First selective S1P receptor modulator in gastroenterology

Ozanimod offers a new treatment option for adult patients with moderate to severe active ulcerative colitis (UC) who have had an inadequate or no response to conventional therapy or a biologic, or who are intolerant of these drugs. Thus, the compound is now approved for two indications: For the treatment of active relapsing-remitting multiple sclerosis (MS) and active UC.

Ozanimod (ZEPOSIA®), in addition to the treatment of adult patients with relapsing-remitting multiple sclerosis (MS), is now also indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have responded inadequately to, no longer respond to, or are intolerant of conventional therapy or a biologic agent. It is a novel mechanism of action through selective modulation of the S1P receptor [1,2], which when administered orally 1× daily [1] exhibits potent efficacy through rapid response, sustained remission [1,2], and a good safety profile [2,3].

The S1P receptor modulator and its potential

UC treatment options have been researched for over 60 years, starting in the 1950s when the first placebo-controlled studies on the use of corticosteroids were published, to the first use of immunosuppressants, to the first placebo-controlled studies on the use of aminosalicylates. Since 2005, further progress has been made with the first biologic approved in the EU for moderate-to-severe active UC (Fig. 1) [4–8]. In the last decade in particular, there have been many new approvals and thus new ways to treat patients, explains Pascal Juillerat, MD, a specialist in gastroenterology and hepatology at the Centre Crohn et colite in Lausanne.

Practical experience with biologics therapies in UC patients has shown that they demonstrate efficacy in 50-60% of patients [9,10], which can last up to 24 months on average [11]. Thus, there is less dependence on corticosteroids [9]. However, an estimated 7-65% of patients discontinue treatment with biologics within ≤12 months of treatment [9,11,12]. In 8-36% of patients, the dosage even has to be increased [9–11] and 4.5-20% of patients switch to another biologic within the treatment [11,12]. Small molecule drugs (SMDs) represent a new treatment option in this case. These act intracellularly, are administered orally and their half-life is short. Moreover, in contrast to biologics, SMDs are not antigenic (Table 1) [13].

Biologically active sphingosine-1-phosphate (S1P) is a lipid mediator known as a “small molecule” involved in many important physiological processes [14,15]. It is found in a low micromolar range in plasma, in a high nanomolar range in lymph, and in very low concentrations in tissue [14,16–20]. Tissue-specific S1P secretion and its extracellular metabolism facilitate the formation of S1P gradients in different biological compartments and enable selective receptor activation at different sites [17,21]. Strictly regulated mechanisms ensure that S1P ligand is present in lymphoid tissues in lower amounts than in lymphatic fluid and blood circulation, resulting in a vascular S1P concentration gradient. Binding of S1P to the S1P1 receptor expressed by lymphocytes allows lymphocytes to exit lymphoid tissues into the circulation via the S1P gradient, with internalization of the S1P1 receptor occurring at high S1P concentrations. S1P is essential for lymphocyte trafficking, vascularization, and neurogenesis and has been identified as an important second messenger in the development and chronification of inflammation [22]. It is the natural ligand for the 5 G protein-coupled receptors (GPCRs) of the S1P receptor family (S1P1-5) [33].

Binding of S1P to the S1P1 receptor on the lymphocyte surface regulates the egress of most lymphocytes from lymphoid tissue [14,24]. In this process, S1P binds to the S1P1 receptor on the surface of lymphocytes [14,25] and the complex is internalized into the cell [14,24]. S1P1 returns to the plasma membrane and is recycled [14,24]. Lymphocytes exit the lymphoid tissue by following a concentration gradient of S1P between the lymphoid tissue (low), the bloodstream (high), and the inflamed tissue (high) [14,24,26]. In IBD, activated lymphocytes drive an acute inflammatory response and maintain chronic inflammation in the gut [28–30]. The S1P level is thus elevated [25–27].

