mocravimod (KRP-203) / Kyorin, Priothera - LARVOL DELTA

MO-TRANS update: A randomized, double-blind, placebo-controlled, multi-center phase III study of mocravimod (MOC) as maintenance treatment in AML patients undergoing allogeneic hematopoietic cell transplantation (ASH 2025) - P1, P3 | "Use of ATG,alemtuzumab, cyclosporine A (CsA), and abatacept is excluded; other GvHD prophylaxis agents such aspost-transplant cyclophosphamide (PTCy) are permitted. There is an unmet medical need to maintain CR after allo-HCT, especially in AMLpatients with high risk factors or previous relapse. The MO-TRANS study aims to validate the therapeuticpotential of MOC in reducing relapse and GvHD in patients allografted for AML."

Clinical • P3 data • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Chronic Graft versus Host Disease • Diabetes • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Macular Edema • Metabolic Disorders • Ocular Inflammation • Ophthalmology • Transplantation • Uveitis

Sphingosine-1-phosphate receptor modulators overcome FLT3 inhibitor resistance in Acute Myeloid Leukemia with FLT3-ITD and NRAS mutations through sphingosine kinase 1/AKT pathway downregulation. (ASH 2025) - "SphK1 is linked toFLT3 inhibitor resistance, as prolonged sorafenib exposure was shown to activate the Sphk1/S1P axis.Here we studied the efficacy of targeting Sphk1 with sphingosine-1-phosphate receptor (S1PR)modulators in conjunction with FLT3 inhibitors to overcome FLT3 inhibitor resistance mediated by NRASmutations in AML cells with FLT3-ITD. MethodsMOLM-14 and MV4-11 human FLT3-ITD AML cell lines with NRAS mutations including G12D, G12S, G12C,Q61K and Q61H and FLT3-ITD AML patient blasts with G13V and G13D mutations were cultured with theFLT3 inhibitors gilteritinib (10 nM) or quizartinib (1 nM) and/or the S1PR modulators fingolimod (FTY720; 2.5 μM) or mocravimod (KRP203; 5 μM)...ConclusionsThe S1PR agonists fingolimod (FTY720) and mocravimod (KRP203) resensitize FLT3-ITD AML cellsharboring G12D, G12S, Q61K, and Q61H, but not G12C, NRAS mutations to FLT3 inhibitors. The datasupport potential clinical efficacy of combination regimens with these clinically applicable..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ANXA5 • BAD • FLT3 • NRAS • SPHK1 • STAT5

Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors. (PubMed, bioRxiv) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • NRAS • SPHK1

The novel sphingosine-1-phosphate receptor modulator KRP-203 prevents myocardial ischemia-reperfusion injury by preserving mitochondrial function through activation of the RISK and SAFE signaling pathways. (PubMed, Cell Biol Toxicol) - "Mechanistically, KRP-203 selectively activates S1PR1 on cardiomyocytes, triggering the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways to maintain mitochondrial integrity. These findings provide fresh perspectives on the pharmacological properties of KRP-203."

Journal • Cardiovascular • Myocardial Ischemia • Reperfusion Injury • JAK2 • S1PR1 • S1PR2 • STAT3

Clinical Assessment of Mocravimod As a Victim of Drug-Drug Interactions Via CYP3A Metabolism and Transporters (ASH 2024) - "Preliminary pharmacokinetic (PK) modeling of phase 1b data suggested that CYP3A4 inhibitors and cyclosporin (CsA) could increase exposure to MOC significantly. Given the co-administration of MOC with CYP3A4 inhibitors (e.g. azoles and CsA) in allo-HCT patients, two phase 1 studies were conducted to evaluate the drug-drug interactions (DDI) of MOC in combination with itraconazole (ITZ) or CsA.MethodsTwo phase 1, open-label fixed sequence studies were conducted in healthy volunteers (HV) to assess the effects of multiple dosing of a strong cytochrome P450 (CYP) 3A4 and P-glycoprotein (gP) inhibitor ITZ and multiple dosing of a strong CYP3A4, P-gp and BCRP inhibitor CsA on the single-dose pharmacokinetics of MOC...The PK of MOC and MOC-P are bioequivalent with or without co-administration of multiple doses of the strong CYP3A4 inhibitor ITZ and a minor interaction is observed when co-administered with CsA. Taken together, MOC can be co-administered with CYP3A4 inhibitors..."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

MO-TRANS: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase III Study of Mocravimod (MOC) As Adjunctive and Maintenance Treatment in AML Patients Undergoing Allogeneic Hematopoietic Cell Transplantation (ASH 2024) - P3 | "Patients are stratified by remission status (complete remission : CR1 vs CR2), the presence of measurable residual disease (MRD positive vs MRD negative), and the type of GvHD prophylaxis used (tacrolimus (TAC) vs cyclosporin A (CsA) based)...GvHD prophylaxis must be based on TAC or CsA and may include any additional medication except for anti-thymocyte globulin (ATG), alemtuzumab, and abatacept. The use of post-transplant cyclophosphamide is allowed...As of July 29, 2024, 88 patients have been randomized. ClinicalTrials.gov identifier NCT05429632."

