Summary Basis of Decision for Velsipity

Clinical Pharmacology

Etrasimod, the medicinal ingredient in Velsipity, is a sphingosine 1-phosphate (S1P) receptor modulator that exhibits selectivity to S1P receptors 1 (S1P1), S1P4 and S1P5, with no activation of S1P2 receptors and minimal activation of S1P3 receptors. At the S1P1 receptor, etrasimod activates G-protein signalling and β-arrestin recruitment. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood thereby lowering the number of activated lymphocytes in the tissue.

The mechanism by which etrasimod exerts therapeutic effects in patients with ulcerative colitis (UC) is unknown but may involve reducing lymphocyte migration into sites of inflammation. The etrasimod-induced reduction of lymphocytes in the peripheral circulation has differential effects on leucocyte subpopulations, with greater decreases in cells involved in the adaptive immune response. Etrasimod has minimal impact on cells involved in innate immune response, which contribute to immunosurveillance.

In vitro studies performed using human-derived biomaterials identified that etrasimod binds extensively to plasma proteins. Recombinant human cytochrome P450 (CYP) enzyme experiments demonstrated that CYP2C8, CYP2C9 and CYP3A4 mediate the majority of etrasimod metabolism (38%, 37%, 22%, respectively) with minor contributions of CYP2C19 and CYP2J2. Furthermore, UGT1A7 is involved in etrasimod glucuronidation. In vitro metabolism of etrasimod produced four predominant metabolites: M1, M2, M3, and M6. Furthermore, M2 and M3 are also converted to glucuronidation metabolites M4 and M5.

In the reviewed studies, 395 healthy adult subjects received at least one dose of etrasimod. Data from these subjects formed the pharmacokinetic (PK) and safety population set. Single and multiple ascending‑dose studies in humans established that etrasimod is absorbed quickly (maximum concentration [T_max] at approximately 4 hours) and demonstrates dose-proportional increases in PK metrics. Repeat dosing at proposed subclinical (0.7 mg to 1.35 mg) and clinical doses (2 mg) resulted in drug accumulation, with an area under the concentration-time curve (AUC) approximately 2.5-fold higher after 21 day once daily dosing versus the AUC after a single dose.

The pharmacokinetics of etrasimod were comparable across White, Black, Chinese, and Japanese subjects, with slightly elevated exposures in Japanese versus Caucasian subjects resulting from lower body weight. The administration of etrasimod resulted in a transient decrease in heart rate, with a maximum decrease of approximately 5 to 20 bpm on Day 1 approximately 4 to 8 hours post dose, thus generally coinciding with the T_max. This effect led to bradycardia (i.e., heart rate less than 60 bpm) in some subjects, although it was not considered adverse. A cardiodynamic study demonstrated that gradual dose escalation was ineffective at mitigating the effect of first dose on decreases in heart rate, thereby determining that dose-escalation is not necessary. Etrasimod also caused transient prolongation of the PR interval, which was most pronounced on Day 1 of dosing, with a maximum placebo-corrected, change in PR interval relative to baseline (ΔΔPR) increase of approximately 5 to 16 msec observed at the 2 mg clinical dose. Following administration of a clinical or subclinical dose of etrasimod, first-degree or second-degree atrioventricular block (PR interval greater than 200 msec) was observed in 7 of 363 (1.9%) subjects evaluated in the Phase I PK studies. These effects were observed in healthy adult subjects with no adverse cardiac history. Together, these data are consistent with activation of S1P receptors in the heart, inducing a decrease in cyclic adenosine monophosphate (cAMP) levels and activation of G protein-coupled inwardly rectifying potassium (GIRK) channels (as demonstrated in non-clinical pharmacology studies) resulting in atrial myocyte hyperpolarization.

An absorption, distribution, metabolism, and excretion (ADME) study in male subjects showed comparable results to ADME studies performed in dogs and rats. The results of the study identified predominant plasma protein binding, relatively little first pass metabolism (etrasimod was the most abundant plasma metabolite, with smaller contributions of M3 and M6), more extensive biotransformation prior to elimination, which occurred primarily via hepatobiliary excretion (82% of recovered drug was detected in feces as 10 metabolites) and a smaller elimination via the renal pathway (4.9% of recovered drug detected in urine as 21 metabolites).

