Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Brussels, Belgium
Pharmacotherapeutic group: Immunosuppressants, selective immonsuppressants
ATC code: L04AE05
Etrasimod is a sphingosine-1-phosphate (S1P) receptor modulator that binds to S1P receptors 1, 4 and 5 (S1P1,4,5) and is a balanced G-protein and beta-arrestin agonist at S1P1. Etrasimod has minimal activity on S1P3 and no activity on S1P2. 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 UC is unknown but may involve the reduction of 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 known to be involved in driving UC pathology. Etrasimod has minimal impact on cells involved in innate immune response, which contribute to immunosurveillance.
Etrasimod may result in a transient decrease in heart rate and AV conduction upon treatment initiation (see sections 4.4 and 4.8). On Day 1, in UC patients from ELEVATE UC 52 and ELEVATE UC 12, 33% of subjects had bradycardia (nadir HR below 60 bpm within the first 4 hours), or significant bradycardia in 2.5% (HR nadir below 50 bpm). No patients had HR <40 bpm following the first dose. The greatest mean decrease in heart rate was observed at Hour 2 or 3 post dose. On Day 1, the mean (SD) change in PR interval from predose to 4 hours post dose with etrasimod was 5.5 msec (18.84). PR interval prolongation >200 msec was recorded on ECG in 5.1% and higher degree prolongation (>230 msec) in 1.8% of subjects.
In controlled clinical studies, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 × 109/L) consistent with the mechanism of action, and lowered lymphocyte counts were maintained during once daily treatment with etrasimod. A reduction in neutrophil counts was observed in controlled clinical studies with etrasimod, mean neutrophil counts were generally in the normal range during etrasimod treatment. Lowered neutrophil counts were maintained on etrasimod treatment and were reversible upon treatment discontinuation.
Peripheral blood B cells [CD19+] and T cells [CD3+], T-helper [CD3+CD4+], and T-cytotoxic [CD3+CD8+] cell subsets were all reduced, while natural killer cells and monocytes were not. T-helper cells were more sensitive to the effects of etrasimod than T-cytotoxic cells.
Peripheral blood absolute lymphocyte counts returned to the normal range in 90% of patients within 1 to 2 weeks of stopping therapy based on a population pharmacokinetic/pharmacodynamic model.
The efficacy of etrasimod were evaluated in 2 randomised, double-blind, placebo-controlled clinical studies (ELEVATE UC 52 and ELEVATE UC 12) in patients 16 to 80 years of age with moderately to severely active ulcerative colitis.
Both studies included patients 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 a biologic (e.g., TNF blocker, anti-integrin, anti-IL12/23).
Enrolled patients had UC confirmed by endoscopy and histopathology with the extent of disease being ≥10 cm from the anal verge. Patients with isolated proctitis were also included in the study provided they met all other inclusion criteria.
Enrolled patients had a modified Mayo score (mMS) of 4 to 9 with an endoscopy score (ES) ≥2 and rectal bleeding (RB) subscore ≥1. The primary evaluation was based on the population with a mMS of 5 to 9. Patients enrolled across the two studies had a mean age of 40 years with 3 (0.4%) patients less than 18 years of age and 45 (6%) patients 65 years of age or higher; 57% were male, 82% were White, and 13% were Asian.
Patients in these studies may have received the following concomitant UC therapies: stable daily doses of oral aminosalicylates and/or oral corticosteroids (≤20 mg prednisone, ≤ 9 mg budesonide, or equivalent steroid). Concomitant treatment with immunomodulators, biologic therapies, rectal 5-ASA, or rectal corticosteroids was not permitted.
ELEVATE UC 52 was a “treat-through” study, with a total of 433 patients randomised to receive etrasimod 2 mg or placebo at a 2:1 ratio administered orally once daily. Patients remained on their assigned treatment for the duration of the study.
At baseline, enrolled patients had a median mMS of 7, 8% of enrolled patients presented with isolated proctitis. A total of 30% of patients had prior exposure to biologic/JAK inhibitors; a total of 14% of patients had exposure to >1 biologic/JAK inhibitor and 11% of patients had prior exposure to anti-integrins. At baseline, 77% of patients were receiving oral aminosalicylates and 31% of patients were receiving oral corticosteroids.
