Mocravimod, a Selective Sphingosine-1-Phosphate Receptor Modulator, in Allogeneic Hematopoietic Stem Cell Transplantation for Malignancy

• Published in: Transplantation and cellular therapy 2023-01, Vol.29 (1), p.41.e1-41.e9
• Main Authors: Dertschnig, Simone, Gergely, Peter, Finke, Jürgen, Schanz, Urs, Holler, Ernst, Holtick, Udo, Socié, Gérard, Medinger, Michael, Passweg, Jakob, Teshima, Takanori, Stylianou, Christos, Oehen, Stephan, Heim, Dominik, Bucher, Christoph
• Format: Article
• Language: English
• Subjects: Allogeneic HSCT; Graft vs Host Disease - prevention & control; Graft-versus-host disease; Graft-versus-leukemia; Hematologic Neoplasms - therapy; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents - adverse effects; Leukemia, Myeloid, Acute - drug therapy; Methotrexate - therapeutic use; Mocravimod; S1PR modulator; Sphingosine-1-Phosphate Receptors - antagonists & inhibitors
• ISSN: 2666-6367; 2666-6367
• DOI: 10.1016/j.jtct.2022.10.029

•Mocravimod was safe in allogeneic hematopoietic stem cell transplantation recipients.•Mocravimod reduced blood absolute lymphocyte counts temporarily.•CD4+ T cells were more sensitive to mocravimod treatment than CD8+ T cells.•Mocravimod did not affect engraftment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the sole curative option for patients with acute myelogenous leukemia. Outcomes are limited by leukemia relapse, graft-versus-host disease (GVHD), and abnormal immune reconstitution. Mocravimod (KRP203) is an oral sphingosine-1-phosphate receptor (S1PR) modulator that blocks the signal required by T cells to egress from lymph nodes and other lymphoid organs. Mocravimod retains T cell effector function, a main differentiator to immunosuppressants. In preclinical models, mocravimod improves survival by maintaining graft-versus-leukemia (GVL) activity while reducing GVHD. In patients undergoing allo-HSCT for hematological malignancies, mocravimod is postulated to prevent GVHD by redistributing allogeneic donor T cells to lymphoid tissues while allowing a sufficient GVL effect in the lymphoid, where malignant cells usually reside. The primary objective of this study was to assess the safety and tolerability of mocravimod in patients undergoing allo-HSCT for hematologic malignancies. Secondary objectives were to determine the pharmacokinetic profiles of mocravimod and its active metabolite mocravimod-phosphate in this patient group, as well as to assess GVHD-free, relapse free survival at 6 months after the last treatment. In this 2-part, single- and 2-arm randomized, open-label trial, we evaluated the safety, tolerability, and pharmacokinetics of mocravimod in allo-HSCT recipients (ClinicalTrials.gov identifier NCT01830010). Patients received either 1 mg or 3 mg mocravimod per day on top of standard of care GVHD prophylaxis with either cyclosporine A/methotrexate or tacrolimus/methotrexate. We found that mocravimod can be safely added to standard treatment regimens in patients with hematologic malignancies requiring allo-HSCT. Mocravimod resulted in a significant reduction of circulating lymphocyte numbers and had no negative impact on engraftment and transplantation outcomes. Our results indicate that mocravimod is safe and support a larger study to investigate its efficacy in a homogeneous acute myelogenous leukemia patient population undergoing allo-HSCT.