Consistent with its route of elimination, hepatic impairment resulted in increased exposures of etrasimod, M3 and M6, with etrasimod exposures 57% higher in subjects with severe hepatic impairment. This elevated exposure correlated with greater effects on heart rate decreases, PR interval prolongation, and corrected QT interval by Fredericia (QTcF) interval prolongation; therefore, the use in severe hepatic impairment is not recommended.

Renal elimination had negligible effects on etrasimod pharmacokinetics and safety, therefore, no dose adjustment is required in patients with renal impairment.

Drug-Drug Interactions

Drug-drug interaction studies established that inhibitors or inducers of CYP enzymes involved in etrasimod metabolism caused expected changes in exposures, with an up to 84% increase in AUC observed with concomitant fluconazole (CYP2C19, CYP2C9 and CYP3A4 inhibitor), 36% increase in AUC observed with concomitant gemfibrozil (CYP2C8 inhibitor), 30% increase in AUC observed with concomitant itraconazole (CYP3A4 inhibitor), and up to 50% decrease in AUC observed with concomitant rifampin (CYP2C8, CYP2C9, CYP2C19 and CYP3A4 inducer).

Concomitant medications that increased etrasimod exposures were not associated with changes in the safety profile of etrasimod, while no lymphocyte population measurements were performed to assess whether medications that reduced etrasimod exposures affected the pharmacodynamic effect of etrasimod. For these reasons, concomitant administration of drugs that inhibit or induce more than one CYP enzyme involved in etrasimod metabolism is not recommended. In addition, use of concomitant drugs that strongly inhibit CYP2C8 or CYP3A4 is not recommended in individuals who are poor CYP2C9 metabolizers (due to carrying the CYP2C9*3 allelic variant).

An assessment was conducted on the effect of concomitant administration of etrasimod and a monophasic oral contraceptive consisting of ethinyl estradiol and levonorgestrel as females receiving etrasimod are likely to opt for this contraception to avoid pregnancy while on therapy. Concomitant administration did not affect the pharmacodynamics of either drug. Compared to the administration of an oral contraceptive alone, concomitant etrasimod induced a small but not clinically significant increase in the AUC of ethinyl estradiol (24%) and levonorgestrel (32%). Concomitant use of etrasimod and an oral contraceptive caused four subjects to experience mild elevated hepatic enzymes, who had not experienced this with the oral contraceptive alone. In one subject, this was more pronounced. These findings suggest that concomitant use of etrasimod increases the risk of oral contraceptive-induced elevated hepatic enzymes and/or cholestasis.

Comparative Bioavailability

A Phase I study was conducted in healthy adult subjects to establish a bridge between the proposed commercial tablet formulation (2 mg etrasimod) and the clinical tablet formulation (2 mg etrasimod) of Velsipity. The rate and extent of absorption of etrasimod following single-dose administration under fasting conditions was comparable between the two formulations. The results demonstrated that the proposed commercial tablet formulation was successfully bridged to the clinical tablet formulation. When the proposed commercial tablet formulation was administered with a high-fat, high-calorie meal, the rate and extent of absorption of etrasimod was comparable to its administration under fasting conditions. Food delayed the median time to peak concentration by 2 hours.

QT Prolongation

A Phase I randomized, double-blind, placebo- and positive-controlled study was conducted to investigate the effect of multiple doses of etrasimod on the QT interval in healthy subjects. Exposure-response modelling showed that at plasma concentrations approximately 1.4-fold higher than expected clinically, the placebo-corrected change from baseline increase in the QTcF was 4.3 msec (90% confidence interval [CI]: 1.46, 7.18).

In a thorough QT study, incidences of QTcF values >450 msec and ≤480 msec were observed in one subject (3.3%) following a single 2 mg etrasimod dose, and in two subjects (6.7%) following a once‑daily 2 mg etrasimod dose for 7 days. Although infrequent, incidences of on-therapy QTcF >450msec and ≤480msec were observed in other Phase I studies, these findings were not associated with adverse events. However, during Phase I development of etrasimod, no subjects were studied with a baseline QTc >450 msec (male) or >480 msec (female) and thus the QTc prolongation effect in these subjects is unknown and may potentially lead to adverse events.

