Selective Sphingosine 1-phosphate Research Articles

Tamuzimod in patients with moderately-to-severely active ulcerative colitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 induction trial.

Tamuzimod (VTX002) is a selective sphingosine 1-phosphate receptor 1 modulator in development for ulcerative colitis. We aimed to assess the safety and efficacy of tamuzimod in patients with moderately-to-severely active ulcerative colitis. This double-blind, randomised, placebo-controlled, phase 2 induction trial was conducted at 122 centres across 15 countries in Asia, Europe, and North America. Patients aged 18-80 years with a modified Mayo score (MMS) of 4-9 and an inadequate response or a loss of response, or intolerance to one or more approved ulcerative colitis therapies were randomly assigned (1:1:1) to once-daily oral tamuzimod (60 mg or 30 mg) or placebo for 13 weeks. Randomisation was stratified by previous advanced therapy, baseline corticosteroid, and baseline MMS. The primary endpoint was clinical remission (defined as an MMS stool frequency subscore of ≤1, rectal bleeding subscore of 0, and endoscopic subscore ≤1, excluding friability) at week 13. Adverse events and laboratory abnormalities were assessed for safety. Efficacy and safety analyses included all randomly assigned patients who received at least one study dose, with the efficacy analysis restricted to patients with a baseline MMS of 5-9 based on regulatory feedback. The study was registered with ClinicalTrials.gov, NCT05156125, and EudraCT, 2021-003050-23. Between Nov 4, 2021, and Aug 30, 2023, 367 patients were screened, and 213 (mean age 40·6 years [SD 14·2]; 116 [54%] males and 97 [46%] females) were randomly assigned to tamuzimod 60 mg (n=70), tamuzimod 30 mg (n=73), or placebo (n=70). Two in the tamuzimod 30 mg group and two in the tamuzimod 60 mg group with baseline modified Mayo score of 4 were excluded from the efficacy analysis. At week 13, clinical remission was reached by 19 (28%) of 68 patients receiving tamuzimod 60 mg, 17 (24%) of 71 patients receiving tamuzimod 30 mg, and eight (11%) of 70 patients receiving placebo (risk difference 16·5% [95% CI 3·2 to 29·4], p=0·018, for tamuzimod 60 mg vs placebo and 12·5% [-0·2 to 24·9], p=0·041, for tamuzimod 30 mg vs placebo). Treatment-emergent adverse events occurred in 33 (47%) of 70 patients receiving tamuzimod 60 mg, 34 (47%) of 73 patients receiving tamuzimod 30 mg, and 24 (34%) of 70 patients receiving placebo. Most adverse events were mild or moderate. The most frequently reported treatment-emergent adverse events (in ≥5% of in any treatment group) were upper respiratory tract infection (six [9%] of 70 patients in the tamuzimod 60 mg group, one [1%] of 73 in the tamuzimod 30 mg group, and one [1%] of 70 in the placebo group), anaemia (three [3%], four [5%], and six [9%]), and headache (four [6%], five [7%], and two [3%]). No adverse events of atrioventricular block, bradycardia, macular oedema, severe or opportunistic infections, malignancies, or deaths occurred. Induction therapy with tamuzimod was effective and well tolerated in patients with ulcerative colitis. These results and the favourable risk-benefit profile of tamuzimod collectively support the continued clinical development of tamuzimod for the treatment of moderately-to-severely active ulcerative colitis. Ventyx Biosciences.

The Current Landscape in the Development of Small-molecule Modulators Targeting Sphingosine-1-phosphate Receptors to Treat Neurodegenerative Diseases.

Sphingosine 1-phosphate (S1P) is extensively researched as a lysophospholipid and is crucial in various physiological and pathological processes. It achieves this via signalling through five different subtypes of G protein-coupled receptors (GPCRs), namely S1PR1 to S1PR5. S1PR modulators possess the ability to traverse the blood-brain barrier, potentially leading to direct actions within the Central Nervous System (CNS). S1PR modulators specifically bind to receptors located on the surface of naive and central memory lymphocytes, causing these cells to be trapped or confined within the lymph node. The investigation of the S1P pathway has resulted in the approval of three S1PR modulators, namely fingolimod, siponimod, and ozanimod, as medications for the treatment of patients suffering from Multiple Sclerosis (MS). Additionally, new S1PR modulators, such as ponesimod and etrasimod, are currently being developed and tested in clinical trials. Research on the creation of S1P modulators in neurodegenerative illnesses is ongoing as scientists continue to explore novel possibilities for selective S1P modulators. This study provides a concise overview of sphingolipid metabolism, the mechanism by which S1P receptors are affected, and the structural characteristics of several small molecule S1P modulators, with a particular focus on their structure-activity connections.

