Abstract
New meta‐analyses are presented that provide further evidence supporting the effectiveness of oral prolonged‐release mesalazine compared to other oral mesalazines as induction therapy in patients with moderately active ulcerative colitis.
Keywords: aminosalicylates, delayed‐release, effectiveness, inflammatory bowel disease, mesalamine
Introduction
Mesalazine (5‐aminosalicylate, 5‐ASA) is the recommended first‐line treatment for mild to moderate ulcerative colitis (UC). 1 , 2 Oral prolonged‐release mesalazine (hereafter OPRM; Pentasa; Ferring Pharmaceuticals) is a time‐dependent release formulation of mesalazine, containing granules coated with cellulose polymers, and provides a continuous release of 5‐ASA throughout the gastrointestinal tract, independent of luminal pH and gut transit time. 3 Commensurate with its indication, the major clinical evidence presented for OPRM in UC has tended to cover the spectrum of mild to moderate disease severity, 4 with limited separate analyses of patients with moderate disease alone or head‐to‐head comparisons with other mesalazines. The analyses presented here provide further supporting evidence for the effectiveness of OPRM as induction therapy in patients with moderately active UC.
Evidence
Meta‐analyses were conducted to compare high‐dose (4 g) OPRM with other oral mesalazine formulations (4.8 g) using a Bayesian inferential aggregate of binomial stochastic distribution functions with 10 000 sampling iterations (WINBUGS 1.4.3, Imperial College and MRC, UK). The included studies were identified from two published systematic literature reviews: one focused specifically on OPRM, which included previously unpublished data 4 ; and the other undertaken by Cochrane, which included all mesalazines for induction of remission in UC. 5 Targeted literature searches were also carried out to identify any additional studies published subsequent to these two reviews. The first analysis compared OPRM 4 g/day (Trial 000174) 6 and MMX mesalazine 4.8 g/day 7 using the endpoint of induction of combined clinical and endoscopic remission, with placebo as the common comparator (link between OPRM and MMX mesalazine). In this analysis, no significant difference was found, with the peak of the difference distribution almost precisely coinciding with the zero point (representing the position where the treatment efficacies are equivalent; Fig. 1a). A second analysis compared OPRM 4 g/day (Trial 000174) 6 with Eudragit‐S‐coated mesalazine (ESM hereafter) 4.8 g/day (ASCEND II 8 and III 9 ) for the achievement of composite remission, using ESM 2.4 g/day and placebo 7 as the common comparators. Here, the zero point was within the 80% the credible interval, again indicating no significant difference between treatments (Fig. 1b). Limitations of the meta‐analyses included variation across studies in how moderate disease and remission were defined (Table 1). Bayesian meta‐analyses account for heterogeneity across studies by enabling prior probability component variables to comply with their unique distributions through Gibbs sampling (Markov chain Monte Carlo, MCMC) during the process of generating posterior probabilities.
Figure 1.
Oral prolonged‐release mesalazine 4 g/day versus MMX mesalazine 4.8 g/day (a) and Eudragit‐S‐coated mesalazine 4.8 g/day (b) for the induction of remission in patients with moderate ulcerative colitis.
Table 1.
Definitions of remission from studies included in meta‐analyses of oral prolonged‐release mesalazine 4 g/day versus MMX mesalazine 4.8 g/day and Eudragit‐S‐coated mesalazine 4.8 g/day for the induction of remission in patients with moderate ulcerative colitis (UC)
| Study | Treatment | Definition of remission |
|---|---|---|
| Trial 000174 6 | Oral prolonged‐release mesalazine 4 g/day, placebo | Clinical and endoscopic response score of rectal bleeding scores of 0 and stool frequency score of 0 or 1 with at least 1 point decrease from baseline, with an endoscopic score of 0 or 1. Moderate disease is defined as a modified Mayo score of 7–10 |
| Kamm et al. 2007 7 | MMX 4.8 g/day, Eudragit‐S‐coated mesalazine 2.4 g/day, Placebo | Modified UC‐DAI score of ≤1 with a score of 0 for rectal bleeding and stool frequency and at least 1‐point reduction from baseline in sigmoidoscopy score. Moderate disease is defined as modified UC‐DAI score of 6–10 |
| ASCEND II 8 | Eudragit‐S‐coated mesalazine 2.4 g/day, Eudragit‐S‐coated mesalazine 4.8 g/day | Complete remission defined as normal stool frequency, no rectal bleeding, patient's functional assessment score of 0, normal endoscopy findings, and PGA assessment score 0. Moderate disease is defined as a PGA score of 2 |
| ASCEND III 9 | Eudragit‐S‐coated mesalazine 2.4 g/day, Eudragit‐S‐coated mesalazine 4.8 g/day | Complete remission defined as PGA score of 0 (i.e. complete resolution or normalization of stool frequency, rectal bleeding, and sigmoidoscopy with contact friability assessment score). Moderate disease is defined as PGA score of ≥1 point in both the stool frequency and rectal bleeding clinical assessments and a score of ≥2 points in the sigmoidoscopy assessment with a positive friability assessment |
PGA, Physician's Global Assessment; UC‐DAI, UC Disease Activity Index.
