MASITINIB FOR THE TREATMENT OF SICKLE CELL DISEASE

Abstract

A 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof, in particular masitinib or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of sickle cell disease in a patient in need thereof. Also, a 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof, in particular masitinib or a pharmaceutically acceptable salt or solvate thereof, for use in the prevention and/or treatment of acute chest syndrome (ACS) in a sickle cell disease patient in need thereof.

Claims

1.-15. (canceled)

16. A method for treating sickle cell disease (SCD) in a patient in need thereof, comprising administering to the patient a 2-aminoarylthiazole derivative of formula (II): ##STR00007## wherein: R.sub.1 is selected independently from hydrogen, halogen, (C.sub.1-C.sub.10) alkyl, (C.sub.3-C.sub.10) cycloalkyl group, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, a solubilizing group, and (C.sub.1-C.sub.10) alkyl substituted by a solubilizing group; and m is 0-5, or a pharmaceutically acceptable salt or solvate thereof.

17. The method according to claim 16, wherein the 2-aminoarylthiazole derivative of formula (II), or a pharmaceutically acceptable salt or solvate thereof, is masitinib or a pharmaceutically acceptable salt or solvate thereof.

18. The method according to claim 17, wherein the pharmaceutically acceptable salt of masitinib is masitinib mesilate.

19. The method according to claim 16, wherein the sickle cell disease is hemoglobin SS or hemoglobin Sβ.sup.0 disease.

20. The method according to claim 16, wherein the patient is a SCD patient with an increased risk of developing acute chest syndrome (ACS).

21. The method according to claim 20, wherein the SCD patient with an increased risk of developing ACS is a SCD patient with at least one of the following: asthma, pulmonary hypertension, bronchial hyperreactivity, atopy, respiratory infection, reactive airway disease, exposure to morphine, active smoking, and/or chronic passive smoking (also referred to as environmental exposure smoking).

22. The method according to claim 16, wherein the method is for the prevention and/or treatment of a sickle cell crisis (SCC), a vaso-occlusive crisis (VOC), and/or acute chest syndrome (ACS) in a SCD patient in need thereof.

23. The method according to claim 16, wherein the method is for the prevention and/or treatment of acute chest syndrome (ACS) in a SCD patient in need thereof.

24. The method according to claim 23, wherein ACS is unrelated to any other manifestation or complication of sickle cell disease.

25. The method according to claim 16, wherein the 2-aminoarylthiazole derivative of formula (II), or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

26. The method according to claim 16, wherein the 2-aminoarylthiazole derivative of formula (II), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose ranging from about 1 mg/kg/day to about 12 mg/kg/day.

27. The method according to claim 16, wherein the 2-aminoarylthiazole derivative of formula (II), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 3 mg/kg/day, 4.5 mg/kg/day, or 6 mg/kg/day.

28. The method according to claim 16, wherein the 2-aminoarylthiazole derivative of formula (II), or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of about 3.0 mg/kg/day during at least 4 weeks, then at a dose of about 4.5 mg/kg/day during at least 4 weeks, and at a dose of about 6.0 mg/kg/day thereafter, with each dose escalation being subjected to toxicity controls.

29. The method according to claim 16, wherein the 2-aminoarylthiazole derivative of formula (II), or a pharmaceutically acceptable salt or solvate thereof, is administered with at least one further pharmaceutically active agent.

30. The method according to claim 29, wherein the at least one further pharmaceutically active agent is selected from the group consisting of hydroxyurea, erythropoietin, L-glutamine, crizanlizumab, rivipansel, ticagrelor, defibrotide, SC411, and voxelotor.

31. The method according to claim 29, wherein the at least one further pharmaceutically active agent is selected from the group consisting of hydroxyurea, erythropoietin, L-glutamine, and crizanlizumab.

32. The method according to claim 29, wherein the at least one further pharmaceutically active agent is hydroxyurea or erythropoietin.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0186] FIG. 1 is a graph showing the survival over time, following injection with substance P, of wild-type (WT) mice (WT—negative control group), untreated SCD mice (SCD—positive control group), and SCD mice pre-treated with masitinib at a dose of 100 mg/kg/day via gavage for 4 days prior to injection of substance P (SCD Masitinib). Time 0 is the time of injection of substance P.