Clinical • P3 data • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation • S1PR1

Clinical assessment of mocravimod as a victim of drug-drug interactions via CYP3A4 metabolism and transporters. (PubMed, Clin Pharmacol Drug Dev) - "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."

Journal • Acute Myelogenous Leukemia • Breast Cancer • Cardiovascular • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Transplantation • CYP3A4

MO-TRANS: Mocravimod as Adjunctive and Maintenance Treatment in AML Patients Undergoing Allo-HCT (clinicaltrials.gov) - P3 | N=366 | Recruiting | Sponsor: Priothera SAS | Trial primary completion date: Nov 2028 ➔ May 2027

Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Priothera Secures €1.7 million i-Nov Funding by Bpifrance for Rare Blood Cancer Clinical Program (GlobeNewswire) - "Priothera...announced that it has been awarded nearly €1.7 million in non-dilutive funding through the i-Nov innovation competition....The funding will support Priothera’s clinical programme to evaluate whether adding mocravimod to commercial CAR-T cell therapies could improve patient outcomes....Priothera continues to advance mocravimod in the MO-TRANS global Phase 3 study for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (allo-HCT)."

Financing • Acute Myelogenous Leukemia

MO-TRANS: Mocravimod as Adjunctive and Maintenance Treatment in AML Patients Undergoing Allo-HCT (clinicaltrials.gov) - P3 | N=366 | Recruiting | Sponsor: Priothera SAS | Active, not recruiting ➔ Recruiting | N=249 ➔ 366 | Trial completion date: Nov 2028 ➔ Nov 2029 | Trial primary completion date: Nov 2027 ➔ Nov 2028

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Priothera Appoints Dr. Jens Hasskarl as Chief Medical Officer to Drive Late-Stage Clinical Development of Mocravimod, a S1P Receptor Modulator for Acute Myeloid Leukemia (AML) (GlobeNewswire) - "Dr. Hasskarl will oversee the global Phase 3 clinical study MO-TRANS of mocravimod, which is being developed as an adjunctive treatment in acute myeloid leukemia (AML) to enhance the curative potential of allogeneic hematopoietic cell transplantation (allo-HCT)."

Commercial • Acute Myelogenous Leukemia

MO-TRANS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTER PHASE III STUDY OF MOCRAVIMOD (MOC) AS ADJUNCTIVE AND MAINTENANCE TREATMENT IN AML PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (EBMT 2025) - P3 | "Patients are stratified by complete remission (CR1 vs CR2), measurable residual disease (MRD positive vs MRD negative), and the GvHD prophylaxis used (tacrolimus (TAC) vs cyclosporin A (CsA))...GvHD prophylaxis must be based on TAC or CsA and may include any additional medication except for anti-thymocyte globulin, alemtuzumab, and abatacept... Relapse remains the primary cause of treatment failure in AML patients undergoing allo-HCT, ultimately resulting in shorter OS. There is an unmet medical need in the maintenance setting after allo-HCT. MOC´s potential is to enhance GvL while suppressing GvHD by decoupling these two related processes."

Clinical • P3 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Immunology • Transplantation • S1PR1

MO-TRANS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTER PHASE III STUDY OF MOCRAVIMOD (MOC) AS ADJUNCTIVE AND MAINTENANCE TREATMENT IN AML PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (EBMT 2025) - P3 | "Patients are stratified by complete remission (CR1 vs CR2), measurable residual disease (MRD positive vs MRD negative), and the GvHD prophylaxis used (tacrolimus (TAC) vs cyclosporin A (CsA))...GvHD prophylaxis must be based on TAC or CsA and may include any additional medication except for anti-thymocyte globulin, alemtuzumab, and abatacept... Relapse remains the primary cause of treatment failure in AML patients undergoing allo-HCT, ultimately resulting in shorter OS. There is an unmet medical need in the maintenance setting after allo-HCT. MOC´s potential is to enhance GvL while suppressing GvHD by decoupling these two related processes."

Clinical • P3 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Immunology • Transplantation • S1PR1

MO-TRANS: Mocravimod As Adjunctive and Maintenance Treatment in AML Patients Undergoing Allo-HCT (clinicaltrials.gov) - P3 | N=249 | Active, not recruiting | Sponsor: Priothera SAS | Trial completion date: Nov 2025 ➔ Nov 2028 | Trial primary completion date: Nov 2025 ➔ Nov 2027

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Priothera to Present Trial in Progress Poster for Mocravimod at 2024 American Society of Hematology (ASH) Annual Meeting (GlobeNewswire) - "Priothera Ltd...announces that it will present a Trial in Progress poster on the MO-TRANS Phase 3 study, at the American Society of Hematology (ASH) Annual Meeting taking place December 7-10, 2024, in San Diego, California."

