Drug Evaluation
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Novel extended release budesonide formulation for treatment of ulcerative colitis 1.
Introduction
2.
Budesonide MMX
3.
Conclusion
4.
Expert opinion
Klaudia Farkas & Tama´s Molna´r† University of Szeged, First Department of Medicine, Szeged, Hungary
Introduction: Budesonide, a synthetic, non-halogenated corticosteroid, has been introduced in the topical treatment of ulcerative colitis (UC). Budesonide MMX, a novel, once-daily oral formulation of budesonide that uses a multi-matrix system (MMX) technology to extend the release of budesonide throughout the colon proved to be effective for the treatment of active UC. The focus of this review is the current status of budesonide MMX in extensive and left-sided UC. Areas covered: This paper covers the recent studies of budesonide MMX to describe its efficacy and safety in the treatment of mild-to-moderately active left-sided UC. A literature search and review of budesonide MMX were carried out using the PubMed database up to August 2013. Expert opinion: Clinical studies of budesonide MMX in adults with mild-tomoderately active UC demonstrated its efficacy and tolerability in achieving clinical and endoscopic remission. Although one trial is still ongoing, budesonide MMX 9 mg tablets represented the first orally administered topical corticosteroid formulation targeting the entire colon for the management of patients with active, mild-to-moderate UC. Keywords: budesonide, MMX formula, topical activity, ulcerative colitis Expert Opin. Pharmacother. (2014) 15(1):131-137
1.
Introduction
Ulcerative colitis (UC) is the leading form of chronic inflammatory bowel diseases (IBD) characterized by diffuse mucosal inflammation of the colon and rectum and presented with intermittent remissions and relapses [1]. Corticosteroids play an important role in the management of acute episodes of UC; However, their longterm use is not recommended because of several well-known potential side effects. Budesonide (Box 1) is a synthetic, non-halogenated corticosteroid structurally related to prednisolone [2]. Due to the strong affinity to glucocorticoid receptors and the high first-pass hepatic metabolism, systemic bioavailability of budesonide is only 10 -- 15%; therefore, it has a potent local anti-inflammatory activity [3]. Budesonide capsules start to release their content at a pH of over 5.5 when reaching the ileum and ascending colon [2]. Thus, the main target of budesonide therapy is Crohn’s disease (CD) with mild-to-moderate distal ileal and right-sided colonic location; it has less clinical benefit compared to prednisolone in the treatment of mild-to-moderate UC [4,5]. However, budesonide proved to be effective as enema therapy for ulcerative proctosigmoiditis. Budesonide multi-matrix system (MMX), a novel, once-daily oral formulation of budesonide that uses a MMX technology to extend the release of budesonide throughout the colon proved to be effective for the treatment of active UC [6,7].
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Box 1. Drug summary.
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Drug name Phase Indication Pharmacology description
Route of administration Chemical formula
Pivotal trial(s)
Budesonide MMX III Mild-to-moderate ulcerative colitis Oral, extended release formulation of budesonide. The formulation contains budesonide in an extended release tablet core. The tablet core is enteric-coated to protect dissolution in gastric juice, which delays budesonide release until exposure to a pH > 7 in the small intestine. Upon disintegration of the coating, the core matrix provides extended release of budesonide in a time-dependent manner Oral 16a,17-butylidendioxy-11b, 21-dihydroxy-1,4-pregnadien-3, 20-dione Contribute Phase IIIb study
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
2.
Budesonide MMX
Overview of the market The currently available non-biological therapies for active UC are oral aminosalicylates (mesalazine, sulphasalazine), topical mesalazine (enemas, suppositories), oral and topical steroids, and thiopurines [8]. According to the latest ECCO guidelines, oral 5-ASA is recommended in the treatment of left-sided and extensive UC with mild-to-moderate severity in combination with topical mesalazine if needed. Systemic corticosteroids are suggested to be used in non-responsive cases (ECCO Statement 5B, 5C) [9]. The risk of several adverse events associated with the use of systemic corticosteroids has prompted the development of less toxic steroid compounds. These oral locally active drugs have improved safety profile and constitute an important alternative to the classic steroids for patients with mild-to-moderate active UC as induction treatment. Budesonide has shown beneficial effects when used as an enema for UC [10], although, despite a better side-effect profile than that of prednisolone, there is no evidence to recommend the use of oral budesonide for active UC. A limited number of trials are available on the efficacy of budesonide for induction of remission in UC with controversial results [4,11-13]. The lower efficacy of budesonide in left-sided and extensive UC is supposed to be due to the high topical and low systematic activity of the drug. L€ofberg et al. examined the efficacy and safety of budesonide in an oral controlled-release formulation in extensive or left-sided, mild-to-moderately active UC. They performed a 9-week, randomized, double-blind, controlled trial, 2.1
132
