Tascinimod or its pharmaceutically acceptable salts for use in the treatment of myelodysplastic syndromes

Abstract

1. Tasquinimod or a pharma- ceutically acceptable salt thereof for use in the treatment of myelodysplastic syndromes (MDS).

Description

[Technical Field]

[0001] This invention relates to a novel use of the quinoline derivative tascinimod. More specifically, this invention relates to tascinimod or pharmaceutically acceptable salts thereof for use in the treatment of myelodysplastic syndromes. [Background technology]

[0002] Tascinimod and methods for its preparation are described in international applications PCT / SE99 / 00676, published as WO 99 / 55678, and PCT / SE99 / 01270, published as WO 00 / 03991, which also disclose the usefulness of tascinimod and several other quinoline carboxamides for the treatment of autoimmune diseases, such as multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and psoriasis, as well as diseases in which pathological inflammation plays a major role, such as asthma, atherosclerosis, stroke, and Alzheimer's disease.

[0003] Methods for preparing tascinimod are also disclosed in international application PCT / SE2003 / 000780, published as WO 03 / 106424, and in international application PCT / EP2011 / 061490, published as WO 2012 / 004338. The deuterated form of tascinimod is described in international application PCT / EP2012 / 061798, published as WO 2012 / 175541.

[0004] The use of various quinoline carboxamides for the treatment of cancer, and more specifically solid tumors, such as prostate cancer and breast cancer, is disclosed in international application PCT / SE00 / 02055, published as WO 01 / 30758. Some of these compounds have been found to promote tumorigenesis, affect inhibitory and pro-angiogenic cells in the tumor microenvironment, and bind to and inhibit the interaction of the immunomodulatory protein (S100A9) involved in the establishment of the premetastatic niche.

[0005] International application PCT / EP2015 / 075769, published as WO 2016 / 078921, discloses tascinimod for use in the treatment of leukemia, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia.

[0006] International application PCT / EP2015 / 071391, published as WO 2016 / 042112, discloses tascinimod for use in the treatment of multiple myeloma.

[0007] International application PCT / EP2016 / 053288, published as WO 2016 / 146329, discloses taskinimod for use in combination with PD-1 and / or PD-L1 inhibitors in the treatment of cancer, particularly bladder cancer.

[0008] Myelodysplastic syndrome (MDS) is a heterogeneous spectrum of chronic myelogenesis or clonal hematopoietic stem cell disorder that manifests as symptomatic cytopenia, ineffective hematopoiesis, cellular morphological dysplasia, and a significant risk of progression to acute myeloid leukemia.

[0009] MDS is one of the most common hematopoietic neoplasms in the elderly population with a median age of 65–70 years. However, the disease can develop at any age. There are no obvious risk factors for primary MDS, but for secondary MDS, DNA damage from previous chemotherapy or radiotherapy is a well-known risk factor. Furthermore, in the pediatric population, MDS may occur in association with hereditary bone marrow dysfunction (e.g., Fanconi anemia or congenital dyskeratosis).

[0010] Multiple biological processes govern the proliferation and differentiation of hematopoietic precursors into mature blood cells. Molecular modifications of hematopoietic stem cells that disrupt any of these processes are essential to the pathogenesis of MDS. Approximately 80–90% of MDS patients have somatic mutations in their hematopoietic stem cells. The type and incidence of somatic mutations contribute to dysfunctional signaling pathways in MDS and are associated with disease prognosis and responsiveness to several drugs. In addition to molecular modifications of hematopoietic stem cells, the surrounding bone marrow niche plays a central role in the pathogenesis of MDS. Abnormal inflammatory signaling, including activation of the NLRP3 inflammasome, can promote the selection, maintenance, and progression of malignant MDS clones.

[0011] MDS patients may be asymptomatic at diagnosis, but up to 80% suffer from anemia. Patients primarily experience symptoms associated with cytopenia, such as fatigue and weakness due to anemia, infections associated with neutropenia, or bleeding due to thrombocytopenia. Approximately one-third of MDS patients progress to acute myeloid leukemia.

[0012] The MDS Revised International Prognostic System (IPSS-R) is the most commonly used prognostic system for determining disease outcomes. The model presents five risk categories based on the degree of cytopenia, myeloblast percentage, and cytogenetic subgroups.

[0013] Although MDS is one of the most common hematopoietic neoplasms in the elderly population, only limited treatment options are available. In addition to supportive care, only five drugs (erythropoietin, ruspatercept, the iron chelator deferasirox, the immunomodulator lenalidomide, and the hypomethylating agent azacitidine) are approved in Europe. The only curative treatment is allogeneic hematopoietic stem cell transplantation, but this is not feasible for many elderly patients.

[0014] Supportive care includes blood transfusions, treatment with erythropoiesis-promoting agents, and antibiotic therapy. Blood transfusions are a method of providing red blood cells, white blood cells, or platelets to replace blood cells destroyed by disease or treatment. Frequent red blood cell transfusions can lead to iron overload and associated organ toxicity, resulting in poor clinical outcomes. Iron chelation therapy using deferasirox may improve patient outcomes. Erythropoiesis-promoting agents (ESAs) are administered to increase the number of mature red blood cells produced by the body and alleviate the effects of anemia. Granulocyte colony-stimulating factor (G-CSF) may also be administered with ESAs to help improve treatment performance. Finally, antibiotic therapy can be used to combat infections.

[0015] Drug therapy includes, for example, treatment with lenalidomide, which is approved only for patients with myelodysplastic syndromes characterized by a sole deletion of (5q) chromosomal abnormality who require frequent red blood cell transfusions. Transfusion-dependent MDS patients with ring sideroblasts who are refractory to ESA or unlikely to respond to ESA can be treated with ruspatercept. The hypomethylating agent azacitidine can be used to treat myelodysplastic syndromes in the advanced stages of the disease to slow its progression to acute myeloid leukemia. Classical chemotherapy is usually used only before stem cell transplantation in patients with higher blast counts to reduce the tumor cell burden.

[0016] During allogeneic stem cell transplantation, stem cells (immature blood cells) are collected from the blood or bone marrow of a healthy donor and reinjected into the MDS patient after the completion of conditioning therapy. The donor hematopoietic stem cells replace the patient's original bone marrow, restoring the body's blood cells (a process called engraftment). [Overview of the project]

[0017] The first aspect is tascinimod or a pharmaceutically acceptable salt thereof for use in the treatment of myelodysplastic syndromes.

[0018] Another aspect is the use of tasquinimod or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of myelodysplastic syndromes.

[0019] Yet another aspect is a pharmaceutical dosage form for the treatment of myelodysplastic syndromes, comprising a therapeutically effective amount of tasquinimod or a pharmaceutically acceptable salt thereof.

[0020] Another aspect is a method for treating myelodysplastic syndromes in a mammal that requires treatment of myelodysplastic syndromes, which is a method by administration to the mammal of a therapeutically effective amount of tasquinimod or a pharmaceutically acceptable salt thereof.

[0021] Those other aspects and embodiments will become apparent from the following description and claims.

