Regulatory Decision Summary for Octasa

Health Canada considers that the benefit-harm-uncertainty profile of Octasa (1,600 mg mesalamine delayed-release tablets) is favourable for the induction of remission in adult patients with moderate active ulcerative colitis (UC).

The proposed indication was supported by the results of a Phase 3 pivotal, multi-national, multi-centre, randomized, double-blind, active-controlled, non-inferiority trial (TP0503). The study included two phases: an induction phase (TP0503_I) and an open-label extension phase (TP0503_M).

Study TP0503_I was conducted in 817 patients with mild to moderately active UC for an 8-week induction of remission phase. In this part of the study, 409 patients were treated with 3.2 g/day Octasa 1,600 mg taken once daily in the morning and 408 patients were treated with 3.2g/day ASACOL 400 mg taken twice daily in the morning and evening. ASACOL was selected as the active comparator because it is an established and effective treatment of mild to moderate UC. Please note that the recent discontinuation of ASACOL 400 mg (DIN 01997580) did not impact the adequacy of the clinical data package filing of Octasa 1,600 mg. The primary efficacy endpoint was the induction of clinical and endoscopic remission at week 8. The clinical and endoscopic remission were defined as Mayo score of ≤2 with no individual sub-score >1. The Mayo score for UC disease activity provides an assessment of disease severity. Octasa was non-inferior to the active control with a one-sided non-inferiority margin of -10%. Rates of clinical and endoscopic remission in the per protocol (PP) analysis set were 22.4% and 24.6% in patients treated with Octasa and the active control, respectively. In a sub-group analysis based on the severity of disease, non-inferiority was not demonstrated in patients with mild active UC, therefore the indication in mild UC could not be authorized. The results of the secondary efficacy endpoint of endoscopic remission was supportive of non-inferiority; however, the study could not demonstrate non-inferiority for the secondary endpoints of endoscopic response, clinical remission, rectal bleeding sub-score of 0, or clinical and endoscopic response.

Study TP0503_M was conducted in 476 patients who were in remission (remitters; 202 patients) or who had some response to treatment (responders; 274 patients) at week 12 for a 26-week maintenance period. The primary objective of this phase was to assess the long-term safety and tolerability of Octasa 1,600 mg and to demonstrate maintenance of clinical remission at week 38 (end of study). This phase of the study was not comparative and had a duration of 26 weeks, which is not consistent with established international guidelines for designing studies for the development of treatments for UC (i.e., FDA or EMA) that stipulate a maintenance phase of at least 52 weeks in a comparative setting. Furthermore, the primary efficacy endpoint at week 38 was maintenance of clinical remission, which was different from the primary endpoint assessed in the induction phase of this study (clinical and endoscopic remission). Finally, a trend in declining clinical remission/response rates was observed by week 38. Overall, the study design and analyses were considered exploratory as they did not provide adequate evidence for regulatory decision-making. Therefore, the proposed indication for maintenance of remission was not granted.

Mesalamine has a long history of use and therefore has a well-established and well-characterized safety profile for the indication population. Octasa 1,600 mg was well-tolerated in the submitted studies. In the pivotal study, 409 patients received Octasa 1,600 mg. Most adverse reactions of mild to moderate severity, and were adverse reactions common to oral mesalamine treatment, including abdominal pain, diarrhea, nausea, and vomiting. The most commonly reported treatment-emergent adverse events (TEAEs) were abdominal pain (1.5% vs. 0.7% in Octasa 1,600 mg and the active comparator, respectively), alanine aminotransferase increased (1.2% vs. 0.5%), hematuria (1.2% vs. 0.5%), leukocyturia (1.2% vs. 0.5%), and proteinuria (1.0% vs.0.5%). It is notable that in the pivotal induction trial, patients in the Octasa 1,600 mggroup experienced a higher proportion of TEAEs than those treated with the active comparator (32% vs. 26.5% respectively). Extensive post-marketing experience supports the safety of oral mesalamine use. Overall, the risks are considered to be manageable through labelling in the Product Monograph.

Overall, the anticipated benefits of Octasa 1,600 mg was expected to outweigh its risks under the conditions of use recommended in the Octasa 1,600 mg Product Monograph at this time.