The Velsipity Product Monograph conveys the primary analysis data from this study, informing caregivers of the magnitude of QTc changes measured and recommending that advice from a cardiologist be sought in patients with long QTc intervals (QTcF ≥450 msec in males, ≥470 msec in females) and/or who are receiving anti-arrhythmic medication that may have additive effects on QT interval when used with Velsipity.

Population Pharmacokinetics

Population pharmacokinetic analysis demonstrated that etrasimod exposure is not significantly affected by age, race, sex, bilirubin levels, or tobacco use, but did indicate that body weight and estimated glomerular filtration rate (eGFR) are covariates significantly affecting exposures. Systemic exposure (AUC) was 24% lower in subjects weighing 110 kg vs. 70 kg and 23% higher in subjects weighing 50 kg vs. 70 kg.

Exposure-efficacy modelling demonstrated a positive correlation between exposure and efficacy endpoints. Covariates that negatively affected efficacy endpoints were an MMS greater than 6, prior Janus kinase (JAK) therapy, concomitant corticosteroids, and Japanese race.

No dose adjustment was deemed necessary for geriatric patients, considering comparable PK exposures and efficacy responses versus non-geriatric subjects. The Product Monograph cautions that geriatric patients are more likely to have higher body weight, impaired renal and hepatic function, and may be receiving concomitant medication, all of which could influence the pharmacokinetics and efficacy of Velsipity. Considering the lack of clinical data for adolescent subjects, the reliability of model-derived simulations from this patient population could not be verified. Therefore, adolescent subjects were removed from the proposed indication.

Overall, the clinical pharmacology data support the use of Velsipity for the recommended indication. For further details, please refer to the Velsipity Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Velsipity was primarily evaluated in two pivotal Phase III studies: ELEVATE UC 52 (APD334-301) and ELEVATE UC 12 (APD334-302). Both studies were double-blind, randomized, placebo-controlled, multi-centre studies conducted worldwide, including Canada. In total, the studies included 788 patients between the ages of 16 and 78 years with a confirmed diagnosis of moderately to severely active ulcerative colitis (UC) for at least 3 months.

The mean age of patients for both studies was 40.4 years. In ELEVATE UC 52, 55.4% of patients were male and 44.6% were female, whereas, 58.8% of patients were male and 41.2% were female in ELEVATE UC 12. For both studies, the majority of the patients were from eastern Europe.

Each patient’s disease severity was assessed using the modified Mayo score (mMS). The mMS ranged from 0 to 9 and was composed of three subscores, each ranging from 0 to 3, for the following: patient-reported rectal bleeding (RB), patient reported stool frequency (SF), and findings on a centrally read endoscopy score (ES). The baseline mMS was 6.6 for patients in ELEVATE UC 52 and 6.7 for those in ELEVATE UC 12, with scores ranging from 4 to 9 for both studies. These scores included an ES subscore of 2 or higher and an RB subscore of 1 or higher. An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions, whereas a score of 3 was defined by spontaneous bleeding and ulceration. An RB subscore of 1 was defined as streaks of blood with stool less than 50% of the time, whereas a subscore of 2 was obvious blood with the stool most of the time, and a subscore of 3 was blood passing alone. An SF subscore of 0 was defined as a normal number of stools for he patient, a subscore of 1 was 1 to 2 stools more than normal, a subscore of 2 was 3 to 4 stools more than normal, and a subscore of 3 was 5 stools or more compared to normal. Patients with moderate disease had an mMS of 7 or lower and patients with severe disease had an mMS greater than 7. In addition, patients had also demonstrated prior treatment failure, i.e., an inadequate response to, loss of response to, or intolerance to at least one conventional therapy (i.e., 5-acetylsalicylic acid [ASA], corticosteroids, immunosuppressants, etc.). A subset of patients had also demonstrated an inadequate response or intolerance to biologic agents (i.e., adalimumab, certolizumab, infliximab, ustekinumab, vedolizumab, and/or natalizumab), or Janus kinase (JAK) inhibitors (i.e. tofacitinib), while another subset of patients were naïve to biologic therapy.