Brief Description of the Drawings

[0022] [Figure 1] It is a graph showing the S100A9 concentration (pg / ml) in bone marrow obtained from healthy patients (control), low-risk MDS (LR-MDS) patients and high-risk MDS (HR-MDS) patients, respectively. [Figure 2] It is a diagram showing Western blots of phosphorylated IRAK1 (80 kDa), NF-κB-p65 (65 kDa) and gasdermin (50 kDa) in MDS MSCs after treatment with S100A9 or S100A9 and tasquinimod for 48 hours. GAPDH (38 kDa) served as a reference protein. Lane 1 = untreated control; Lane 2 = treated with S100A9; Lane 3 = treated with S100A9 / tasquinimod. [Figure 3]This bar graph shows the mRNA expression levels of IL-1β, IL-18, Casp1, and PD-L1 obtained by real-time PCR of MDS MSCs after 48 hours of treatment with tascinimod alone (TASQ), S100A9 alone (S100A9), or both S100A9 and tascinimod (S100A9+TASQ). The amplification products of IL-1β, IL-18, Casp1, and PD-L1 were normalized to endogenous GAPDH expression, and untreated MSCs were set to 1 (=control). [Figure 4] This figure shows Western blots of PD-L1 in healthy and CMML MSCs after 48 hours of treatment with S100A9 and Tascinimod. Lane 1 = untreated control; Lane 2 = treated with Tascinimod; Lane 3 = treated with S100A9; Lane 3 = treated with S100A9 and Tascinimod. [Figure 5] This figure shows Western blots of phosphorylated IRAK1 (80kDa), NF-κB-p65 (65kDa), and gasdermin (50kDa) in MDS MSCs after 48 hours of treatment with TNF-α and tascinimod. GAPDH (38kDa) was used as a comparison protein. Lane 1 = treated with TNF-α; Lane 2 = treated with TNF-α and tascinimod. [Figure 6a] This bar graph shows the quantitative determination of CAF-C when MDS MSCs were co-cultured with hematopoietic progenitor cells at 1, 2, 3, and 4 weeks in the absence of both S100A9 and tascinimod ("absence"), in the presence of tascinimod (TASQ), in the presence of S100A9 (S100A9), and in the presence of both S100A9 and tascinimod (S100A9+TASQ). [Figure 6b]This bar graph shows the number of colonies / 300 cells in a CFU assay performed using MDS MSC cells co-cultured with hematopoietic progenitor cells harvested after seeding 300 cells in methylcellulose medium fortified with recombinant cytokine (MethoCult® H4435, STEMCELL Technologies) and co-culturing them for 1 week in the presence of S100A9, in the presence of both S100A9 and tascinimod, or in the absence of both S100A9 and tascinimod ("control"). After 2 weeks, colonies were counted and classified under a microscope or using the STEMvision® system (STEMCELL Technologies). [Figure 6c] This bar graph shows the number of colonies / 300 cells in a CFU assay performed using MDS MSC cells and hematopoietic progenitor cells harvested after co-culturing 300 cells in methylcellulose medium fortified with recombinant cytokine (MethoCult® H4435, STEMCELL Technologies) for 1 week in the presence or absence of tascinimod ("TASQ") or ("absence"). After 2 weeks, colonies were counted and classified under a microscope or using the STEMvision® system (STEMCELL Technologies). [Modes for carrying out the invention]

[0023] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains.

[0024] The abbreviations and acronyms used in this text are expected to be familiar to those skilled in the art, but for clarity, the meanings of some of them are given below in this specification. ALP (Alkaline Phosphatase) αSMA α-Smooth Muscle Actin BCA bicinchoninate assay BFU-E erythroid burst-forming units BM bone marrow CAF-C cobblestone-like region forming cells cDNA complementary DNA CFU Colony Formation Units CFU-E erythroblast colony-forming units CFU-GEMM: Colony-forming units of granulocytes, erythrocytes, monocytes, and megakaryocytes. CFU-GM Granulocyte / Macrophage Colony-Organizing Units CMML (Chronic Myelomonocytic Leukemia) Cy Cyanine DAPI 4',6-Diamidino-2-phenylindole DMEM Dulbecco's modified Eagle medium dT Deoxythymidine ECAR extracellular acidification rate ECL-enhanced chemical luminescence EDTA (Ethylenediaminetetraacetic acid) ELISA (Enzyme-Linked Immunoadsorption Assay) FCCP Carbonylcyanide-p-trifluoromethoxyphenylhydrazone FCS fetal bovine serum FLT3-L fms-like tyrosine kinase 3 ligand GAPDH Glyceraldehyde 3-phosphate dehydrogenase HRP Horseradish Peroxidase HSA Human Serum Albumin HSC(s) hematopoietic stem cell(s) IgG (Immunoglobulin G) IL Interleukin IRAK1 Interleukin-1 Receptor-Related Kinase 1 MDS (Myelodysplastic Syndrome) MDS-RS (Myelodysplastic Syndrome with Sideroblasts in the Ring) MSC(s) Mesenchymal stem cells (multiple stem cells possible) NF-κB is a nuclear factor-κ light chain enhancer for activated B cells. OCR oxygen consumption rate PBMC peripheral blood mononuclear cells PBS (Phosphate-buffered Saline) PD-1 programmed cell death protein 1 PD-L1 programmed dead ligand 1 RIPA Radioimmunoprecipitation Assay RNA (ribonucleic acid) ROS (Reactive Oxygen Species) ROX Carboxy-X-Rhodamine RT-PCR (Real-time Polymerase Chain Reaction) SCF Stem Cell Factor SDS Sodium Dodecyl Sulfate TLR4 Toll-like receptor 4 TNF-α tumor necrosis factor α

[0025] The compound Tascinimod, or 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide, has the following structural formula. [ka]

[0026] "Optional" or "optional" means that the event or situation described below may or may not occur, and that the description includes cases where the event or situation may or may not occur.

[0027] "Pharmacologically acceptable" means useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes those acceptable for veterinary use and use as human pharmaceuticals.

[0028] Examples of pharmaceutically acceptable salts include alkali metal ions (as counterions), such as Li. + kaNa + Or K + Salts of, or alkaline earth metal ions, such as Mg 2+ Or Ca 2+ A salt of, or any other pharmaceutically acceptable metal ion, such as Zn2+ Or Al 3+ Salts of; or pharmaceutically acceptable salts formed with organic bases such as diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, or tromethamine.

[0029] "Therapeutic effective dose" means the amount of tascinimod or a pharmaceutically acceptable salt thereof that, when administered to a subject to treat a condition (in this case, MDS), is sufficient to produce such treatment for the condition. The "therapeutic effective dose" varies depending, for example, on the age and relative health of the subject being treated, the progression of the condition, the route and form of administration, and the possible additional use of other drugs, for example, in combination therapy. In some embodiments, the "effective dose" is measured by a statistically significant change in one or more signs, subjective symptoms, objective symptoms, diagnostic tests, vital signs, etc., to produce a therapeutic effect (e.g., treat, prevent, inhibit, alleviate, promote, improve, increase, reduce, etc.). In another embodiment, the "effective dose" is measured by the absence of a statistically significant change in one or more signs, subjective symptoms, objective symptoms, diagnostic tests, vital signs, etc., to suppress, manage, or prevent the condition.

