Sphingosine 1-Phosphate Modulation in Inflammatory Bowel Diseases

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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10071735

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic, disabling conditions affecting the gastrointestinal tract and characterized by an abnormal immune response to intestinal microflora in genetically susceptible individuals. For their progressive behavior, the recommended management involves optimal and early treatment, in order to prevent complications such as corticosteroids’ need, hospitalization, surgery and disability and dysplasia/cancer. Most S1P modulators are reported to be safe and effective in the treatment of both UC and CD. High and satisfactory rates of clinical remission as well as endoscopic improvement and remission can be achieved with these molecules. Safety alarms remain rather low, although the S1P binding to two of its G protein-coupled receptors, 2 and 3 (S1PR2 and S1PR3), may be associated with cardiovascular risks.

sphingosine 1-phosphate small molecules ulcerative colitis Crohn’s disease

1. Fingolimod

Fingolimod/FTY720 is an oral non-selective phingosine 1-phosphate (S1P) modulator that binds S1PR1-3-4-5 ^[1]. Fingolimod was the first S1P modulator investigated in immune-mediated diseases ^[1] and was approved by the Food and Drug Administration (FDA) for the treatment of the relapsing multiple sclerosing ^[2]. In this setting, Fingolimod could reduce the circulating lymphocytes approximately by 70% ^[3]^[4].

In the field of inflammatory bowel diseases (IBDs), fingolimod exhibited encouraging results in animal models of IBDs. Indeed, treatment with this drug ameliorated chronic colitis in IL-10-gene-deficient mouse models and in Th1-mediated-2,4,6-trinitrobenzene-sulfonic-acid colitis ^[5]^[6]. Unfortunately, the cardiac safety profile is one of the main concerns regarding fingolimod, as transient cardiac events, such as bradycardia and atrioventricular block, have been detected ^[7]^[8]. In addition, during fingolimod treatment, a rising of liver enzymes was also observed, which resulted in drug discontinuation ^[1]. Therefore, due to the adverse events detected, fingolimod has not been tested in IBD human experimentations in favor of more selective S1PR modulators ^[1].

2. Ozanimod

Ozanimod/RPC1063 is a new oral S1P receptor modulator that binds with high selectivity to S1P1 and S1P5 receptors, preventing the mobilization of lymphocytes from peripheral lymphoid organs to inflammatory sites ^[9]. In regard to pharmacokinetics, ozanimod is characterized by slow absorption (median Tmax of 8 h; mean terminal elimination half-life of 21 h), and it is broadly metabolized into circulating active metabolites ^[1]. CYP2C8 has an important role in the drug’s metabolism, while CYP3A and P-glycoprotein contribute to a lesser extent ^[1].

The efficacy and safety data from two phase III trials had already led to the approval of ozanimod for the treatment of relapsing forms of multiple sclerosis ^[10]^[11].

Ozanimod lacks immunogenicity, has a high oral bioavailability, achieves peak concentrations after approximately 6 h and has a short half-life of about 19 h ^[12].

Regarding ulcerative colitis (UC), the TOUCHSTONE phase II, double-blind, randomized clinical trial firstly reported that ozanimod achieved better clinical, endoscopic and histologic outcomes in patients with moderate to severe UC compared to placebo ^[13]. In particular, clinical remission at 8 weeks (the primary outcome) was achieved in 16% and 14% of the patients in the ozanimod 1 mg and 0.5 mg group vs. 6% in the placebo group (p = 0.048 and p = 0.14, respectively) ^[13]. Endoscopic healing (Mayo endoscopy sub-score ≤1) was observed in 34% and in 28% of the patients in the 1 mg and 0.5 mg ozanimod group, respectively, being 12% in the placebo group (p = 0.002 and p = 0.03, respectively) ^[13].

