Regulatory Decision Summary for Mezera

Health Canada considers that the benefit-harm-uncertainty profile of Mezera (mesalamine delayed-release tablets) is favorable for the induction of remission in adult patients with active mild to moderate acute ulcerative colitis.

The indication is supported by the results of two Phase 3, multi-centre, double-blind, randomized, non-inferiority, controlled studies conducted in adults with mild to moderate ulcerative colitis (i.e., Study SAT-14 and Study SAT-25). The patients’ eligibility criteria for both studies were generally comparable.

Study SAT-14, which was considered to be the pivotal Phase 3 trial, was conducted in Australia and Eastern Europe in 260 patients with mild to moderately active ulcerative colitis for an 8-week induction phase. In this study, 133 patients were treated with 2 x 500 mg TID (3 g/day) Mezera tablets (mesalamine, delayed-release tablets) and 127 patients were treated with 2 x 500 mg TID (3 g/day) of the active control tablets (mesalamine, ethylcellulose-coated extended-release tablets). The primary efficacy endpoint was the rate of clinical remission (complete response) at the final examination, which was defined as a Clinical Activity Index (CAI) ≤ 4. CAI is an index scale ranging from 0 to 29 points and is the sum score of seven variables: bowel movement frequency, presence of blood, general well-being, abdominal pain, temperature due to colitis, extraintestinal manifestations, and laboratory findings (erythrocyte sedimentation rate and hemoglobin). Patients with endoscopically confirmed mild to moderate active ulcerative colitis, defined by a CAI of 6 to 12 and an endoscopic index ≥ 4 were eligible to participate in this study. The endoscopic index scale ranges from 0 to 12. Mezera was non-inferior to the active control with a non-inferiority margin of -13% (actual observed value of -12.4%, and p-value of 0.0198). Rates of clinical remission in the per protocol analysis set were 68.8% and 68.9% in patients treated with Mezera and active control, respectively. The results of secondary efficacy endpoints were supportive of non-inferiority. Notably, in a post-hoc analysis using a more stringent definition of remission (i.e., CAI ≤ 4 with number of stool subscore of 0, and number of bloody stools subscore of 0), the rates of clinical remission were 39.5% and 34.0% in patients treated with Mezera and the active control, respectively.

Study SAT-25, which was considered to be a supportive study using the to-be-marketed formulation, was conducted in 306 patients with mild to moderately active ulcerative colitis in Europe for 8 weeks. In this study, 151 patients were treated with 1 g TID (3 g/day) mesalamine delayed-release tablets and 155 patients were treated with 2 x 500 mg TID (3 g/day) Mezera (mesalamine, delayed-release tablets, active control). Mezera was the active control in this study, which is why the results are only considered supportive. The primary efficacy endpoint was the percentage of patients in clinical remission at the final examination, defined as the CAI ≤ 4 with stool frequency subscore of 0 and rectal bleeding subscore of 0, which is comparable to the more stringent post-hoc analysis conducted in SAT-14. The rates of clinical remission in the per protocol analysis were 46.6% in the comparator arm and 38.6% in the Mezera arm (compared to 39.5% for Mezera in SAT-14 for a similar endpoint). The rate of clinical remission defined in the same way as the primary efficacy endpoint (CAI ≤4) in the pivotal SAT-14 was 70.9% in the comparator arm and 73.5% in the Mezera arm (compared to 68.8% for Mezera in SAT-14). Therefore, the efficacy outcomes for Mezera were in line with those in SAT-14. Overall, taken together, the results from the two studies supports the efficacy of Mezera in the indication of induction of remission in patients with mild to moderately active ulcerative colitis.

Mesalamine has a long history of use for this indication and therefore has a well-established and well-characterized safety profile for the indicated population. Mezera was well-tolerated in the submitted studies. In the pivotal SAT-14 study, 131 patients received Mezera tablets. Adverse reactions were reported in 18.3% of patients treated with Mezera and 22.0% of patients treated with the active control. Most were mild or moderate in severity, and are adverse reactions common to oral mesalamine treatment. The most common adverse events reported in patients treated with Mezera were headache (26.0%), abdominal pain (5.3%), nausea (3.8%), and viral infections (2.3%). No new safety signals were identified in the submitted studies. Serious adverse events were not common (≤ 8 patients) and were usually classified as deteriorations of the underlying disease. Extensive post-marketing experience supports the safety of oral mesalamine use. Overall, the risks associated with mesalamine use are considered to be manageable through the inclusion of appropriate contraindications, warnings, and cautionary statements in the Product Monograph and post-market monitoring.

Overall, the anticipated benefits of Mezera are expected to outweigh its risks under the conditions of use recommended in the Mezera (mesalamine delayed-release tablets) Product Monograph at this time.