Potential mechanism of action of ozanimod

Binding of ozanimod to S1P1 receptor on the lymphocyte surface may lead to sustained internalization of the receptor and decreased ability of lymphocytes to respond to the S1P gradient [31,32]. Ozanimod-induced internalization and degradation of the S1P1 receptor prevent the exit of activated lymphocytes from the lymphoid tissue, thereby reducing the circulation of pro-inflammatory lymphocytes to the intestinal mucosa. Internalization of the S1P1 receptor is thought to interfere with the lymphocyte response to the S1P gradient between lymphoid tissue, the bloodstream, and inflamed tissue [31,32]. This results in decreased migration of pro-inflammatory lymphocytes from lymphoid tissues into the bloodstream [31] and may prevent migration of lymphocytes into the gut. Ozanimod may have additional effects on, S1P receptors expressed in the intestine, which are still being investigated.

The effects of S1P are mediated by an entire family of G protein-coupled S1P receptors. In total, there are five different receptor subtypes that are expressed on different cell types and mediate different functions via them. Receptor subtype 1 is essential for lymphocyte migration. Receptor subtype 5 is also modulated by ozanimod, but this binding probably plays only a minor role. The other receptor subtypes 2-4, which play almost no role in the dysregulation of the immune response in IBD, remain virtually unaffected by therapy with ozanimod. For subtypes 1 and 5, ozanimod and its active metabolites are highly selective, avoiding undesirable off-target effects at the other S1P receptor subtypes.

In patients receiving continuous placebo, the mean ALC level remained stable over time between 1.8-2.1 ×^109/L1. In patients treated with ozanimod during induction and maintenance therapy, mean ALC decreased to 43-45% of baseline (0.79 ×^109/L) at the end of induction and then remained at approximately the same level during maintenance therapy. In patients who switched from ozanimod induction to placebo for maintenance therapy, mean ALC levels recovered within eight weeks and returned to pretreatment levels within 18 weeks after ozanimod discontinuation [33].

Ozanimod primarily decreases the circulation of CD19+ B cells and CD3+ T cells involved in the regulation of inflammation [34]. The reduction is dose-dependent and results in minimal to no decrease in monocytes, NK and NKT cells [34]. The induced reduction of lymphocytes in the peripheral circulation has different effects on the subpopulations of leukocytes, with a greater decrease in cells involved in the adaptive immune response. Ozanimod has minimal effects on cells involved in the innate immune response that contribute to immune surveillance [35], allowing for continued effective immune defense against, for example, infections or developing tumors.

A look at effectiveness – the TRUE NORTH study

To illustrate the efficacy data of ozanimod, Prof. Alain Schoepfer, M.D., Chief of Medicine and Deputy Head of the Division of Gastroenterology and Hepatology at the Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, refers to the TRUE NORTH study. A Phase 3, multicenter, randomized, double-blind, placebo-controlled study of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Of the 1831 patients who underwent screening, 1012 were enrolled in the study. A total of 645 patients participated in Cohort 1 and were randomly assigned to receive either ozanimod (429 patients) or placebo (216 patients) in a double-blind fashion; 367 patients received open-label ozanimod in Cohort 2. Eligible patients were between 18 and 75 years of age and had moderately to severely active UC (Mayo total score 6-12, endoscopic subscore ≥2, rectal bleeding subscore ≥1, stool frequency subscore ≥1). Stable oral aminosalicylates, prednisone (≤20 mg/day), or budesonide MMX before screening and during induction were allowed. Patients were excluded from the study if they had not responded to induction therapy with at least two biologics approved for the treatment of ulcerative colitis, had clinically relevant cardiac disease, or had uveitis or macular edema. After 10 weeks, patients who responded clinically to ozanimod in either cohort were re-randomized to receive double-blind ozanimod or placebo for the maintenance phase (through week 52). The primary endpoint for both time periods was the percentage of patients with clinical remission as determined by the three-part Mayo score. Patients with relapse had the option to switch to open-label extension (ozanimod 0.92 mg) within the maintenance phase and thus continue to benefit from the drug [36,37].