[0187] FIG. 2 is a combination of histological images showing the lung tissue of wild-type (WT) mice (negative control group), untreated SCD mice (positive control group), and SCD mice pre-treated with masitinib (100 mg/kg/day via gavage for 4 days prior to injection of substance P), following injection with substance P. The lung tissue was processed immediately after death by cervical dislocation and fixed in 10% buffered formalin. FIG. 2A shows the lung tissue of a WT mouse stained with hematoxylin and eosin. FIG. 2B shows the lung tissue of a SCD mouse stained with hematoxylin and eosin. FIG. 2C shows the lung tissue of a SCD mouse which suffered a vaso-occlusive crisis (VOC) stained with hematoxylin and eosin. FIG. 2D shows the lung tissue of a SCD mouse which was treated with masitinib (100 mg/kg/day via gavage for 4 days prior to injection of substance P) stained with hematoxylin and eosin. FIG. 2E shows the lung tissue of a WT mouse stained with an anti-FcϵRIα primary antibody and a fluorophore secondary antibody. FIG. 2F shows the lung tissue of a SCD mouse stained with an anti-FcϵRIα primary antibody and a fluorophore secondary antibody. FIG. 2G shows the lung tissue of a SCD mouse which suffered a vaso-occlusive crisis (VOC) stained with an anti-FcϵRIα primary antibody and a fluorophore secondary antibody. FIG. 2H shows the lung tissue of a SCD mouse which was treated with masitinib (100 mg/kg/day via gavage for 4 days prior to injection of substance P) stained with an anti-FccRIa primary antibody and a fluorophore secondary antibody.

EXAMPLES

[0188] The present invention is further illustrated by the following examples.

Example 1

[0189] Materials and Methods

[0190] Material

[0191] Mice

[0192] The Townes transgenic mouse model was utilized for this study (Wu L C et al., Blood 2006;108:1183-1188). A total of 18 mice were assigned to 3 treatment groups; namely: SCD (HbSS mice) treated with masitinib (SCD Masitinib—intervention group), untreated SCD mice (SCD—positive control group), and WT mice (WT—negative control group).

[0193] The HbSS-Townes mouse model was created on a mixed genetic background in which the murine adult α-globin genes were replaced with the human α-globin gene (genotype: Hba hα/hα) and the murine adult β-globin genes were replaced with human sickle βS- and fetal Aγ-globin gene fragments linked together (genotype: Hbb hAγβS/hAγβS) (Nguyen J, et al., Blood 2014;124(21):4916). HbSS-Townes mice have anemia, a shortened red blood cell half-life of 2.5 days and a severe disease phenotype. Control HbAA-Townes mice were created by replacing the murine globin genes with human α-globin gene (genotype: Hba hα/hα) and linked human βA- and fetal Aγ-globins (genotype: Hbb hAγβA/hAγβA).

[0194] Reagents

[0195] Mice were administered freshly prepared solutions of substance P (4 to 40 mg/kg) via intravenous injection.

[0196] Mice in the intervention group were administered masitinib at 100 mg/kg/day via gavage for 4 days prior to injection of substance P.

[0197] Methods

[0198] SCD Mice Model

[0199] Townes transgenic sickle mice were characterized genetically by qPCR. All mice used in the experiments were 12- to 14-week old and were pathogen free.

[0200] Immunostaining

[0201] Lung tissue was processed immediately after death by cervical dislocation and fixed in 10% buffered formalin. For analysis of the lung tissue cellular structure, samples were stained with hematoxylin and eosin. For analysis of mast cell infiltration, samples were stained with an anti-FcϵRIα primary antibody and a fluorophore secondary antibody.

[0202] Results

[0203] Vaso-occlusive crisis (VOC) occurrence and overall survival were analyzed in the mice. After injection of substance P, all mice from the untreated SCD group (positive control group) experienced VOC and 83% died in the first 3 hours. In stark contrast, SCD mice pretreated with masitinib did not present any VOC and none died (FIG. 1).

[0204] The cause of death was then analyzed. Lungs were processed immediately after death by cervical dislocation and were fixed in 10% buffered formalin. Lung tissue sections were stained with hematoxylin and eosin. For immunofluorescence, lung tissue sections were incubated with an anti-FcϵRIα primary antibody and then stained with a fluorophore secondary antibody. As shown in FIG. 2, the lung tissue of SCD mice treated with masitinib (FIGS. 2D and 2H) was infiltrated by FccRI-positive cells (i.e., mast cells) to a far lesser degree than untreated SCD mice (positive control) (FIGS. 2B-C and 2F-G), and edema was also reduced.

[0205] The limited infiltration of the lung tissue of SCD mice treated with masitinib by FccRI-positive cells and the absence or limited edema demonstrate that said SCD mice treated with masitinib did not develop ACS.

[0206] These results show that the treatment of SCD mice with masitinib results in an eradication of VOC, a complete absence of ACS and of SCD-related death, with a reduction in mast cell infiltration of the lung.

Example 2

[0207] A phase 2 clinical trial of masitinib in SCD patients is initiated, wherein masitinib or a placebo is administered orally to human SCD patients at a dose of 3 mg/kg/day, 4.5 mg/kg/day or 6 mg/kg/day.

[0208] The SCD patients to receive masitinib are SS or Sβ.sup.0 sickle cell disease patients and may be receiving treatment with hydroxyurea, erythropoietin and/or chronic transfusion.

[0209] The phase 2 clinical trial is designed as a multicenter, randomized, double-blind, placebo-controlled, 2-parallel groups clinical trial.