Both studies included a screening period and a 12-week treatment period, however for ELEVATE UC 52, this was followed by a 40-week treatment period. Patients were randomized 2:1 to receive Velsipity (2 mg etrasimod) or placebo orally once daily for 52 weeks (ELEVATE UC 52) or for 12 weeks (ELEVATE UC 12). The use of concomitant UC therapies was permitted, including stable daily doses of oral aminosalicylates and/or oral corticosteroids (20 mg or less of prednisone, 9 mg or less of budesonide, or an equivalent steroid). Concomitant treatment with immunomodulators, biologic therapies, rectal 5-ASA, or rectal corticosteroids was not permitted.

The primary efficacy endpoint for both pivotal studies was the proportion of patients achieving clinical remission per mMS at Week 12 (ELEVATE UC 52 and ELEVATE UC 12) and at Week 52 (ELEVATE UC 52 only). Clinical remission was defined as an SF subscore of 0 (or of 1 with a 1 point or greater decrease from baseline), an RB subscore of 0, and an ES subscore less than or equal to 1 (excluding friability). Efficacy was evaluated in patients who were randomized and received at least one dose of study treatment and who had a baseline mMS of 5-9, corresponding to moderately to severely active UC. The exclusion of patients with an mMS of 4 from the primary analysis was considered acceptable and appropriate as they did not reflect the proposed indicated population. The study population was considered representative of the indicated population, that is patients with moderate to severe UC who had prior treatment failure to conventional or advanced therapy.

Multiplicity controlled secondary endpoints included the proportion of patients achieving endoscopic improvement, symptomatic remission, and histologic-endoscopic mucosal improvement at Week 12 (both studies) and at Week 52 (ELEVATE UC 52). In addition, corticosteroid-free clinical remission and maintenance of clinical remission (at Week 12 and Week 52) were multiplicity‑controlled endpoints in ELEVATE UC 52.

The primary endpoint was met in both pivotal studies. A statistically significant higher proportion of patients achieved clinical remission per mMS in the Velsipity groups compared to placebo at Week 12 for both studies and also at Week 52 for the ELEVATE UC 52 study. At Week 12, the proportion of Velsipity-treated patients achieving clinical remission was 74/274 (27%) and 55/222 (24.8%) for ELEVATE UC 52 and ELEVATE UC 12, respectively. In comparison, for placebo-treated patients, 10/135 (7.4%) and 17/112 (15.2%) achieved clinical remission for ELEVATE UC 52 and ELEVATE UC 12, respectively. The adjusted response rate differences from placebo were 19.6% and 9.6% in the ELEVATE UC 52 and ELEVATE UC 12, respectively. At Week 52 in ELEVATE UC 52, the proportion of subjects achieving clinical remission was 88/274 (32.1%) for those treated with Velsipity and 9/135 (6.7%) for those treated with placebo. The adjusted response difference from placebo was 25.45%. In both studies at Week 12 and in the ELEVATE UC 52 at Week 52, there was a higher proportion of patients achieving clinical remission both in patients with and without prior failure of advanced therapy (biologic or JAK inhibitor).

Velsipity was also statistically significantly superior to placebo for all multiplicity‑controlled secondary endpoints, including endoscopic improvement, symptomatic remission, histologic-endoscopic mucosal improvement, corticosteroid-free clinical remission, and maintenance of clinical remission. Importantly, in patients treated with Velsipity, a significantly greater proportion of patients achieved corticosteroid‑free clinical remission at Week 52 compared to placebo control (88/274; 32% vs. 9/135; 7%). In addition, maintenance of clinical remission (at both Week 12 and Week 52) occurred in 49/274 (18%) of Velsipity-treated patients compared to 3/135 (2%) patients in the placebo groups.

Dose-Ranging Study

A Phase II study (APD334-003) was conducted to evaluate two doses of etrasimod (1 mg and 2 mg given once daily) as compared with placebo for the induction of remission in patients with moderately to severely active UC. The purpose of the study was to identify the dose of Velsipity for use in the Phase III studies.

The primary endpoint was the change from baseline in mMS as compared to placebo-control. The mean decrease from baseline was -1.5 in placebo-control, -1.94 in the 1 mg etrasimod group, and -2.49 in the 2 mg etrasimod group. The mean difference compared to placebo was -0.43 (p = 0.1457) for the 1 mg etrasimod group and -0.99 (p = 0.0091) for the 2 mg etrasimod group. The change from baseline in mMS as compared to the placebo control was numerically and statistically superior for the 2 mg etrasimod group.