[0030] In this specification, the terms “treatment” or “to treat” refer to a method for obtaining beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, the reduction or improvement of one or more symptoms of the treated condition, whether detectable or undetectable; a reduction in the extent of the condition; stabilization of the condition (i.e., no worsening); prevention of the spread of the condition; delay or slowing of the progression of the condition; improvement or remission of the condition; and remission (whether partial or complete remission). The term may also mean extending survival compared to the survival expected without treatment.

[0031] MDS patients are primarily affected by cytopenia, including anemia, thrombocytopenia, neutropenia, bisystem cytopenia, pancytopenia, and their associated symptoms, such as fatigue, anemia, weakness, internal bleeding or bleeding tendencies, fever, bone pain, shortness of breath, and frequent infections.

[0032] The term "mammal" refers to humans or any mammalian animal, such as primates, domesticated animals, pets, or laboratory animals. Preferably, the mammal is human.

[0033] Mammalian subjects (e.g., humans) that can be suitably treated according to the present invention may be subjects suffering from MDS or subjects at risk of developing (increasing) MDS.

[0034] In this specification, "MDS" refers to a group of acquired hematopoietic disorders characterized by peripheral cytopenia and normoplastic or hyperplastic bone marrow. Subtypes of MDS include MDS with dysplasia of one lineage (single lineage), MDS with dysplasia of multiple lineages, MDS with ring sideroblasts (MDS-RS), MDS with a single deletion as a chromosomal abnormality, such as MDS with a single deletion of (5q), MDS with blast cell proliferation, and unclassifiable MDS.

[0035] The WHO classified various forms of MDS into different subtypes based on criteria such as the percentage of myeloblasts in the bone marrow, the presence of abnormal erythrocyte precursors (ring sideroblasts) in the bone marrow, the number of abnormal cell types known as dysplastic lineages in the bone marrow, and the genetic profile of bone marrow cells, as follows:

[0036] Cytopenia in MDS (MDS-SLD)-1 or 2 lineages with dysplasia in a single lineage; in the bone marrow, ≥10% of one cell line has dysplasia and <5% have blasts. MDS with multisystemic dysplasia (MDS-MLD)-1 to 3 systemic cytopenia, monocytes <1 × 10⁻¹⁰ 9 / L; In the bone marrow, ≥10% of cells in ≥2 hematopoietic lineages show dysplasia, ring sideroblasts <15% (or, if SF3B1 mutation is present, ring sideroblasts <5%), blasts <5%. MDS with ring sideroblasts (MDS-RS) - anemia, no blasts; in the bone marrow, ≥15% of erythrocyte precursors are ring sideroblasts, or if the SF3B1 mutation is present, ≥5% of ring sideroblasts. MDS-anemia with isolated deletion of (5q), thrombocytopenia or thrombocytopenia; in the bone marrow, one lineage of erythrocyte dysplasia, isolated deletion of (5q), and one other abnormality other than blast cells <5% ± 7 / (7q) deletion. MDS (MDS-EB)-1 to 3 lineages with increased blasts, 0 to 3 dysplastic myeloid lineages, and 5-9% blasts in the bone marrow or 2-4% blasts in the blood (MDS-EB1), or 10-19% blasts in the bone marrow or 5-19% blasts in the blood (MDS-EB2). Unclassifiable MDS - cytopenia, blasts ±1% on at least two occasions; monophyletic dysplasia or absence of dysplasia but characteristic MDS cytogenetic properties, blasts <5% in the bone marrow.

[0037] The WHO classification also includes a provisional category for childhood refractory cytopenia, characterized by <2% cytopenia and blasts in peripheral blood, and <5% dysplasia in 1-3 lineages and blasts in the bone marrow.

[0038] Additionally, according to the WHO classification, CMML (CMML-0, CMML-1, CMML-2) and MDS / MPN-RS-T are classic MDS / MPN duplication syndromes.

[0039] The classification developed by the WHO is used herein to define various subtypes of MDS, but unless otherwise specified or evident from the context, the term MDS herein is considered to include any subtype of MDS, including, for example, CMML, and any of the subtypes shown above. However, in some embodiments, MDS is more specifically MDS having monophyletic dysplasia as defined herein above. In some embodiments, MDS is more specifically MDS having polyphyletic dysplasia as defined herein above (MDS-MLD). In some embodiments, MDS is more specifically MDS with ring sideroblasts as defined herein above (MDS-RS). In some embodiments, MDS is more specifically MDS with a solitary deletion of (5q) as defined herein above. In some embodiments, MDS is more specifically MDS with blast proliferation as defined herein above (MDS-EB). In some embodiments, MDS is more specifically unclassifiable MDS as defined herein above. In some embodiments, MDS is more specifically childhood refractory cytopenia as defined above herein. In some embodiments, MDS includes CMML. In some other embodiments, MDS does not include CMML.

[0040] In addition to the above diagnostic classification system, a prognostic system called the Revised International Prognostic Scoring System (IPSS-R) has been developed. According to it, MDS can be classified as very low risk, low risk, intermediate risk, high risk or very high risk. See the guidance published by Greenberg, Tuechler, Schanz et al., Revised International Prognostic Scoring System (IPSS-R for Myelodysplastic Syndrome, Blood, 120: 2454, 2012), and Schanz J et al. (J Clin Oncology, 2012; 30:820). This system uses hemoglobin count (g / dl), absolute neutrophil count (×10 9 / L), platelets (×10 9 / L), bone marrow blasts (%), and the cytogenetic category of MDS. The cytogenetic category is defined as very good, good, intermediate, poor, or very poor based on the presence of several cytogenetic abnormalities, as shown in Table 1.

[0041]

Table 1

[0042] The cytogenetic prognostic subgroup and the respective cut-off values of the above criteria for patients (hemoglobin count (g / dl), absolute neutrophil count (ANC) (×10 9 / L), platelets (×10 9 / L), bone marrow blasts (%)) are scored as shown in Table 2.

[0043]

Table 2

[0044] The total risk score obtained is used to classify MDS into the IPSS-R prognostic risk categories as shown in Table 3.

[0045]

Table 3

[0046] Finally, based on data from over 7,000 patients, IPSS-R correlated each prognostic risk category with median survival (years) and median time to 25% AML progression, as shown in Table 4.

[0047] [Table 4]

[0048] In some embodiments, the indication for MDS includes various forms of anemia, such as refractory anemia, refractory anemia with ring sideroblasts, refractory anemia with blast cell proliferation, refractory anemia with transitional blast cell proliferation, and chronic myelomonocytic leukemia. In some embodiments, the indication for MDS excludes MDS that has developed into leukemia. In some embodiments, the patient does not have leukemia.

[0049] In some embodiments, tascinimod is for use in the treatment of MDS classified by a risk score according to the Revised International Prognostic System for Myelodysplastic Syndromes (IPSS-R) as described herein.

[0050] Unless otherwise specified herein, MDS may fall within any of the identified risk categories as determined by the use of the revised International Prognostic System for Surgical Assessment (IPSS-R) described above.

