Regulatory Decision Summary for Octasa

Ulcerative colitis (UC) is a wide-spread and potentially serious inflammatory condition of the colon with unknown aetiology. Treatment with mesalazine (also known as 5-aminosalicylic acid or mesalamine) is considered as the therapeutic gold standard for the induction and maintenance of remission in mild to moderately UC.

To support the approval for Octasa 800 mg delayed-release tablets at a dose of 4.8 g/day given in three divided daily doses for the treatment of moderately active UC, two pivotal clinical studies (TP0203 and TP0205) using the intended marketed formulation were submitted by the Sponsor. Additionally, several published clinical reports, and a periodic safety update report (covering a period of February 2010 to February 2015), were also submitted as supportive evidence.

The pivotal clinical trial TP0203 was a multi-national, multicentre, randomised, placebo-controlled, double-blind phase III study. This study was submitted in support of the "remission of induction claim". The primary objective of the TP0203 study was to determine the efficacy of Octasa 4.8 g/day (800 mg tablets) to induce remission in subjects with mild to moderate active UC. One hundred forty (140) subjects received Octasa and 141 subjects received placebo. The study treatment period was 10 weeks. All treatment regimens were orally administered, with or without food.

The primary efficacy endpoint was the proportion of subjects who achieved clinical remission at the week 6 visit. Health Canada considered clinical remission and endoscopic remission at week 10 to be the important endpoints to measure primary efficacy. Therefore, although the study failed to meet the primary efficacy endpoint at week 6, the study achieved its objective through the secondary efficacy endpoints, which were the proportion of subjects who achieved clinical remission and endoscopic remissions at the week 10 visit. These secondary endpoints were deemed to be clinically relevant and statistically valid. For the intent-to-treat (ITT) population, clinical remission at week 10 was achieved in 57 (40.7%) of the subjects who received Octasa and 30 (21.3%) of the subjects who received placebo (p <0.001; 95% CI 8.6%, 29.6%). For endoscopic remission at week 10, this was achieved in 73 (52.1%) of the subjects who received Octasa and 52 (36.9%) of the subjects who received placebo (p = 0.010; 95% CI 3.6%, 26.3%). A similar trend for clinical remission was observed at week 6; however, statistical significance was not achieved at week 6. Endoscopic remission at week 6 was achieved in 64 (45.7%) of the subjects who received Octasa and 35 (24.8%) of the subjects who received placebo (p <0.001; 95% CI 9.7%, 31.3%).

The mild and moderate subgroups were un-evenly distributed (21.4% vs. 78.7%) in TP0203 study. The small patient numbers with mild disease were not considered to be clinically and statistically adequate to demonstrate the efficacy of Octasa in the treatment of patients with mild UC. As a result, the proposed indication was revised to be focused only on the treatment of patients with moderately active UC.

The "maintenance of remission indication" was not clinically investigated by the sponsor using the intended Octasa 800 mg formulation. The sponsor claimed that Octasa 400 mg and Octasa 800 mg tablets have similar in vivo and in vitro properties. To support their claim, the sponsor submitted (i) a pivotal biopharmaceutics study (TP0205) to demonstrate the bridging of data between Octasa 400 mg and Octasa 800 mg tablets; (ii) published clinical reports. The information provided in these submitted reports was considered insufficient to support the "maintenance of remission" indication. Therefore, the Sponsor was recommended to revise the proposed indication by removing the maintenance indication.

The pivotal TP0203 study demonstrated that Octasa was well tolerated. Treatment related undesirable effects in the Octasa group with the highest reporting rate were worsening of ulcerative colitis (3.6%), haematuria (2.9%) and ketonuria (2.1%). All adverse drug reactions associated with the use of Octasa 800 mg tablets were of mild to moderate severity. Octasa has not been studied in enough patients with renal insufficiency, hepatic insufficiency, age ≥65, age <18, or in women who are pregnant or nursing to assess safety and efficacy in these populations. No significant new information on the safety of Octasa was brought to light and no new information was identified from post-marketing surveillance concerning the safety of long-term mesalazine treatment. Reports from uncontrolled clinical studies and post-marketing reporting systems for mesalamine suggested a rare incidence of blood dyscrasias, i.e., agranulocytosis, neutropenia, pancytopenia, in patients who were 65 years or older. Caution should be taken to closely monitor blood cell counts during mesalamine therapy.

The information in this submission provides sufficient evidence to support a favourable benefit/risk ratio of Octasa 800 mg delayed-release tablets for the treatment of moderately active ulcerative colitis under the conditions of use described in the approved Product Monograph.