and compared treatments with 10 mg budesonide or 40 mg prednisolone daily, both tapered gradually. Thirty-four patients received budesonide, and 38 patients received prednisolone. They found that the mean endoscopic scores improved significantly in both groups without statistical difference. Budesonide had no impact on the morning plasma cortisol levels during the entire study period, while 25 of 33 (75.8%) patients in the prednisolone group had plasma cortisol levels below the lower reference limit at some point during the study [4]. A Cochrane review by Sherlock et al. concluded that oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy and there was no significant benefit from oral budesonide in comparison with placebo for inducing clinical remission after 4 weeks of treatment [11]. The included trials also provided data regarding the effects of budesonide on adrenocortical function. In comparison with prednisolone, budesonide did not appear to impact upon the adrenocortical axis in the small pilot study by L€ofberg et al. [4]; however, when compared with placebo, it caused some suppression of cortisol production [12]. Gastrointestinal adverse events were also more common in the budesonide-treated group in this study. Gross et al. compared the efficacy of oral 9 mg budesonide and 3 g mesalazine granules in mild-to-moderately active UC. Fewer patients achieved clinical remission and mucosal healing with budesonide versus mesalazine (39.5 vs 54.8% and 30.5 vs 39.2%) [13]. However, it should be noted that the remission of UC was attained in about 40% of patients treated with budesonide. The efficacy of topical budesonide in distal UC is also controversial. A double-blind multicenter trial from 1998 proved the efficacy of budesonide enema versus placebo in active distal UC/proctitis [14]. Despite the study of Le´mann et al. showing that budesonide enema 2 mg/100 ml was as efficient as 5-ASA enema in the treatment of active distal UC [15], the controlled, open, randomized study of Hartmann et al. revealed that mesalazine enema was associated with a significantly higher remission rate compared with budesonide enema in active left-sided enema [16]. Beclometasone dipropionate (BDP) is also a topically acting oral steroid to treat mild-to-moderately active UC, although it has been licensed in the treatment of UC in only a few countries yet. In the study of Rizzello et al. beclomethasone was associated with a significant clinical, endoscopic and histological benefit after 4 weeks of treatment [17]. Beclomethasone proved to be more effective than 5-ASA in patients with active left-sided or extensive colitis and presented a good safety profile with no inhibition of pituitary adrenal function detected [18]. In the study of Balzano et al. both oral beclomethasone and prednisolone achieved comparable clinical and endoscopic efficacy in the treatment of mild-to-moderate UC, with oral beclomethasone presenting less steroid-related adverse effects [19]. However, the efficacy of beclomethasone as a maintenance therapy has to be evaluated by controlled prospective studies.
Expert Opin. Pharmacother. (2014) 15(1)
Budesonide
Introduction to budesonide MMX Budesonide MMX is manufactured by Cosmo Pharmaceuticals S.p.A., Lainate, Italy Santarus and received FDA approval for the induction of remission in patients with active, mild-tomoderate UC in January 2013. The drug consists of round, film-coated, gastro-resistant, extended-release tablets, with multi-matrix structure (MMX) containing 9 mg budesonide. Budesonide MMX is administered once daily. Budesonide MMX is similar in its tolerability profile, adverse effects and contraindications to other budesonide formulations. 2.2
Chemistry The chemical structure of budesonide is 16a,17-butylidendioxy-11b,21-dihydroxy-1,4-pregnadien-3,20-dione. Budesonide MMX is characterized by multi-matrix system -- a colonic release system consisting of an inner lipophilic matrix in which the active ingredient was dispersed, an outer hydrophilic matrix generated by in situ hydration of selected polymer chains and a third amphiphilic matrix promoting the inert matrix wettability [7].
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2.3
Pharmacodynamics Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsic potency of the drug is about 200-fold that of cortisol and 15-fold that of prednisolone. Budesonide therapy may also be associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal axis function. 2.4
Pharmacokinetics and metabolism Budesonide is a locally-acting glucocorticosteroid with an extensive, primarily hepatic, metabolism after oral administration. It is rapidly absorbed and biotransformed by cytochrome P450 (CYP) 3A to metabolites with negligible glucocorticoid activity. A low systemic availability of 9 -- 21% of budesonide indicates extensive first-pass elimination. Pharmacokinetics appears unaffected by gender, age, and renal impairment, although systemic availability was 2.5-fold higher in patients with cirrhosis compared with healthy controls. Strong CYP3A4 inhibitors, such as ketoconazole, will inhibit the metabolism of budesonide [20]. MMX is a special drug-release system characterized by a pH-dependent hydrophilic and inert matrix that acts as a gastroprotective layer. The matrix traps the drug and excipients in a net of hydrophilic and amphypatic polymeric material. As the pH of the bowel lumen increases over 7, the outer layer melts and delivery of the drug commences. The inert matrix allows controlled drug release by increasing the mucosal intestinal surface that can be reached by the active drug. The amphipathic polymeric matrix increases both solubility of the drug and relaxation of the hydrophilic material, resulting in a “swelling” controlled drug release [21,22]. 2.5
Phase I studies In the study by Brunner et al. [7], gastrointestinal transit of budesonide MMX was examined with the use of pharmacoscintigrapy in 12 healthy subjects. 153Sm-labelled MMX budesonide tablets reached the colonic region after a mean of 9.8 h. Initial tablet disintegration was observed in the ileum in 42% of subjects, whereas in 33%, the main site of disintegration was either the ascending or transverse colon. 96% of the dose that was absorbed into the systemic circulation occurred during the time at which the tablet was passing through the colon. Budesonide plasma concentrations were first detected after 6.8 ± 3.2 h, whereas maximum plasma concentrations were reached approximately 7 h later, that is, 14.0 ± 7.7 h after drug administration. These findings suggest that drug release began before breakdown of the tablet matrix. Food intake significantly decreased the rate and extent of budesonide absorption. A single-center, open-label, single-dose, Phase I, randomized 3-period crossover study by Nicholls et al. [23] was conducted on 12 healthy volunteers receiving single doses of budesonide MMX (Uceris) 6 mg, budesonide MMX (Uceris) 9 mg, or budesonide (Entocort EC) 9 mg. The Uceris 9 mg and Entocort EC 9 mg formulations had comparable area under the concentration--time curve (AUC) data, but Uceris 9 mg had a notably longer time to first appearance in plasma, and a delayed time to maximum concentration compared with Entocort EC 9 mg. This study provided pharmacokinetic data suggesting that Uceris undergoes in vivo dissolution in a more distal region of the GI tract compared with the Entocort EC formulation. 2.5.1