This study also had 3 multiplicity‑controlled secondary endpoints, all of which were statistically and numerically superior to placebo control for the 2 mg etrasimod group. These results were supported by the exposure-response analysis which demonstrated that Velsipity exposures associated with a 2 mg once-daily dosing regimen were predicted to maximize efficacy across clinical and endoscopic endpoints in subjects with UC. Therefore, the 2 mg once-daily dose was selected as the most appropriate for the pivotal Phase III studies.

Indication

The New Drug Submission for Velsipity was filed by the sponsor with the following proposed indication:

Velsipity is indicated 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.

Health Canada revised the proposed indication to reflect the patient population of the pivotal studies. The two Phase III studies included three adolescent subjects (16 to 17 years), only one of whom was randomized to treatment with Velsipity. This was an insufficient number of patients 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 was recommended. Accordingly, Health Canada approved the following indication:

Velsipity (etrasimod) is indicated 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.

Overall Analysis of Efficacy

The findings from the pivotal studies support the 2 mg dose of Velsipity as an effective treatment for UC. Treatment effects at this dose were superior to placebo, with point estimates greater than 10% for all primary and secondary endpoints. The pivotal studies demonstrated that Velsipity is an effective therapy regardless of baseline disease severity, baseline use of corticosteroids or 5-ASA, or demographic characteristics (geographic location, age, gender, race and body weight). Velsipity was not effective for patients who had previously failed two biologic/JAK inhibitor therapies.

For more information, refer to the Velsipity Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Velsipity was primarily supported by data from the pivotal randomized, double-blind, placebo-controlled Phase III studies (ELEVATE UC 52 and ELEVATE UC 12). Additional data was evaluated from a Phase II placebo-controlled, dose-ranging study from 50 patients who received the 2 mg dose of Velsipity once daily and from patients in extension studies of the above studies. The design of these studies is discussed in the Clinical Efficacy section above.

A total of 942 patients received at least one dose of Velsipity 2 mg representing 757.9 patient years of exposure. Of these patients, 132 had at least 52 weeks of exposure. Overall, the most common adverse drug reactions were lymphopenia (11%) and headache (7%). At the time of authorization, limited long-term data was available to support chronic use of Velsipity.

In the 52-week ELEVATE UC 52 study, the most common adverse reactions in the Velsipity treatment group that occurred more frequently than in the placebo group were: headache (9.3%), elevated liver enzymes (5.9%), dizziness (5.2%), arthralgia (4.5%), urinary tract infection (3.5%), hypertension (3.1%), nausea (3.1%), hypercholesterolemia (2.8%), and upper respiratory tract infection (2.8%). The adverse reactions at 12 weeks in the ELEVATE UC 52 and the APD334-003 study were consistent with the data at 52 weeks. Pyrexia was the only adverse reaction identified in patients treated for up to 12 weeks that was not present in the 52‑week study.

Relevant serious adverse reactions in ELEVATE UC 52 were coronavirus disease 2019 (COVID-19) pneumonia, bacterial pneumonia, arthralgia, chest pain, migraine, elevated hepatic enzymes, and anemia. In the 12‑week studies, the relevant serious adverse reactions were coronary artery disease and migraine. There were no deaths in the studies.

At Week 52, the most frequently reported TEAEs that occurred in 2% of more of patients and more frequently in the Velsipity group than the placebo group 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).

Etrasimod, the medicinal ingredient in Velsipity, is sphingosine 1 phosphate (S1P) receptor modulator. Known safety concerns associated with other marketed S1P receptor modulators were investigated as adverse events of special interest (AESIs). The TEAEs of special interest included cardiovascular events (i.e., bradycardia, hypertension, and atrioventricular [AV] conduction delay), infections (i.e., herpes viral infection), severe infection, liver injury, macular edema, and pulmonary disorders. Two other AESIs of this drug class, posterior reversible encephalopathy syndrome and malignancies, did not occur in the clinical studies.

In ELEVATE UC 52, the frequency of infection was 24.9% in the Velsipity group compared to 22.2% in the placebo group. For the 12‑week studies, the frequency of infection in patients treated with Velsipity was 14% vs. 11.8% in patients treated with placebo. The frequency of herpes viral infections in ELEVATE UC 52 was higher in the Velsipity group (1.7%) as compared to the placebo group (0.7%).

