Central versus peripheral drug exposure ratio, a key differentiator for siponimod over fingolimod ?

Siponimod, a potent and selective sphingosine-1-phosphate (S1P1,5) agonist, is the only therapeutic agent that has shown efficacy on disability progression, decline in cognitive processing speed, total brain volume loss, gray matter atrophy, and signs of demyelination in patients with secondary progressive multiple sclerosis (SPMS). Although the pathophysiology of progression in SPMS and primary progressive MS (PPMS) is thought to be similar, fingolimod, the prototype S1P1,3,45 agonist, failed to show efficacy on disability progression in PPMS. Differentiating the mechanisms of siponimod’s effects on progression from those of fingolimod is believed to be key to better understand the key characteristics that could make siponimod uniquely efficacious in progressive MS (PMS). Here, we compared the dose-dependent central vs peripheral drug exposure of siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady state drug blood levels, with a similar central nervous system (CNS)/blood drug-exposure ratio (CNS/BloodDER) in both healthy and EAE mice. In contrast, fingolimod treatment achieved dose-proportional increases in fingolimod/fingolimod-P drug blood levels with a CNS/BloodDER that was markedly increased in EAE vs healthy mice. These results, taken together with recent preclinical observations implying a bell-shaped dose-effect relationship for S1P receptor-dependent central effects, suggest that at human-equivalent therapeutic doses an increase in CNS/BloodDER with loss of central efficacy for fingolimod/fingolimod-P but not for siponimod. Therefore, CNS/bloodDER is a potential new differentiator for siponimod over fingolimod, that warrants further investigation and clinical validation

Guidance on mucositis assessment from the MASCC Mucositis Study Group and ISOO: an international Delphi studyResearch in context

Summary: Background: Mucositis is a common and highly impactful side effect of conventional and emerging cancer therapy and thus the subject of intense investigation. Although common practice, mucositis assessment is heterogeneously adopted and poorly guided, impacting evidence synthesis and translation. The Multinational Association of Supportive Care in Cancer (MASCC) Mucositis Study Group (MSG) therefore aimed to establish expert recommendations for how existing mucositis assessment tools should be used, in clinical care and trials contexts, to improve the consistency of mucositis assessment. Methods: This study was conducted over two stages (January 2022–July 2023). The first phase involved a survey to MASCC-MSG members (January 2022–May 2022), capturing current practices, challenges and preferences. These then informed the second phase, in which a set of initial recommendations were prepared and refined using the Delphi method (February 2023–May 2023). Consensus was defined as agreement on a parameter by >80% of respondents. Findings: Seventy-two MASCC-MSG members completed the first phase of the study (37 females, 34 males, mainly oral care specialists). High variability was noted in the use of mucositis assessment tools, with a high reliance on clinician assessment compared to patient reported outcome measures (PROMs, 47% vs 3%, 37% used a combination). The World Health Organization (WHO) and Common Terminology Criteria for Adverse Events (CTCAE) scales were most commonly used to assess mucositis across multiple settings. Initial recommendations were reviewed by experienced MSG members and following two rounds of Delphi survey consensus was achieved in 91 of 100 recommendations. For example, in patients receiving chemotherapy, the recommended tool for clinician assessment in clinical practice is WHO for oral mucositis (89.5% consensus), and WHO or CTCAE for gastrointestinal mucositis (85.7% consensus). The recommended PROM in clinical trials is OMD/WQ for oral mucositis (93.3% consensus), and PRO-CTCAE for gastrointestinal mucositis (83.3% consensus). Interpretation: These new recommendations provide much needed guidance on mucositis assessment and may be applied in both clinical practice and research to streamline comparison and synthesis of global data sets, thus accelerating translation of new knowledge into clinical practice. Funding: No funding was received