In the subsequent randomized, double-blind, placebo-controlled phase III study, the TRUE NORTH trial, in the treatment arm with ozanimod, higher clinical response (defined as a reduction in the total Mayo score of ≥3 points and ≥30% from baseline or in the three-component Mayo score of ≥2 points and ≥35% from baseline, as well as a reduction in the rectal-bleeding sub-score of ≥1 point or an absolute rectal-bleeding sub-score of ≤1 point) rates during both induction (47.8% vs. 25.9%, p < 0.001) and maintenance (60.0% vs. 41.0%, p < 0.001) were observed ^[14]. Clinical remission rates were significantly higher compared to placebo during both induction (18.4% vs. 6.0%, p < 0.001) and maintenance (37.0% vs. 18.5%, p < 0.001) ^[14]. Additionally, a significant improvement with ozanimod during both phases was found for other key secondary end points, such as maintenance of remission, mucosal healing, histologic remission and durable remission ^[14].

The long-term efficacy and safety of ozanimod in UC was recently reported in an interim analysis of the OLE of the TRUE NORTH trial: 34% of the whole study population and 55% of the responders continued to maintain a clinical response after 94 weeks of OLE ^[15].

As concerns Crohn’s disease (CD), in the phase II multicenter, uncontrolled, prospective observer-blinded endpoint STEPSTONE trial, which enrolled 69 patients with moderately to severely active CD, treated with ozanimod 1 mg once daily for a 12-week-induction phase, a reduction from baseline in the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was detected (mean change of −2.2); endoscopic remission (SES-CD score ≤4 and ≥2 point decrease in the SES-CD score with no sub-score >1) and endoscopic response (≥50% decrease in SES-CD) were achieved by 10.1% and 23.2% of the patients, respectively ^[16]. Moreover, the mean change in the Crohn’s Disease Activity Index (CDAI) score was of 130.4 ^[16]: 27 (39.1%) and 39 (56.5%) patients reached clinical remission (CDAI score <150) and clinical response (CDAI decrease of ≥100 from baseline), respectively ^[16]. Finally, the histological improvement in terms of the mean change from baseline in the Geboes Histology Activity Score and Robart’s Histopathology Index was also observed in the treated patients ^[16].

Several phase III placebo-controlled trials for ozanimod in patients with moderately to severely active CD (NCT03440385, NCT03464097, NCT03467958, NCT03440372, https://clinicaltrials.gov, accessed on 7 June 2022) are currently ongoing and/or actively recruiting.

With respect to adverse events (AEs), ozanimod demonstrated a good safety profile in IBD patients. Most of the AEs reported by II and III phase trials were not directly related to the drug, and the absolute number of the observed drug-related AEs was very low.

In detail, in the TRUE NORTH trial, the serious AEs rate and the treatment discontinuation rate were higher in the placebo arm ^[14]. Although phase II and III trials data showed a favorable cardiac safety profile, a transient dose-dependent heart rate reduction was observed after the first dose of ozanimod (five patients with bradycardia during induction) ^[13]^[17]. To mitigate this risk, a seven-day gradual dose escalation upon treatment initiation is recommended ^[13]^[14]^[16]^[18]. Additionally, ozanimod is contraindicated in patients with cardiovascular and/or cerebrovascular disorders, in those with some conduction abnormalities (such as Mobitz type II second-degree or third-degree atrioventricular block, sick sinus syndrome or sinoatrial block, except those with a functioning pacemaker) or with severe untreated sleep apnea ^[18]. In case of other cardiac-related risk factors, ECG abnormalities or a drug history for medications which can cause bradycardia and a delay of cardiac conduction, a cardiologic evaluation is required ^[18].

In the STEPSTONE trial, no cases of bradycardia or arrhythmias occurred in the treated CD patients ^[16].

Due to a slightly increased risk of macular edema (two episodes during induction and one during maintenance), an ophthalmological evaluation at baseline is only recommended in patients at a high risk of macular edema (history of diabetes, uveitis) ^[13]^[14]^[16].

