VELSIPITY Film-coated tablet Ref.[107279] Active ingredients: Etrasimod

Reduction in Blood Lymphocyte Counts

VELSIPITY causes a reduction in peripheral blood lymphocyte count [see Warnings and Precautions (5.1)]. In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 × 10⁹/L) and the lower lymphocyte counts were maintained during treatment with VELSIPITY.

Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing VELSIPITY 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks.

Reduction in Heart Rate and AV Conduction Delays

VELSIPITY may result in a transient decrease in heart rate and AV conduction upon treatment initiation [see Warnings and Precautions (5.2)]. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of VELSIPITY on Day 1.

Cardiac Electrophysiology

At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation.

Pulmonary Function

Reductions in absolute FEV₁ were observed in subjects treated with VELSIPITY [see Warnings and Precautions (5.9)].

Drug Interaction Studies

No clinically significant differences in heart rate reduction were observed when etrasimod was used concomitantly with stable beta blocker treatment. The effect of concomitant use of etrasimod with a calcium channel blocker on heart rate reduction is unknown [see Drug Interactions (7)].

Etrasimod mean (SD) steady-state maximum plasma concentration (C_max) was 113 (27.5) ng/mL and area under the time concentration curve at the dosing interval (AUC_tau) was 2162 (488) ng*h/mL at the recommended dosage. Etrasimod C_max and AUC are approximately dose proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose.

Absorption

The median (range) time to reach etrasimod C_max (T_max) is approximately 4 hours (range 2 to 8 hours) after oral administration.

Effect of Food

No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of VELSIPITY with a high-fat meal (800 to 1000 calories) [see Dosage and Administration (2.2)].

Distribution

The mean apparent volume of distribution of etrasimod is 66 (24) L. Etrasimod plasma protein binding is 97.9%.

Elimination

The mean plasma elimination half-life (t_1/2) of etrasimod is approximately 30 hours with an apparent steady-state oral clearance of approximately 1 L/h after oral administration.

Metabolism

Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma.

Excretion

Approximately 82% of total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of etrasimod were observed based on age (>65 years), sex, body weight, race, ethnicity, disease (healthy subjects vs. subjects with ulcerative colitis), and severe renal impairment (eGFR ≤29 mL/min).

Patients with Hepatic Impairment

Etrasimod AUC increased by 13% in subjects with mild (Child-Pugh A), 29% in moderate (Child-Pugh B), and 57% in severe (Child-Pugh C) hepatic impairment, respectively, compared with subjects with normal liver function. No clinically significant difference in the unbound etrasimod AUC was observed [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Combined moderate CYP2C9 and CYP3A4 inhibitors: Concomitant use of etrasimod with steady-state fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod AUC by 84% [see Drug Interactions (7)].

Combined CYP3A4 (strong), CYP2C8 (moderate) and CYP2C9 (moderate) inducers: Concomitant use of etrasimod with rifampin (strong CYP3A4, moderate CYP2C8, and CYP2C9 inducer) decreased etrasimod AUC by 49% [see Drug Interactions (7)].

Oral Contraceptives: No clinically significant differences in the pharmacokinetics and pharmacodynamics of oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were observed when used concomitantly with etrasimod.

Other Drugs: Itraconazole (a P-gp and strong CYP3A inhibitor) increased etrasimod AUC by 32%. Gemfibrozil (an inhibitor of OATP1B1 and OAT3 and a strong inhibitor of CYP2C8) increased etrasimod AUC by 36%. These effects are unlikely to be clinically significant.

In Vitro Studies

Based on in vitro studies, etrasimod is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, nor an inducer of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.

Etrasimod is not an inhibitor of UGT1A3, UGT1A4, UGT1A9, UGT2B7, or UGT2B17 in vitro.

Etrasimod is not a substrate or an inhibitor of P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2-K transporters.

CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when VELSIPITY is used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4 [see Drug Interactions (7) and Use in Specific Populations (8.7)].