Unique pharmacological properties of etrasimod among S1P receptor modulators.

Etrasimod (ADP334) is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis and in development for the treatment of immune-mediated inflammatory diseases. Interaction between S1P and its five receptor subtypes (S1P1-S1P5) plays a role in several physiologic systems, including the cardiovascular and immune systems. Since differences in S1PR binding and downstream intracellular signaling could contribute to distinct profiles of drug efficacy and safety, we directly compared the S1P1-5 selectivity profile of etrasimod to three marketed S1PR modulators: fingolimod, ozanimod, and siponimod. Using both heterologous expression systems and human umbilical vein endothelial cells that spontaneously express S1P1, we profiled key S1P1 downstream signaling pathways and found that etrasimod had similar potency to the other tested S1PR modulators in promoting β-arrestin recruitment and S1P1 internalization. However, etrasimod was notably less potent than other S1PR modulators in assays measuring S1P1-mediated G protein activation (GTPγS binding and cAMP inhibition). Relatively lower potency of etrasimod in inducing G protein signaling corresponded to significantly diminished activation of human cardiac G protein-coupled inwardly rectifying potassium channels when compared to ozanimod. Together with pharmacokinetic properties, this hell profile of etrasimod may contribute to the positive benefit risk profile of etrasimod observed during the phase III ELEVATE UC 52 and ELEVATE UC 12 trials in patients with moderately to severely active ulcerative colitis.

Anticancer Effects of BAF312 (Siponimod) in Epithelial Ovarian Cancer.

Epithelial ovarian cancer (EOC) is a lethal disease that is the fifth leading cause of cancer-related death in women. BAF312 (siponimod) is a potent and selective sphingosine-1-phosphate (S1P) receptor modulator that has been approved as a treatment for multiple sclerosis. In addition to its immunomodulatory action, BAF312 shows preclinical antitumor effects in several cancer types. This study sought to determine whether BAF312 had anticancer properties against EOC using in vitro and in vivo models. EOC cell lines A2780, SKOV3ip1, A2780-CP20, and SKOV3-TR were treated with BAF312 and tested for cell proliferation, apoptosis, and migration using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, fluorescence-activated cell sorting, and migration assays. We investigated the expression of sphingosine-1-phosphate receptor 1 (S1PR1) in most EOC cell lines through western blot analysis. To investigate potential mechanisms, western blot analysis was used to assess the expression of AKT serine/threonine kinase 1 (AKT) and extracellular-regulated kinase (ERK) after BAF312 treatment. We also created poly(D,L-lactide-co-glycolide) nanoparticles encapsulating BAF312 (PLGA-NP-BAF312) for in vivo therapy. The average size and zeta potential of PLGA-NP-BAF312 were determined using dynamic light scattering. The therapeutic efficacy of PLGA-NP-BAF312 was tested in an A2780 tumor-bearing orthotopic mouse model of EOC. S1PR1 was overexpressed in most EOC cell lines. BAF312 significantly reduced cell proliferation and migration while inducing significant apoptosis in all EOC cell lines. PLGA-NP-BAF312 treatment significantly reduced tumor weights in A2780 tumor-bearing mice. Furthermore, the anticancer effects of BAF312 were associated with reduced phosphorylation of ERK and AKT. Our findings show that BAF312 has significant anticancer effects in EOC cells by inhibiting the ERK and AKT pathways, and might potentially be used to treat EOCs.

Efficacy and Safety of Etrasimod in Patients with Ulcerative Colitis in Japan: Data from the Phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN Trials

Introduction: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we report the primary analysis of a phase 3 trial evaluating the efficacy and safety of etrasimod in patients from Japan with moderately to severely active UC. Methods: Patients from Japan who completed the 12-week ELEVATE UC 12 induction trial could enroll in the 40-week ELEVATE UC 40 JAPAN maintenance trial for a combined 52-week treatment period. Patients in this Japan cohort continued their baseline assigned treatment (etrasimod 2 mg QD or placebo) from ELEVATE UC 12. Efficacy was assessed at week 12 and week 52. Treatment-emergent adverse events (TEAEs) pooled from both trials were assessed up to 52 weeks of exposure. Results: The Japan cohort comprised 32 and 16 patients who received etrasimod and placebo, respectively. A numerically greater proportion of patients who received etrasimod versus placebo achieved clinical remission at week 12 (etrasimod: 14.3%; placebo: 7.1%) and week 52 (etrasimod: 25.0%; placebo: 7.1%); a similar trend was observed for all key secondary efficacy endpoints. TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients who received etrasimod and placebo, respectively. No new safety signals were detected. Conclusion: In these induction and maintenance trials evaluating etrasimod in patients from Japan with UC, numerically higher proportions of patients who received etrasimod versus placebo achieved efficacy endpoints. Efficacy and safety findings were consistent with those from the global ELEVATE UC trial populations.