Efficacy results in the induction and maintenance phase

At week 10, the percentage of patients with clinical remission was significantly higher in the ozanimod group than in the placebo group (18.4% vs. 6.0%, p<0.001). Significant improvements with ozanimod compared to placebo were also observed with respect to the three main secondary endpoints of clinical response, endoscopic improvement and mucosal healing (p<0.001 for all comparisons). The percentage of patients with histologic remission was 10.8 percentage points (95% confidence interval, 5.8 to 15.8) higher with ozanimod than with placebo. Efficacy results in patients in Cohort 2 were similar to results in patients treated with ozanimod in Cohort 1.

Of the 457 patients who responded to ozanimod during the induction phase and were subsequently randomized to the maintenance phase, 37.0% in the ozanimod group and 18.5% in the placebo group had clinical remission at week 52 (p<0.001). All major secondary endpoints were also significantly improved by ozanimod therapy compared with placebo at week 52; the incidence of histologic remission also improved with ozanimod therapy. Treatment effect sizes in patients with TNF antagonist exposure were similar to those in patients without such exposure. The results of the sensitivity analyses for the primary endpoint (during both the induction and maintenance phases) were consistent with those of the primary analysis.

A post-hoc analysis showed that the subscales for rectal bleeding and stool frequency decreased at week two (i.e., one week after completion of dose adjustment during the induction phase) in patients receiving ozanimod. A greater reduction in fecal calprotectin levels from baseline was observed with ozanimod than with placebo in both the induction and maintenance phases.

Figure 2 [36] shows the primary end point (shaded area) and key secondary end points of the induction phase (cohort 1) at week 10 under A and the primary end point (shaded area) and key secondary end points of the maintenance phase at week 52 under B. The percentages of patients with each end point (as well as the number and total number of patients) are shown, and differences between groups are expressed in percentage points with 95% confidence intervals (CI). The endpoints are given in the order of the hierarchical test procedure. The modified intention-to-treat population included all patients randomized to receive at least one dose of ozanimod or placebo. Analysis in the induction phase was based on the two-sided Cochran-Mantel-Haenszel test and stratified by glucocorticoid use at screening and prior use of a TNF antagonist. Analysis in the maintenance phase was based on the two-sided Cochran-Mantel-Haenszel test and stratified by clinical remission status at week 10 of the induction phase and glucocorticoid use at week 10 of the induction phase. Missing data were handled by imputing “nonresponse.” Clinical remission was defined as a rectal bleeding subscore of 0, a stool frequency subscore of 1 or less (plus a reduction of ≥1 point from baseline), and a mucosal endoscopy subscore of 1 or less, without friability. Clinical response was defined as a reduction in the three-component Mayo score of at least 2 points and at least 35% from baseline and a reduction in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 1 or less. Endoscopic improvement was defined as a mucosal endoscopy subscore of 1 or less, without friability. Mucosal healing was defined as endoscopic improvement plus histologic remission (i.e., a Geboes score of <2.0 on a scale of 0 to 5.4, with higher scores indicating more severe inflammation and an absence of neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no destruction of crypts, and no erosions, ulcerations, or granulation tissue). Maintenance of remission was defined as clinical remission at 52 weeks in the subgroup of patients with remission at week 10. Glucocorticoid-free remission was defined as clinical remission after 52 weeks without taking glucocorticoids for at least 12 weeks. Sustained remission was defined as remission at both week 10 and week 52.