The frequency of hypertension in Velsipity-treated patients was higher in both the ELEVATE UC 52 study and the 12‑week studies (2.8% and 1.3% for Velsipity vs. 0 and 0.9% for placebo, respectively).

In the ELEVATE UC 52 study, the frequency of liver injury was the same between Velsipity 2 mg and placebo-control groups at 1.4%, but in the 12‑week studies, the frequency of liver injury was higher in Velsipity 2 mg (1.3%) compared to placebo-control (0).

In ELEVATE UC 52, macular edema was reported in one patient (0.3%) treated with Velsipity and in no patients receiving placebo. In the 12‑week studies, macular edema was reported in one patient (0.4%) treated with Velsipity and in one patient (0.9%) receiving placebo.

There were significant changes in cardiovascular vital signs following initial administration of Velsipity that did not occur in the placebo groups. Like other S1P receptor modulators, Velsipity reduces heart rate following administration of the initial dose. On Day 1, in patients from ELEVATE UC 52 and ELEVATE UC 12, the greatest mean decrease in heart rate was 7.3 bpm, observed 2 to 3 hours post dose. Post-first dose cardiovascular effects (i.e., bradycardia, AV conduction delay, abnormal T-wave) resulted in 7 of 577 (1.2%) patients in the Velsipity group discontinuing study treatment. Twenty-nine patients (29/577; 5%) treated with Velsipity required post first dose extended cardiac monitoring as they did not meet the predefined discharge criteria of: heart rate greater than 50 bpm or no more than 10 bpm lower than the pre-dose (baseline) value, no evidence of second degree or higher AV block, and no cardiac symptoms (e.g., chest pain, palpitations, lightheadedness, shortness of breath, or syncope). Primary or secondary degree AV block was identified in 12/577 (2.1%) patients treated with Velsipity post first dose administration. This was not present on baseline electrocardiogram readings of these patients. Bradycardia, as an adverse reaction, was seen in 1.9% of Velsipity-treated patients compared to 0 in placebo-treated patients throughout the clinical development program.

Reductions in forced expiratory volume over 1 minute (FEV1) and forced vital capacity (FVC) were observed in patients treated with Velsipity. In ELEVATE UC 52 and ELEVATE UC 12, by Week 12, the absolute change in mean FEV1 in patients treated with Velsipity was -49 mL, compared to -19 mL for placebo. There was no further decline relative to placebo by Week 52. There were no relevant changes in pulmonary function in the 12-week studies. Pulmonary disorder AESIs occurred at the similar frequency in both treatment groups in ELEVATE UC 52, with one patient in each group having an airflow obstruction of either FEV1 decreased or FEV1/FVC ratio decreased. There were no pulmonary disorder AESIs in the 12‑week studies.

Five patients receiving Velsipity became pregnant during the clinical studies. One patient had an elective abortion, one had a spontaneous abortion, and one had an anembryonic gestation. The outcome of the other two pregnancies was not known. Exposure to Velsipity occurred during the first trimester in all pregnancies. There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to Velsipity during pregnancy.

Overall, the safety profile of Velsipity is generally consistent with that of other S1P receptor modulators. Appropriate warnings and precautions are in place in the approved Velsipity Product Monograph to address the identified safety concerns. For more information, refer to the Velsipity Product Monograph, approved by Health Canada and available through the Drug Product Database.

Non-clinical pharmacology was assessed using data from pharmacodynamic, pharmacokinetic (PK), and safety pharmacology studies.

In vitro studies were conducted in overexpression systems that expressed recombinant human or animal receptors of the S1P family (S1P1‑S1P5) or in human cells that expressed endogenous S1P receptors. When binding to S1P1, S1P4 or S1P5 receptors, etrasimod induced the recruitment of β‑arrestin. By comparing the half‑maximal effective concentration (EC50) between the natural ligand, S1P, and etrasimod, it was shown that etrasimod was a full agonist of S1P1, but only a partial agonist of S1P4 and S1P5, while no activation of β‑arrestin recruitment occurred at S1P2 and S1P3. Consistent with β‑arrestin recruitment, etrasimod induced S1P1 receptor internalization in Chinese hamster ovary (CHO) cells. Etrasimod also activated G‑protein coupled signalling at the S1P1 and S1P5 receptors, as evidenced by guanosine 5'‑O‑[gamma‑thio]triphosphate (GTPyS) recruitment. This resulted in reductions in stimulated cyclic adenosine monophosphate (cAMP) levels in both S1P1‑overexpression systems and in S1P1‑expressing primary human umbilical vein endothelial cells, and activation of G protein‑coupled inwardly rectifying potassium (GIRK)‑dependent K+ currents in isolated human atrial myocytes.