Trial status • Acute Myelogenous Leukemia

MO-TRANS: Mocravimod As Adjunctive and Maintenance Treatment in AML Patients Undergoing Allo-HCT (clinicaltrials.gov) - P3 | N=249 | Active, not recruiting | Sponsor: Priothera SAS | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Sphingosine-1-phosphate (S1P) receptor type 1 signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice. (PubMed, JCI Insight) - "A similar macrophage phenotype was observed in mice administered S1P1-selective agonist KRP203...Atherosclerotic lesions in aortic roots and brachiocephalic arteries were profoundly or moderately reduced in mice with high and low S1P1 overexpression in macrophages, respectively. We conclude that S1P1 signaling polarizes macrophages towards an anti-atherogenic functional phenotype and countervails the development of atherosclerosis in mice."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • BCL6 • IL10 • IL1R1 • IL5 • IRF8 • LAMTOR2 • LAMTOR3 • MAFB • MERTK

EUROAPI and Priothera enter into CDMO collaboration to advance oncology project (GlobeNewswire) - "EUROAPI announces today the implementation of a 5-year development and manufacturing agreement with Priothera, a biotechnology company specializing in molecules for the treatment of hematological malignancies and for the improvement of CAR-T cell therapies. Priothera is headquartered in Dublin, Ireland, and has a subsidiary in Saint-Louis (Haut-Rhin), France. As part of this collaboration, EUROAPI will develop and industrialize the manufacturing process of mocravimod, an innovative oncology molecule, through its Contract Development and Manufacturing Organization (CDMO) activity. This project will be carried out at EUROAPI’s Budapest site, its center of excellence for complex chemistry."

Licensing / partnership • Hematological Malignancies

A high dose KRP203 induces cytoplasmic vacuoles associated with altered phosphoinositide segregation and endosome expansion. (PubMed, Biochem Biophys Res Commun) - "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."

Journal • Oncology • PTEN

MOCRAVIMOD DOES NOT HAVE A CLINICALLY RELEVANT DRUG-DRUG INTERACTION WITH STRONG CYP3A4 INHIBITOR ITRACONAZOLE (EBMT 2024) - "MOC and ITZ were generally well tolerated when administered alone or in combination. The PK of MOC and MOC-P are bioequivalent with or without co-administration of multiple doses of the strong CYP3A4 inhibitor ITZ. Taken together, MOC can be co-administered with CYP3A4 inhibitors such as azoles without dosage adjustments in allo-HCT patients."

Clinical • Acute Myelogenous Leukemia • Cardiovascular • Hematological Malignancies • Leukemia • Oncology • Transplantation

MOCRAVIMOD FAVOURABLY AFFECTS OVERALL SURVIVAL IN PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (EBMT 2024) - P1, P3 | " In this multicenter, open label trial 23 patients comprising different hematologic diseases were included across three treatment arms to receive a daily oral dose of either 3mg MOC+cyclosporine A (CsA), 1mg MOC+CsA or 3mg MOC+tacrolimus (Tac). This post hoc analysis demonstrated an OS benefit for pts with hematologic diseases receiving MOC as add-on treatment to allo-HCT in comparison to a matched real-world cohort undergoing allo-HCT without MOC. These data support the development of MOC as an adjunctive and maintenance treatment to allo-HCT, which is currently evaluated in the Phase III MO-TRANS trial, a worldwide double-blind trial investigating the GvL effect of MOC translating into prolonged relapse-free-survival and OS in AML pts undergoing allo-HCT (NCT05429632)"

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation

Priothera – US FDA grants Orphan Drug Designation to mocravimod to improve the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hematologic malignancies (GlobeNewswire) - "Priothera Ltd...announced that the US Food and Drug Administration (FDA) has granted Orphan Drug designation (ODD) to mocravimod for the ‘treatment to improve outcome following hematopoietic stem cell transplantation in hematologic malignancies’....Mocravimod, a sphingosine-1-phosphate (S1P) receptor modulator, is being investigated in a pivotal global Phase 3 study - MO-TRANS (NCT05429632) - evaluating the efficacy and safety of mocravimod as an adjunctive and maintenance therapy to allo-HSCT. The study which is enrolling approximately 250 adult Acute Myeloid Leukemia (AML) patients, is ongoing in the US, Europe, Southeast Asia and Latin America."

Orphan drug • Trial status • Acute Myelogenous Leukemia • Transplantation

Orphan Designation: Treatment to improve outcome following hematopoietic stem cell transplantation in hematologic malignancies (FDA) - Date Designated: 11/14/2023

Orphan drug • Graft versus Host Disease • Immunology • Transplantation

Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells. (PubMed, Biochem Biophys Res Commun) - "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."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • PIK3CA

MO-TRANS: Mocravimod as Adjunctive and Maintenance Treatment in AML Patients Undergoing Allo-HCT (clinicaltrials.gov) - P3 | N=249 | Recruiting | Sponsor: Priothera SAS | Trial primary completion date: Aug 2025 ➔ Nov 2025

Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology