P3, N=300, Recruiting, Vanda Pharmaceuticals | Not yet recruiting --> Recruiting

While fingolimod showed limited evidence on remyelination, more promising effects were observed with selective S1PR1/5 modulators such as siponimod and ponesimod. Several compounds displayed bell-shaped dose-response patterns, highlighting the importance of dosing and treatment paradigms. Collectively, these findings indicate S1PR-based therapies primarily limit demyelination, with limited evidence of remyelination, emphasising the need for more efficacious S1P modulators to improve MS outcomes.

Moreover, FTY720 co-treatment resensitized G12D NRAS-mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70 S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS-mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy.

Building on our work with the structurally related compound KRP203, we show that high-dose FTY720 produces isozyme-divergent modulation across phosphoinositide kinases and biases PIKFYVE activity toward phosphatidylinositol, a pattern we term ASURA (Asymmetric Simultaneous Uncoupling of Related Activities). Patient-derived glioblastoma (GBM) neurospheres were sensitive to FTY720, and co-treatment with a PI3Kα-selective inhibitor augmented growth suppression in U87MG cells. Together, these data support a model in which ASURA-dose FTY720 disrupts phosphoinositide-regulated trafficking and nutrient access, imposing intracellular nutrient stress that culminates in tumor-cell death.

P3, N=300, Not yet recruiting, Vanda Pharmaceuticals

The PK of mocravimod and mocravimod-phosphate were bioequivalent with or without co-administration of multiple doses of itraconazole and a moderate interaction is observed when co-administered with cyclosporin. The most commonly-reported treatment-emergent adverse events were bradycardia and decreased lymphocyte count, which are expected side effects for S1PR modulators.

P3, N=366, Recruiting, Priothera SAS | Trial primary completion date: Nov 2028 --> May 2027

P3, N=366, Recruiting, Priothera SAS | Active, not recruiting --> Recruiting | N=249 --> 366 | Trial completion date: Nov 2028 --> Nov 2029 | Trial primary completion date: Nov 2027 --> Nov 2028

P3, N=249, Active, not recruiting, Priothera SAS | Trial completion date: Nov 2025 --> Nov 2028 | Trial primary completion date: Nov 2025 --> Nov 2027

P3, N=249, Active, not recruiting, Priothera SAS | Recruiting --> Active, not recruiting

These results suggest a model that noncanonical spatial reorganization of phosphoinositides by KRP203 alters the endosomal maturation process, leading to vacuolization. Taken together, this study reveals a previously unrecognized bioactivity of KRP203 as a vacuole-inducing agent and its unique mechanism of phosphoinositide modulation, providing a new insight of phosphoinositide regulation into vacuolization-associated diseases and their molecular pathologies.

P3, N=877, Completed, Actelion | Active, not recruiting --> Completed