The co-primary endpoints were the proportion of patients achieving clinical remission at Week 12 and at Week 52, with clinical remission defined as stool frequency (SF) subscore of 0 (or 1 with a ≥1-point decrease from baseline), RB subscore of 0, and ES ≤1 (excluding friability). The secondary endpoints included the proportion of patients achieving endoscopic improvement, symptomatic remission, mucosal healing, clinical response, corticosteroid-free clinical remission, and sustained clinical remission. The primary analysis was conducted at Week 12 and at Week 52 in patients with moderately to severely active disease, defined as mMS 5 to 9 (see Table 2).
Of the 433 patients randomised, 91.7% and 86.1% of the patients completed Week 12 in the etrasimod and placebo group, respectively. Beginning with Week 12, patients with no improvement from baseline or who met disease worsening criteria could discontinue per the discretion of the investigator and could continue in the open label extension study. In this treatthrough study 55.7% and 31.9% completed Week 52 treatment in the etrasimod and placebo group, respectively.
A significantly greater proportion of patients treated with etrasimod achieved clinical remission, endoscopic improvement, symptomatic remission, and mucosal healing at Week 12 and at Week 52, corticosteroid-free clinical remission and sustained clinical remission at Week 52, compared to placebo (see Table 2).
Table 2. Proportion of patients meeting efficacy endpoints at Week 12 and at Week 52 in ELEVATE UC 52:
| Placebo N=135 | Etrasimod 2 mg N=274 | Treatment difference (95% CI)a | |||
|---|---|---|---|---|---|
| n | % | n | % | ||
| Week 12 endpoints | |||||
| Clinical remissionb | 10 | 7% | 74 | 27% | 20% (13%, 27%)l |
| No prior biologic/ JAK inhibitor exposure | 9/93 | 10% | 60/194 | 31% | |
| Prior biologic/ JAK inhibitor exposure | 1/42 | 2% | 14/80 | 18% | |
| Endoscopic improvementc | 19 | 14% | 96 | 35% | 21% (13%, 29%)l |
| No prior biologic/ JAK inhibitor exposure | 17/93 | 18% | 76/194 | 39% | |
| Prior biologic/ JAK inhibitor exposure | 2/42 | 5% | 20/80 | 25% | |
| Symptomatic remissiond | 29 | 22% | 126 | 46% | 25% (15%, 34%)l |
| No prior biologic/ JAK inhibitor exposure | 22/93 | 24% | 101/194 | 52% | |
| Prior biologic/ JAK inhibitor exposure | 7/42 | 17% | 25/80 | 31% | |
| Mucosal healinge | 6 | 4% | 58 | 21% | 17% (11%, 23%)l |
| No prior biologic/ JAK inhibitor exposure | 6/93 | 7% | 47/194 | 24% | |
| Prior biologic/ JAK inhibitor exposure | 0/42 | 0% | 11/80 | 14% | |
| Clinical responsef | 46 | 34% | 171 | 62% | 28% (19%, 38%)l |
| No prior biologic/ JAK inhibitor exposure | 35/93 | 38% | 132/194 | 68% | |
| Prior biologic/ JAK inhibitor exposure | 11/42 | 26% | 39/80 | 49% | |
| Week 52 endpoints | |||||
| Clinical remissionb | 9 | 7% | 88 | 32% | 25% (18%, 32%)l |
| No prior biologic/ JAK inhibitor exposure | 7/93 | 8% | 71/194 | 37% | |
| Prior biologic/ JAK inhibitor exposure | 2/42 | 5% | 17/80 | 21% | |
| Endoscopic improvementc | 14 | 10% | 102 | 37% | 27% (19%, 34%)l |
| No prior biologic/ JAK inhibitor exposure | 12/93 | 13% | 78/194 | 40% | |
| Prior biologic/ JAK inhibitor exposure | 2/42 | 5% | 24/80 | 30% | |
| Symptomatic remissiond | 25 | 19% | 119 | 43% | 25% (16%, 34%)l |
| No prior biologic/ JAK inhibitor exposure | 19/93 | 20% | 97/194 | 50% | |
| Prior biologic/ JAK inhibitor exposure | 6/42 | 14% | 22/80 | 28% | |
| Mucosal healinge | 11 | 8% | 73 | 27% | 18% (11%, 25%)l |
| No prior biologic/ JAK inhibitor exposure | 10/93 | 11% | 55/194 | 28% | |
| Prior biologic/ JAK inhibitor exposure | 1/42 | 2% | 18/80 | 23% | |
| Clinical responsef | 31 | 23% | 132 | 48% | 25% (16%, 34%)l |
| No prior biologic/ JAK inhibitor exposure | 25/93 | 27% | 103/194 | 53% | |
| Prior biologic/ JAK inhibitor exposure | 6/42 | 14% | 29/80 | 36% | |
| Sustained clinical remissiong | 3 | 2% | 49 | 18% | 16% (11%, 21%)k |
| No prior biologic/ JAK inhibitor exposure | 2/93 | 2% | 41/194 | 21% | |
| Prior biologic/ JAK inhibitor exposure | 1/42 | 2% | 8/80 | 10% | |
| Corticosteroid-free clinical remissionh | 9 | 7% | 88 | 32% | 25% (18%, 32%)l |
| No prior biologic/ JAK inhibitor exposure | 7/93 | 8% | 71/194 | 37% | |
| Prior biologic/ JAK inhibitor exposure | 2/42 | 5% | 17/80 | 21% | |
| Corticosteroid-free clinical remission among patients treated with corticosteroids at baselinei | 3/40 | 8% | 27/87 | 31% | 23% (10%, 36%)l |
| No prior biologic/ JAK inhibitor exposure | 2/26 | 8% | 22/59 | 37% | |
| Prior biologic/ JAK inhibitor exposure | 1/14 | 7% | 5/28 | 18% | |
| Corticosteroid-free symptomatic remissionj | 25 | 19% | 119 | 43% | 25% |
| No prior biologic/ JAK inhibitor exposure | 19/93 | 20% | 97/194 | 50% | |
| Prior biologic/ JAK inhibitor exposure | 6/42 | 14% | 22/80 | 28% | |
| Corticosteroid-free endoscopic improvementk | 14 | 10% | 101 | 37% | 26% (19%, 34%)l |
| No prior biologic/ JAK inhibitor exposure | 12/93 | 13% | 78/194 | 40% | |
| Prior biologic/ JAK inhibitor exposure | 2/42 | 5% | 23/80 | 29% | |
a Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).
b Clinical remission was defined as SF subscore of 0 (or 1 with a ≥1-point decrease from baseline), RB subscore of 0, and ES ≤1 (excluding friability). c Endoscopic improvement was defined as ES ≤1 (excluding friability).
d Symptomatic remission was defined as SF subscore of 0 (or 1 with a ≥1-point decrease from baseline) and RB subscore of 0.
e Mucosal healing was defined as ES ≤1 (excluding friability) with histologic remission (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).
f Clinical response was 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.
g Sustained clinical remission was defined as clinical remission at both Week 12 and Week 52.
h Corticosteroid-free clinical remission was defined as clinical remission at Week 52 without receiving corticosteroids for at least 12 weeks immediately prior to Week 52.
i Corticosteroid-free clinical remission among patients treated with corticosteroids at baseline was defined as clinical remission at Week 52 without receiving corticosteroids for at least 12 weeks immediately prior to Week 52 among patients treated with corticosteroids at baseline.
j Corticosteroid-free symptomatic remission was defined as SF subscore of 0 (or 1 with a ≥1-point decrease from baseline) and RB subscore of 0 for at least 12 weeks immediately prior to Week 52.
k Corticosteroid-free endoscopic improvement was defined as ES ≤1 (excluding friability) for at least 12 weeks immediately prior to Week 52.
l p<0.001.
The efficacy results in patients with mMS of 4 (including ES ≥2 and RB subscore ≥1) were consistent with those of the primary analysis.
A greater proportion of patients with isolated proctitis at baseline treated with etrasimod compared to placebo achieved clinical remission at Week 12 (46% vs 29%) and Week 52 (42% vs 14%).