[0051] In some embodiments, the MDS belongs to a risk category defined as very low (having a risk score of 1.5 or less), low (having a risk score greater than 1.5 and 3 or less), or moderate (having a risk score greater than 3 and 4.5 or less). In some of these embodiments, the MDS belongs to a risk category defined as low or moderate, for example, moderate. In some other embodiments, the MDS belongs to a risk category defined as very low or low, for example, low. In yet another embodiment, the MDS belongs to a risk category defined as very low.

[0052] In some other embodiments, the MDS belongs to a risk category defined as moderate, high (having a risk score greater than 4.5 and less than or equal to 6), or very high (having a risk score greater than 6). In some of these embodiments, the MDS belongs to a risk category defined as moderate or high, for example, high. In some other embodiments, the MDS belongs to a risk category defined as high or very high, for example, very high.

[0053] Anemia is a significant, if not the primary, cause of pathological condition and quality of life impairment in MDS patients, particularly those with lower risk MDS (e.g., very low risk, low risk, or moderate risk MDS). Therefore, in some embodiments, tascinimod is used in the treatment of anemia in patients with lower risk MDS. In some embodiments, tascinimod is used in the treatment of anemia associated with MDS. In some embodiments, tascinimod is used in the treatment of MDS with anemia as a symptom. In some embodiments, anemia is selected from refractory anemia, refractory anemia with ring sideroblasts, refractory anemia with blast plaque, refractory anemia with transitional blast plaque, and chronic myelomonocytic leukemia. In some embodiments, the anemia is refractory anemia. In some embodiments, the anemia is refractory anemia with ring sideroblasts. In some embodiments, the anemia is refractory anemia with blast plaque. In some embodiments, the anemia is refractory anemia with blast proliferation during the transitional phase and chronic myelomonocytic leukemia.

[0054] In some embodiments, tascinimod is for use in the treatment of MDS in patients in whom at least one clinical parameter selected from hemoglobin count, absolute neutrophil count, platelet count, myeloblast (%), and cytogenetic abnormalities has been determined.

[0055] For example, in some embodiments, MDS belongs to a cytogenetic prognosis subgroup called "very good," as defined in Table 1. In some other embodiments, MDS belongs to a cytogenetic prognosis subgroup called "good," as defined in Table 1. In yet another embodiment, MDS belongs to a cytogenetic prognosis subgroup called "moderate," as defined in Table 1. In yet another embodiment, MDS belongs to a cytogenetic prognosis subgroup called "poor," as defined in Table 1. In yet another embodiment, MDS belongs to a cytogenetic prognosis subgroup called "very poor," as defined in Table 1.

[0056] In some embodiments, MDS patients have less than 2% BM blasts. In some embodiments, MDS patients have 2% or more and less than 5% BM blasts. In some embodiments, MDS patients have 5% or more and less than 10% BM blasts. In some embodiments, MDS patients have more than 10% BM blasts.

[0057] In some embodiments, MDS patients have a hemoglobin level of 10 g / dl or higher. In some embodiments, MDS patients have a hemoglobin level of 8 g / dl or higher and less than 10 g / dl. In some embodiments, MDS patients have a hemoglobin level of less than 8 g / dl.

[0058] In some embodiments, MDS patients are 100 × 10 9 Having a platelet count of 50 × 10⁶ / L or more. 9 / L or more, 100 x 10 9 Having a platelet count of less than / L. In some embodiments, MDS patients have 50 × 10 9 Having a platelet count of less than / L

[0059] In some embodiments, MDS patients are 0.8 × 10 9 They have an absolute neutrophil count of 0.8 × 10⁻¹⁶ / L or higher. In some embodiments, MDS patients have an absolute neutrophil count of 0.8 × 10⁻¹⁶ / L or higher. 9 Having an absolute neutrophil count of less than / L

[0060] In some embodiments, tascinimod is provided for use in a treatment method comprising the step of improving one or more hematological parameters in mammals suffering from or at risk of developing MDS (e.g., MDS mammal patients). Such improvements in hematological parameters may be selected from a decrease in myoblasts, an increase in hemoglobin, an increase in platelets, an increase in neutrophils, a decrease in hepcidin, a reduction in the number of red blood cell transfusion units, a reduction in transfusion frequency, and a reduction in transfusion dependence.

[0061] As described above in this specification, tascinimod, its pharmaceutically acceptable salts, its deuterated form, its crystalline salt, and pharmaceutical compositions containing the compound and its salts, as well as methods for preparing such compounds, their salts, their deuterated form, and pharmaceutical compositions containing the compound and its salts, are described in WO 99 / 55678, WO 00 / 03991, WO 03 / 106424, WO 2005 / 074899, WO 2012 / 004338 and WO 2012 / 175541 (see above), and these documents are incorporated into this application by reference as a whole by this specification.

[0062] In some embodiments, any reference to tascinimod also includes its deuterated form. As described above in this specification, the deuterated form of tascinimod and methods for preparing such forms are described in WO 2012 / 175541. Thus, in some embodiments, tascinimod has a deuterium concentration of at least 70%, more preferably at least 90%, at the carboxamide-N-methyl group.

[0063] In some embodiments, tascinimod is de-deuterated and has a deuterium content corresponding to the natural abundance of deuterium.

[0064] The present invention comprises tascinimod or a pharmaceutically acceptable salt thereof, formulated as a pharmaceutical composition, optionally together with a pharmaceutically acceptable excipient, such as a carrier, for use in the treatment of MDS.

[0065] In some embodiments, pharmaceutically acceptable salts of tascinimod are used.

[0066] The pharmaceutical composition may be suitable for enteral administration to mammals (especially humans), such as rectally or orally, or for parenteral administration, and may contain a therapeutically effective amount of tascinimod or a pharmaceutically acceptable salt thereof as the active ingredient, together with optionally pharmaceutically acceptable excipients, such as a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is defined herein and depends, for example, on the mammalian species, body weight, age, individual disease state, individual pharmacokinetic data, and mode of administration.

[0067] For enteral administration, such as oral administration, tascinimod can be formulated in a wide variety of dosage forms. The pharmaceutically acceptable carrier may be solid or liquid. Solid formulations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is generally a fine solid mixture with the fine active ingredient. In tablets, the active ingredient is generally mixed in a suitable proportion with a carrier having the required binding capacity and compressed into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting-point waxes, and cocoa butter.

[0068] Other forms suitable for oral administration include liquid preparations, such as emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions, or solid preparations intended to be converted to liquid preparations immediately before use. Emulsifiers may be prepared as solutions, for example, aqueous propylene glycol solutions, or may contain emulsifiers, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and viscosity modifiers. Aqueous suspensions may be prepared by dispersing the fine active ingredient in water with a viscous material, such as natural or synthetic rubber, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Solid preparations include solutions, suspensions, and emulsions, which may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, viscosity modifiers, solubilizers, and the like.

[0069] Exemplary compositions for rectal administration include, for example, suppositories containing suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters, or polyethylene glycol, which are solid at room temperature but liquefy and / or dissolve in the rectal lumen to release the drug.