2.6
Clinical efficacy Phase II studies
2.6.1
Unpublished Phase II (CB-01-02/05) dose-finding, doubleblind, multicenter, comparative, pilot efficacy, and safety study was conducted in patients with active mild or moderate UC comparing budesonide MMX 3 mg, budesonide MMX 9 mg, and placebo over 8 weeks of treatment. Budesonide MMX 9 mg appeared to have better measured efficacy outcomes compared to budesonide MMX 3 mg or placebo. However, statistical difference would not be observed due to the small size of the study [24]. The randomized, placebo-controlled, parallel-group, pilot, multi-center efficacy study by D’Haens et al. was conducted in patients with active mild or moderate left-sided UC with two treatment arms. Treatment A was budesonide MMX 9 mg once daily in both period 1 and 2 for a total of 8 weeks’ treatment, and treatment B was placebo tablet once daily for 4 weeks during period 1 and budesonide MMX 9 mg once daily for 4 weeks during period 2. After 4 weeks, 47.1% of the patients in the budesonide-MMX group achieved relevant clinical improvement (remission or a Clinical Activity Index [CAI] reduction by at least 50%) versus 33.3% of patients on placebo. In addition, 47.1% of budesonide patients and
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another 33.3% of placebo recipients improved without remission by 4 weeks. The CAI reduction was significant with budesonide (p < 0.0001) tablets and not with placebo (p = 0.1). The morning plasma cortisol level appears to decrease with increased duration of budesonide MMX 9 mg treatment. 47% of patient who were treated with budesonide MMX 9 mg for 4 weeks and 79% of patients who were treated with budesonide MMX 9 mg for 8 consecutive weeks had abnormal response to ACTH stimulation test [12]. Phase III studies In a Phase III, multicenter, randomized, double-blind, double-dummy, placebo-controlled Core I trial Sandborn et al. [25] evaluated the efficacy of budesonide MMX for induction of remission in 509 patients with active, mildto-moderate UC. Clinical activity was determined by Ulcerative Colitis Disease Activity Index (UCDAI) score. Patients were randomly assigned to groups that were given budesonide MMX (9 mg or 6 mg), mesalamine (2.4 g), or placebo for 8 weeks. The primary endpoint was a combined clinical and endoscopic remission at week 8. The rates of combined clinical and endoscopic remission at week 8 among subjects given budesonide MMX 9 mg or 6 mg or mesalamine were 17.9, 13.2, and 12.1% compared with 7.4% for placebo (p = 0.0143, p = 0.1393, and p = 0.2200). Significant association was shown only between patients receiving budesonide MMX 9 mg and placebo. The trial was not powered to directly compare budesonide MMX and mesalamine. In the Core II study [26] combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4, 8.3, 12.6 and 4.5%. The difference between budesonide MMX 9 mg and placebo was significant (p = 0.0047). Budesonide MMX 9 mg was associated with higher rates of clinical (42.2 vs 33.7%) and endoscopic improvement (42.2 vs 31.5%) versus placebo. The rate of histological healing (16.5 vs 6.7%; p = 0.0361) and proportion of patients with symptom resolution (23.9 vs 11.2%; p = 0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Clinical and endoscopic improvement rates were numerically higher in patients treated with budesonide MMX 9 mg than in the Entocort EC control arm. However, the study was not powered to detect statistical significance between the budesonide MMX and Entocort EC treatment groups. This trial enrolled a total of 511 patients. The CORE I and II studies were designed only to evaluate short-term efficacy and not maintenance therapy. Budesonide MMX might be continued for longer than 8 weeks in patients with mild but persistently active disease, but this is not supported by the current data and needs further evaluation.
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2.6.2
Safety and tolerability Previous studies have been shown that fewer adverse effects occurred in patients treated with budesonide compared to those treated with conventional steroids [11]. Similarly, 2.7
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budesonide preserved better adrenal function than conventional steroids. In CD studies, the relative risk (RR) of steroid-related side effects was 0.99 in patients administered with budesonide compared to those administered with placebo, and 0.64 compared to patients administered with conventional corticosteroids. Only the RR of decreased response to ACTH stimulation was increased by the use of budesonide [27]. Every study showed that treatment with budesonide MMX was generally well tolerated with an overall safety profile comparable to that of placebo. In the study of D’Haens et al. the most frequent adverse event was headache (11.86%). Other frequent events were abdominal pain, common cold, diarrhea, flatulence and influenza [12]. In this study, neither morning cortisol nor pituitary--adrenal axis was more frequently suppressed with budesonide tablets than with placebo. In Core I, the majority of the adverse events were mild or moderate. The percentage of patients with severe adverse events was highest in the placebo group (12.4%) compared with the budesonide MMX 9 mg group (6.3%), budesonide MMX 6 mg group (9.5%), and mesalamine 2.4 g group (5.5%). Potential glucocorticoid effects were observed in 10.1% of patients in the placebo group, 11.8% of patients in the budesonide MMX 9 mg group, 5.6% of patients in the budesonide MMX 6 mg group, and 7.9% of patients in the mesalamine group [25]. In the Core II study, the number of patients with treatment-related adverse events and serious adverse events were similar in the placebo, budesonide MMX 9 mg and 6 mg and Entocort EC groups. The majority of the adverse events were mild or moderate, with the most frequent events of the relapse of UC and headache. The most common glucocorticoid-related symptoms were mood changes, sleep changes, and insomnia [26]. Reductions in morning plasma cortisol levels occurred more frequently in budesonide MMX groups and the Entocort EC group. However, mean morning plasma cortisol levels remained within the normal range at all times.
