mocravimod (KRP-203)

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.

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, p70S6K 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 of these combinations.

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.

At cellular levels, 3 h of KRP203 treatment induces a prominent increase of PI(3)P and moderate increase of PI(5)P, PI(3,5)P and PI(3,4,5)P levels in U87MG cells. Collectively, the finding of multimodal activity of KRP203 towards multi-phosphoinositide kinases may open a novel basis to modulate cellular processes, potentially leading to more effective treatments for diseases associated with phosphoinositide signaling pathways.

Clinically-relevant acute GvHD events (grade II-IV) were slightly lower, but comparable to controls when mocravimod was administered. Taken together, data are supportive of mocravimod's mode of action and bring additional evidence of fewer relapses for allo-HCT patients treated with S1PR modulators.

7 AML pts were included in CKRP203A2105 across three treatment arms (3mg MOC+cyclosporine (CsA)/methotrexate (MTX) (part 1), 1mg MOC+CsA/MTX and 3mg MOC+tacrolimus (Tac)/MTX (part 2)). Taken together, this post hoc analysis suggests a possible survival benefit for AML pts undergoing allo-HCT who receive an additional treatment with MOC. Only 1 AML pt relapsed whilst being on MOC treatment. This further supports the development of MOC as an adjunctive and maintenance treatment to allo-HCT in a homogeneous AML patient population and provides a rationale for a treatment period of 12-months for MOC which will be investigated further in the current MO-TRANS trial (NCT05429632).

Leukemia-injected recipients were treated with mocravimod (day 0-42) alone or in combination with short-term (day 0-14) or long-term (day 0-42) cyclosporine (CSP). Mocravimod primarily reduced CD4+ donor T-cell expansion while sparing CD8+ T cells after allo-BMT, which ameliorated chronic GVHD and contributed to persisted GVL effects after mocravimod-treatment.