Regulatory Decision Summary for Velsipity

This New Drug Submission for a New Active Substance was filed to obtain market authorization for Velsipity (etrasimod tablets, 2 mg) for the treatment of patients 16 years of age and older with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment. Upon review, an indication for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment is recommended.

The proposed indication was supported by the results of two pivotal Phase 3 double-blind, randomized, placebo-controlled multi-center studies (APD334-301 and -302) in adults and adolescents ≥16 years of age. The studies were conducted worldwide, including Canada, in 788 adults and adolescents (≥16 and ≤78 years) with a confirmed diagnosis of moderately to severely active ulcerative colitis (UC) for at least 3 months. A subset of subjects also had demonstrated an inadequate response or intolerance to advanced treatment (i.e., biologic agents or JAK inhibitors) or were naïve to biologic therapy.

The proposed indication was supported by the results of two pivotal Phase 3 double-blind, randomized, placebo-controlled multi-center studies (APD334-301 and -302) in adults and adolescents ≥16 years of age. Subjects were treated with Velsipity (etrasimod 2 mg daily) for 52 weeks and 12 weeks, in studies APD334-301 and APD334-302, respectively.

The primary efficacy endpoint in the pivotal studies was the proportion of subjects achieving clinical remission per modified Mayo Score (mMS) at Week 12 (APD334-301 and -302) and Week 52 (APD3343-301 only). The mMS ranges from 0 to 9 and is composed of patient-reported rectal bleeding (RB) and stool frequency (SF) symptomatic subscores and a centrally read endoscopy score (ES). Patients enrolled in the studies had mMS of 4-9, with an ES ≥2 and a RB ≥1. Clinical remission was defined as a SF subscore = 0 (or = 1 with a ≥1-point decrease from Baseline), RB subscore = 0, and ES ≤1 (excluding friability). Efficacy was evaluated in subjects with a mMS of 5-9, which corresponds with moderately to severely active UC. The primary endpoint was met in the pivotal Phase 3 studies. A statistically significantly higher proportion of patients in the Velsipity group achieved clinical remission per mMS at Week 12 (APD334-301 and -302) and Week 52 (APD334-301). At Week 12 the proportion of patients achieving clinical remission in studies APD334-301 and -302, respectively, was 74/274 (27%) and 55/222 (24.8%) for Velsipity and for placebo was 10/135 (7.4%) and 17/112 (15.2%). At Week 52 in APD334-301 the proportion of subjects achieving clinical remission was 88/274 (32.1%) for Velsipity and 9/135 (6.7%) for placebo. At Week 12 and Week 52, subgroup analysis showed efficacy even in patients who have had prior treatment failure. Velsipity was also statistically and clinically significantly superior to placebo for all multiplicity controlled endpoints, including endoscopic improvement, symptomatic remission, histologic-endoscopic mucosal improvement, corticosteroid-free clinical remission, and maintenance of clinical remission, further supporting the efficacy of Velsipity in the proposed indicated population.

The safety review was based on data from one Phase 2 dose-ranging study, the two pivotal Phase 3 studies, an ongoing Phase 3 study efficacy and safety study in east Asian countries, and extension studies for subjects from the Phase 2 dose-ranging study and from the Phase 3 studies. There is limited long-term data to support the chronic use of Velsipity. In total, there were a total of 132 patients with at least 52 weeks of exposure to VELSIPITY. At week 52, the most frequent (≥2%) treatment emergent adverse events that occurred more frequently in the Velsipity group than placebo were headache (9.3% vs 4.9%), dizziness (5.2% vs 2.1%), elevated liver enzymes (5.9% vs 4.9%), arthralgia (4.5% vs 2.1%), urinary tract infection (3.5% vs 2.1%), hypertension (3.1% vs 0.7%), nausea (3.1% vs 1.4%), hypercholesterolemia (2.8% vs 0), and upper respiratory tract infection (2.7% vs 0). Pyrexia (3.5% vs 2.4%) was the only adverse reaction identified in patients treated for up to 12 week that was not present in the 52 week study. There were no deaths in the UC clinical development program.

Etrasimod is a sphingosine 1 phosphate (S1P) receptor modulator. Adverse reactions of special interest associated with S1P receptor modulators were identified in the clinical program, including bradycardia, hypertension, AV conduction delay, herpes viral infection, severe infection, liver injury, macular edema, and pulmonary disorders. Posterior reversible encephalopathy syndrome and malignancies, other adverse events of special interest to this class, did not occur in the clinical trial program. The Product Monograph is sufficiently labelled to mitigate these risks.

The Phase 3 studies included 3 adolescent subjects (ages 16-17), with 1 subject randomized to Velsipity and the other 2 randomized to placebo. This was an insufficient number of subjects to evaluate the efficacy and safety of Velsipity in this population, nor to validate the population pharmacokinetic, pharmacokinetic/pharmacodynamic, and exposure-response modelling, used to support the indication in adolescents 16 years of age and older. Therefore, no pediatric indication is recommended.

In addition to the Product Monograph, risk mitigation measures are outlined in the Risk Management Plan (RMP) for Velsipity. They include educational materials for patients and health care professionals to enhance awareness and knowledge of the risk of serious and opportunistic infections, first-dose cardiovascular effects, effect on pregnancy and the fetus, use during breast-feeding, macular edema, serious liver injury, and malignancy.

Overall, the anticipated benefits of Velsipity are expected to outweigh the risks under the conditions of use recommended in the Product Monograph and with post-market requirements outlined in the RMP.

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