Regulatory affairs CORE I was conducted in North America and India. CORE II was conducted in Europe, Australia, Israel, and Russia. The approved dosage of budesonide MMX in the USA is 9 mg under the trade name Uceris. 2.8
3.
Conclusion
Budesonide MMX represents the first orally administered topical corticosteroid formulation specifically targeting the entire colon. Budesonide MMX 9 mg proved to be safe, well-tolerated, and more effective than placebo for inducing combined clinical and endoscopic remission in patients with mild-to-moderate active left-sided UC.
Expert Opin. Pharmacother. (2014) 15(1)
Budesonide
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4.
Expert opinion
Developments in corticosteroid chemistry have led to the development of anti-inflammatory glucocorticoids with enhanced topical potency and less systemic activity. Budesonide has been formulated in oral controlled released formulations that minimise proximal absorption and allow high drug concentrations in the ileum and caecum. However, due to the increased potency at the steroid receptor, suppression of the hypothalamic-pituitary-adrenal axis can occur with treatment. Budesonide in a controlled ileal release formulation, administered as 9 mg/day is the favoured therapy to induce remission in mildly active, localised ileocaecal CD, because it proved to be superior to both placebo and mesalazine. However, budesonide is significantly less effective than conventional steroids for induction of remission, particularly among patients with severe disease. Since the oral locally active budesonide is characterized by a favourable safety profile it emerged to compose an alternative to systemic steroids in the treatment of mild-tomoderate active UC. Despite the limited evidence regarding the efficacy of budesonide at inducing clinical and endoscopic remission in patients with UC, it proved to be effective as only a topical compound in cases of left-sided colitis and shown to be significantly less effective than conventional steroids when used orally for induction of remission in active UC. The novel formulation of budesonide with the MMX delivery system allows the drug to be active in the bowel mucosa without systemic absorption. Due to extensive first-pass elimination, the systemic bioavailability of budesonide decreases only to 10 -- 15% compared with other corticosteroid formulations causing less steroid related side effects. In case of MMX-tablets, drug release seems to begin before breakdown of the tablet matrix. Furthermore, 96% of budesonide absorption took place during the time that the tablets were passing the region between the ascending and the descending/sigmoid colon underlying the efficiency of the colon targeting release kinetics of the new MMX structure. However, it should also be added that dietary and inter-individual variabilities may influence the gastrointestinal transit. The goal of budesonide MMX treatment is to maintain the efficacy of corticosteroids with minimising systemic side
effects. Currently, the role of budesonide MMX as induction treatment for UC patients is still a matter of debate. Although it proved to be more effective than placebo, data about the comparison of the efficacy of budesonide MMX with mesalazine, mesalazine MMX and topically active budesonide are still missing. Furthermore, the accurate indication for budesonide MMX therapy is also lacking. Although studies were performed in patients with mild-to-moderate UC, patients with distal, left-sided and extensive colitis were enrolled in the Phase III trials. Core I study revealed that the clinical and endoscopic remission rate for budesonide MMX 9 mg was significantly greater than placebo in patients with left-sided disease. However, for extensive disease, clinical and endoscopic remission rates were numerically but not significantly greater in the budesonide MMX 9 mg group compared with patients receiving placebo. The studies were not powered to detect differences between MMX and placebo among subsets of patients with left-sided disease or extensive disease. Although some trials are still ongoing, the recently available results about the transit parameters, low systemic bioavailability, the efficacy and the lack of significant drug-related adverse events are promising and may confirm the place of this new formulation of budesonide in the treatment of UC. The more positive safety profile of budesonide has encouraged some investigators to attempt to identify whether budesonide could be effective as CD treatment, unfortunately achieving poor results. Randomized, controlled trials would be ideal to examine the long-term efficacy of budesonide MMX in comparison with placebo and mesalamine preparations as well. These studies are essential to take a stand on the role of budesonide MMX in the management of active UC.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. The collection, analysis and interpretation of data were made by the independent authors as was the writing of this article and the decision to submit this article for publication in this journal.
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L€ofberg R, Danielsson A, Suhr O, et al. Oral budesonide versus prednisolone in patients with active extensive and leftsided ulcerative colitis. Gastroenterology 1996;110:1713-18 Randomized, double-blind, controlled trial showing orally administered budesonide gave an overall treatment result in active ulcerative colitis without suppression of plasma cortisol levels. Edsba¨cker S, Andersson T. Pharmacokinetics of budesonide (EntocortTM EC) capsules for Crohn’s Disease. Clin Pharmacokinet 2004;43:803-21 Brunner M, Vogelsang H, Greinwald R, et al. Colonic spread and serum pharmacokinetics of budesonide foam in patients with mildly to moderately active ulcerative colitis. Aliment Pharmacol Ther 2005;22:463-70 Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol 2006;61:31-8 Important study evaluating the gastrointestinal transit, release and absorption of budesonide from tablets with a new MMX formulation.