[0070] Tascinimod may also be administered parenterally, for example by injection or infusion, such as intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intraventricular, synovial, intrasternal, intrathecal, intrafocal, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion. Therefore, for parenteral administration, the pharmaceutical composition may take the form of a sterile injection or infusion preparation, for example, as a sterile aqueous or oily suspension. This suspension may be formulated using a suitable dispersant or wetting agent (e.g., Tween® 80) and a suspending agent according to techniques known in the art. The sterile injection or infusion preparation may also be a sterile injection or infusion solution or suspension in a diluent or solvent acceptable for non-toxic parenteral administration. For example, the pharmaceutical composition may be a solution in 1,3-butanediol. Other examples of acceptable vehicles and solvents that may be employed in the compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution, and isotonic saline. Furthermore, sterile non-volatile oils are commonly used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable preparations, as are pharmaceutically acceptable natural oils such as olive oil or castor oil, particularly in their polyoxyethylated forms. These oil solutions or suspensions may also include long-chain alcohol diluents or dispersants.

[0071] The parenteral solution may also contain a suitable stabilizer and, if necessary, a buffering agent. Suitable stabilizers include antioxidants, such as sodium bisulfate, sodium sulfite, or ascorbic acid, either alone or in combination, citric acid and its salts, and sodium EDTA. The parenteral solution may also contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0072] Standard procedures for selecting and preparing suitable pharmaceutical dosage forms are described, for example, in "Pharmaceutics - The Science of Dosage Form Design," MB Aulton, Churchill Livingstone, 2nd edition, 2002 (ISBN 0443055173, 9780443055171). Methods for preparing suitable pharmaceutical excipients, such as carriers, and pharmaceutical dosage forms are also described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference in the field of pharmaceutical formulation technology.

[0073] A pharmaceutical composition (which may also be referred to herein as a pharmaceutical dosage form or drug) comprises a therapeutically effective amount of tascinimod or a pharmaceutically acceptable salt thereof, which may include, for example, about 1% to about 95%, preferably about 20% to about 90%, of tascinimod or a salt thereof together with at least one pharmaceutically acceptable excipient. Generally, tascinimod or a salt thereof is administered in a therapeutically effective amount by any of the acceptable modes of administration of the activator that serve similar utility.

[0074] For example, injection or rectal administration of tascinimod or its salts may be attempted if necessary, but oral administration is generally considered the most convenient.

[0075] The dosage level and frequency are determined by the treating physician, taking into account factors such as the patient's sex, age, weight, and relative health, the severity of MDS, the chosen route and form of administration, and the additional use of other drugs, such as in combination therapy.

[0076] Generally, a daily dose of at least 0.001 mg / kg of body weight, or 0.002 mg / kg of body weight, or 0.005 mg / kg of body weight, or 0.01 mg / kg of body weight, and up to a maximum of 0.2 mg / kg of body weight, or 0.1 mg / kg of body weight, or 0.05 mg / kg of body weight, or 0.02 mg / kg of body weight, is intended.

[0077] In one embodiment, taskinimod is administered at a dose of 0.05 to 0.15 mg / day, or 0.08 to 0.1 mg / day, for example, 0.1 mg / day.

[0078] In one embodiment, taskinimod is administered at a dose of 0.1 to 0.3 mg / day, or 0.15 to 0.25 mg / day, for example, 0.2 mg / day.

[0079] In one embodiment, taskinimod is administered in a dose of 0.1 to 1 mg / day, or 0.2 to 0.8 mg / day, for example, 0.5 mg / day.

[0080] In one embodiment, taskinimod is administered at a dose of 0.2 to 1.5 mg / day, or 0.4 to 1.2 mg / day, for example, 0.8 mg / day.

[0081] In one embodiment, taskinimod is administered at a dose of 0.5 to 2 mg / day, or 0.8 to 1.2 mg / day, for example, 1 mg / day.

[0082] In one embodiment, taskinimod is administered at a dose of 0.8 to 3 mg / day, or 1 to 2.5 mg / day, for example, 2 mg / day.

[0083] In one embodiment, taskinimod is administered in a dose of 1-6 mg / day or 2-4 mg / day, for example, 3 mg / day.

[0084] In some embodiments, the dosage may be gradually adjusted, or so-called escalation, to reach optimal results. For example, dosage escalation may include starting with a low daily dose, e.g., 0.25 mg, and maintaining this dose level for one or two weeks. If no significant side effects that may contraindicate dose increases are encountered, the level may be increased, e.g., 0.5 mg / day, for one or two weeks, after which another increase may be attempted to reach a daily dose of 1 mg, etc. In such a manner, if any significant side effects occur after the escalation of the dosage, the dosage may be reduced again to the previous level.

[0085] Possible side effects include those commonly encountered with this type of treatment, such as gastrointestinal disorders, fatigue, and flu-like syndrome, which are thought to be related to the dosage.

[0086] Tascinimod is preferably administered daily, for example, 1 to 3 times a day, or 1 to 2 times a day, for example, once a day. In some embodiments, the drug is administered less frequently, for example, every two days, once a week, etc. It should also be noted that when a pharmaceutically acceptable salt of tascinimod is administered, the equivalent dose is the dose that produces the non-salt form of the compound of the indicated dose.

[0087] In its broadest sense, the present invention relates to tascinimod or a pharmaceutically acceptable salt thereof for use in the treatment of MDS. In some embodiments, the MDS is selected from any of the subtypes described herein.

[0088] Biological assays Materials and methods patient Heparinized BM samples were obtained from untreated MDS patients (low-risk MDS, low-risk MDS with 5q deletion, high-risk MDS, and CMML) at standard diagnostic aspiration, and from hematologically healthy donors undergoing total hip replacement surgery. Samples were analyzed for S100A9 levels using the Human DuoSet ELISA kit (R&D Systems) according to the manufacturer's instructions.

[0089] cell culture BM mononuclear cells were isolated by Percoll gradient centrifugation, and MSCs were grown as adherent monolayers in DMEM / 10% FCS. Passages 2-5 were used in the experiment.

[0090] To mimic inflammatory conditions, in vitro cultured MSCs were treated with recombinant S100A8, S100A9, or S100A8 / 9 heterodimers (1.5 μg / ml each) or TNF-α (10 ng / ml) in or without tascinimod (10 μM) for different durations depending on the subsequent experiment. Hematopoietic stem cell / progenitor cells (HSPCs) for co-culture were isolated using CD34 antibody-conjugate magnetic beads according to the manufacturer's instructions (Miltenyi Biotec) and added to CellGro medium (CellGenix) containing stem cell factor (SCF), FLT3-L, and IL-3 (10 ng / ml each).

[0091] Peripheral blood mononuclear cells (PBMCs) were prepared by Ficol-HighPac density centrifugation.

[0092] Cloning assay CAF-C assays were performed over 4 weeks using pre-treated healthy or MDS MSC layers. 1000 magnetically separated CD34+ cells were added to StemMACS® HSC-CFU complete medium (Miltenyi Biotec).