Furthermore, although a mean decrease of approximately 45% from baseline was observed in lymphocyte count (26.8% and 31.7% in the induction cohorts and 43.5% in the maintenance cohort), no severe infectious safety signals have been reported ^[13]^[14]^[16]. The infections’ rate in ozanimod-treated UC patients was comparable with placebo during induction (9.9% vs. 10.7%) and higher during maintenance (23% vs. 11.9%), but with serious infections occurring more frequently in the placebo arm (0.9% vs. 1.8%) ^[13]^[14]. Of note, the herpes zoster infections rate was higher with ozanimod during both induction (0.4% vs. 0%) and maintenance (2.2% vs. 0%) ^[13]^[14].

The elevation of transaminases occurred in 2.6% and in 1.6% of IBDs ^[16]-treated patients in the induction cohorts and in 4.8% during maintenance; however, it was described as usually transient (15–30 days) and unrelated to liver damage ^[13]^[14]. As regards drug interactions, the co-administration of MAO inhibitors and CYP2C8 inhibitors or inducers is contraindicated ^[18]. Additionally, ozanimod should not be used in subjects with hepatic impairment, end-stage renal disease and in pregnancy and breast-feeding due to lacking safety data in these groups ^[18]. Moreover, the coadministration of other immunomodulating drugs has not been investigated and, because of the additive risk of immunosuppression, should be avoided.

Based on these efficacy and safety data, ozanimod was approved by regulatory authorities for the treatment of moderate to severe UC. Newly published data on the OLE extension of the TRUE NORTH clinical trial have confirmed the efficacy and safety profile of ozanimod with rates of 0.9% of serious infections and of 0.4% of macular edema in the maintenance cohort ^[19]. Finally, two patients developed cancer during the OLE extension: one basal cell carcinoma and one rectal adenocarcinoma ^[19].

Recent data on long-term cardiac safety of ozanimod (from the phase 3 ulcerative colitis (UC) True North trial and multiple sclerosis (MS) 12-month SUNBEAM and 24-month RADIANCE trials) have shown that, in maintenance, cardiac-related AEs occurred in 1.3% (3/230) of treated patients in the continuous ozanimod group, and no clinically significant heart rate or electrocardiographic changes were related to chronic treatment up to month 24 of ozanimod therapy ^[20].

In the first real-world experience in relatively treatment-refractory UC patients, ozanimod showed a good tolerability and an efficiency and safety profile consistent with trials’ results ^[21]. Of note, despite the small sample size, efficiency was not significantly affected by prior therapy exposure ^[21].

The most recent post hoc analysis data on mucosal healing (MH) in UC patients treated with ozanimod showed that 44/230 (19.1%) patients achieved MH at week 10, being MH associated with ameliorated clinical outcomes (i.e., clinical remission, corticosteroid-free remission) at week 52 irrespective of previous treatment with anti-TNF ^[22].

3. Etrasimod

Etrasimod/APD334 (ArenaTM) is an investigational, once-daily orally administered selective S1P1R, S1P4R and S1P5R modulator. This molecule has been proven with promising results in several immune-mediated diseases (i.e., multiple sclerosis), including also IBDs. Concerning pharmacokinetics, etrasimod metabolization primarily involves hepatobiliary excretion thorough processes such as oxidation, dehydrogenation, glucuronidation and sulfation ^[1].

Preliminary data had reported that etrasimod rapidly decreases mean lymphocyte counts both in healthy volunteers and in UC patients with UC, with a subsequent lymphocyte recovery within 5% of baseline levels after 7 days from discontinuation ^[23]^[24].