Etrasimod Corticosteroid-Free Efficacy, Impact of Concomitant Corticosteroids on Efficacy and Safety, and Corticosteroid-Sparing Effect in UC: Analyses of the ELEVATE UC Clinical Programme

Abstract Background Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). This post hoc analysis reports efficacy and safety by baseline corticosteroid use in the ELEVATE UC clinical programme. Methods Patients with UC received etrasimod 2 mg or placebo for up to 52 weeks. Corticosteroid use was permitted; tapering was recommended from Week 12. Efficacy was assessed at Weeks 12 and 52 in ELEVATE UC 52, and Week 12 in ELEVATE UC 12, in patients in the corticosteroid (CS) and no-CS subgroups. CS-free efficacy at Week 52 was assessed in patients with baseline CS use. Results In ELEVATE UC 52 and ELEVATE UC 12, 93/289 (32.2%) and 65/238 (27.3%) patients receiving etrasimod and 42/144 (29.2%) and 34/116 (29.3%) patients receiving placebo, respectively, had concomitant CS use at baseline. In the CS and no-CS subgroups, higher proportions of patients who received etrasimod vs placebo achieved clinical remission (p < 0.05) in ELEVATE UC 52 at Weeks 12 (CS: 32.3% vs 16.7%; no-CS: 26.0% vs 4.9%) and 52 (CS: 31.2% vs 9.5%; no-CS: 33.2% vs 6.9%). In the CS subgroup, significantly more patients receiving etrasimod than placebo achieved CS-free clinical remission at Week 52 (31.2% vs 7.1%). No increases in infection rates were observed with baseline CS use. Safety was comparable between subgroups. Conclusions Etrasimod demonstrated efficacy in inducing and maintaining remission in both subgroups. CSfree remission was achieved in the CS subgroup. Safety was consistent, with no increase in infections.

Long-term effects of siponimod on cardiovascular and autonomic nervous system in secondary progressive multiple sclerosis.

Siponimod, a second-generation, selective sphingosine 1-phosphate receptor (S1PR) 1 and 5 modulator, represents an important therapeutic choice for active secondary progressive multiple sclerosis (SPMS). Besides the beneficial immunomodulatory effects, siponimod impacts cardiovascular function through S1PR1 modulation. Short-term vagomimetic effects on cardiac activity have proved to be mitigated by dose titration. However, long-term consequences are less known. This study aimed to investigate the long-term impact of siponimod on cardiac autonomic modulation in people with SPMS (pwSPMS). Heart rate variability (HRV) and vascular hemodynamic parameters were evaluated using Multiple Trigonometric Regressive Spectral analysis in 47 pwSPMS before siponimod therapy and after one, three, six and 12months of treatment. Autonomic activation tests (tilt test for the sympathetic and deep breathing test for the parasympathetic cardiac modulation) were performed at each examination. pwSPMS preserved regular cardiovascular modulation responses during the autonomic tests reflected in the variation of several HRV parameters, such as RMSSD, pNN50, total power of HRV, high-frequency and low-frequency bands of the spectral domain or hemodynamic vascular parameters (Cwk, Zao, TPR, MAP) and baroreflex sensitivity (BRS). In the long-term follow-up, RMSSD, pNN50, total power, BRS and CwK presented a significant decrease, underlining a reduction of the parasympathetic and a shift towards sympathetic predominance in cardiac autonomic modulation that tends to stabilise after 1year of treatment. Due to dose titration, the short-term effects of siponimod on cardiac autonomic modulation are mitigated. The long-term impact on cardiac autonomic modulation is similar to fingolimod. The autonomic activation tests showed normal cardiovascular responses during 1-year follow-up in pwSPMS, confirming the safety profile of siponimod. Further research on autonomic function could reveal whether the observed sympathetic activation is a compensatory response to S1P signaling intervention or a feature of the disease, while also shedding light on the role of S1PR modulation in MS.