CYP2C9 intermediate metabolizers (e.g., *1/*2, *1/*3, *2/*2) may have decreased clearance of etrasimod when VELSIPITY is used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4; however, the effect on VELSIPITY exposure in CYP2C9 intermediate metabolizers with concomitant CYP2C8 or CYP3A4 inhibitors is not known.

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2 to 3% in White populations, 0.5 to 4% in Asian populations, and <1% in African-American populations. Other decreased or nonfunctional CYP2C9 alleles (e.g., *5, *6, *8, *11) are more prevalent in African-American populations.

Carcinogenesis

Oral carcinogenicity studies with etrasimod were conducted in mice and rats. In mice administered etrasimod (2, 6, or 20 mg/kg/day) for up to 104 weeks, there was an increase in hemangiosarcoma and hemangioma in males and females at 6 and 20 mg/kg/day (exposures approximately 42 and 121 times, respectively, the exposure at the MRHD of 2 mg, based on AUC comparison). In rats, oral administration of etrasimod (2, 6, or 20 mg/kg/day) for up to 91 weeks did not result in an increase in tumors (male and female exposures 80 and 179 times, respectively, the exposure at the MRHD).

Mutagenesis

Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays.

Impairment of Fertility

Etrasimod administered orally to male rats at 25, 100, or 200 mg/kg/day from pre-mating through mating had no adverse effects on male fertility at exposures up to 467 times the exposure at the MRHD of 2 mg, based on AUC comparison. Etrasimod administered orally to female rats at 1, 2, or 4 mg/kg/day from pre-mating to implantation had no adverse effects on female fertility at exposures up to 21 times the exposure at the MRHD.

The efficacy of VELSIPITY was evaluated in 2 randomized, double-blind, placebo-controlled clinical studies [UC-1 (NCT03945188) and UC-2 (NCT03996369)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response, loss of response, or intolerance to one or more of the following treatment options: oral aminosalicylates, corticosteroids, thiopurines, Janus kinase (JAK) inhibitors, or biologic therapies (e.g., TNF blocker, anti-integrin, anti-IL12/23). UC-1 was a 52-week study and UC-2 was a 12-week study. In both studies, subjects were randomized to VELSIPITY or placebo and continued on treatment for the entire duration of the study.

Disease severity was assessed based on the modified Mayo score (mMS), a 3-component Mayo score (0 to 9) which consists of the following subscores (0 to 3 for each subscore): stool frequency (SF), rectal bleeding (RB), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions, and a score of 3 was defined by spontaneous bleeding and ulceration.

Subjects in these studies may have received other concomitant UC therapies including stable daily doses of oral aminosalicylates and/or oral corticosteroids (≤20 mg/day prednisone, ≤9 mg/day budesonide, or equivalent steroid). Concomitant treatment with immunomodulators (e.g., thiopurines, methotrexate), biologic therapies, JAK inhibitors, rectal 5-ASA, or rectal corticosteroids was not permitted.

Endpoints and Results Study UC-1

In UC-1, efficacy was evaluated in 408 adult subjects with a baseline mMS of 5 to 9 (median of 7), including a centrally read endoscopy subscore of 2 or 3. Subjects were randomized 2:1 to receive VELSIPITY 2 mg or placebo administered orally once daily. Subjects had a mean age of 41 years (range 18 to 78 years); 45% were female; and 89% identified as White, 7% as Asian, 2% as Black or African American, 1% as American Indian or Alaska Native, and 1% did not report their racial group. A total of 30% of subjects had prior exposure to biologic/JAK inhibitors and a total of 14% of subjects had exposure to >1 biologic/JAK inhibitor. At baseline, 68% of subjects were receiving oral aminosalicylates and 31% of subjects were receiving oral corticosteroids.

The coprimary endpoints were the proportion of subjects achieving clinical remission at Week 12 and at Week 52. The secondary endpoints included the proportion of subjects achieving endoscopic improvement, histologic-endoscopic mucosal improvement, corticosteroid-free clinical remission, and maintenance of clinical remission (see Table 4).