As concerns UC, in the phase-2 OASIS study (NCT02447302, https://clinicaltrials.gov, accessed on 7 June 2022), including moderately-to-severely active UC with previous failure or intolerance to conventional or biologic therapy randomly assigned to etrasimod 1 mg (n = 52) or 2 mg (n = 50) or placebo (n = 54), etrasimod (2 mg/day) was shown to significantly improve clinical symptoms at week 12, assessed through a modified Mayo Clinic score (MCS) compared with a placebo (difference from placebo, 0.99 points; 90%CI 0.30–1.68; p = 0.009) ^[25]. In more detail, 33.0% of the UC patients receiving etrasimod (2 mg/day) compared with 8.1% of those in the placebo arm achieved clinical remission, defined as MCS ≤ 1 (p < 0.001) ^[25]. Among the secondary endpoints, a significantly higher amount of UC patients treated with etrasimod (2 mg/day) achieved endoscopic improvement at week 12 as compared with the placebo (41.8% vs. 17.8%; 90%CI 9.8%–39.0%; p = 0.003) ^[25].

Interestingly, histologic improvement (Geboes score <3.1) and histologic remission (Geboes score <2.0) were reported in 31.7% and in 19.5% of patients in the treatment arm (etrasimod 2 mg/day), respectively, vs. 10.2% and 6.1% in the placebo group, respectively (p = 0.006 and p = 0.03) ^[25]. With respect to safety, no life-threatening, drug-related adverse events (AE) and no deaths occurred during the study ^[25]. Cardiac AEs were reported in three cases receiving etrasimod 2 mg: a second-degree atrioventricular block type 1 (one patient) and first-degree atrioventricular block (two patients) ^[25].

Efficacy data were confirmed in the open-label extension (OLE) of the OASIS trial: at the end of treatment (week 46 or 52), 64% (72/112) and 33% (37/112) of the patients achieved clinical response and clinical remission, respectively, while 43% (48/112) of the patients showed endoscopic improvement, and endoscopic improvement was sustained from week 12 in more than two-thirds of patients ^[26]. Overall, steroid-free clinical remission was observed in 22% of patients at the end of treatment (week 46 or 52) ^[26]. In deeper detail, 65.2% (73/112) of the treated patients did not use oral corticosteroids at any time during the OLE ^[26].

The results of the OLE of the OASIS study reported that most AEs (94.4%) were of mild or moderate severity, and the most commonly occurring AEs were the worsening of UC (19%, 21/112 patients) and anemia (11%, 12/112 patients) ^[26]. Neither treatment-related serious infections nor infections of severity grade ≥3 were observed, and no patient died during the study ^[26]. Two cases of herpes zoster were reported ^[26].

Regarding cardiac AEs, one patient experienced heart rate lowering (with a nadir of 48 beats/min, grade 1 severity), without a need for dose change or treatment discontinuation ^[26]. Moreover, three patients receiving etrasimod 2 mg experienced a first-degree atrio-ventricular block, either clinically insignificant or of grade 1 severity; no patient discontinued etrasimod due to atrio-ventricular block ^[26].

The ELEVATE phase III trial (NCT03996369, NCT03945188, NCT03950232, https://clinicaltrials.gov, accessed on 7 June 2022) is currently enrolling moderately to severely active UC patients.

As concerns induction with etrasimod in UC patients, in the ELEVATE UC 12, clinical remission was observed in 24.8% of treated patients vs. 15.2% of the placebo group, respectively (p = 0.026) ^[27].

Preliminary results from the ELEVATE UC 52 have shown that the clinical remission rate was over three-times-higher in the treatment group with etrasimod compared with placebo at 12 weeks (27% vs. 7.4%; p ˂ 0.001) and over four-times-higher at 52 weeks (32.1% vs. 6.7%; p ˂ 0.001) ^[27]. Of note, all secondary efficacy endpoints, including endoscopic improvement, symptomatic remission, clinical response, and mucosal healing, were additionally met in both trials ^[27]. Furthermore, about 912 patients have been currently enrolled in the ongoing open-label extension study ELEVATE UC OLE, which is expected to be completed in 2027.

Regarding CD, CULTIVATE (NCT04173273, https://clinicaltrials.gov, accessed on 7 June 2022) is the ongoing phase II/III study aiming to enroll 1265 patients to evaluate the safety and efficacy of etrasimod, and it will assess, in its five sub-studies, the efficient dose of this molecule in the induction, maintenance/extension and long-term extension.

