Ponesimod: An Oral Second-Generation Selective Sphingosine 1-Phosphate Receptor Modulator for the Treatment of Multiple Sclerosis

Abstract

Objective: To describe the safety, efficacy, and potential role in therapy of ponesimod, which was recently approved by the Food and Drug Administration (FDA) as a therapeutic option for the treatment of multiple sclerosis (MS). Data Sources: A PubMed literature search using the following terms: ponesimod and MS (January 1, 2012-October 31, 2022). FDA product labeling was also reviewed for pertinent data sources. Study Selection and Data Extraction: All relevant English-language articles examining efficacy and/or safety of ponesimod were considered for inclusion. Data Synthesis: Ponesimod is an orally administered second-generation sphingosine 1-phospate (S1-P) receptor modulator classified as a disease modifying treatment (DMT) for MS. Clinical studies have shown that ponesimod prevents relapse in patients with relapsing-remitting MS (RRMS) and has superior efficacy compared with teriflunomide. Nasopharyngitis, upper respiratory tract infections, headache, high blood pressure, and liver dysfunction were some of the common adverse effects associated with ponesimod. Dyspnea, bradyarrhythmias, atrioventricular conduction delays, and macular edema were some of the rare but serious adverse effects associated with ponesimod. Relevance to Patient Care and Clinical Practice in Comparison With Existing Agents: Some advantages of ponesimod over other S1-P receptor modulators approved for RRMS include selectivity for the S1-P1 receptor and short half-life, which allows for quick reversal of immunosuppressive effects. However, data from long-term efficacy and safety studies and more direct comparison studies with other DMTs are required. Conclusion: Currently available data suggest that ponesimod is a useful addition to other high-efficacy DMTs available to treat patients with MS.

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice

“… 22 , 23 Ponesimod attenuates inflammation, demyelination and axonal loss in the brain and spinal cord of mice with experimental autoimmune encephalomyelitis (EAE), an animal model for MS. 24 Recently, Ponesimod has been approved by the FDA for MS therapy. 25 Tissue distribution studies show that Ponesimod can penetrate the blood–brain-barrier and partition to the brain and spinal cord. 19 , 26 These studies indicate that, in addition to preventing access of lymphocytes to the CNS, Ponesimod may have also direct effects on neuroprotection and anti-neuroinflammation via downregulating S1PR1 cell signaling pathways in neural cells.…”

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

“…Antibody drugs against S1P have also been developed and are currently in clinical development [ 183 , 215 ]. A number of molecularly targeted drugs that act more specifically on S1P receptors have been developed and are being tested in clinical trials as potential treatments for multiple sclerosis and inflammatory bowel disease [ 226 , 227 , 228 , 229 ].…”

“…Therefore, the development of therapies targeting S1P signaling requires the selection of target patient groups, the development of S1P signaling inhibitors, and consideration of combination therapy with anti-cancer drugs and molecular-targeted drugs. A variety of agents have been developed to regulate S1P signaling, each with different targets, and clinical development strategies must be tailored to the pathophysiology of the cancer [ 181 , 226 , 227 , 228 , 229 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 ]. S1P signaling inhibitors developed to date, which could be applied to cancer therapy, are listed in Table 1 .…”

Pathogenic sphingosine 1-phosphate pathway in psoriasis: a critical review of its pathogenic significance and potential as a therapeutic target

“…Myśliwiec et al [69] also suggested that S1P is an intermediate link between psoriasis and multiple metabolic-related diseases. Since S1P signaling is involved in multiple immune functions, targeted S1P therapeutics have been clinically validated for a variety of immune diseases, such as nonalcoholic fatty liver disease (NAFLD), multiple sclerosis (MS), ischemic stroke, and coronary artery disease [70][71][72][73]. In the last decade, the role of S1P and its signaling in recalcitrant skin diseases has also been elucidated.…”