-ASA) showed by one study, and the advantage of budesonide MMX over budesonide reported in the other study, was only 5.8 and 4.8%, respectively. The evidence supporting the use of budesonide MMX at a dose of 6 mg for maintenance is weak. Therefore, the effective dosage should be 9 mg also in maintenance, but not for > 4 – 6 months, because a prolonged treatment has showed to increase the rate of side effects.

Keywords::

• budesonide
• local therapy
• multi-matrix system
• ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease, which mainly affects the colonic mucosa, only rarely passing the superficial intestinal layer [1].

Because of this feature, the main treatment of mild to moderate forms of UC has been addressed to using drugs, such as 5-ASA compounds, that work by local activity.

The principal delivery systems that have been employed in order to release the 5-ASA compounds in the inflamed part of the colon entail eudragit L and S, diazo-bond link and, more recently, multi-matrix (MMX) system.

Budesonide is a steroid with high affinity for the glucocorticoid receptor. Its affinity is 195-fold greater than hydrocortisone. It is on market as nasal, oral and rectal formulations. The budesonide oral formulation is absorbed by the ileum and ascending colon and undergoes 90% first-pass metabolism. Because of this property, it has been employed as local therapy for treating inflammation in the distal ileum and right colon, limiting patient's systemic exposure. The formulation of gastro-resistant, controlled release capsule of budesonide (Entocort), at a dose of 9 mg/day, has been demonstrated to be more effective than placebo and seems non-inferior when compared with conventional oral steroids for treating mild to moderately active Crohn's disease (CD) involving the distal ileum and/or right colon. Vice versa, a Cochrane review investigating the efficacy of oral budesonide was published in 2010 and concluded that there was no evidence to suggest that oral budesonide is effective for the induction of remission in UC [2].

Budesonide rectal enema or foam is also used as treatment of distal UC. In two randomized trials, enema was superior to placebo for inducing remission. In one of the studies, which was extended for 12 months, enema was not effective in maintaining remission [3].

Failure of active UC to respond to 5-ASA therapy is an indication for oral or parenteral steroids treatment. Prednisolone, among the steroids, is the most commonly used. However, steroid therapy is burdened by important side effects especially if the treatment lasts a long period of time. Then, budesonide can be a valid alternative to systemic steroid employment.

Oral budesonide in this setting, however, has given unsatisfactory results probably ascribed to a delivery system, which does not permit a good contact of the drug in the left part of the colon.

Budesonide MMX is a gastro-resistant prolonged release tablet developed by Cosmo Technologies Ltd, designed to release the drug throughout the entire colon, overcoming the limited use of other budesonide formulation for treating UC, especially in the left-sided location. The MMX system has been already employed for delivering 5-ASA. 5-ASA delivered by MMX system has shown a small advantage over other 5-ASA compounds in the treatment of UC probably because of higher concentration of drug in the left colon [4].

Documentation of efficacy of budesonide MMX in inducing UC remission is based on two pivotal studies and one supporting study [5-7]. The better results were obtained by the 9 mg dose.

The two pivotal studies involving 919 patients adopted a very strict criterion of success defined as a combination of clinical and endoscopic remission with a ulcerative colitis disease activity index (UCDAI) score ≤ 1 point, with subscores of 0 for both rectal bleeding and stool frequency [5,6]. Obtaining this level of remission could have reduced the rates of success in these two trials in all the arms, budesonide MMX 9 and 6 mg, Asacol 2.4 g, Entocort 9 mg and Placebo. Nevertheless, the two trials registered absolute differences of 10 and 13% between budesonide MMX 9 mg and placebo that, although statistically significant, were much lower than the rates of success reported in previous trials with mesalazines.

Can we then adopt budesonide MMX at the dose of 9 mg as treatment of UC refractory to mesalazines? Can this therapy substitute the reliable treatment with systemic steroids? Can the probable reduction of side effects counterbalance the increased cost? And finally, can the treatment by budesonide MMX be continued in maintenance?

In one of the two pivotal trials, the therapeutic advantage of budesonide MMX 9 mg over Asacol 2.4 g was only 5.8% and there was no therapeutic advantage over 5-ASA concerning clinical improvement [5]. Although Asacol was a non-powered reference arm suggested as active control, we should consider that 65.3% of the patients treated by Asacol had a moderate flare and that, in case of moderate activity, a recent Cochrane review suggests that patients with moderately active disease may benefit from an initial dosage of 4 to 4.8 g of mesalazine [8-11].

Furthermore, the formulation of budesonide MMX is designed to provide a homogeneous distribution of budesonide throughout the entire colon. This delivery system should ensure in UC a superior efficacy over Entocort, which is a budesonide preparation mainly delivered in the terminal ileum and right colon. However, in the second pivotal study, the advantage of budesonide MMX over Entocort at 8 weeks was only 4.8% [6]. Moreover, the delivery system MMX seems to influence the different efficacy of treatment following the disease location: the better results of budesonide MMX in the two studies were obtained in the left colon, while, when the inflammation was extended over the splenic flexure, the advantage over placebo was not more statistically significant. For this reason, the comparison with Asacol, which has a different delivery system, could have been misleading, given that two different drugs and two different delivery systems were compared.

The tolerability of budesonide is well established: compared with conventional steroids it is associated with fewer steroid-related adverse events. The most common side effects associated with budesonide oral capsules are gastrointestinal and endocrine system-related events, with only rare occurrences of the clinically severe adverse events associated with traditional systemic steroids [12]. It's probable that with short-term treatment of budesonide MMX the steroid side effects are still further reduced. However, it has been shown that maintenance treatment with oral budesonide may be associated with lumbar spine and femoral neck bone loss [13]. It is also well known that the number of steroid-related side effects increases when the treatment is prolonged. In all the studies on 9 mg budesonide MMX at 8 weeks a decline of cortisol levels has been registered, even if this decrease did not appear to be translated into an increase in clinical glucocorticoid effect. This datum makes the use of 9 mg in maintenance inadvisable [14]. One abstract reports that budesonide MMX employed for 12 months at the dose of 6 mg reduced the relapse rate of UC but the difference from placebo was not statistically significant [15]. However, the prolonged treatment did not modify the bone mineral density but 30% of patients had an abnormal adrenal function.

From these data, one can suggest that the effective dose of budesonide MMX should be 9 mg also in maintenance, given that the evidence supporting 6 mg for maintenance is weak. A strategy could be to prolong budesonide MMX 9 mg for not > 4 – 6 months, probably increasing the rate of remission and, similarly to the strategy employed in CD, using it as a bridge therapy to thiopurine. More studies however, are warranted to clarify such an approach.

Finally, before adopting this new drug in the therapeutic armamentarium of UC resistant to mesalazines, more data must be explored:

- Does budesonide MMX work better than a mesalazine with the same delivery system at the dose of 4.8 g?

- Is budesonide MMX a good stepping stone for permitting thiopurine to be effective?

- Is budesonide MMX as a stepping stone to thiopurine comparable to a short course of oral steroid regarding efficacy and number of side effects?

Declaration of interest

C Prantera is a Consultant for Giuliani. ML Scribano has no conflict of interest to declare.