At Week 2 (first study visit), a greater proportion of patients treated with etrasimod compared to placebo achieved symptomatic remission (16% vs 11%). At Week 4, a greater proportion of patients treated with etrasimod compared to placebo achieved complete symptomatic remission (11% vs 4%) defined as a SF subscore of 0 and RB subscore of 0.
Normalisation of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of patients treated with etrasimod 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 2%).
Endoscopic remission and Geboes histologic score <2.0 (indicating no neutrophils in crypts or lamina propria and no increase in eosinophil, no crypt destruction, and no erosions, ulcerations, or granulation tissue) were achieved by a greater proportion of patients treated with etrasimod compared to placebo at Week 12 (11% vs 2%) and at Week 52 (18% vs 5%).
At Week 12, a greater proportion of patients treated with etrasimod compared to placebo had absence of abdominal pain (27% vs 13%) and absence of bowel urgency (19% vs 7%). At Week 52, a greater proportion of patients treated with etrasimod compared to placebo had absence of abdominal pain (22% vs 7%) and absence of bowel urgency (19% vs 8%).
Patients treated with etrasimod compared to placebo demonstrated greater improvement from baseline in the total IBDQ score. Changes in IBDQ total score at Week 12 from baseline with etrasimod compared to placebo were 42.8 and 27.4, respectively and changes in IBDQ total score at Week 52 from baseline with etrasimod compared to placebo were 55.8 and 38.1, respectively.
In ELEVATE UC 12, a total of 354 patients were randomised to receive etrasimod 2 mg or placebo at a 2:1 ratio administered orally once daily.
At baseline, enrolled patients had a median mMS of 7, with 5.6% of patients having mMS of 4, and 67% having mMS 5 to 7 (moderately active disease), and 27.4% having mMS >7 (severely active disease). 8% of enrolled patients presented with isolated proctitis. A total of 33% of patients had prior exposure to biologic/JAK inhibitors; a total of 18% of patients had exposure to >1 biologic/JAK inhibitor and 12% of patients had prior exposure to anti-integrins. At baseline, 83% of patients were receiving oral aminosalicylates and 28% of patients were receiving oral corticosteroids.
Of the 354 patients randomised, 89.5% and 88.8% of the patients completed Week 12 in the etrasimod and placebo group, respectively.
The primary endpoint was the proportion of patients achieving clinical remission at Week 12. The secondary endpoints included the proportion of patients achieving endoscopic improvement, symptomatic remission, mucosal healing, and clinical response at Week 12. The primary analysis was conducted at Week 12 in patients with moderately to severely active disease, defined as mMS 5 to 9 (see Table 3).
A significantly greater proportion of patients treated with etrasimod achieved clinical remission, endoscopic improvement, symptomatic remission, and mucosal healing at Week 12, compared to placebo (see Table 3).
Table 3. Proportion of patients meeting efficacy endpoints at Week 12 in ELEVATE UC 12:
| Endpoints | Placebo N=112 | Etrasimod 2 mg N=222 | Treatment difference (95% CI)a | ||
|---|---|---|---|---|---|
| n | % | n | % | ||
| Clinical remissionb | 17 | 15% | 55 | 25% | 10% (1%, 18%)g |
| No prior biologic/JAK inhibitor exposure | 12/74 | 16% | 41/148 | 28% | |
| Prior biologic/JAK inhibitor exposure | 5/38 | 13% | 14/74 | 19% | |
| Endoscopic improvementc | 21 | 19% | 68 | 31% | 12% (3%, 21%)g |
| No prior biologic/JAK inhibitor exposure | 14/74 | 19% | 51/148 | 35% | |
| Prior biologic/JAK inhibitor exposure | 7/38 | 18% | 17/74 | 23% | |
| Symptomatic remissiond | 33 | 30% | 104 | 47% | 17% (7%, 28%)g |
| No prior biologic/JAK inhibitor exposure | 23/74 | 31% | 73/148 | 49% | |
| Prior biologic/JAK inhibitor exposure | 10/38 | 26% | 31/74 | 42% | |
| Mucosal healinge | 10 | 9% | 36 | 16% | 7% (1%, 14%)g |
| No prior biologic/JAK inhibitor exposure | 8/74 | 11% | 28/148 | 19% | |
| Prior biologic/JAK inhibitor exposure | 2/38 | 5% | 8/74 | 11% | |
| Clinical responsef | 46 | 41% | 138 | 62% | 21% (10%, 32%)h |
| No prior biologic/JAK inhibitor exposure | 32/74 | 43% | 97/148 | 66% | |
| Prior biologic/JAK inhibitor exposure | 14/38 | 37% | 41/74 | 55% | |
a Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).