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Clinical trial: Preliminary efficacy and safety study of a new Budesonide-MMX 9 mg extended-release tablets in patients with active left-sided ulcerative colitis. J Crohn’s Colitis 2010;4:153-60 An important study confirming the efficacy and safety of budesonideMMX 9 mg tablets in active, left-sided UC. Gross V, Bunganic I, Belousova EA, et al. 3 g mesalazine granules are superior to 9 mg budesonide for achieving remission in active ulcerative colitis: a double-blind, double-dummy, randomised trial. J Crohns Colitis 2011;5:129-38 A randomised, double-blind, double-dummy, multicentre study demonstrating the non-inferiority for oral 9 mg budesonide versus 3 g mesalazine granules administered once daily for achieving remission in mild-to-moderately active UC. Hanauer SB, Robinson M, Pruitt R, et al. Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study. U.S. Budesonide enema study group. Gastroenterology 1998;115:525-32 Le´mann M, Galian A, Rutgeerts P, et al. Comparison of budesonide and 5aminosalycilic acid enemas in active distal ulcerative colitis. Aliment Pharmacol Ther 1995;9:557-62 Hartmann F, Stein J; Budmesa-Study Group. Clinical trial: controlled, open, randomized multicentre study comparing the effects of treatment on quality of life, safety and efficacy of budesonide or mesalazine enemas in active left-sided ulcerative colitis. Aliment Pharmacol Ther 2010;32:368-76 Rizzello F, Gionchetti P, Galeazzi R, et al. Oral beclomethasone dipropionate in patients with mild to moderate ulcerative colitis: a dose-finding study. Adv Ther 2001;18:261-71 Expert Opin. Pharmacother. (2014) 15(1)
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Affiliation
Klaudia Farkas & Tama´s Molna´r† MD † Author for correspondence University of Szeged, First Department of Medicine, 8--10 Koranyifasor, Szeged, H6720, Hungary E-mail: [email protected]
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Novel extended release budesonide formulation for treatment of ulcerative colitis 1.
Introduction
2.
Budesonide MMX
3.
Conclusion
4.
Expert opinion
Klaudia Farkas & Tama´s Molna´r† University of Szeged, First Department of Medicine, Szeged, Hungary
Introduction: Budesonide, a synthetic, non-halogenated corticosteroid, has been introduced in the topical treatment of ulcerative colitis (UC). Budesonide MMX, a novel, once-daily oral formulation of budesonide that uses a multi-matrix system (MMX) technology to extend the release of budesonide throughout the colon proved to be effective for the treatment of active UC. The focus of this review is the current status of budesonide MMX in extensive and left-sided UC. Areas covered: This paper covers the recent studies of budesonide MMX to describe its efficacy and safety in the treatment of mild-to-moderately active left-sided UC. A literature search and review of budesonide MMX were carried out using the PubMed database up to August 2013. Expert opinion: Clinical studies of budesonide MMX in adults with mild-tomoderately active UC demonstrated its efficacy and tolerability in achieving clinical and endoscopic remission. Although one trial is still ongoing, budesonide MMX 9 mg tablets represented the first orally administered topical corticosteroid formulation targeting the entire colon for the management of patients with active, mild-to-moderate UC. Keywords: budesonide, MMX formula, topical activity, ulcerative colitis Expert Opin. Pharmacother. (2014) 15(1):131-137
1.
Introduction
Ulcerative colitis (UC) is the leading form of chronic inflammatory bowel diseases (IBD) characterized by diffuse mucosal inflammation of the colon and rectum and presented with intermittent remissions and relapses [1]. Corticosteroids play an important role in the management of acute episodes of UC; However, their longterm use is not recommended because of several well-known potential side effects. Budesonide (Box 1) is a synthetic, non-halogenated corticosteroid structurally related to prednisolone [2]. Due to the strong affinity to glucocorticoid receptors and the high first-pass hepatic metabolism, systemic bioavailability of budesonide is only 10 -- 15%; therefore, it has a potent local anti-inflammatory activity [3]. Budesonide capsules start to release their content at a pH of over 5.5 when reaching the ileum and ascending colon [2]. Thus, the main target of budesonide therapy is Crohn’s disease (CD) with mild-to-moderate distal ileal and right-sided colonic location; it has less clinical benefit compared to prednisolone in the treatment of mild-to-moderate UC [4,5]. However, budesonide proved to be effective as enema therapy for ulcerative proctosigmoiditis. Budesonide multi-matrix system (MMX), a novel, once-daily oral formulation of budesonide that uses a MMX technology to extend the release of budesonide throughout the colon proved to be effective for the treatment of active UC [6,7].
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Box 1. Drug summary.
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Drug name Phase Indication Pharmacology description
Route of administration Chemical formula
Pivotal trial(s)
Budesonide MMX III Mild-to-moderate ulcerative colitis Oral, extended release formulation of budesonide. The formulation contains budesonide in an extended release tablet core. The tablet core is enteric-coated to protect dissolution in gastric juice, which delays budesonide release until exposure to a pH > 7 in the small intestine. Upon disintegration of the coating, the core matrix provides extended release of budesonide in a time-dependent manner Oral 16a,17-butylidendioxy-11b, 21-dihydroxy-1,4-pregnadien-3, 20-dione Contribute Phase IIIb study
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
2.
