HK1261581B - Use of masitinib for treatment of an amyotrophic lateral sclerosis patient subpopulation - Google Patents

Description

Use of masitinib for the treatment of subpopulations of patients with amyotrophic lateral sclerosis

Technical Field

The present invention relates to a method for treating patients with non-aggressive or moderately aggressive amyotrophic lateral sclerosis (ALS), whose rate of change on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) before the start of treatment was <1.1 points per month, comprising administering a tyrosine kinase inhibitor or a mast cell inhibitor, in particular masitinib or a pharmaceutically acceptable salt or solvate thereof, optionally in combination with at least one pharmaceutically active ingredient.

Background Art

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis that reflects the degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem, and spinal cord [Wijesekera LC et al., Orphanet J Rare Dis. 2009 Feb 3;4:3].

Approximately two-thirds of patients with typical ALS have the spinal form of the disease (limb-onset) and present with symptoms associated with localized muscle weakness and wasting, where the onset of symptoms may begin distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened, atrophied limbs, affecting manual dexterity and gait. Patients with bulbar-onset ALS typically experience dysarthria and difficulty swallowing solids or liquids. Limb symptoms can occur almost simultaneously with bulbar-onset symptoms, with the vast majority of cases developing limb symptoms within 1 to 2 years. Paralysis is progressive, with death resulting from respiratory failure within 2 to 3 years in bulbar-onset cases and within 3 to 5 years in limb-onset ALS.

Most ALS cases are sporadic, but 5% to 10% are familial, with 20% involving mutations in the SOD1 gene (21q22.11), approximately 2% to 5% involving mutations in the TARDBP gene (1p36.22), which encodes TAR DNA-binding protein 43 (TDP-43), and 1% to 2% involving mutations in the VCP gene (9p13.3), which encodes valosin-containing proteins. SOD1 mutations are involved in 2% of apparently sporadic cases, and TARDBP mutations have also been identified in sporadic cases.

Although some genetic risk factors have been identified, the cause of ALS remains unclear. A recent review of the role of environmental risk factors in the development of ALS concluded that no single environmental factor is consistently associated with the risk of developing ALS. Most authors favor the hypothesis of a complex genetic-environmental interaction as the cause of motor neuron degeneration.

The precise molecular pathways that cause motor neuron degeneration in ALS are unknown, but as in other neurodegenerative diseases, it likely involves a complex interplay of multiple pathogenic cellular mechanisms, which may not be mutually exclusive. These factors include genetic factors, excitotoxicity, oxidative stress, mitochondrial dysfunction, impaired axonal transport, neurofilament aggregation, protein aggregation, inflammatory dysfunction, and contributions from non-neuronal cells.

There is increasing evidence that inflammatory dysfunction and non-neuronal cells may play a role in the pathogenesis of ALS [Wijesekera LC et al., Orphanet J Rare Dis, 2009 Feb 3;4:3]. Activation of microglia and dendritic cells is a prominent pathological phenomenon in human ALS and transgenic SOD1 mice. These activated non-neuronal cells produce inflammatory cytokines such as interleukins, COX-2, TNFα, and MCP-1, and evidence of upregulation has been found in cerebrospinal fluid or spinal cord specimens from ALS patients or in vitro models. Neuroinflammation caused by glial cell activation is now established as an important aspect of ALS pathology [Philips T et al., Lancet Neurol. 2011;10:253-263]. At specific disease stages in humans, both microglia and astrocytes are significantly activated or proliferate [Turner MR et al., Neurobiol Dis 2004;15:601-9]. There is also evidence that all components of the neurovascular unit, including the blood-brain and blood-spinal cord barriers, are impaired in patients and animal models of ALS [Garbuzova-Davis S. Amyotroph Lateral Scler, 2008 Dec;9(6):375-6].

Another non-neuronal cell of emerging significance is mast cells. It is well known that mast cells play a prominent role in all inflammatory processes by expressing receptors for molecules that are normally involved in this response. In addition, mast cells release a large number of various mediators that maintain the inflammatory network and regulate the permeability of the blood-brain barrier (BBB) [Skaper SD et al., Immunol 2014; 141: 314-327]. Importantly, mast cells and neuronal cells connect by activating microglia in response to proinflammatory cytokines released by mast cells [Skaper SD et al., Immunol 2014; 141: 314-327].

In clinical practice, it has been observed that ALS patients experience different rates of disease progression. It is hypothesized that different rates of disease progression reflect different pathogenesis of ALS, thus affecting the efficacy of treatments targeting any specific disease mechanism. In other words, the variability within the overall ALS population with respect to disease progression can be explained by different subgroups of ALS patients.

There are at least two highly distinct subgroups of ALS patients within the overall ALS population, which can be distinguished from each other by the progression of appropriate clinical markers of disease burden: "rapid progressors" (also known as "aggressive ALS") who progress at a relatively rapid rate, and "normal progressors" (also known as "non-aggressive or moderately aggressive ALS") who progress at a relatively slow rate. The former subgroup represents a more aggressive and differentiated form of the disease, with patients at higher risk of death (significantly shortened median survival) or tracheotomy [Kimura F et al., Neurology 2006; 66: 265-267]. The latter "normal progressor" subgroup represents the majority of ALS patients.