Endoscopic, Histologic, and Composite Endpoints in Patients With Ulcerative Colitis Treated With Etrasimod

Histologic remission, a potentially important treatment target in ulcerative colitis (UC), is associated with favorable long-term outcomes. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. This post-hoc analysis of the ELEVATE UC program evaluated the efficacy of etrasimod according to histologic and composite (histologic/endoscopic/symptomatic) endpoints and examined their prognostic value. Patients with moderately to severely active UC were randomized 2:1 to once-daily oral etrasimod 2 mg or placebo. Histologic and composite endpoints, including disease clearance (endoscopic/histologic/symptomatic remission), were assessed at Weeks 12 (ELEVATE UC 52; ELEVATE UC 12) and 52 (ELEVATE UC 52). Logistic regressions examined associations between baseline and Week 12 histologic/composite endpoints and Week 52 outcomes. At Weeks 12 and 52, significant improvements with etrasimod vs placebo were observed in histologic/composite outcomes, including endoscopic improvement-histologic remission and disease clearance. The proportion of patients treated with etrasimod achieving clinical remission at Week 52 was higher among those with disease clearance at Week 12 vs those without disease clearance (73.9% [17/23] vs 28.3% [71/251]). Histologic improvement and endoscopic improvement at Week 12 were moderately and strongly associated with clinical remission at Week 52 (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.27-4.41; and OR, 6.36; 95% CI, 3.47-11.64, respectively). Histologic remission and endoscopic improvement at Week 12 were strongly associated with endoscopic improvement-histologic remission at Week 52 (OR, 3.21; 95% CI, 1.70-6.06 and OR, 5.47; 95% CI, 2.89-10.36, respectively). Etrasimod was superior to placebo for achievement of stringent histologic and composite endpoints. gov, Number: NCT03945188; ClinicalTrials.gov, Number: NCT03996369.

The Effect of Etrasimod on Fecal Calprotectin and High-sensitivity C-reactive Protein: Results From the ELEVATE UC Clinical Program.

Biomarkers offer potential alternatives to endoscopies in monitoring ulcerative colitis (UC) progression and therapeutic response. This post hoc analysis of the ELEVATE UC clinical program assessed potential predictive values of fecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) as biomarkers and associated responses to etrasimod, an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC, in 2 phase 3 clinical trials. In ELEVATE UC 52 and ELEVATE UC 12, patients were randomized 2:1 to 2mg of etrasimod once daily or placebo for 52 or 12 weeks, respectively. Fecal calprotectin/hsCRP differences between responders and nonresponders for efficacy end points (clinical remission, clinical response, endoscopic improvement-histologic remission [EIHR]) were assessed by Wilcoxon P-values. Sensitivity and specificity were presented as receiver operating characteristics (ROC) curves with area under the curve (AUC). In ELEVATE UC 52 and ELEVATE UC 12, 289 and 238 patients received etrasimod and 144 and 116 received placebo, respectively. Baseline fCAL/hsCRP concentrations were generally balanced. Both trials had lower week-12 median fCAL levels in week-12 responders vs nonresponders receiving etrasimod for clinical remission, clinical response, and EIHR (all P < .001), with similar trends for hsCRP levels (all P < .01). For etrasimod, AUCs for fCAL/hsCRP and EIHR were 0.85/0.74 (week 12; ELEVATE UC 52), 0.83/0.69 (week 52; ELEVATE UC 52), and 0.80/0.65 (week 12; ELEVATE UC 12). Fecal calprotectin/hsCRP levels decreased with etrasimod treatment; ROC analyses indicated a prognostic correlation between fCAL changes during induction and short-/long-term treatment response.

Impact of Prior Biologic or Janus Kinase Inhibitor Therapy on Efficacy and Safety of Etrasimod in the ELEVATE UC 52 and ELEVATE UC 12 Trials.

Etrasimod is an oral, once daily, selective, sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission [p < 0.05] in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p = 0.033; experienced: 18.9% vs 13.2%, p = 0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [N = 90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p = 0.030], but not clinical remission [9.8% vs 3.4%, p = 0.248], with etrasimod vs placebo. Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo. NCT03945188; NCT03996369.

Signet-Ring Cell Adenocarcinoma of the Lung Associated with Fingolimod Treatment in a Patient with Multiple Sclerosis

Fingolimod is a selective sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) as monotherapy, in cases of first-line treatment failure, or as a first option in aggressive forms. The appearance of neoplasms is among the infrequent side effects of treatment. This is a case report on an MS patient treated with Fingolimod who developed pulmonary signet-ring cell adenocarcinoma of the lung and features a discussion of the drug’s possible involvement in the development of these types of neoplasms.