[0093] 300 cells were seeded in fortified methylcellulose medium containing recombinant cytokines (MethoCult® H4435, STEMCELL Technologies), co-cultured for one week, and then harvested for a CFU assay. Colonies were counted after two weeks and classified under a microscope or using the STEMvision® system (STEMCELL Technologies).

[0094] MSC differentiation assay Adipogenesis and osteogenic differentiation are important functional characteristics of MSCs, and these often change in MDS, leading to changes in bone metabolism. Therefore, the effects of tascinimod on adipogenesis and osteogenic differentiation were assayed as follows.

[0095] MSC in a 6-well plate (5x10 3 MSCs / cm 2 Seeds were seeded in ) and cultured in DMEM for approximately 4 days until subconfluent, then subjected to either lipogenesis (0.5 mM 1-methyl-3-butylisoxanthine, 1 μM dexamethasone, 100 μM indomethacin, 10 μM insulin) or osteogenic differentiation (0.1 μM dexamethasone, 0.2 mM ascorbate-2-phosphate, 10 mM β-glycerophosphate). Lipidogenesis was evaluated by oil red O staining after 21 days. Differentiation was categorized into the following stages according to microscopic analysis: 0 = no differentiation; 1 = 25% of culture wells contain differentiated cells; 2 = 50% of culture wells contain differentiated cells; 3 = 75% of culture wells contain differentiated cells; 4 = 100% of culture wells contain differentiated cells. Osteogenesis was determined by von Kossa staining, and the catalytic activity of ALP was determined.

[0096] Detection of reactive oxygen species (ROS) levels The inflammatory microenvironment of myelodysplastic bone marrow can lead to increased ROS levels, which can result in abnormal cellular function. Therefore, the effect of tascinimod on ROS levels in MSCs is assayed using the CellROX® Deep Red Flow Cytometry Assay Kit (Thermo Fisher) according to the manufacturer's instructions.

[0097] Seahorse metabolic extracellular flux profiling The effects of tascinimod on cellular metabolism are investigated using the Seahorse system (Agilent Technologies). MSCs are seeded in Seahorse 96-well plates. Cell mitostress testing (XF Cell Mito Stress Test Kit, Agilent Technologies) is performed according to a standard protocol. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) are detected after injection of oligomycin (1 mM), carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP, 0.5 mM), and a combination of rotenone and antimycin (Rot / AA, 0.5 mM). OCR is measured using an XF96 analyzer and Wave software (version 2.2.0).

[0098] Western blot Whole-cell solubilizes were prepared using RIPA lysis buffer containing a proteinase inhibitor. Protein concentrations were determined using a BCA protein assay kit. Isoprotein amounts were separated by SDS-polyacrylamide gel electrophoresis and transferred to polyvinylidene fluoride membranes. Primary antibodies against IRAK1, NF-κB-p65, and gasdermin, along with OXPHOS, were used overnight at 4°C, followed by detection of specific proteins using secondary antibodies: HRP-conjugate goat anti-mouse IgG (Invitrogen) or donkey anti-rabbit IgG (GE Healthcare). The blots were incubated with ECL Plus Western blotting reagent (Amersham), and signals were acquired using the LAS3000 imaging system.

[0099] RT-PCR RNA was isolated from MSCs using the RNeasy Mini kit (Qiagen) and reverse transcribed into cDNA using the RevertAid® cDNA synthesis kit (Thermo Fisher) containing oligo-dT primers. Relative target levels were determined using comparative CT (ΔΔCT). RT-PCR was performed on a Taqman® Fast 3500 cycler (Applied Biosystems) using the SYBR Green / ROX PCR master mix (Thermo Fisher) and target-specific primers for caspase 1, IL1β, IL18, PD-L1, PD-1, and GAPDH as housekeeping genes. Amplification products were normalized to endogenous GAPDH control.

[0100] immunohistochemistry Bone marrow tissue from MDS patients and healthy donors was characterized by multiplex immunohistochemistry. This method determined the sequence and spatial distribution of CD271+ MSCs, CD68+ macrophages, and CD66b+ neutrophils with a single stain and analyzed using the VECTRA® imaging system.

[0101] Immunofluorescence staining and confocal laser scanning microscopy S100A9 / Tascinimod-treated MSCs were fixed with 4% paraformaldehyde. Cells were permeabilized with PBS containing 0.1% Triton™ X-100 (T-PBS), blocked with T-PBS (IF-Buffer) containing 10% FCS and 1% HSA, and incubated overnight at 4°C with antibodies against αSMA, NFκB, or PD-L1. Secondary antibodies, polyclonal sheep-anti-rabbit-Cy3 or polyclonal goat-anti-mouse-Cy2, were incubated at room temperature for 1 hour. Cell nuclei were counterstained with DAPI. Image analysis was performed using a confocal microscope (LSM800, Carl Zeiss) and ZEN software.

[0102] Isolation and characterization of extracellular vesicles (EVs) from tascinimod-treated MSCs Extracellular vesicles (EVs) play a crucial role in intercellular communication. These membrane-bound small particles carry various bioactive substances, such as small RNAs, mRNAs, and proteins. They originate from endosomal compartments or budding directly from the cell membrane. To test the effects of S100A9 and tascinimod on MSC-derived EVs, they are isolated from serum-free culture supernatant using the ExoEasy Maxi kit (Qiagen). EV concentration and size are detected by nanoparticle tracking analysis (NTA) using a ZetaView® instrument. miRNAs are isolated using the miRNeasy kit (Qiagen) and subjected to Taqman assays using specific primers, for example, miR-145 and miR-146a. The functional effects of S100A9 / tascinimod-primed MSC-derived EVs are analyzed by incubation with PBMCs or HSPCs and subsequent flow cytometry.

[0103] result Higher S100A9 levels were detected in the BM plasma of MDS patients compared to healthy controls, with the highest levels observed in low-risk MDS patients (Figure 1).

[0104] In vitro, the relevant S100A9 mRNA expression could not be detected in cultured MDS or healthy MSCs. This suggests that this cell type does not represent the main source of S100A9 in the bone marrow microenvironment. Rather, staining of BM tissue showed S100A8 and S100A9 expression mainly by CD66b+ neutrophils, with a smaller range of expression observed by CD68+ macrophages.

[0105] Treatment of MDS MSCs with S100A9 cells induced TLR4 downstream signaling, as evidenced by increased expression of IRAK1 and NF-κB-p65. Furthermore, higher expression of gasdermin was detected. Gasdermin is the inducer of pyroptosis in S100A9 treated cells. Addition of tascinimod inhibited the expression of the described proteins, indicating a reduction in induced inflammation (Figure 2).

[0106] mRNA expression of inflammatory cytokines, such as IL-1β and IL-18, and their activator caspase 1, increased MSCs after treatment with S100A9, and this increase was inhibited in the presence of tascinimod (Figure 3).