There are no available treatments to halt or reverse the progression of ALS, whether it is non-aggressive, moderately aggressive, or aggressive. In the 20 years since the registration of riluzole, the only approved medicine for ALS, there has been no improvement in the efficacy of available treatments. This is despite the fact that riluzole (100 mg) provides only a modest survival benefit, very modest functional improvement, and is an expensive medication, estimated to cost approximately $10,000 per patient per year in the United States.

A comprehensive review of riluzole for the treatment of ALS by Miller and colleagues considered evidence from four randomized clinical trials involving 1477 patients with ALS treated with riluzole [Miller RG et al. Cochrane Database Syst Rev. 2012 Mar 14;3:CD001447]. The results of this meta-analysis suggest that 100 mg of riluzole may prolong median survival in patients with ALS by 2 to 3 months compared with participants taking placebo, and that the safety of the drug is not a major concern. Data directly measuring quality of life were not available from the published trials. Furthermore, riluzole had no beneficial effects on patient function in any of the randomized trials considered individually. Only when the data were combined were small beneficial effects on bulbar and limb function, but no effect on muscle strength, observed; however, the authors caution that these functional results should be interpreted with caution.

Many symptomatic therapies do not slow disease progression but do affect quality of life and appear to be helpful to individuals in the clinical setting (Table 1 lists a variety of symptomatic therapies commonly used to treat ALS [Jenkins TM et al., Curr Opin Neurol, 2014 Oct;27(5):524-31]). However, the evidence for significant benefit is weak, and further randomized clinical trials are needed to provide a stronger evidence base. This view is reflected in the Cochrane systematic review of treatments for spasticity in ALS by Ashworth and colleagues (published in 2006 and updated in 2011) [Ashworth NL et al., Cochrane Database of Systematic Reviews, 2006, Issue 1, Number: CD004156].

Table 1: Summary of commonly used symptomatic treatments in patients with ALS [Adapted from Jenkins 2014]

In summary, due to the variability and complexity of ALS disease itself and the lack of standard and clinically meaningful effective treatments, the treatment of ALS remains a challenge for clinicians.

Furthermore, current treatments do not take into account the rate of disease progression, ie, the difference between non-aggressive or moderately aggressive ALS versus aggressive ALS.

There appear to be no known approved or investigational drugs that demonstrate a cure for ALS. Furthermore, the efficacy of known drugs is limited and decreases over time, and adverse side effects have been reported. Therefore, there is a continuing need to identify new targeted drugs with increased efficacy for the treatment of ALS, particularly the non-aggressive or moderately aggressive forms of ALS that affect the majority of ALS patients.

Summary of the Invention

Therefore, the present invention relates to a method for treating non-aggressive or moderately aggressive amyotrophic lateral sclerosis (ALS) comprising administering to a subject in need thereof a tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, optionally in combination with at least one pharmaceutically active ingredient.

The present invention also relates to a method for treating non-aggressive or moderately aggressive ALS, comprising administering to a subject in need thereof at least one tyrosine kinase inhibitor selected from c-Kit, Lyn, Fyn, PDGFR, and CSF1R, or any combination thereof, optionally in combination with at least one pharmaceutically active ingredient.

The present invention aims to solve the technical problem of providing an active ingredient for the treatment of patients suffering from non-aggressive or moderately aggressive ALS.

In one embodiment, non-aggressive or moderately aggressive ALS is defined as a progression of less than 1.1 points per month on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score before the start of treatment.

In another embodiment, non-aggressive or moderately aggressive ALS is defined as a rate of change in ALSFRS-R score of less than 1.1 points per month from the date of the first ALS-related symptom to the time of first treatment (baseline).

In one embodiment, non-aggressive ALS is defined as a progression of less than 0.8 points per month on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score before the start of treatment. In another embodiment, non-aggressive ALS is defined as a rate of change of less than 0.8 points per month on the ALSFRS-R score from the date of the first ALS-related symptom to the time of the first treatment (baseline).

In one embodiment, moderately aggressive ALS is defined as a progression of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score before the start of treatment of less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points/month). In another embodiment, moderately aggressive ALS is defined as a rate of change of the ALSFRS-R score of less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points/month) from the date of the first ALS-related symptom to the first treatment time (baseline).

Therefore, the present invention also relates to a method for treating patients with non-aggressive or moderately aggressive ALS (i.e., patients whose ALSFRS-R score progresses by less than 1.1 points per month before the start of treatment), comprising administering to a subject in need thereof a tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, optionally in combination with at least one pharmaceutically active ingredient.

The present invention relates to a method for treating a patient suffering from amyotrophic lateral sclerosis (ALS) whose ALSFRS-R score progression before the start of treatment is less than 1.1 points per month, the method comprising administering to a subject in need thereof a tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, optionally in combination with at least one pharmaceutically active ingredient.

In one embodiment, the patient's ALSFRS-R score progresses by less than 0.8 points per month before the start of treatment. In another embodiment, the patient's ALSFRS-R score progresses by less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points/month) before the start of treatment.