Budesonide MMX
Overview of the market The currently available non-biological therapies for active UC are oral aminosalicylates (mesalazine, sulphasalazine), topical mesalazine (enemas, suppositories), oral and topical steroids, and thiopurines [8]. According to the latest ECCO guidelines, oral 5-ASA is recommended in the treatment of left-sided and extensive UC with mild-to-moderate severity in combination with topical mesalazine if needed. Systemic corticosteroids are suggested to be used in non-responsive cases (ECCO Statement 5B, 5C) [9]. The risk of several adverse events associated with the use of systemic corticosteroids has prompted the development of less toxic steroid compounds. These oral locally active drugs have improved safety profile and constitute an important alternative to the classic steroids for patients with mild-to-moderate active UC as induction treatment. Budesonide has shown beneficial effects when used as an enema for UC [10], although, despite a better side-effect profile than that of prednisolone, there is no evidence to recommend the use of oral budesonide for active UC. A limited number of trials are available on the efficacy of budesonide for induction of remission in UC with controversial results [4,11-13]. The lower efficacy of budesonide in left-sided and extensive UC is supposed to be due to the high topical and low systematic activity of the drug. L€ofberg et al. examined the efficacy and safety of budesonide in an oral controlled-release formulation in extensive or left-sided, mild-to-moderately active UC. They performed a 9-week, randomized, double-blind, controlled trial, 2.1
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and compared treatments with 10 mg budesonide or 40 mg prednisolone daily, both tapered gradually. Thirty-four patients received budesonide, and 38 patients received prednisolone. They found that the mean endoscopic scores improved significantly in both groups without statistical difference. Budesonide had no impact on the morning plasma cortisol levels during the entire study period, while 25 of 33 (75.8%) patients in the prednisolone group had plasma cortisol levels below the lower reference limit at some point during the study [4]. A Cochrane review by Sherlock et al. concluded that oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy and there was no significant benefit from oral budesonide in comparison with placebo for inducing clinical remission after 4 weeks of treatment [11]. The included trials also provided data regarding the effects of budesonide on adrenocortical function. In comparison with prednisolone, budesonide did not appear to impact upon the adrenocortical axis in the small pilot study by L€ofberg et al. [4]; however, when compared with placebo, it caused some suppression of cortisol production [12]. Gastrointestinal adverse events were also more common in the budesonide-treated group in this study. Gross et al. compared the efficacy of oral 9 mg budesonide and 3 g mesalazine granules in mild-to-moderately active UC. Fewer patients achieved clinical remission and mucosal healing with budesonide versus mesalazine (39.5 vs 54.8% and 30.5 vs 39.2%) [13]. However, it should be noted that the remission of UC was attained in about 40% of patients treated with budesonide. The efficacy of topical budesonide in distal UC is also controversial. A double-blind multicenter trial from 1998 proved the efficacy of budesonide enema versus placebo in active distal UC/proctitis [14]. Despite the study of Le´mann et al. showing that budesonide enema 2 mg/100 ml was as efficient as 5-ASA enema in the treatment of active distal UC [15], the controlled, open, randomized study of Hartmann et al. revealed that mesalazine enema was associated with a significantly higher remission rate compared with budesonide enema in active left-sided enema [16]. Beclometasone dipropionate (BDP) is also a topically acting oral steroid to treat mild-to-moderately active UC, although it has been licensed in the treatment of UC in only a few countries yet. In the study of Rizzello et al. beclomethasone was associated with a significant clinical, endoscopic and histological benefit after 4 weeks of treatment [17]. Beclomethasone proved to be more effective than 5-ASA in patients with active left-sided or extensive colitis and presented a good safety profile with no inhibition of pituitary adrenal function detected [18]. In the study of Balzano et al. both oral beclomethasone and prednisolone achieved comparable clinical and endoscopic efficacy in the treatment of mild-to-moderate UC, with oral beclomethasone presenting less steroid-related adverse effects [19]. However, the efficacy of beclomethasone as a maintenance therapy has to be evaluated by controlled prospective studies.
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Budesonide
Introduction to budesonide MMX Budesonide MMX is manufactured by Cosmo Pharmaceuticals S.p.A., Lainate, Italy Santarus and received FDA approval for the induction of remission in patients with active, mild-tomoderate UC in January 2013. The drug consists of round, film-coated, gastro-resistant, extended-release tablets, with multi-matrix structure (MMX) containing 9 mg budesonide. Budesonide MMX is administered once daily. Budesonide MMX is similar in its tolerability profile, adverse effects and contraindications to other budesonide formulations. 2.2
Chemistry The chemical structure of budesonide is 16a,17-butylidendioxy-11b,21-dihydroxy-1,4-pregnadien-3,20-dione. Budesonide MMX is characterized by multi-matrix system -- a colonic release system consisting of an inner lipophilic matrix in which the active ingredient was dispersed, an outer hydrophilic matrix generated by in situ hydration of selected polymer chains and a third amphiphilic matrix promoting the inert matrix wettability [7].
