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

  • Transplant Cell Ther. 2023 Jan;29(1):41.e1-41.e9. doi: 10.1016/j.jtct.2022.10.029.
Simone Dertschnig  1 ,  Peter Gergely  2 ,  Jürgen Finke  3 ,  Urs Schanz  4 ,  Ernst Holler  5 ,  Udo Holtick  6 ,  Gérard Socié  7 ,  Michael Medinger  8 ,  Jakob Passweg  8 ,  Takanori Teshima  9 ,  Christos Stylianou  10 ,  Stephan Oehen  11 ,  Dominik Heim  8 ,  Christoph Bucher  8
Affiliations
  • 1. Priothera SAS, St Louis, France. Electronic address: [email protected].
  • 2. Novartis Institute of Biomedical Research, Basel, Switzerland.
  • 3. University of Freiburg Medical Center, Freiburg, Germany.
  • 4. Department of Medical Oncology and Hematology, Zurich University and University Hospital, Zurich, Switzerland.
  • 5. University Hospital, Regensburg, Germany.
  • 6. Department I of Internal Medicine, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany.
  • 7. APHP Hospital Saint Louis & University of Paris, Paris, France.
  • 8. University Hospital, Basel, Switzerland.
  • 9. Hokkaido University, Faculty of Medicine, Sapporo, Japan.
  • 10. ClinBAY Ltd, Limassol, Cyprus.
  • 11. Priothera SAS, St Louis, France; Novartis Institute of Biomedical Research, Basel, Switzerland.
PMID: 36343893 DOI: 10.1016/j.jtct.2022.10.029
Abstract

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.

Keywords
Allogeneic HSCT; Graft-versus-host disease; Graft-versus-leukemia; Mocravimod; S1PR modulator.
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