In vivo primary pharmacodynamic (PD) studies investigated the PD effect of etrasimod using mouse models of autoimmune, T-cell driven pro-inflammatory diseases, including colitis. Etrasimod was shown to reduce disease symptoms and pathogenesis, as evidenced by reversal of disease-induced tissue damage, histopathological changes, and pro-inflammatory cytokine upregulation. This was associated with reduced mature T cells, helper T cells, and B cell numbers at the site of injury, as well as higher lymph node T cell populations, indicating reduced egress into the systemic circulation. This was consistent with the proposed mechanism of action of etrasimod. Etrasimod was effective as a prophylactic intervention, or, more pertinent to this submission, as a therapeutic intervention, and its effects were generally comparable with the effect of another S1P modulator, fingolimod (currently marketed in Canada for multiple sclerosis). These findings were also consistent with PK/PD studies performed in mouse, rat, dog, and monkey, in which single doses of etrasimod induced dose-dependent, reversible reductions in blood lymphocyte populations. The plasma concentration resulting in 50% reduction in lymphocyte populations ranged from 23.4 ng/mL to 46.3 ng/mL which are 4.8- and 2.4-fold below concentrations expected to be achieved clinically.

Secondary pharmacology studies in vitro did not identify any clinically significant off-target effects of etrasimod on a panel of human cell surface receptors/transporters or enzymes. Furthermore, in vivo safety pharmacology studies did not identify significant safety concerns with respect to the central nervous system or respiratory system in rats when exposure levels was up to 858-fold higher than is expected clinically. The administration of etrasimod to dogs caused transient increases in systolic blood pressure (BP), diastolic BP, and mean arterial BP within first 6 hours of dosing. In addition, decreases in heart rate were observed in all animals, that were most pronounced 7 to 18 h post dose and marginally higher in etrasimod-treated animals compared to control animals. These findings were deemed non-adverse and occurred at exposure levels 381‑fold higher than is expected clinically. No etrasimod‑related effects on pulse pressure, body temperature, or ECG parameters including PR interval and QTc interval, were noted. Although animals administered etrasimod showed a statistically significant reduction in QTcV interval, consistent with in vitro findings of etrasimod‑stimulated human Ether‑à‑go‑go‑Related Gene (hERG) channel activation, this was attributed to overcorrection for heart rate changes and deemed non‑adverse.

The PK profile of etrasimod was assessed in non-clinical species. The time to peak concentration was similar in mice, rats, and dogs (approximately 8 hours) but faster in monkeys (3.3 hours). Bioavailability ranged from 44% in monkeys to 100% in mice. Etrasimod was found to be extensively bound to protein and preferentially resided in the plasma component of the blood. Administration of a single dose to rats induced wide-spread distribution to all tissues evaluated, except the eye lens, while multiple dosing resulted in distribution to all tissues evaluated, including the eye lens. These data demonstrated that etrasimod has the capacity to cross the blood-brain, blood-testes, and blood-follicle barrier. Unchanged etrasimod was the predominant metabolite found in Sprague Dawley rats and dogs, administered radiolabelled etrasimod, compromising approximately 60% and 80% of the plasma radioactivity, respectively, with a small number of other minor quantifiable oxidative metabolites. In Long Evans rats, the M6 metabolite was much more abundant in plasma, indicating that more extensive first-pass metabolism occurred in these animals. Etrasimod was predominantly eliminated by hepatobiliary clearance, with approximately 96% recovered radiolabelled drug detected in feces and less than 1% recovered radiolabelled drug detected in urine in both rats and dogs. Up to 19 etrasimod metabolites were found in bile samples from Sprague Dawley rats and up to 16 metabolites were detected in dog fecal samples. Together, these data indicate extensive biotransformation of etrasimod in bile prior to excretion in feces.