Etrasimod for the Treatment of Ulcerative Colitis: Analysis of Infection Events from the ELEVATE UC Clinical Programme.

Infections are a safety concern in patients with ulcerative colitis [UC]. Etrasimod is an oral, once daily [QD], selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE programme. Proportions, incidence rates [IRs; per 100 patient-years], and descriptive analyses of all serious, severe, herpes zoster and opportunistic infections are reported in the Pivotal UC cohort [ELEVATE UC 52 and ELEVATE UC 12]. Cox regression models evaluated potential baseline risk factors. In this analysis [n = 787], proportions [IRs] of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three [0.6%] and five [1.9%] patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group [etrasimod: 0.4%; placebo: 0.8%], all localised and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count [ALC] < 0.2 × 109/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred. Patients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC < 0.5 × 109/L and infection events was observed. Longer-term follow-up will further characterise the etrasimod safety profile. Clinicaltrials.gov: NCT03945188; NCT03996369.

Safety, Pharmacokinetics, and Pharmacodynamics of Etrasimod: Single and Multiple Ascending Dose Studies in Healthy Adults.

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator in development for immune-mediated inflammatory diseases (IMIDs). Here, we report the human safety, pharmacokinetics, and pharmacodynamics of etrasimod obtained from both a single ascending dose (SAD; 0.1-5mg) study and a multiple ascending dose (MAD; 0.35-3mg once daily) study. Overall, 99 healthy volunteers (SAD n = 40, MAD n = 59) completed the 2 studies. Evaluated single and multiple doses were well tolerated up to 3mg without severe adverse events (AEs). Gastrointestinal disorders were the most common etrasimod-related AEs. Over the evaluated single- and multiple-dose ranges, dose-proportional and marginally greater-than-dose-proportional etrasimod plasma exposure were observed, respectively. At steady state, etrasimod oral clearance and half-life mean values ranged from 1.0 to 1.2 L/h and 29.7 to 36.4 hours, respectively. Dose-dependent total peripheral lymphocyte reductions occurred following etrasimod single and multiple dosing. Etrasimod multiple dosing resulted in reductions from baseline in total lymphocyte counts ranging from 41.1% to 68.8% after 21 days. Lymphocyte counts returned to normal range within 7 days following treatment discontinuation. Heart rate lowering from pretreatment baseline on etrasimod dosing was typically mild, with mean reductions seen after the first dose of up to 19.5bpm (5mg dose). The favorable safety, pharmacokinetic, and pharmacodynamic properties of etrasimod in humans supported its further development and warranted its investigation for treatment of IMIDs.

Etrasimod: First Approval.

Etrasimod (VELSIPITY™) is an orally available, small-molecule selective sphingosine-1-phosphate (S1P) receptor modulator being developed by Pfizer for the treatment of ulcerative colitis and other immune-mediated inflammatory disorders. Etrasimod is selective for S1P receptor subtypes S1P1, S1P4 and S1P5 while having minimal activity on S1P3 and no activity on S1P2. Etrasimod received its first approval, in the USA, in October 2023 for the treatment of moderately to severely active ulcerative colitis in adults. Subsequently, the European Medicines Agency adopted a positive opinion in December 2023, recommending the granting of marketing authorisation for etrasimod for the treatment of patients aged ≥ 16years with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy, or a biological agent. Etrasimod is also under regulatory review for the treatment of ulcerative colitis in several other countries. Clinical development of etrasimod for use in the treatment of Crohn's disease, atopic dermatitis, eosinophilic oesophagitis and alopecia areata is ongoing worldwide. This article summarises the milestones in the development of etrasimod leading to this first approval for the treatment of ulcerative colitis in adults.