Safety profile and tolerability

As of September 30, 2020, 760 pa-tients (65.5%) were treated with ozanimod 0.92 mg for ≥1 year and 432 (37.3%) for ≥2 years. Adverse events (TEAEs) occurred in 70% of patients, and lymphopenia was among the more common. During the first three months of ozanimod treatment, the proportion of patients with TEAEs was highest and decreased thereafter. There was no accumulation of TEAEs with increasing duration of therapy and increasing exposure of patients. TEAEs led to treatment discontinuation in 8.0% of patients in the studies [38], explains PD Dr. med. Luc Biedermann, Senior Physician Clinic Gastroenterology and Hepatology at the University Hospital Zurich. Overall, the incidence of TEAEs in the induction phase was 40.1% in patients receiving ozanimod and 38% in patients receiving placebo, whereas the overall incidence of TEAEs in the maintenance phase was 49.1% with ozanimod and 36.6% with placebo. During the induction phase, the most common TEAEs in patients receiving ozanimod and placebo, respectively, were anemia (4.2% vs. 5.6%), nasopharyngitis (3.5% vs. 1.4%), and headache (3.3% vs. 1.9%) During maintenance therapy, the most common TEAEs in patients receiving ozanimod and placebo, respectively, were elevated alanine aminotransferase, elevated γ-glutamyltransferase, arthralgia, nasopharyngitis, and headache, all of which occurred in less than 5% of patients. Serious TEAEs occurred in 4.0% of pa-tients on ozanimod versus 3.2% on placebo during the induction phase. Whereas serious TEAEs during maintenance therapy occurred in 5.2% of patients on ozanimod and in 7.9% of patients in the ozanimod/placebo group (Table 2) [36].

Decline in absolute lymphocyte counts: A mean decrease in absolute lymphocyte counts (ALC) to 47% of baseline was observed in ozanimod-treated patients at the last treatment assessment. The mean ALC value was 1.93 cells ×^109/L at baseline and 0.84 cells ×^109/L at the last assessment after treatment. The reduction in ALC levels was evident at week 5 (the first post-baseline assessment) and persisted throughout long-term treatment, consistent with the expected mechanism of action of ozanimod. In all treatment groups, the mean baseline ALC value was within the normal range (defined as 1.02-3.36 ×^109/L). In patients switched from ozanimod induction treatment to placebo for maintenance therapy, ALC at week 52 was 8.3% below the lower limit of the normal range (<1.02 ×^109/L), compared with 7.0% of patients receiving continuous placebo. No discontinuations of ozanimod because of low ALC (<0.5 ×^109/L or <0.2 ×^109/L) were reported, nor were any serious or opportunistic infections with concurrent ALC <0.2 ×^109/L(Table 3) [33].

Infections during the study phases: During the controlled UC initiation phase, the proportion of patients with infection TEAEs was 9.9% and 10.7% in ozanimod and placebo patients, respectively; the proportion of patients with serious infection TEAEs was 0.8% and 0.4% in ozanimod and placebo patients, respectively. In all UC studies, exposure-adjusted incidence rates of infectious TEAEs were 22.81 and 31.43 per 100 PJ for ozanimod and placebo patients, respectively; exposure-adjusted incidence rates of serious infectious TEAEs were 1.32 and 2.84 per 100 PJ for ozanimod and placebo patients, respectively. The most common infection TEAEs in both pools were nasopharyngitis and URTI. Furthermore, during the controlled UC induction phase, herpes zoster infections were observed in 0.4% and 0% of ozanimod-treated patients versus placebo, respectively; in all UC trials, herpes zoster infections were observed in 2.2% and 0.4% of ozanimod-treated patients versus placebo, respectively (Table 4) [39,40]. Regardless of the use of corticosteroids at screening, the incidence of infections (any severity) was higher with ozanimod than with placebo; however, the incidence of severe infections was similar between ozanimod and placebo. The incidence of infections and serious infections per 100 PJ was generally lower in patients treated with ozanimod than placebo. Infections in patients receiving ozanimod were mostly characterized by non-serious upper respiratory tract infections and nasopharyngitis. IRs per 100 PY for opportunistic infections were higher with ozanimod, including non-serious herpes zoster infections.

Hepatotoxicity: Hepatic enzyme elevations that occurred in patients treated with ozanimod were asymptomatic. Less than 1% of patients achieved an ALT or AST level >5 × ULN. In most patients, the elevations regressed with continued treatment, and no patients experienced severe drug-related liver injury (Table 5) [39,40].

