Sphingosine-1-phosphate receptor modulators versus interferon beta for the treatment of relapsing-remitting multiple sclerosis: findings from randomized controlled trials.

BACKGROUND: As one kind of disease-modifying therapies, sphingosine-1-phosphate receptor (S1PR) modulators such as fingolimod, ozanimod, and siponimod have been approved or are being developed to treat multiple sclerosis (MS). Several randomized controlled trials (RCT) have been implemented to compare the efficacy and safety of S1PR modulators versus interferon beta in the treatment of people with relapsing-remitting multiple sclerosis (RRMS). METHOD: We searched RCTs which were implemented from January 2010 to June 2020 by searching PubMed, Embase, Cochrane Library databases, and the Central Register of Controlled Trials. Finally, five RCTs were included in our study after carefully choosing. RESULT: We pooled 4304 patients from 5 RCTs. The primary outcome was the annualized relapse rate. We found that the annualized relapse rate in the S1PR modulator group is 20% less than that in the interferon beta group (95%CI, - 0.32 to - 0.07, P = 0.002). S1PR modulators led to a significant reduction in number of new or enlarging T2 lesions per scan and number of gadolinium-enhancing lesions compared with interferon beta. Moreover, S1PR modulators can also improve 54-item multiple sclerosis quality of life (MSQOL-54) physical health composite score (P = 0.0005). CONCLUSION: S1PR modulators exhibited good efficacy and safety for the treatment of RRMS compared with interferon beta. According to follow-up trials, S1PR modulators can improve MSQOL-54 physical health composite score so that it may be beneficial to neurological recovery which need more research to confirm.

Safety and Effectiveness of Thiopurines and Small Molecules in Elderly Patients with Inflammatory Bowel Diseases.

The management of inflammatory bowel diseases (IBD) requires weighing an individual patient's therapeutic benefits and therapy-related complication risks. The immunomodulators that have been commonly used so far in IBD therapy are thiopurines, including 6-mercaptopurine and azathioprine. As our understanding of the IBD pathomechanisms is widening, new therapeutic approaches are being introduced, including the Janus kinase (JAK) inhibitors and Sphingosine 1-phosphate receptor (S1PR) modulators' development. Non-selective JAK inhibitors are represented by tofacitinib, while selective JAK inhibitors comprise filgotinib and upadacitinib. As for the S1PR modulators, ozanimod and etrasimod are approved for UC therapy. The number of elderly patients with IBD is growing; therefore, this review aimed to evaluate the effectiveness and safety of the oral immunomodulators among the subjects aged ≥60. Possible complications limit the use of thiopurines in senior patients. Likewise, the promising effectiveness of new drugs in IBD therapy in those with additional risk factors might be confined by the risk of serious adverse events. However, the data regarding this issue are limited.

Potential adverse events associated with sphingosine-1-phosphate (S1P) receptor modulators in patients with multiple sclerosis: an analysis of the FDA adverse event reporting system (FAERS) database.

Objective: Sphingosine-1-phosphate receptor (S1PR) modulators have recently attracted increasing attention for the treatment of multiple sclerosis (MS). Despite their preference in the clinic, multiple adverse events (AEs) continue to be reported every year. This study aimed to investigate the potential AEs as well as related important medical events (IMEs) signal associated with S1PR modulators, including fingolimod, siponimod and ozanimod in a real-world study using the FDA Adverse Event Reporting System (FAERS) database. Methods: All data were collected from the FAERS database, spanning from the fourth quarter of 2010(2010Q4) to the second quarter of 2023 (2023Q2). Potential AE and IME signals of S1PR modulators were identified based on a disproportionality analysis using the reporting odds ratio (ROR), proportional reporting ratio (PRR), and the bayesian confidence propagation neural network of information components (IC). Results: Overall, 276,436 reports of fingolimod, 20,972 reports of siponimod and 10,742 reports of ozanimod were analyzed from the FAERS database. Among reports, females were more prone to develop AEs (73.71% for females vs. 23.21% for males), and more than 50% of patients suffered from AEs were between 18 and 64 years. Subsequently, we investigated the top 20 AEs associated with the signal strength of S1PR modulators at the preferred term (PT) level, and identified 31 (8 vs. 11 vs. 12, respectively) unlabeled risk signals such as thrombosis, uterine disorder and reproductive system and breast disorders. Furthermore, we discovered that the S1PR modulator reported variations in the possible IMEs, and that the IMEs associated with ocular events were reported frequently. It's interesting to note that infection and malignancy are prominent signals with both fingolimod and siponimod in the top 20 PTs related to mortality reports. Conclusion: The present investigation highlights the possible safety risks associated with S1PR modulators. The majority of AEs are generally consistent with previous studies and are mentioned in the prescribing instructions, however, several unexpected AE signals have also been observed. Ozanimod showed the lowest signal intensity and a better safety profile than the other S1PR modulators. Due to the short marketing time of drugs and the limitations of spontaneous reporting database, further research is required to identify potential AEs related to S1PR modulators.

A comprehensive review of varicella-zoster virus, herpes simplex virus and cryptococcal infections associated with sphingosine-1-phosphate receptor modulators in multiple sclerosis patients.

Sphingosine-1-phosphate (S1P) receptor modulators are a new class of oral disease-modifying therapies used for Multiple Sclerosis (MS). These are immunomodulatory drugs and can thus increase the risk of certain infections in these patients. This paper summarizes the existing data on the most common opportunistic infections associated with the drugs in this class: Varicella Zoster Virus (VZV), Herpes Simplex Virus (HSV), and Cryptococcus neoformans. A literature review and descriptive analysis of reported cases and clinical phase III study findings on the incidences of these infections were conducted using PubMed and Google Scholar. Results regarding fingolimod, siponimod, ozanimod, and ponesimod were obtained. Overall, the incidence of these infections was found to be extremely low in MS patients treated with S1P receptor modulators. Among the four drugs in this class, the incidence rates of VZV, HSV, and cryptococcal infections were either similar or slightly higher than placebo, with some infections not reported in cases of ozanimod and ponesimod. Most of these resulted in favorable outcomes, with very few disabilities or fatalities. However, this paper highlights the increasing relevance of assessing infectious risk factors to promote the early identification of serious complications related to these drugs. Opportunistic infections should be considered in the differential diagnosis of an MS relapse in the setting of disease-modifying treatment.

An Overview of the Efficacy and Safety of Ozanimod for the Treatment of Relapsing Multiple Sclerosis.

Multiple sclerosis (MS) is a complex disease of the central nervous system that can cause permanent disability in young adults. A large armamentarium is available for its management and is increasing over time. Ozanimod is an oral drug belonging to the sphingosine-1-phosphate receptor (S1PR) modulator family recently approved in different countries for MS with active disease. It selectively modulates S1PR1 and S1PR5 to prevent autoreactive lymphocytes from entering the central nervous system (CNS), where they can determine inflammation and neurodegeneration. Ozanimod was tested in one Phase II and two Phase III pivotal trials and was shown to be effective and well tolerated. Moreover, further investigations, including comparative trials with other S1P modulators and MS disease-modifying drugs, are needed to better define placement in MS treatment. Furthermore, ozanimod is currently under evaluation for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, in international phase III studies. This article retraces the itinerary leading to the approval of ozanimod for MS treatment and its peculiarities and potentiality inside the S1PR modulator family.