b Clinical remission was defined as SF subscore of 0 (or 1 with a ≥1-point decrease from baseline), RB subscore of 0, and ES ≤1 (excluding friability).
c Endoscopic improvement was defined as ES ≤1 (excluding friability).
d Symptomatic remission was defined as SF subscore of 0 (or 1 with a ≥1-point decrease from baseline) and RB subscore of 0.
e Mucosal healing was defined as ES ≤1 (excluding friability) with histologic remission (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).
f Clinical response was 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.
g p<0.05.
h p<0.001.
The efficacy results in patients with mMS of 4 (including ES ≥2 and RB subscore ≥1) were consistent with those of the primary analysis.
A greater proportion of patients with isolated proctitis at baseline treated with etrasimod compared to placebo achieved clinical remission at Week 12 (39% vs 8%).
At Week 4, a greater proportion of patients treated with etrasimod compared to placebo achieved symptomatic remission (28% vs 16%) and complete symptomatic remission (12% vs 4%) defined as a SF subscore of 0 and RB subscore of 0.
Normalisation of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of patients treated with etrasimod compared to placebo achieved endoscopic remission by Week 12 (17% vs 8%).
Endoscopic remission and Geboes histologic score <2.0 (indicating no neutrophils in crypts or lamina propria and no increase in eosinophil, no crypt destruction, and no erosions, ulcerations, or granulation tissue) were achieved by a greater proportion of patients treated with etrasimod compared to placebo at Week 12 (10% vs 5%).
At Week 12, a greater proportion of patients treated with etrasimod compared to placebo had absence of abdominal pain (32% vs 18%) and absence of bowel urgency (21% vs 12%).
Patients treated with etrasimod compared to placebo demonstrated greater improvement from baseline in the total IBDQ score. Changes in IBDQ total score at Week 12 from baseline with etrasimod compared to placebo were 47.5 and 30.2, respectively.
The European Medicines Agency has deferred the obligation to submit the results of studies with etrasimod in one or more subsets of the paediatric population in UC (see section 4.2 for information on paediatric use).
Following etrasimod single oral dosing, Cmax and AUC increased approximately dose-proportionally in the dose-range studied (0.1 mg to 5 mg). Following multiple dosing, mean Cmax and AUC increased slightly more than dose proportional from 0.7 mg to 2 mg. Steady state plasma concentrations are reached within 7 days following 2 mg once daily dosing, with a mean Cmax of 113 ng/mL and AUCtau of 2163 h*ng/mL. Estimated steady state etrasimod accumulation ratio ranges from about 2- to 3–fold. The pharmacokinetics of etrasimod is similar in healthy subjects and subjects with UC.
The time (Tmax) to reach maximum plasma concentrations (Cmax) after oral administration of immediate release oral pharmaceutical forms of etrasimod is approximately 4 hours (range 2–8 hours). Etrasimod absorption is extensive, based on high permeability and observation of relatively little intact etrasimod eliminated in the faeces (11.2% of administered radioactive dose).
Food intake can result in slightly delayed absorption (the median Tmax increased by 2 hours). Food does not have an effect on etrasimod exposure measures (Cmax and AUC); therefore, etrasimod can be administered without regard to meals.
Etrasimod distributes to body tissues with a mean oral volume of distribution (Vz/F) of 66 L. Etrasimod is highly bound to human plasma proteins (97.9%), primarily albumin and mainly distributed in the plasma fraction of whole blood with blood-to-plasma ratio of 0.7.
Etrasimod is extensively metabolised via CYP2C8 (38%), CYP2C9 (37%), and CYP3A4 (22%), and with minor contributions via CYP2C19 and CYP2J2. The major circulating component in plasma is unchanged etrasimod and main metabolites M3 and M6. Etrasimod contributes to the majority of S1P pharmacology (>90%). Etrasimod is extensively metabolised by oxidation, dehydrogenation, and conjugation by UGTs and sulfotransferases.
Etrasimod is not a substrate of P-gp, BCRP, OATP1B1/3, OAT1/3, or OCT1/2 transporters. Medicinal products that are inhibitors of these transporters are unlikely to impact the pharmacokinetics of etrasimod.
After oral administration, the apparent steady state oral clearance (CL/F) was approximately 1 L/h. The mean plasma effective elimination half-life (t1/2) of etrasimod is approximately 30 hours.
Etrasimod is primarily eliminated hepatically with 82% recovery of a total radioactive dose in the faeces and 4.89% in the urine. Unchanged etrasimod was only detected in faeces, but not in urine.
In vitro studies indicate that, at the recommended dose of 2 mg once daily, etrasimod is unlikely to show any clinically relevant interaction potential for CYP or membrane transporters.
No dose adjustments are needed in patients with renal impairment as Cmax and AUC were comparable between subjects with severe renal impairment and subjects with normal renal function (see section 4.2). The severe renal impairment cohort included 2 subjects with eGFR ≤29 mL/min (not on haemodialysis), and 6 subjects with ESRD who received haemodialysis prior to administration of etrasimod. The impact of haemodialysis performed after etrasimod administration has not been evaluated.
Etrasimod is contraindicated in patients with severe hepatic impairment. No dose adjustments are needed in patients with mild or moderate hepatic impairment (see section 4.2). The total etrasimod AUC parameters are 13%, 29%, and 57% higher in subjects with mild, moderate, and severe hepatic impairment, respectively, compared with subjects with normal liver function for the 2 mg single dose studied.
Population pharmacokinetic analyses showed that age did not have an effect on the pharmacokinetics of etrasimod in patients over 65 years of age (n=40 (3.7%) of patients were aged ≥65). There is no meaningful difference in the pharmacokinetics in elderly patients compared to younger patients.
The systemic exposure of etrasimod 2 mg is not altered by body weight differences to a clinically meaningful extent in patients with body weight ≥40 kg. In patients with body weight below 40 kg, an approximately 1.5-fold increase in exposure is predicted (see section 4.2).
Population pharmacokinetics analysis showed that sex, race, or ethnicity has no clinicially significant effect on etrasimod pharmacokinetics.
A population pharmacokinetics analysis predicted similar etrasimod exposures in adult and older adolescent (16 to <18 years old) patients with UC.
No data are available on administration of etrasimod to paediatric or adolescent patients below the age of 16 years.
Nonclinical data reveal no special hazard for etrasimod in humans with the following exception: changes in the left ventricular arteries (hypertrophy/hyperplasia of the tunica media) were observed in 3- and 9- month repeat-dose toxicity studies in dogs at exposures ≥ 24 times the recommended human dose (RHD) exposure based on AUC. The relevance of this finding for humans is uncertain. Furthermore, the exposure to the most abundant human metabolites (M3 and M6) was investigated in rats only. The relevance for humans is uncertain.
Etrasimod did not affect male and female fertility in rats up to the highest dose tested, representing an approximate 467-fold exposure margin based on human systemic exposures at the RHD for males and 21-fold for females.
Etrasimod administration to pregnant rats and rabbits daily during organogenesis resulted in post-implantation loss with a corresponding lower number of viable foetuses and foetal external, visceral, and/or skeletal malformations and variations in the absence of maternal toxicity. Malformations were observed at the lowest dose tested in rats with maternal plasma AUC approximately 5 times that in humans at the RHD. The exposure at the no-adverse-effect dose (2 mg/kg/day) in the rabbit was approximately 0.8 times, that in humans at the RHD of 2 mg/day.
Following daily oral administration of etrasimod through pregnancy and lactation in rats, decreased mean pup weights, lower pup viability, and reduced fertility and reproductive performance (reduction in implantations and increased preimplantation loss) in F1 pups were observed. Plasma exposure (AUC) in dams at the lowest dose tested was equivalent (1.1 times) to those in humans at the RHD. Etrasimod was detected in the plasma of F1 pups, indicating exposure from the milk of the lactating dam.
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