Further evidence in moderate UC was derived from a double‐blinded, randomized controlled trial, which compared OPRM 2.25 g/day and ESM 2.4 g/day. 10 In this study, there was no significant difference reported between the two mesalazine formulations for decrease in Ulcerative Colitis Disease Activity Index (UC‐DAI) scores (primary study outcome; difference between treatments: 0.1; 95% confidence interval [CI]: −1.3 to 1.6). 10 A dose of 3.6 g/day ESM was found to be more efficacious than OPRM 2.25 g/day (P = 0.003), evidencing the increased efficacy with higher doses of mesalazine. 10 Real‐world evidence on the use of OPRM was identified in the recently published QUARTZ study, which found no differences in outcomes (clinical remission, endoscopic activity, or relapse rates) between those with mild or moderate disease. 11 This study also reported that OPRM significantly improved the mean Short Inflammatory Bowel Disease Questionnaire (SIBDQ) scores after 8 weeks′ treatment in patients with moderate disease (43.3 vs 35.9 at baseline; P < 0.001), which was maintained at month 12. 11
As a proxy for greater disease severity, meta‐analyses were undertaken of data from patients with pancolitis from two studies of OPRM 2–4 g versus placebo (Hanauer et al., 12 PEN2A‐23_UC II 13 ). Using a random effects model, which accounts for heterogeneity between studies by assuming that source data are not drawn from a common population (Microsoft Excel 365), OPRM resulted in significantly higher rates of complete or marked improvement in Physician's Global Assessment (absolute risk difference [ARD]: 22%; 95% CI: 7–37%) and significantly lower rates of treatment failure (ARD: 21%; 95% CI: 7–34%) compared to placebo. For patients with pancolitis, the PINCE study 14 , 15 reported significantly higher improvement rates (weeks 2, 4, and 8) and remission rate (week 8) with combined OPRM (4 g/day) and enema treatment (1 g/day) than oral therapy (4 g/day) alone.
Conclusion
The new analyses presented here provide further evidence that OPRM is an effective treatment for the induction of remission in patients with moderately active UC.
Declaration of conflict of interest: KP is an employee of Ferring Pharmaceuticals. JF is an employee of Violicom Medical Limited that has received funding from Ferring for work on various projects. ST has received grants/research support from AbbVie, Buhlmann, Celgene, IOIBD, Janssen, Lilly, Pfizer, Takeda, UCB, Vifor, and Norman Collisson Foundation; Consulting Fees from Abacus, AbbVie, Actial, ai4gi, Alcimed, Allergan, Amgen, Aptel, Arena, Asahi, Aspen, Astellas, Atlantic, AstraZeneca, Barco, Biocare, Biogen, BLPharma, Boehringer Ingelheim, BMS, Buhlmann, Calcico, Celgene, Cellerix, Cerimon, ChemoCentryx, Chiesi, CisBio, ComCast, Coronado, Cosmo, Ducentis, Dynavax, Elan, Enterome, Falk, Ferring, FPRT Bio, Galapagos, Genentech/Roche, Genzyme, Gilead, Glenmark, Grunenthal, GSK, GW Pharmaceuticals, Immunocore, Immunometabolism, Indigo, Janssen, Lexicon, Lilly, Medarex, Medtrix, Merck, Merrimack, Millenium, Neovacs, Novartis, Novo Nordisk, NPS‐Nycomed, Ocera, Optima, Origin, Otsuka, Palau, Pentax, Pfizer, Pharmaventure, Phillips, P&G, Pronota, Proximagen, Resolute, Robarts, Sandoz, Santarus, Satisfai, Sensyne, Shire, SigmoidPharma, Souffinez, Syndermix, Synthon, Takeda, Theravance, Tigenix, Tillotts, Topivert, Trino Therapeutics with Wellcome Trust, TxCell, UCB Pharma, Vertex, VHsquared, Vifor, Warner Chilcott and Zeria; and Speaker fees from AbbVie, Amgen, Biogen, Falk; Ferring, Janssen, Pfizer, Shire, Takeda, UCB. ST holds no stocks or share options.