[0107] As a potential downstream target that may inhibit efficient hematopoiesis in MDS, PD-L1 is induced by S100A9 and can be suppressed by tascinimod at both the mRNA and protein levels. Basal PD-L1 expression was found to be significantly higher in CMML than in healthy MSCs (Figure 4). Surprisingly, downregulation of PD-L1 was observed in both MSCs from healthy volunteers and MSCs from CMML MDS patients, even in the absence of S100A9, when using tascinimod. This is also surprising, as it had previously been reported that tascinimod upregulates PD-L1 expression (Oncoimmunology, 2016, Vol. 5, No. 6, e1145333).

[0108] S100A9 treatment increased αSMA expression in MSCs, which is typical for MSC differentiation into myofibroblasts present in the tumor microenvironment. Simultaneously, increased nuclear expression of NF-κB was observed. Tascinimod treatment reduced both αSMA and NF-κB expression.

[0109] Adipogenesis is often pathologically increased in MDS MSCs. The addition of tascinimod reduced the number of adipocytes by 25-50% after 14 days of culture in differentiation medium, as detected by oil red O-positive cells.

[0110] Addition of TNF-α to MSC cultures increased the expression of IRAK1, NF-κB-p65, and gasdermin. Conversely, the addition of tascinimod inhibited the expression of these proteins (Figure 5). This also indicates that the effect of tascinimod in MSCs cannot be related to S100A9.

[0111] Since functional alterations of MSCs induced by inflammasome activation significantly impact MDS progression, we investigated the potential of tascinimod treatment of stromal cells to alter subsequent support for normal hematopoiesis. For this purpose, we used MSC / HSPC in vitro cocultures in which the stromal layer was pre-treated with a combination of S100A9 and tascinimod. Clearly, treatment with S100A9 reduced the number of CAF-Cs and CFUs in subsequent clonalization assays, indicating interference with hematopoietic support by MSCs. Both the number of CAF-Cs and CFUs could be increased by tascinimod (Figure 6a-c).

[0112] PD-1 (the receptor for PD-L1) expression in co-cultured HSPCs was controlled in the same way as its ligand in treated MSCs.

[0113] Based on the above findings, it appears that pathological inflammatory activation in myelodysplastic bone marrow can be rescued by tascinimod through inhibition of NF-κB-p65 signaling and PD-L1 / PD-1 expression in MSCs. These effects improve hematopoietic support by MSCs, thereby improving anemia and cytopenia in MDS patients.

[0114] Finally, results from MSC differentiation assays show that tascinimod can reduce adipogenic differentiation and improve osteogenic differentiation. Results from CellROX® Deep Red flow cytometry assays show that tascinimod can block the increase in ROS levels in MSCs. Results from Seahorse metabolic extracellular flux profiling show that the effects of tascinimod lead to reduced cellular stress and improved respiratory reserve, which is a read on cellular metabolic compatibility.

[0115] In vitro results and in vivo verification Promising in vitro results will be validated in vivo in different mouse models. These models will use genetically modified mice that develop typical symptoms of MDS, such as anemia and cytopenia (e.g., B6;129-Trp53bp1 tm1Jc Patients ( / J and NUP98 / HOXD13) were treated with taskinimod. Peripheral blood counts were recorded weekly, and bone marrow was finally analyzed after 20 weeks. These experiments demonstrate that taskinimod can partially restore functional hematopoiesis.

[0116] Furthermore, HSPCs co-cultured with pre-treated MSCs as described above will be transplanted into immunodeficient NSG mice, and the potential improved engraftment of cells derived from the tascinimod-pre-treated co-culture will be analyzed. Peripheral blood from the recipients will be obtained every 3-4 weeks by venous puncture of the posterior orbital venous plexus, stained with antibodies against human CD45 and CD34, and the amount of human cells will be analyzed by flow cytometry. A final bone marrow analysis will be performed after 20 weeks. The claims as submitted for the patent application are described below. [Claim 1] Tascinimod or a pharmaceutically acceptable salt thereof for use in the treatment of myelodysplastic syndrome (MDS) in mammalian patients. [Claim 2] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the treatment is administered orally. [Claim 3] The treatment is the administration of tascinimod or a pharmaceutically acceptable salt thereof in an amount of 0.001 mg to 0.2 mg per day at a rate of tascinimod / kg of body weight, or a corresponding amount of a pharmaceutically acceptable salt thereof, for use according to claim 1 or 2. [Claim 4] Tascinimod or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the treatment is an administration of tascinimod or a pharmaceutically acceptable salt thereof 1 to 3 times daily. [Claim 5] Tascinimod or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 4, wherein tascinimod or a pharmaceutically acceptable salt thereof is administered in a solid dosage form. [Claim 6] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 5, wherein the solid dosage form is a capsule, tablet, or pill. [Claim 7] Tascinimod or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 4, wherein Tascinimod or a pharmaceutically acceptable salt thereof is administered in the form of a solution or suspension in a liquid vehicle. [Claim 8] Tascinimod or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 7, wherein the treatment further comprises radiotherapy and / or autologous stem cell transplantation. [Claim 9] Tascinimod or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 8, wherein the MDS is selected from MDS having dysplasia in one lineage (single lineage), MDS having dysplasia in multiple lineages, MDS with ring sideroblasts (MDS-RS), MDS with a solitary deletion of (5q) or other chromosomal abnormalities, MDS with blast cell proliferation, and unclassifiable MDS. [Claim 10] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein the MDS is an MDS having dysplasia in one lineage (single lineage). [Claim 11] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein the MDS is an MDS having polysystemic dysplasia. [Claim 12] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein MDS is MDS with ring sideroblasts (MDS-RS). [Claim 13] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein the MDS is an MDS in which a single deletion constitutes a chromosomal abnormality. [Claim 14] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein the MDS is an MDS with blast cell proliferation. [Claim 15] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein the MDS is an unclassifiable type MDS. [Claim 16] Tascinimod or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 15, wherein the MDS is a very low-risk MDS, a low-risk MDS, a moderate-risk MDS, a high-risk MDS, or a very high-risk MDS. [Claim 17] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 16, wherein the MDS is a very low-risk MDS. [Claim 18] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 16, wherein the MDS is a low-risk MDS. [Claim 19] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 16, wherein the MDS is a moderate-risk MDS. [Claim 20] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 16, wherein the MDS is a high-risk MDS. [Claim 21] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 16, wherein the MDS is a very high-risk MDS. [Claim 22] Tascinimod or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein MDS comprises chronic myelomonocytic leukemia. [Claim 23] Tuscinimod or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 22, for improving one or more hematological parameters in a mammalian patient, wherein the improvement includes a decrease in myoblasts, an increase in hemoglobin, an increase in platelets, an increase in neutrophils, a decrease in hepcidin, a reduction in the number of red blood cell transfusion units, a reduction in transfusion frequency, and / or a reduction in transfusion dependence. [Claim 24] The use of tascinimod or a pharmaceutically acceptable salt thereof for the manufacture of pharmaceuticals for the treatment of myelodysplastic syndrome (MDS). [Claim 25] The use according to claim 24, wherein the pharmaceutical product is suitable for oral administration. [Claim 26] The use according to claim 24 or 25, wherein the drug is suitable for administration of tascinimod in an amount of 0.001 mg to 0.2 mg per day at a rate of tascinimod / kg of body weight, or a corresponding amount of its pharmaceutically acceptable salt. [Claim 27] The use according to any one of claims 24 to 26, wherein the pharmaceutical product is suitable for administration one to three times a day. [Claim 28] The use according to any one of claims 24 to 27, wherein the pharmaceutical product is in solid dosage form. [Claim 29] The use according to claim 28, wherein the solid dosage form is a capsule, a tablet, or a pill. [Claim 30] The use according to any one of claims 24 to 27, wherein the pharmaceutical product contains tascinimod or a pharmaceutically acceptable salt thereof dissolved or suspended in a liquid vehicle. [Claim 31] The use according to any one of claims 24 to 30, wherein MDS is selected from MDS having dysplasia in one lineage (single lineage), MDS having dysplasia in multiple lineages, MDS with ring sideroblasts (MDS-RS), MDS with a solitary deletion of (5q) or other chromosomal abnormalities, MDS with blast cell proliferation, and unclassifiable MDS. [Claim 32] The use according to any one of claims 24 to 31, wherein the MDS is a very low-risk MDS, a low-risk MDS, a moderate-risk MDS, a high-risk MDS, or a very high-risk MDS. [Claim 33] The use of MDS according to claim 24, wherein MDS includes chronic myelomonocytic leukemia. [Claim 34] The use according to any one of claims 24 to 33, wherein the drug is a drug for improving one or more hematological parameters in a mammalian patient, the improvement comprising a decrease in myoblasts, an increase in hemoglobin, an increase in platelets, an increase in neutrophils, a decrease in hepcidin, a reduction in the number of red blood cell transfusion units, a reduction in transfusion frequency, and / or a reduction in transfusion dependence. [Claim 35] A method for treating myelodysplastic syndrome (MDS) in mammals requiring treatment for MDS, the method comprising administering a therapeutically effective dose of tascinimod or a pharmaceutically acceptable salt thereof to the mammal. [Claim 36] The method according to claim 35, wherein the treatment is administered orally. [Claim 37] The method according to claim 35 or 36, wherein the treatment is the administration of tascinimod in an amount of 0.001 mg to 0.2 mg per day at a dose per kg of body weight, or a corresponding amount of its pharmaceutically acceptable salt. [Claim 38] The method according to any one of claims 35 to 37, wherein the treatment is an administration of tascinimod or a pharmaceutically acceptable salt thereof one to three times daily. [Claim 39] The method according to any one of claims 35 to 38, wherein tascinimod or a pharmaceutically acceptable salt thereof is administered in a solid dosage form. [Claim 40] The method according to claim 39, wherein the solid dosage form is a capsule, a tablet, or a pill. [Claim 41] The method according to any one of claims 35 to 38, wherein tascinimod or a pharmaceutically acceptable salt thereof is administered in the form of a solution or suspension in a liquid vehicle. [Claim 42] The method according to any one of claims 35 to 41, wherein the procedure further comprises radiotherapy and / or autologous stem cell transplantation. [Claim 43] The method according to any one of claims 35 to 42, wherein the MDS is selected from MDS having dysplasia in one lineage (single lineage), MDS having dysplasia in multiple lineages, MDS with ring sideroblasts (MDS-RS), MDS with a solitary deletion of (5q) or other chromosomal abnormalities, MDS with blast proliferation, and unclassifiable MDS. [Claim 44] The method according to any one of claims 35 to 43, wherein the MDS is a very low-risk MDS, a low-risk MDS, a moderate-risk MDS, a high-risk MDS, or a very high-risk MDS. [Claim 45] The method according to claim 35, wherein MDS includes chronic myelomonocytic leukemia. [Claim 46] A method according to any one of claims 35 to 45 for improving one or more hematological parameters in a mammalian patient, wherein the improvement includes a decrease in myoblasts, an increase in hemoglobin, an increase in platelets, an increase in neutrophils, a decrease in hepcidin, a reduction in the number of red blood cell transfusion units, a reduction in transfusion frequency, and / or a reduction in transfusion dependence.