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2.3
Pharmacodynamics Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsic potency of the drug is about 200-fold that of cortisol and 15-fold that of prednisolone. Budesonide therapy may also be associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal axis function. 2.4
Pharmacokinetics and metabolism Budesonide is a locally-acting glucocorticosteroid with an extensive, primarily hepatic, metabolism after oral administration. It is rapidly absorbed and biotransformed by cytochrome P450 (CYP) 3A to metabolites with negligible glucocorticoid activity. A low systemic availability of 9 -- 21% of budesonide indicates extensive first-pass elimination. Pharmacokinetics appears unaffected by gender, age, and renal impairment, although systemic availability was 2.5-fold higher in patients with cirrhosis compared with healthy controls. Strong CYP3A4 inhibitors, such as ketoconazole, will inhibit the metabolism of budesonide [20]. MMX is a special drug-release system characterized by a pH-dependent hydrophilic and inert matrix that acts as a gastroprotective layer. The matrix traps the drug and excipients in a net of hydrophilic and amphypatic polymeric material. As the pH of the bowel lumen increases over 7, the outer layer melts and delivery of the drug commences. The inert matrix allows controlled drug release by increasing the mucosal intestinal surface that can be reached by the active drug. The amphipathic polymeric matrix increases both solubility of the drug and relaxation of the hydrophilic material, resulting in a “swelling” controlled drug release [21,22]. 2.5
Phase I studies In the study by Brunner et al. [7], gastrointestinal transit of budesonide MMX was examined with the use of pharmacoscintigrapy in 12 healthy subjects. 153Sm-labelled MMX budesonide tablets reached the colonic region after a mean of 9.8 h. Initial tablet disintegration was observed in the ileum in 42% of subjects, whereas in 33%, the main site of disintegration was either the ascending or transverse colon. 96% of the dose that was absorbed into the systemic circulation occurred during the time at which the tablet was passing through the colon. Budesonide plasma concentrations were first detected after 6.8 ± 3.2 h, whereas maximum plasma concentrations were reached approximately 7 h later, that is, 14.0 ± 7.7 h after drug administration. These findings suggest that drug release began before breakdown of the tablet matrix. Food intake significantly decreased the rate and extent of budesonide absorption. A single-center, open-label, single-dose, Phase I, randomized 3-period crossover study by Nicholls et al. [23] was conducted on 12 healthy volunteers receiving single doses of budesonide MMX (Uceris) 6 mg, budesonide MMX (Uceris) 9 mg, or budesonide (Entocort EC) 9 mg. The Uceris 9 mg and Entocort EC 9 mg formulations had comparable area under the concentration--time curve (AUC) data, but Uceris 9 mg had a notably longer time to first appearance in plasma, and a delayed time to maximum concentration compared with Entocort EC 9 mg. This study provided pharmacokinetic data suggesting that Uceris undergoes in vivo dissolution in a more distal region of the GI tract compared with the Entocort EC formulation. 2.5.1
2.6
Clinical efficacy Phase II studies
2.6.1
Unpublished Phase II (CB-01-02/05) dose-finding, doubleblind, multicenter, comparative, pilot efficacy, and safety study was conducted in patients with active mild or moderate UC comparing budesonide MMX 3 mg, budesonide MMX 9 mg, and placebo over 8 weeks of treatment. Budesonide MMX 9 mg appeared to have better measured efficacy outcomes compared to budesonide MMX 3 mg or placebo. However, statistical difference would not be observed due to the small size of the study [24]. The randomized, placebo-controlled, parallel-group, pilot, multi-center efficacy study by D’Haens et al. was conducted in patients with active mild or moderate left-sided UC with two treatment arms. Treatment A was budesonide MMX 9 mg once daily in both period 1 and 2 for a total of 8 weeks’ treatment, and treatment B was placebo tablet once daily for 4 weeks during period 1 and budesonide MMX 9 mg once daily for 4 weeks during period 2. After 4 weeks, 47.1% of the patients in the budesonide-MMX group achieved relevant clinical improvement (remission or a Clinical Activity Index [CAI] reduction by at least 50%) versus 33.3% of patients on placebo. In addition, 47.1% of budesonide patients and
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another 33.3% of placebo recipients improved without remission by 4 weeks. The CAI reduction was significant with budesonide (p < 0.0001) tablets and not with placebo (p = 0.1). The morning plasma cortisol level appears to decrease with increased duration of budesonide MMX 9 mg treatment. 47% of patient who were treated with budesonide MMX 9 mg for 4 weeks and 79% of patients who were treated with budesonide MMX 9 mg for 8 consecutive weeks had abnormal response to ACTH stimulation test [12]. Phase III studies In a Phase III, multicenter, randomized, double-blind, double-dummy, placebo-controlled Core I trial Sandborn et al. [25] evaluated the efficacy of budesonide MMX for induction of remission in 509 patients with active, mildto-moderate UC. Clinical activity was determined by Ulcerative Colitis Disease Activity Index (UCDAI) score. Patients were randomly assigned to groups that were given budesonide MMX (9 mg or 6 mg), mesalamine (2.4 g), or placebo for 8 weeks. The primary endpoint was a combined clinical and endoscopic remission at week 8. The rates of combined clinical and endoscopic remission at week 8 among subjects given budesonide MMX 9 mg or 6 mg or mesalamine were 17.9, 13.2, and 12.1% compared with 7.4% for placebo (p = 0.0143, p = 0.1393, and p = 0.2200). Significant association was shown only between patients receiving budesonide MMX 9 mg and placebo. The trial was not powered to directly compare budesonide MMX and mesalamine. In the Core II study [26] combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4, 8.3, 12.6 and 4.5%. The difference between budesonide MMX 9 mg and placebo was significant (p = 0.0047). Budesonide MMX 9 mg was associated with higher rates of clinical (42.2 vs 33.7%) and endoscopic improvement (42.2 vs 31.5%) versus placebo. The rate of histological healing (16.5 vs 6.7%; p = 0.0361) and proportion of patients with symptom resolution (23.9 vs 11.2%; p = 0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Clinical and endoscopic improvement rates were numerically higher in patients treated with budesonide MMX 9 mg than in the Entocort EC control arm. However, the study was not powered to detect statistical significance between the budesonide MMX and Entocort EC treatment groups. This trial enrolled a total of 511 patients. The CORE I and II studies were designed only to evaluate short-term efficacy and not maintenance therapy. Budesonide MMX might be continued for longer than 8 weeks in patients with mild but persistently active disease, but this is not supported by the current data and needs further evaluation.