4. Amiselimod

Amiselimod/MT-1303 is a novel oral selective S1P1 receptor modulator, which has been investigated for various immune-mediated diseases, such as multiple sclerosis, psoriasis, systemic lupus erythematosus and also IBD ^[28]^[29]. The higher affinity of Amiselimod for the S1P1 receptor than for S1P2-5 receptors makes this drug safer with respect to the cardiac profile compared to other non-selective S1P receptor modulators ^[28]. Indeed, amiselimod displayed a better cardiac safety than fingolimod in a phase I study ^[30].

Amiselimod and its active metabolite (S-amiselimod phosphate) have a half-life time 10-fold longer than ozanimod (380–420 h), reaching the steady-state concentration after about 10 weeks ^[1]. The pharmacokinetics profile of amiselimod appears more favorable for the cardiac profile, since low initial doses of the drug can lower the potential for bradycardia ^[31].

Regarding its efficacy in IBD, amiselimod was demonstrated to inhibit chronic colitis in mice models, preventing the egress of lymphocytes into the periphery and inhibiting the infiltration of Th1 and Th17 cells into the colon ^[32]. However, in a phase II, multicenter, randomized, placebo-controlled clinical trial that evaluated its efficacy and safety in moderate to severe CD, there was no significant difference in the proportion of subjects obtaining the primary endpoint (clinical response: CDAI 100 at week 12) between the amiselimod arm (0.4 mg daily) and the placebo arm (48% vs. 54.1%, respectively; OR 0.79; 95%CI 0.31–1.98) ^[33].