P283 Efficacy and safety of etrasimod in patients with moderately to severely active UC in Japan: Integrated analysis of the phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN trials

Abstract Background Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). We evaluated efficacy and safety among Japanese patients with moderately to severely active UC with contextualisation to the global population. Methods ELEVATE UC 40 JAPAN (NCT04706793) was a multicentre, double-blind, 40-week trial of patients from Japan who completed the 12-week phase 3 ELEVATE UC 12 induction trial (NCT03996369; study design described elsewhere1), resulting in a combined 52-week treatment period. Eligible patients were aged 16–80 years with documented history of inadequate/loss of response or intolerance to ≥1 approved UC therapies. Patients (hereafter the ‘Japan cohort’) continued baseline-assigned treatments from ELEVATE UC 12 (etrasimod 2 mg QD or placebo QD). Efficacy was assessed at Weeks 12 and 52 in patients with a Modified Mayo score (MMS) 5–9; the primary endpoint was clinical remission at Weeks 12 and 52. Pooled treatment-emergent adverse events (TEAEs) from ELEVATE UC 12 and ELEVATE UC 40 JAPAN were assessed up to Week 52. Results The Japan cohort comprised 32 and 16 patients receiving etrasimod and placebo, respectively; 28 and 14 patients with an MMS of 5–9, respectively, were included in the analysis. Baseline demographics were similar between treatment groups. A numerically higher proportion of patients receiving etrasimod vs placebo achieved the primary efficacy endpoint (Figure). Similar patterns were observed for all key secondary endpoints (Table). TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients receiving etrasimod vs placebo, respectively. The safety of etrasimod was similar between Japanese and global UC populations. Conclusion In this Japanese population, numerically higher proportions of patients achieved all efficacy endpoints with etrasimod vs placebo. Efficacy and safety findings were consistent with the global ELEVATE UC population.1 Reference 1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171.

P127 Sphingosine-1-Phosphate Receptor Blockade with Etrasimod alters Lymphocyte Trafficking in Crohn's Disease: Insights from High-Dimensional Phenotypic Mapping

Abstract Background The blockade of lymphocyte trafficking from the lymph nodes (LNs) towards the intestinal mucosa is an effective approach for the treatment of ulcerative colitis (UC). Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor (S1PR) modulator, which is currently also under investigation for Crohn’s disease (CD). The therapeutic mechanism of action of S1PR modulators in the context of inflammatory bowel disease (IBD) is not completely understood. It is hypothesized that both B and T- cell populations are affected by this treatment and are retained in the peripheral LNs, reducing circulating lymphocytes and resulting in fewer immune cells available to traffic in the gastrointestinal tract. Etrasimod has been reported to induce a partial and selective reduction of lymphocyte subsets in the blood of healthy subjects, but the direct effect of S1PR modulators on LN leukocytes has not been evaluated. The aim of this study was to investigate changes in leukocyte subpopulations in peripheral LNs and peripheral blood (PB) in response to S1PR inhibition with etrasimod in patients with CD. Methods CD patients with moderate to severe disease activity, participating in the Phase 2, double-blinded, non-placebo-controlled portion of the CULTIVATE trial, were eligible for this sub-study. At baseline and after 14 weeks of etrasimod induction treatment (2 or 3 mg/day), 10cc of PB and 4 ultrasound guided biopsy samples of an inguinal LN were obtained. The isolated peripheral blood mononuclear cells (PBMCs) and LN leukocyte populations, were analyzed at single cell level via high-dimensional immunophenotyping through mass cytometry (CyTOF) at both timepoints. Results We observed that in the LNs, the numbers/percentages of naïve, central and effector memory T-helper cells, as well as, of CD8+ naïve T-cells were increased after treatment with etrasimod. There was a decrease in the proportion of these cell populations in peripheral blood. Circulating naïve and memory B-cells were reduced, while these subsets where also slightly reduced in the LN compartment. Innate immune cell populations were not significantly altered. Conclusion Etrasimod induction treatment resulted in an increase of both naïve and central memory T-lymphocyte subsets in inguinal LNs, with a corresponding decrease in the periphery. The effect on the frequency of B-cells was not consistent in the LNs and PB, while innate immunotypes and T-regs, were not significantly affected. Despite the limited sample size, these selective effects were consistent with previously published PB immunophenotyping studies with etrasimod. This study was conducted as a collaboration between Amsterdam UMC and Pfizer.

P540 Non-serious adverse events in patients with ulcerative colitis receiving etrasimod: An analysis of the phase 2 OASIS and phase 3 ELEVATE UC 52 and ELEVATE UC 12 clinical trials