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2.6.2
Safety and tolerability Previous studies have been shown that fewer adverse effects occurred in patients treated with budesonide compared to those treated with conventional steroids [11]. Similarly, 2.7
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budesonide preserved better adrenal function than conventional steroids. In CD studies, the relative risk (RR) of steroid-related side effects was 0.99 in patients administered with budesonide compared to those administered with placebo, and 0.64 compared to patients administered with conventional corticosteroids. Only the RR of decreased response to ACTH stimulation was increased by the use of budesonide [27]. Every study showed that treatment with budesonide MMX was generally well tolerated with an overall safety profile comparable to that of placebo. In the study of D’Haens et al. the most frequent adverse event was headache (11.86%). Other frequent events were abdominal pain, common cold, diarrhea, flatulence and influenza [12]. In this study, neither morning cortisol nor pituitary--adrenal axis was more frequently suppressed with budesonide tablets than with placebo. In Core I, the majority of the adverse events were mild or moderate. The percentage of patients with severe adverse events was highest in the placebo group (12.4%) compared with the budesonide MMX 9 mg group (6.3%), budesonide MMX 6 mg group (9.5%), and mesalamine 2.4 g group (5.5%). Potential glucocorticoid effects were observed in 10.1% of patients in the placebo group, 11.8% of patients in the budesonide MMX 9 mg group, 5.6% of patients in the budesonide MMX 6 mg group, and 7.9% of patients in the mesalamine group [25]. In the Core II study, the number of patients with treatment-related adverse events and serious adverse events were similar in the placebo, budesonide MMX 9 mg and 6 mg and Entocort EC groups. The majority of the adverse events were mild or moderate, with the most frequent events of the relapse of UC and headache. The most common glucocorticoid-related symptoms were mood changes, sleep changes, and insomnia [26]. Reductions in morning plasma cortisol levels occurred more frequently in budesonide MMX groups and the Entocort EC group. However, mean morning plasma cortisol levels remained within the normal range at all times.
Regulatory affairs CORE I was conducted in North America and India. CORE II was conducted in Europe, Australia, Israel, and Russia. The approved dosage of budesonide MMX in the USA is 9 mg under the trade name Uceris. 2.8
3.
Conclusion
Budesonide MMX represents the first orally administered topical corticosteroid formulation specifically targeting the entire colon. Budesonide MMX 9 mg proved to be safe, well-tolerated, and more effective than placebo for inducing combined clinical and endoscopic remission in patients with mild-to-moderate active left-sided UC.
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Budesonide
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4.
Expert opinion
Developments in corticosteroid chemistry have led to the development of anti-inflammatory glucocorticoids with enhanced topical potency and less systemic activity. Budesonide has been formulated in oral controlled released formulations that minimise proximal absorption and allow high drug concentrations in the ileum and caecum. However, due to the increased potency at the steroid receptor, suppression of the hypothalamic-pituitary-adrenal axis can occur with treatment. Budesonide in a controlled ileal release formulation, administered as 9 mg/day is the favoured therapy to induce remission in mildly active, localised ileocaecal CD, because it proved to be superior to both placebo and mesalazine. However, budesonide is significantly less effective than conventional steroids for induction of remission, particularly among patients with severe disease. Since the oral locally active budesonide is characterized by a favourable safety profile it emerged to compose an alternative to systemic steroids in the treatment of mild-tomoderate active UC. Despite the limited evidence regarding the efficacy of budesonide at inducing clinical and endoscopic remission in patients with UC, it proved to be effective as only a topical compound in cases of left-sided colitis and shown to be significantly less effective than conventional steroids when used orally for induction of remission in active UC. The novel formulation of budesonide with the MMX delivery system allows the drug to be active in the bowel mucosa without systemic absorption. Due to extensive first-pass elimination, the systemic bioavailability of budesonide decreases only to 10 -- 15% compared with other corticosteroid formulations causing less steroid related side effects. In case of MMX-tablets, drug release seems to begin before breakdown of the tablet matrix. Furthermore, 96% of budesonide absorption took place during the time that the tablets were passing the region between the ascending and the descending/sigmoid colon underlying the efficiency of the colon targeting release kinetics of the new MMX structure. However, it should also be added that dietary and inter-individual variabilities may influence the gastrointestinal transit. The goal of budesonide MMX treatment is to maintain the efficacy of corticosteroids with minimising systemic side
effects. Currently, the role of budesonide MMX as induction treatment for UC patients is still a matter of debate. Although it proved to be more effective than placebo, data about the comparison of the efficacy of budesonide MMX with mesalazine, mesalazine MMX and topically active budesonide are still missing. Furthermore, the accurate indication for budesonide MMX therapy is also lacking. Although studies were performed in patients with mild-to-moderate UC, patients with distal, left-sided and extensive colitis were enrolled in the Phase III trials. Core I study revealed that the clinical and endoscopic remission rate for budesonide MMX 9 mg was significantly greater than placebo in patients with left-sided disease. However, for extensive disease, clinical and endoscopic remission rates were numerically but not significantly greater in the budesonide MMX 9 mg group compared with patients receiving placebo. The studies were not powered to detect differences between MMX and placebo among subsets of patients with left-sided disease or extensive disease. Although some trials are still ongoing, the recently available results about the transit parameters, low systemic bioavailability, the efficacy and the lack of significant drug-related adverse events are promising and may confirm the place of this new formulation of budesonide in the treatment of UC. The more positive safety profile of budesonide has encouraged some investigators to attempt to identify whether budesonide could be effective as CD treatment, unfortunately achieving poor results. Randomized, controlled trials would be ideal to examine the long-term efficacy of budesonide MMX in comparison with placebo and mesalamine preparations as well. These studies are essential to take a stand on the role of budesonide MMX in the management of active UC.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. The collection, analysis and interpretation of data were made by the independent authors as was the writing of this article and the decision to submit this article for publication in this journal.
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Affiliation
Klaudia Farkas & Tama´s Molna´r† MD † Author for correspondence University of Szeged, First Department of Medicine, 8--10 Koranyifasor, Szeged, H6720, Hungary E-mail: [email protected]
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