Claims

1. A pharmaceutical composition comprising tascinimod or a pharmaceutically acceptable salt thereof for the treatment of myelodysplastic syndrome (MDS) in mammalian patients.

2. The pharmaceutical composition according to claim 1, wherein the treatment is administered orally.

3. The pharmaceutical composition according to claim 1 or 2, wherein the treatment is the administration of tascinimod in an amount of 0.001 mg to 0.2 mg per day at a rate of tascinimod / kg of body weight, or a corresponding amount of its pharmaceutically acceptable salt.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the treatment is administered once to three times a day by tascinimod or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein tascinimod or a pharmaceutically acceptable salt thereof is administered in a solid dosage form.

6. The pharmaceutical composition according to claim 5, wherein the solid dosage form is a capsule, a tablet, or a pill.

7. The pharmaceutical composition according to any one of claims 1 to 4, wherein tascinimod or a pharmaceutically acceptable salt thereof is administered in the form of a solution or suspension in a liquid vehicle.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the treatment further comprises radiotherapy and / or autologous stem cell transplantation.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the MDS is selected from MDS having dysplasia in one lineage (single lineage), MDS having dysplasia in multiple lineages, MDS with ring sideroblasts (MDS-RS), MDS with a solitary deletion of (5q) or other MDS where the solitary deletion is a chromosomal abnormality, MDS with blast cell proliferation, and unclassifiable type MDS.

10. The pharmaceutical composition according to claim 9, wherein the MDS is an MDS having dysplasia in one lineage (single lineage).

11. The pharmaceutical composition according to claim 9, wherein the MDS is an MDS having dysplasia in multiple systems.

12. The pharmaceutical composition according to claim 9, wherein the MDS is an MDS with ring sideroblasts (MDS-RS).

13. The pharmaceutical composition according to claim 9, wherein the MDS is an MDS in which a single deletion is a chromosomal abnormality.

14. The pharmaceutical composition according to claim 9, wherein the MDS is an MDS accompanied by an increase in blast cells.

15. The pharmaceutical composition according to claim 9, wherein the MDS is an unclassifiable type MDS.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the MDS is a very low-risk MDS, a low-risk MDS, a moderate-risk MDS, a high-risk MDS, or a very high-risk MDS.

17. The pharmaceutical composition according to claim 16, wherein the MDS is a very low-risk MDS.

18. The pharmaceutical composition according to claim 16, wherein the MDS is a low-risk MDS.

19. The pharmaceutical composition according to claim 16, wherein the MDS is a moderate-risk MDS.

20. The pharmaceutical composition according to claim 16, wherein the MDS is a high-risk MDS.

21. The pharmaceutical composition according to claim 16, wherein the MDS is a very high-risk MDS.

22. The pharmaceutical composition according to claim 1, wherein MDS includes chronic myelomonocytic leukemia.

23. A pharmaceutical composition according to any one of claims 1 to 22 for improving one or more hematological parameters in a mammalian patient, wherein the improvement includes a decrease in myoblasts, an increase in hemoglobin, an increase in platelets, an increase in neutrophils, a decrease in hepcidin, a reduction in the number of red blood cell transfusion units, a reduction in transfusion frequency, and / or a reduction in transfusion dependence.

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