Abstract Background Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Adverse events (AEs) pertaining to tolerability, laboratory and serious AEs are described elsewhere1,2; we present a post hoc analysis of the incidence, onset and duration of the most commonly occurring non-serious AEs in the etrasimod UC clinical programme. Methods Data from the pooled Placebo-controlled UC cohort, derived from the phase 2 OASIS (NCT02447302) and phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) double-blind clinical trials, were included. Cohorts comprised OASIS and ELEVATE UC 12 12-week induction periods alongside the ELEVATE UC 52 12-week induction and 40-week maintenance periods utilising a "treat-through" design. Patients (pts) with moderately to severely active UC were eligible for the etrasimod UC clinical programme. Pts were randomised to etrasimod 1 mg once daily (QD; OASIS only), etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) of non-serious AEs (MedDRA v24.1 Preferred Terms of headache, pyrexia, nausea, fatigue and dizziness) were analysed in the Placebo-controlled UC cohort. Results Among 943 pts (any dose of etrasimod, N=629 [288.1 pt years (PY)]; placebo, N=314 [115.1 PY]), there were 77, 36, 30, 15 and 23 headache, pyrexia, nausea, fatigue and dizziness AEs, respectively. All were non-serious and did not lead to treatment discontinuation, apart from one case of pyrexia in which early termination visits were incomplete. Proportions and IRs (per 100 PY) for headache and dizziness AEs were higher with etrasimod (any dose) vs placebo (IRs: 13.45 vs 8.63 and 6.52 vs 1.69, respectively); IRs for other non-serious AEs were similar in etrasimod (any dose) and placebo groups (Table). Onset of AEs varied over time and most AEs were short in duration (Figure shows onset and duration for headache and dizziness AEs). Most AEs were deemed not related to study treatment by the site investigator. Pts with dizziness on Days 1–3 had similar changes in heart rate vs those with dizziness after Day 3. No consistent trend in heart rate was observed in pts receiving etrasimod with early dizziness. Conclusion Among pts in the etrasimod UC clinical programme, all headache, pyrexia, nausea, fatigue and dizziness events were non-serious. IRs were similar for most non-serious AEs across treatment groups, excluding headache and dizziness. Most non-serious AEs were short in duration and judged as not related to study treatment, suggesting they may not impact on the overall tolerability of etrasimod.

P788 The effect of etrasimod on faecal calprotectin and high-sensitivity C-reactive protein: Results from the ELEVATE UC clinical programme

Abstract Background Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we present a post hoc analysis of efficacy data from two phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12,1 assessing associations with faecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) and responses to etrasimod in patients (pts) with UC. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), pts aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg once daily or placebo. Efficacy endpoints of clinical remission, clinical response and endoscopic improvement-histological remission (EIHR) were measured at Wk 12 (both trials analysed separately) and Wk 52 (ELEVATE UC 52). Differences in median fCAL and hsCRP between responders and nonresponders (based on criteria for each endpoint) were assessed. Wilcoxon p values were calculated for responder analyses. Sensitivity and specificity based on fCAL and hsCRP concentrations were presented as receiver operating characteristic (ROC) curves with area under the curve (AUC). Results In ELEVATE UC 52 and ELEVATE UC 12, 289 and 238 pts received etrasimod and 144 and 116 received placebo, respectively. Baseline fCAL and hsCRP concentrations were similar across cohorts and levels decreased with etrasimod treatment (median change from baseline at Wk 52 [ELEVATE 52]; -710.56 mg/kg and -0.49 mg/L for fCAL and hsCRP, respectively). Following etrasimod, Wk 12 (both studies) and Wk 52 (ELEVATE UC 52), median fCAL and hsCRP were significantly lower in responders vs nonresponders for all efficacy endpoints (fCAL [ELEVATE UC 52] shown in Table; all endpoints p&amp;lt;0.01). At Wk 4, pts receiving etrasimod who were subsequent responders for efficacy endpoints at Wk 12 had lower median fCAL concentrations vs nonresponders in both trials (all p&amp;lt;0.001; Figure). A similar trend was observed for Wk 4 median fCAL concentrations and responders for efficacy endpoints at Wk 52 (ELEVATE UC 52). Across endpoints in both trials, ROC analyses indicated that both fCAL and hsCRP were consistent in predicting short- and longer-term outcomes, with more pronounced associations at Wk 52. Conclusion In phase 3 trials in pts with UC, fCAL and hsCRP levels decreased with etrasimod treatment. ROC analyses indicated association between fCAL and hsCRP and treatment response at all endpoints, and demonstrated significantly lower fCAL and hsCRP values in responders. These data demonstrate the utility of fCAL and hsCRP to predict and monitor disease control in pts with UC treated with etrasimod. Reference 1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171.

