Regulatory Decision Summary for Myinfla

Epidemiologic studies in patients with inflammatory arthritis have noted that patients treated chronically with colchicine appeared to develop serious adverse cardiovascular events at a lower frequency than those not treated with colchicine. Accordingly, two clinical outcome trials were conducted to study colchicine as an add-on therapy to standard medical treatment of coronary artery disease (CAD).

The pivotal COLCOT trial, a randomized, double-blind, placebo-controlled study, was conducted in 4,745 patients to evaluate colchicine 0.5 mg daily when initiated within 30 days of a documented acute coronary syndrome (ACS) event. It reported a significant relative risk reduction of 23% for the primary composite endpoint, major adverse cardiac events (MACE) 5, that included cardiovascular death, myocardial infarction (MI), resuscitated cardiac arrest, stroke, and urgent hospitalization for angina requiring coronary revascularization (UHARCR) when colchicine was used in addition to standard therapies. All components of the primary composite endpoint trended in favour of colchicine, with stroke and UHARCR being the components that drove the result of the overall composite endpoint significantly.

Another outcome trial, LoDoCo2, served as a supportive trial. A total of 5,522 stable patients with existing CAD were randomized. Most patients had a history of remote ACS, generally longer than 24 months from study randomization, while the remainder had clinically significant documented CAD at study entry, based on pre-specified imaging criteria. In this complementary patient population to the one studied in COLCOT, a similar clinical benefit in reduction of atherothrombotic events was observed, with a statistically significant relative risk reduction of 31% noted for the primary composite endpoint, MACE 4, which included cardiovascular death, MI, ischemic stroke, and ischemia-driven coronary revascularization. All components of the primary composite endpoint trended in favour of colchicine. Both rates of MI and ischemia-driven coronary revascularization were seen to improve significantly with colchicine use.

The safety of colchicine is well-known when used chronically at daily doses of between 0.6 mg and 2.4 mg for non-cardiovascular indications. The two outcome trials have demonstrated acceptable tolerability and safety of colchicine when used at a daily dose of 0.5 mg in patients with coronary artery disease, in addition to standard medical treatments, including low-density lipoprotein (LDL)-lowering treatments (primarily statins), and antithrombotic therapies. Gastrointestinal disorders were the most common adverse reactions observed with colchicine use, however in the pivotal COLCOT trial, the incidence of these events was only modestly elevated compared to placebo. Occasional cutaneous eruptions were also noted.

The non-pivotal clinical studies included two Phase I studies in healthy volunteers. The data covered pharmacokinetics (PK) in human, food effects and comparison with reference products. The general PK parameters are comparable with the referenced colchicine product. No significant food effect was identified, and Myinfla is recommended to be taken with or without food. Severe hepatic impairment, severe renal impairment, strong P-gp inhibitors and strong CYP3A4 inhibitors may significantly increase the colchicine systemic exposure. The therapeutic window for colchicine is narrow, and excessive systemic exposure increases adverse drug reactions such as gastrointestinal symptoms leading to volume depletion, multisystem organ dysfunction, and death. Therefore, hepatic impairment, renal impairment, as well as concomitant use of CYP3A4 inhibitors/P-gp inhibitors are contraindications, and information was included in the Product Monograph.

The non-clinical program did not have any study evaluating the proposed product, Myinfla. Literature and the review report from the United States Food and Drug Administration (FDA) were consulted. The mechanism of action of colchicine is related to disruption of cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and consequently prevents the activation, degranulation, and migration of neutrophils. Colchicine may also interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β. The activation of caspase-1 may be inhibited by colchicine, which is the enzymatic component of the nucleotide-binding oligomerization domain receptor (NOD-like receptor) family pyrin 3 (NLRP3) inflammasome. Colchicine may increase the threshold for initiation of full-blown inflammasome activation in part by diminishing (without eliminating) sub-clinical inflammation. These effects of colchicine may contribute to the clinical benefit to protect the atherosclerosis plaque. The toxicology section has been assessed with up-to-date information including carcinogenicity, genotoxicity, reproductive and developmental toxicology.

The benefit-risk-uncertainty profile of Myinfla is considered favourable for its use in patients with existing CAD to reduce atherothrombotic events, when used in addition to standard medical therapies, including LDL-cholesterol lowering and antithrombotic agents. Risks and benefits identified during review have been included in the Product Monograph.

For further details about Myinfla, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.