Table 4. Proportion of Subjects with Ulcerative Colitis Meeting Efficacy Endpoints in UC-1 at Week 12 and at Week 52:

CI = confidence interval
^* Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).
^† Clinical remission is defined as SF subscore of 0 or 1, RB subscore of 0, and ES ≤1 (excluding friability).
^‡ p<0.001.
^§ Endoscopic improvement is defined as ES ≤1 (excluding friability).
^¶ Histologic-endoscopic mucosal improvement is defined as ES ≤1 (excluding friability) with Geboes Index score <2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no crypt destruction, erosions, ulcerations, or granulation tissue.
^# Corticosteroid-free clinical remission is defined as clinical remission at Week 52 without receiving corticosteroids for at least 12 weeks prior to Week 52.
^Þ Maintenance of clinical remission is defined as achievement of clinical remission at both Week 12 and Week 52.

The relationship of histologic-endoscopic mucosal improvement at Week 12 or Week 52 to disease progression and longer-term outcomes after Week 52 was not evaluated in Study UC-1.

Clinical Response

A greater proportion of subjects treated with VELSIPITY compared to placebo achieved clinical response, defined as a ≥2 point and ≥30% decrease from baseline in mMS, and a ≥1 point decrease from baseline in RB subscore or an absolute RB subscore ≤1 at Week 12 (62% vs 34%).

Stool Frequency and Rectal Bleeding Subscores

Decreases in SF subscores were observed as early as Week 2 and decreases in RB subscores were observed as early as Week 4 in subjects treated with VELSIPITY compared to placebo.

Endoscopic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of subjects treated with VELSIPITY compared to placebo achieved endoscopic remission by Week 12 (15% vs 4%), Week 52 (26% vs 6%), and both Week 12 and Week 52 (11% vs 1%).

Endpoints and Results Study UC-2

In UC-2, efficacy was evaluated in 333 adult subjects with a baseline mMS of 5 to 9 (median of 7), including a centrally read endoscopy subscore of 2 or 3. Subjects were randomized 2:1 to receive VELSIPITY 2 mg or placebo administered orally once daily. Subjects had a mean age of 41 years (range 18 to 73 years); 41% were female; and 76% identified as White, 19% as Asian, 2% as American Indian or Alaska Native, 1% as Black or African American, and 2% as multiple racial groups or did not report their racial group. A total of 34% of subjects had prior exposure to biologic/JAK inhibitors and a total of 17% of subjects had exposure to >1 biologic/JAK inhibitor. At baseline, 66% of subjects were receiving oral aminosalicylates and 28% of subjects were receiving oral corticosteroids.

The primary endpoint was the proportion of subjects achieving clinical remission at Week 12. The secondary endpoints included the proportion of subjects achieving endoscopic improvement and histologic-endoscopic mucosal improvement at Week 12 (see Table 5).

Table 5. Proportion of Subjects with Ulcerative Colitis Meeting Efficacy Endpoints in UC-2 at Week 12:

CI = confidence interval
^* Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).
^† Clinical remission is defined as SF subscore of 0 or 1, RB subscore of 0, and ES ≤1 (excluding friability).
^‡ p<0.05.
^§ Endoscopic improvement is defined as ES ≤1 (excluding friability).
^¶ Endoscopic-histologic mucosal improvement is defined as ES ≤1 (excluding friability) with Geboes Index score <2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no crypt destruction, erosions, ulcerations, or granulation tissue.

The relationship of histologic-endoscopic mucosal improvement at Week 12 to disease progression and longer-term outcomes after Week 12 was not evaluated in Study UC-2.

Clinical Response

A greater proportion of subjects treated with VELSIPITY compared to placebo achieved clinical response, defined as a ≥2 point and ≥30% decrease from baseline in mMS, and a ≥1 point decrease from baseline in RB subscore or an absolute RB subscore ≤1 at Week 12 (62% vs 41%).

Stool Frequency and Rectal Bleeding Subscores

Decreases in SF subscores were observed as early as Week 2 and decreases in RB subscores were observed as early as Week 4 in subjects treated with VELSIPITY compared to placebo.

Endoscopic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of subjects treated with VELSIPITY compared to placebo achieved endoscopic remission by Week 12 (17% vs 8%).