Financial support: This work was supported by Ferring Pharmaceuticals.
Data availability statement
Data available from the corresponding author upon reasonable request.
References
- 1. Raine T, Bonovas S, Burisch J et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. J. Crohns Colitis. 2022; 16: 2–17. [DOI] [PubMed] [Google Scholar]
- 2. Ko CW, Singh S, Feuerstein JD et al. AGA clinical practice guidelines on the management of mild‐to‐moderate ulcerative colitis. Gastroenterology. 2019; 156: 748–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Ye B, van Langenberg DR. Mesalazine preparations for the treatment of ulcerative colitis: are all created equal? World J. Gastrointest. Pharmacol. Ther. 2015; 6: 137–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Paridaens K, Fullarton JR, Travis SPL. Efficacy and safety of oral Pentasa (prolonged‐release mesalazine) in mild‐to‐moderate ulcerative colitis: a systematic review and meta‐analysis. Curr. Med. Res. Opin. 2021; 37: 1891–900. [DOI] [PubMed] [Google Scholar]
- 5. Murray A, Nguyen TM, Parker CE, Feagan BG, MacDonald JK. Oral 5‐aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst. Rev. 2020; 8: CD000543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Ferring Pharmaceuticals Inc . A randomized, double‐blind, placebo‐controlled, multicenter study investigating the efficacy and safety of mesalamine 4 g extended release granules (sachet) for the induction of clinical and endoscopic remission in active, mild to moderate ulcerative colitis (000174). Clinical Study Report. 2019 Mar; 23426.
- 7. Kamm MA, Sandborn WJ, Gassull M et al. Once‐daily, high‐concentration MMX mesalamine in active ulcerative colitis. Gastroenterology. 2007; 132: 66–75. [DOI] [PubMed] [Google Scholar]
- 8. Hanauer SB, Sandborn WJ, Kornbluth A et al. Delayed‐release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am. J. Gastroenterol. 2005; 100: 2478–85. [DOI] [PubMed] [Google Scholar]
- 9. Sandborn WJ, Regula J, Feagan BG et al. Delayed‐release oral mesalamine 4.8 g/day (800‐mg tablet) is effective for patients with moderately active ulcerative colitis. Gastroenterology. 2009; 137: 1934–43.e1‐3. [DOI] [PubMed] [Google Scholar]
- 10. Ito H, Iida M, Matsumoto T et al. Direct comparison of two different mesalamine formulations for the induction of remission in patients with ulcerative colitis: a double‐blind, randomized study. Inflamm. Bowel Dis. 2010; 16: 1567–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Paupard T, Gonzalez F, Caron B, Siproudhis L, Peyrin‐Biroulet L. Real‐world evidence of quality of life improvement in patients with distal ulcerative colitis treated by mesalazine: the Quartz study. Eur. J. Gastroenterol. Hepatol. 2022; 34: 1203–9. [DOI] [PubMed] [Google Scholar]
- 12. Hanauer S, Schwartz J, Robinson M et al. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Pentasa Study Group. Am. J. Gastroenterol. 1993; 88: 1188–97. [PubMed] [Google Scholar]
- 13. Ferring Pharmaceuticals Inc . Efficacy and safety of oral Pentasa in the treatment of acute exacerbations of ulcerative colitis – II (PEN2A‐23_UC II [PAPR0001]). Clinical Study Report. 1990 Sep; 8‐5404.
- 14. Marteau P, Probert CS, Lindgren S et al. Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study. Gut. 2005; 54: 960–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Probert CS, Dignass AU, Lindgren S, Oudkerk Pool M, Marteau P. Combined oral and rectal mesalazine for the treatment of mild‐to‐moderately active ulcerative colitis: rapid symptom resolution and improvements in quality of life. J. Crohns Colitis. 2014; 8: 200–7. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data available from the corresponding author upon reasonable request.