References

Verstockt, B.; Vetrano, S.; Salas, A.; Nayeri, S.; Duijvestein, M.; Vande Casteele, N. Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 2022, 19, 351–366.
Chaudhry, B.Z.; Cohen, J.A.; Conway, D.S. Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis. Neurotherapeutics 2017, 14, 859–873.
Cohen, J.A.; Barkhof, F.; Comi, G.; Hartung, H.-P.; Khatri, B.O.; Montalban, X.; Pelletier, J.; Capra, R.; Gallo, P.; Izquierdo, G.; et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362, 402–415.
Kappos, L.; Radue, E.-W.; O’Connor, P.; Polman, C.; Hohlfeld, R.; Calabresi, P.; Selmaj, K.; Agoropoulou, C.; Leyk, M.; Zhang-Auberson, L.; et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362, 387–401.
Mizushima, T.; Ito, T.; Kishi, D.; Kai, Y.; Tamagawa, H.; Nezu, R.; Kiyono, H.; Matsuda, H. Therapeutic effects of a new lymphocyte homing reagent FTY720 in interleukin-10 gene-deficient mice with colitis. Inflamm. Bowel Dis. 2004, 10, 182–192.
Daniel, C.; Sartory, N.; Zahn, N.; Geisslinger, G.; Radeke, H.H.; Stein, J.M. FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. J. Immunol. 2007, 178, 2458–2468.
Parigi, T.L.; Roda, G.; Argollo, M.; Gilardi, D.; Danese, S. Is there a role for therapeutic sphingolipids in inflammatory bowel disease? Expert Rev. Gastroenterol. Hepatol. 2020, 14, 47–54.
Vargas, W.S.; Perumal, J.S. Fingolimod and cardiac risk: Latest findings and clinical implications. Ther. Adv. Drug Saf. 2013, 4, 119–124.
Scott, F.L.; Clemons, B.; Brooks, J.; Brahmachary, E.; Powell, R.; Dedman, H.; Desale, H.G.; Timony, G.A.; Martinborough, E.; Rosen, H.; et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br. J. Pharmacol. 2016, 173, 1778–1792.
Cohen, J.A.; Comi, G.; Selmaj, K.W.; Bar-Or, A.; Arnold, D.L.; Steinman, L.; Hartung, H.P.; Montalban, X.; Kubala Havrdová, E.; Cree, B.A.C.; et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): A multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019, 18, 1021–1033.
Comi, G.; Kappos, L.; Selmaj, K.W.; Bar-Or, A.; Arnold, D.L.; Steinman, L.; Hartung, H.P.; Montalban, X.; Kubala Havrdová, E.; Cree, B.A.C.; et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): A multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019, 18, 1009–1020.
Gilardi, D.; Gabbiadini, R.; Allocca, M.; Correale, C.; Fiorino, G.; Furfaro, F.; Zilli, A.; Peyrin-Biroulet, L.; Danese, S. PK, PD, and interactions: The new scenario with JAK inhibitors and S1P receptor modulators, two classes of small molecule drugs, in IBD. Expert Rev. Gastroenterol. Hepatol. 2020, 14, 797–806.
Sndborn, W.J.; Feagan, B.G.; Wolf, D.C.; D’Haens, G.; Vermeire, S.; Hanauer, S.B.; Ghosh, S.; Smith, H.; Cravets, M.; Frohna, P.A.; et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N. Engl. J. Med. 2016, 374, 1754–1762.
Sandborn, W.J.; Feagan, B.G.; D’Haens, G.; Wolf, D.C.; Jovanovic, I.; Hanauer, S.B.; Ghosh, S.; Petersen, A.; Hua, S.Y.; Lee, J.H.; et al. Ozanimod as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 2021, 385, 1280–1291.
Danese, S.; Colombel, J.F.; Ponich, T.; Jovanovic, I.; Bossuyt, P.; Longman, R.; Alekseeva, O.; Petersen, A.; Chitkara, D.; Marta, C.; et al. Long-term use of ozanimod in patients with moderately to severely active Ulcerative Colitis. In Proceedings of the ECCO Congress 2022—DOP44, Virtual, 16–19 February 2022.
Feagan, B.G.; Sandborn, W.J.; Danese, S.; Wolf, D.C.; Liu, W.J.; Hua, S.Y.; Minton, N.; Olson, A.; D’Haens, G. Ozanimod induction therapy for patients with moderate to severe Crohn’s disease: A single-arm, phase 2, prospective observer-blinded endpoint study. Lancet Gastroenterol. Hepatol. 2020, 5, 819–828.
Sandborn, W.J.; Feagan, B.G.; Hanauer, S.; Vermeire, S.; Ghosh, S.; Liu, W.J.; Petersen, A.; Charles, L.; Huang, V.; Usiskin, K.; et al. Long-Term Efficacy and Safety of Ozanimod in Moderately to Severely Active Ulcerative Colitis: Results from the Open-Label Extension of the Randomized, Phase 2 TOUCHSTONE Study. J. Crohns Colitis 2021, 15, 1120–1129.
Zeposia . Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209899s000lbl.pdf (accessed on 7 June 2022).
