Ponesimod in the Treatment of Relapsing Forms of Multiple Sclerosis: An Update on the Emerging Clinical Data

Abstract

Sphingosine 1-phosphate (S1P) receptors are bioactive lipid metabolites that bind five different types of receptors expressed ubiquitously in human body and mediate a broad range of biological functions. Targeting S1P receptors is nowadays a well-established pharmacological strategy to treat multiple sclerosis (MS). However, the adverse events associated with the ancestor (fingolimod), especially in terms of heart conduction and slow reversibility of its pharmacodynamics effect on lymphocytes, have stimulated a search for a S1P modulator with greater selectivity for S1P 1 (the most important immune mechanism to prevent MS-related neuroinflammation). Ponesimod is a second-generation, orally active, directly bioavailable, highly selective, and rapidly reversible modulator of the S1P 1 receptor. Gradual 14-day up-titration of ponesimod mitigates its first-dose effects on heart rate and facilitates its use over fingolimod, as it does not require first-dose cardiac monitoring. Ponesimod is rapidly eliminated within 1 week of discontinuation, thereby representing a more manageable approach in case of vaccination, pregnancy, or adverse events. However, the fast reversibility of ponesimod may also raise concerns about the possibility of a rapid reactivation of disease activity following its discontinuation. Ponesimod was recently approved for the treatment of relapsing MS forms on the basis of a Phase III, double-blind, double-dummy, randomized clinical trial (OPTIMUM) that demonstrated the superiority of ponesimod over teriflunomide on disease activity markers, without unexpected safety concerns. This review summarizes the pharmacodynamic and pharmacokinetic characteristics of ponesimod, and the main Phase II and III studies that led to its approval. Comparisons of ponesimod with other S1P receptor modulators currently available for MS (fingolimod, ozanimod, siponimod) are also provided.

Comparison of Pharmacological Therapies in Relapse Rates in Patients With Relapsing-Remitting Multiple Sclerosis

“…After discontinuation, lymphocyte count returns to baseline values within one week (faster disease reactivation with ponesimod than other S1P modulators). Ponesimod has a selective effect on lymphocytes, showing a decrease in T and B cells in a dose-dependent pattern and no effect on natural killer cells [ 21 ].…”

Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain

“…Currently, four S1P modulators fingolimod, siponimod, ozanimod, and ponesimod have been approved by the U.S. FDA for treating relapsing multiple sclerosis (MS). 5,6 Among the five members of the S1PRs family, S1PR1 is the most abundant subtype and is widely expressed in a variety of tissues. 7 It plays a crucial role in multiple biological pathways and many pathological conditions including autoimmune diseases, inflammatory diseases, cardiovascular disease, and cancer.…”

“…In the past few decades, tremendous efforts have been made in the development of S1PR modulators for the treatment of autoimmune diseases as well as for understanding the biological mechanisms of the S1P/S1PRs pathway. Currently, four S1P modulators fingolimod, siponimod, ozanimod, and ponesimod have been approved by the U.S. FDA for treating relapsing multiple sclerosis (MS). , …”

Ponesimod-Associated Macular Edema: Onset and Resolution

“…Relapsing-remitting multiple sclerosis (RRMS) management has recently benefited from the approval of ponesimod (Ponvory, Janssen), a second-generation modulator of the sphingosine 1-phosphate 1 receptor (S1P 1 R). 1 Ponesimod iterates on previous S1PR modulators such as fingolimod and offers increased selectivity for the S1P 1 R. The medication overwhelms the naturally present S1P concentration gradient, a crucial component of lymphocyte trafficking. [2][3][4] As a result, ponesimod was shown to lower the relapse rate, decrease magnetic resonance imaging endpoints, and provide symptomatic relief when compared with teriflunomide in the OPTIMUM (Oral Ponesi mod Versus Teriflunomide In Relapsing Multiple Sclerosis) phase III trial.…”