P524 Etrasimod shows low risk of adverse events following concomitant use with opioids or antidepressants in patients with ulcerative colitis

Abstract Background Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Unlike the other S1P receptor modulator approved for UC, etrasimod and its metabolites do not have a molecular structure to inhibit monoamine oxidase (MAO).1 Coadministration of drugs that inhibit MAO with opioids and antidepressants may increase the risk of adverse events (AEs), including hypertension.2 This post hoc analysis evaluated the incidence of AEs potentially related to serotonin syndrome in patients taking etrasimod and concomitant opioids or antidepressants in the phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) trials. Methods Safety data pooled from both trials were analysed in patients receiving etrasimod 2 mg QD (up to 52 weeks of exposure) with/without concomitant opioids or antidepressants. We report the proportions of patients who had ≥1 concurrent AE potentially related to serotonin syndrome, consisting of one standardised MedDRA Query, one query based on the Hunter Criteria and supplemental preferred terms (pyrexia, tachycardia and hypertension-related AEs).3 Results Among 527 patients receiving etrasimod, 77 (14.6%) and 35 (6.6%) patients were taking concomitant opioids or antidepressants, respectively. Most patients on concomitant opioids or antidepressants were White (80.0–88.3%); male (50.6–51.4%); their median age was 35.0 (18.0–70.0) and 41.0 (19.0–74.0) years, respectively. More patients with vs without concomitant opioids or antidepressants, respectively, consumed alcohol (40.3% vs 24.7% and 48.6% vs 25.4%) and used tobacco (40.3% vs 20.9% and 34.3% vs 23.0%). The incidence of other AEs potentially related to serotonin syndrome was low and generally comparable in all subgroups; reported rates of pyrexia and tachycardia were similar in patients with/without concomitant opioids or antidepressants (Table). Hypertension-related AEs were infrequent and generally balanced. No AEs per the Hunter Criteria were reported in patients on concomitant opioids or antidepressants (Table). No reported AEs were serious or led to treatment discontinuation among patients taking these concomitant medications. Conclusion The incidence of AEs was low and comparable in patients receiving etrasimod with or without concomitant opioids or antidepressants. This analysis supports the low likelihood of clinically relevant drug–drug interactions between etrasimod and medications commonly prescribed to patients with UC, such as opioids or antidepressants.

P849 Bayesian network meta-analysis of the efficacy of advanced therapies for patients with moderately to severely active ulcerative colitis naïve to advanced therapy

Abstract Background Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). In the absence of head-to-head randomised controlled trials (RCTs), network meta-analyses (NMA) offer insight into the comparative effectiveness of treatment options. NMA were conducted to examine the relative efficacy of etrasimod vs other advanced therapies (AT) with licensed dosing (European Medicines Agency) for the treatment of UC in patients naïve to biologic agents and/or Janus kinase inhibitors. Methods A systematic literature review (SLR) was performed on 15 November 2022, and covered all available records without time limit, using NICE DSU and PRISMA guidelines. NMA were conducted under a Bayesian framework, and a multinomial fixed-effect approach was used to model outcomes, clinical response and clinical remission, in the induction phase and among induction phase responders in the maintenance phase, in patients naïve to AT. Reported outcomes from trials with a treat-through design, such as ELEVATE UC 52, were recalculated to mimic those of a responder re-randomisation design; only responders in the induction phase were analysed in the maintenance phase. Data are presented as median relative risk (RR) of the treatment vs its comparator, along with corresponding 95% credible intervals (CrI). Prespecified sensitivity analyses were performed. Results Of 81 studies identified from the SLR, 21 and 11 RCTs were included in the induction and maintenance networks, respectively. For induction and maintenance phases, all therapies demonstrated benefit over placebo, consistent with phase 3 clinical trial data. In the NMA for clinical remission in the induction phase, etrasimod 2 mg had a statistically significant benefit over adalimumab 80/40 mg and 160/80 mg (RR [95% CrI] for treatment vs etrasimod 0.49 [0.29–0.78] and 0.67 [0.50–0.92], respectively), filgotinib 100 mg (0.55 [0.37–0.84]) and placebo; conversely, upadacitinib 45 mg had statistically significant benefit vs etrasimod (1.47 [1.07–2.03]; Table). There were no statistically significant differences for etrasimod vs other comparators. Similar results were observed for clinical response. In the maintenance phase, there were no statistically significant differences between etrasimod 2 mg and other treatments for clinical remission and clinical response (Table). Conclusion With respect to clinical remission and clinical response during induction and maintenance phases, etrasimod efficacy was similar to most comparators as a first-line AT. Differences in trial design and risk-benefit profiles of AT should be considered when interpreting NMA results.