Ophthalmology: Confirmed macular edema cases were associated with preexisting risk factors and/or comorbidities (Table 6) [39,40].

Cardiovascular: In patients (UC maintenance therapy) treated with ozanimod, there were minimal mean changes from baseline in heart rate at each visit; the mean change from baseline at week 52 was -1.0 bpm (beats per minute) [41]. There were no significant changes in PR, QRS, or QT intervals and no second- or third-degree atrioventricular block during the duration of the studies. Mean SBP and DBP levels were numerically above pretreatment BL levels for ozanimod regardless of rerandomization; DBP levels remained above BL levels in the ozanimod-ozanimod group, and mean SBP and DBP levels returned to near BL levels in ozanimod-placebo patients (Table 7) [41,42].

Malignancy: For ozanimod compared with placebo, the incidence of malignancy in all UC trials was 1.0% and 0.4%, respectively, and the overall IR of malignancy per 100 PJ was 0.63 and 0.81, respectively (Table 8) [39,40].

Take-Home Messages

Ozanimod is the first S1P receptor modulator for the treatment of active moderate-to-severe active ulcerative colitis in adults.
The S1P receptor modulator prevents lymphocytes from leaving secondary lymphoid tissues and results in a decrease in the
circulating lymphocytes in the blood. This may reduce the migration of lymphocytes into the inflamed intestinal tissue.
Immune defense is maintained under ozanimod.
The interim analysis of the TRUE NORTH OLE study provided evidence of long-term durability of ozanimod efficacy.
Overall, safety results were consistent with those previously reported with ozanimod in phase 3 multiple sclerosis trials [43–45].

Literature:

ZEPOSIA® Technical Information, www.swissmedicinfo.ch, 05.2022.
Sandborn WJ: Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2021; 385: 1280-1291.
Rubin DT: Long-term Safety of Ozanimod in Patients with Moderately to Severely Active Ulcerative Colitis (UC) and Relapsing Multiple Sclerosis (MS) Studies. Presented at ACG 2021 Oct, poster P1637.
Mudireddy PR, et al: Lichtenstein GR, ed. Medical Therapy of Ulcerative Colitis. Springer 2014; 1-14.
D’Amico F, et al: Long-term safety of approved biologics for ulcerative colitis. Exp Opin Drug Saf. 2020; 19: 807-816.
Remicade [package insert]. Horsham PA: Janssen Biotech, Inc 2013.
Fernández-Clotet A, et al: JAK Inhibition: The Most Promising Agents in the IBD Pipeline? Curr Pharm Des 2019; 25: 32-40.
Xeljanz [package insert]. New York, NY: Pfizer Inc 2018. Inc 2020.
Patel H, et al: Indicators of suboptimal biologic therapy over time in patients with ulcerative colitis and Crohn’s disease in the United States. PLoS One 2017; 12: e0175099.
Gemayel NC, et al: Dose escalation and switching of biologics in ulcerative colitis: a systematic literature review in real-world evidence. Curr Med Res Opin 2019; 35: 1911.
Khan S, et al: Real-world evidence on adherence persistence, switching and dose escalation with biologics in adult inflammatory bowel disease in the United States: a systematic review. J Clin Pharm Ther 2019; 44: 495.
Null KD, et al: Ulcerative colitis treatment patterns and cost of care. Value Health 2017; 20: 752.
Olivera P, et al: Next generation of small molecules in inflammatory bowel disease. Gut 2017 Feb; 66(2): 199-209.
Aoki M, et al: Sphingosine-1-phosphate signaling in immune cells and inflammation: roles and therapeutic potential. Mediators Inflamm 2016; 2016: 8606878; doi:10.1155/2016/8606878.
Maceyka M: Sphingolipid metabolites in inflammatory disease. Spiegel S. Nature 2014; 510: 58-67.
Rivera J et al: The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol 2008; 8: 753-763.
Obinata H & Hla T: Sphingosine 1-phosphate in coagulation and inflammation. Semin Immunopathol 2012; 34: 73-91.
Thuy AV, et al: Sphingosine 1-phosphate in blood: function, metabolism, and fate Cell Physiol Biochem 2014; 34: 158-171.
Baeyens A, et al: Trends Immunol 2015; 36: 778-787.
Hla T, et al: Biochim Biophys Acta 2008; 1781: 477-482.
Cartier A, Hla T: Sphingosine 1-phosphate: lipid signaling in pathology and therapy. Science 2019; 366: eaar5551.
Aoki M, et al: Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential. Mediators Inflamm 2016; 2016: 8606878.
Brunkhorst R, et al: Fingolimod for the treatment of neurological diseases-state of play and future perspectives. Front Cell Neurosci 2014; 8: 283.
Schwab SR, Cyster JG, et al: Finding a way out: lymphocyte egress from lymphoid organs. Nature Immunol 2007; 8(12): 1295-1301.
Karuppuchamy T, et al: Sphingosine-1-phosphate receptor-1 (S1P 1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease. Mucosal Immunol 2017; 10: 162-171.
Danese S, et al: Targeting S1P in Inflammatory Bowel Disease: New Avenues for Modulating Intestinal Leukocyte Migration. J Crohns Colitis 2018; 12(2): S678-S686.
Suh JH, Saba JD: Sphingosine-1-phosphate in inflammatory bowel disease and colitis-associated colon cancer: the fat’s in the fire. Transl Cancer Res 2015; 4: 469-483.
Neurath MF: Cytokines in inflammatory bowel disease. Nat Rev Immunol 2014; 14: 329-342.
Guan Q: A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease. J Immunol Res. 2019; 2019: 7247238.
Souza HSP, Fiocci C: Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol 2016; 13: 13-27.
Scott FL, 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.
Supplement to Scott FL, et al: Br J Pharmacol 2016; 173: 1778-1792.
D’Haens G, et al. UEGW (virtual) 2021. Presentation P0386. Effect of ozanimod treatment and discontinuation on absolute lymphocyte count in patients with moderately to severely active ulcerative colitis: results from a phase 3 randomized trial.
Harris S, et al: Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS. Neurol Neuroimmunol Neuroinflamm 2020; 7(5): 1-10.
ZEPOSIA, Product information, www.swissmedicinfo.ch; 05.2022. Bristol-Myers Squibb Company.
Sandborn WJ, et al: Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2021; 385:1280-1291.
Sandborn WJ, et al: Supplementary Appendix. N Engl J Med 2021; 385: 1280-1291.
Danese S, et al: UEGW (virtual) 2021. presentation P0442. Long-term safety of ozanimod in patients with moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (MS) studies.
D’Haens G, et al.: DDW (virtual) 2021. oral presentation. Presentation number 128. Safety of Ozanimod in Patients With Moderately to Severely Active Ulcerative Colitis Over Time: Pooled Analysis From Phase 2, Phase 3, and Open-Label Extension Trials.
Rieder F, et al: DDW (virtual) 2021. Poster presentation. Poster number Fr513. Incidence of Infections in Patients With Moderately to Severely Active Ulcerative Colitis Treated With Ozanimod and Relationship to Significant Lymphopenia: Results From a Pooled Safety Analysis.
Long M: AIBD 2021. Poster Presentation. Poster Number 038. Ozanimod First-Dose Cardiac Effects in Patients With Moderately to Severely Active Ulcerative Colitis and Relapsing Multiple Sclerosis.
Armuzzi A: ECCO 2022. Oral presentation number DOP 045. Long-term cardiac safety of ozanimod in phase 3 clinical program of ulcerative colitis and relapsing multiple sclerosis.
Lamb YN, et al: Ozanimod: First Approval. Drugs 2020; 80: 841-848.
Comi G, 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.
Cohen JA, 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.