A single gavage dose of Velsipity was tolerated up to 1,000 mg/kg in dogs and up to 300 mg/kg in mice. Based on oral repeat-dose studies in rats, dogs and mice, Velsipity has reasonable margins of safety at the 2 mg recommended human dose (RHD). The no observable adverse effect level (NOAEL) for repeat dosing in the rat was 150 mg/kg bodyweight (bw)/day (666-times the RHD) based on a 6-month rat toxicity study with a 4-week recovery period. The NOAEL for repeat dosing in the dog was 15 mg/kg bw/day (398-times the RHD) based on a 9-month dog study with a 4-week recovery period. The NOAEL for repeat dosing in the mouse was 20 mg/kg bw/day (102-times the RHD) based on a 90-day mouse toxicity study. Treatment-related effects on the immune system (lower lymphocyte and leukocyte counts, lymphoid depletion, histiocytosis, hyperplasia and/or hypertrophy in the lymph nodes, spleen and thymus) consistent with S1P receptor modulation were observed in all treatment groups across species.

Treatment-related hypertrophy/hyperplasia in the liver was observed in rats and mice. Treatment-related degeneration/inflammation and decreased/altered colloid with hypertrophy of follicular epithelial cells in the thyroid were observed in mice. Thyroid hypertrophy was also observed in rats. Treatment-related hypertrophy/hyperplasia in the tunica media of the heart was observed in dogs and this finding was observed at the end of the recovery period (not reversible). Treatment-related histiocytosis, focal fibrosis, tan discoloration and fibrin deposition in the lung were observed in mice. Conjunctivitis, ocular discharge and sclera injected requiring veterinary intervention was observed in dogs.

Velsipity is unlikely to pose a significant genotoxic risk to humans. It was not mutagenic in an AMES assay and was negative for aneugenicity and clastogenicity in an in vitro chromosomal aberration assay. There were equivocal results in an in vivo rat micronucleus assay; however, the equivocal result is unlikely to be biologically relevant and Velsipity is unlikely to be genotoxic based on the overall weight of evidence.

There is evidence that Velsipity is carcinogenic in the mouse. In a two-year mouse study, hemangiomas and hemangiosarcomas were observed in males and females at the 6 mg/kg bw/day and higher dose levels (42-times or greater than the RHD). The no observable effect level (NOEL) for hemangiomas and hemangiosarcomas was 2 mg/kg bw/day (19-times the RHD). In a two-year rat carcinogenicity study, no treatment-related tumours were observed at the 20 mg/kg bw/day dose level (80-times the RHD).

There were no treatment-related effects on fertility or spermatogenesis in rats. The NOAEL for male fertility was 200 mg/kg bw/day (467-times the RHD) and the NOAEL for female fertility was 4 mg/kg bw/day (21-times the RHD). The difference in the male and female NOAEL was due to dose selection rather than a sex-related difference.

Adverse effects on embryo-fetal, pre- and post-natal development were observed in rats and rabbits. Post implantation loss was observed in rats and rabbits. The embryo-fetal rat NOAEL was not established. The embryo-fetal rat lowest observed adverse effect level (LOAEL) was 1 mg/kg bw/day (5-times the RHD). The embryo-fetal rabbit NOAEL was 2 mg/kg bw/day (0.8-times the RHD). Treatment-related increased gestation length, decreased pup body weights, lower pup viability, lower pup survival during the lactation period and reduced fertility and reproductive performance were observed in rats. Velsipity crosses into the breast milk and was detected in the plasma of pups exposed to the milk of lactating dams. The rat pre- and post-natal developmental NOAEL was 0.4 mg/kg bw/day (1.1-times the RHD).

No adverse effects were observed in the juvenile toxicity study and the treatment-related findings observed in the juvenile rats were similar to the findings observed in the adult rat repeat-dose toxicity studies. The male and female juvenile rat NOAEL was 100 mg/kg bw/day (292-times the RHD).

The results of the non-clinical studies as well as the potential risks to humans have been included in the Velsipity Product Monograph. In view of the intended use of Velsipity, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Velsipity Product Monograph, approved by Health Canada and available through the Drug Product Database.

The chemistry and manufacturing information submitted for Velsipity has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Velsipity is of human or animal origin.