Wolf, D.; Colombel, J.F.; Ponich, T.P.; Jovanovich, I.; Bossuyt, P.; Longman, R.; Alekseeva, O.; Petersen, A.; Chitkara, D.; Marta, C.; et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis—DDW ePoster—Tu1458. Gastroenterology 2022, 162, S-969–S-970.
Armuzzi, A.; Cross, R.K.; Lichtenstein, G.; Danese, S.; Vermeire, S.; Zhou, W.; Sands, B.E.; Dignass, A.; Irving, P. Long-term cardiac safety of ozanimod in phase 3 clinical program of Ulcerative Colitis and relapsing multiple sclerosis. In Proceedings of the ECCO Congress 2022—DOP45, Virtual, 16–19 February 2022.
Cohen, N.A.; Choi, D.; Choden, T.; Cleveland, N.K.; Cohen, R.D.; Rubin, D.T. Ozanimod in the Treatment of Ulcerative Colitis: Initial Real-World Data from a Large Tertiary Center. Clin. Gastroenterol. Hepatol. 2022.
Reinisch, W.; Axelrad, J.; Ahmad, H.A.; Sandborn, W.J.; Feagan, B.G.; D’Haens, G. Early mucosal healing at week 10 with ozanimod predicts clinical outcomes at week 52: Post hoc analysis of the phase 3 True North clinical trial . J. Crohns Colitis 2022, 16 (Suppl. 1), i415.
Schreiber, S.; Morgan, M.; Christopher, L. Etrasimod , a Potent, Selective, Oral S1P Receptor Modulator with Preclinical Autoimmune Disease-Modifying Activity Exhibits Favorable PK/PD Properties in Healthy Volunteers. In Proceedings of the Advances in Inflammatory Bowel Diseases (AIBD), Orlando, FL, USA, 8–10 December 2016.
Peyrin-Biroulet, L.; Adams, J.; Turner, S.; Trokan, L.; Panes, J. Safety and immune modulatory properties of etrasimod , a next-generation oral, selective sphingosine 1-phosphate receptor modulator, in healthy volunteers. In Proceedings of the ECCO Congress, Vienna, Austria, 14–17 February 2018.
Sandborn, W.J.; Peyrin-Biroulet, L.; Zhang, J.; Chiorean, M.; Vermeire, S.; Lee, S.D.; Kühbacher, T.; Yacyshyn, B.; Cabell, C.H.; Naik, S.U.; et al. Efficacy and safety of etrasimod in a phase 2 randomized trial of patients with ulcerative colitis. Gastroenterology 2020, 158, 550–561.
Vermeire, S.; Chiorean, M.; Panés, J.; Peyrin-Biroulet, L.; Zhang, J.; Sands, B.E.; Lazin, K.; Klassen, P.; Naik, S.U.; Cabell, C.H.; et al. Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study. J. Crohns Colitis 2021, 15, 950–959.
Sandborn, W.J.; Sands, B.E.; Feagan, B.G.; D’Haens, G.R.; Danese, S.; Hanauer, S.; Peyrin-Biroulet, L.; Zhang, J.; Chiorean, M.; Vermeire, S.; et al. Etrasimod 2mg once daily as treatment for moderately to severely active ulcerative colitis: Results from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials—Digestive Disease Week (DDW) 2022—Abstract 968a. Gastroenterology 2022, 162, S-1395.
Pérez-Jeldres, T.; Alvarez-Lobos, M.; Rivera-Nieves, J. Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis. Drugs 2021, 81, 985–1002.
McGinley, M.P.; Cohen, J.A. Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions. Lancet 2021, 398, 1184–1194.
Harada, T.; Wilbraham, D.; de La Borderie, G.; Inoue, S.; Bush, J.; Camm, A.J. Cardiac effects of amiselimod compared with fingolimod and placebo: Results of a randomised, parallel-group, phase I study in healthy subjects. Br. J. Clin. Pharmacol. 2017, 83, 1011–1027.
Sugahara, K.; Maeda, Y.; Shimano, K.; Mogami, A.; Kataoka, H.; Ogawa, K.; Hikida, K.; Kumagai, H.; Asayama, M.; Yamamoto, T.; et al. Amiselimod, a novel sphingosine 1-phosphate receptor-1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk. Br. J. Pharmacol. 2017, 174, 15–27.
Shimano, K.; Maeda, Y.; Kataoka, H.; Murase, M.; Mochizuki, S.; Utsumi, H.; Oshita, K.; Sugahara, K. Amiselimod (MT-1303), a novel sphingosine 1-phosphate receptor-1 functional antagonist, inhibits progress of chronic colitis induced by transfer of CD4+CD45RBhigh T cells. PLoS ONE 2019, 14, e0226154.
D’Haens, G.; Danese, S.; Davies, M.; Watanabe, M.; Hibi, T. A Phase II, Multicentre, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability and Efficacy of Amiselimod in Patients with Moderate to Severe Active Crohn’s Disease. J. Crohns Colitis 2022, 16, 746–756.

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