The present invention also relates to an inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, for treating patients with non-aggressive or moderately aggressive ALS (i.e., patients whose ALSFRS-R score progresses by less than 1.1 points per month before the start of treatment).

Therefore, the present invention relates to an inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, for treating patients with amyotrophic lateral sclerosis (ALS) whose ALSFRS-R score progression before the start of treatment is less than 1.1 points per month.

In one embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 0.8 points per month. In another embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month).

The present invention also aims to solve the technical problem of providing an active ingredient that improves the prior art methods for the treatment of non-aggressive or moderately aggressive ALS, more particularly for the treatment of ALS patients whose progression in ALSFRS-R score before the start of treatment is less than 1.1 points per month.

In one embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 0.8 points per month. In another embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month).

In one embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof is an inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of mast cell activity. In another embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of microglial activity. In another embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of mast cell activity and microglial activity.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is a mast cell inhibitor including masetinib, imatinib, sodium cromoglycate, midostaurin, BLU-285, bosutinib, ibrutinib, LAS189386, DP-2618, fostamatinib, nilotinib, dasatinib, sunitinib, axitinib, pazopanib and toceranib.

In another embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is a microglia inhibitor including masetinib, GW2580, pexidartinib, BLZ945, linifanib, OSI-930, imatinib, sunitinib, nilotinib, pazopanib, emactuzumab, FPA008, quizartinib, axitinib, motesanib, cediranib, JNJ-28312141, Ki-20227, MLN-518, sorafenib and SU-14813.

In one embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof is a 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof is masitinib or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof is masitinib mesylate.

Accordingly, the present invention relates to a method for treating non-aggressive or moderately aggressive ALS, particularly non-aggressive or moderately aggressive ALS defined as progression of the ALSFRS-R score of less than 1.1 points per month before the start of treatment, wherein the method comprises administering masitinib or a pharmaceutically acceptable salt or solvate thereof to a human patient in need thereof.

In one embodiment, the methods of the present invention are used to treat patients whose ALSFRS-R score progression is less than 0.8 points per month before the start of treatment. In another embodiment, the methods of the present invention are used to treat patients whose ALSFRS-R score progression is less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month) before the start of treatment.

In one embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof is administered in combination with at least one pharmaceutically active ingredient. The pharmaceutically active ingredient preferably has activity in treating ALS. The pharmaceutically active ingredient is preferably an anti-glutamate compound, in particular riluzole (6-(trifluoromethoxy)benzothiazol-2-amine), topiramate (2,3:4,5-bis-O-(1-methylethylidene)-β-D-pyranose sulfamate, gabapentin (2-[1-(aminomethyl)cyclohexyl]acetic acid), lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine), talampanel ((8R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-diol) [0015] Inhibitors of glutamate carboxypeptidase II. Preferably, the other active pharmaceutical ingredient is riluzole.

The present invention aims to provide an effective therapy for non-aggressive or moderately aggressive ALS at an appropriate dosage, administration route and daily intake.

In one embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, more preferably masitinib mesylate, is administered orally.

In one embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, more preferably masitinib mesylate, is administered twice a day (ie, taken twice daily).

In one embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, more preferably masitinib mesylate, is administered at a daily dose of about 1.0 to about 9.0 mg/kg (mg/kg body weight). In another embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, more preferably masitinib mesylate, is administered at a dose of 1.5 mg/kg, 3.0 mg/kg, 4.5 mg/kg, 6.0 mg/kg, or 7.5 mg/kg, more preferably 3.0 mg/kg/day, 4.5 mg/kg/day, or 6 mg/kg/day (mg/kg body weight/day).

In one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of 3.0 mg/kg/day for at least 4 weeks, followed by 4.5 mg/kg/day for at least 4 weeks, and then 6.0 mg/kg/day, with toxicity controls performed at each increasing dose.

As described above, the present invention also relates to a tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof for use in treating human patients with non-aggressive or moderately aggressive ALS, wherein the patient's ALSFRS-R score progresses by less than 1.1 points per month before the start of treatment, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof is masitinib mesylate.

In one embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 0.8 points per month. In another embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month).

In one embodiment, the tyrosine kinase inhibitor is administered in combination with the at least one pharmaceutically active ingredient in a combined preparation for simultaneous, separate or sequential use.

The present invention also relates to a tyrosine kinase inhibitor as defined in the present invention or a pharmaceutically acceptable salt or solvate thereof for use in treating non-aggressive or moderately aggressive ALS, wherein the tyrosine kinase inhibitor is preferably masitinib.

The present invention also relates to a tyrosine kinase inhibitor as defined in the present invention or a pharmaceutically acceptable salt or solvate thereof, which is used in combination with at least a pharmaceutically active ingredient for the treatment of non-aggressive or moderately aggressive ALS, wherein the tyrosine kinase inhibitor is preferably masitinib, and the pharmaceutically active ingredient is preferably an anti-glutamate compound, especially riluzole, topiramate, gabapentin, lamotrigine, talampanel, ceftriaxone, or a glutamate carboxypeptidase II inhibitor. Preferably, the other pharmaceutically active ingredient is riluzole.

The present invention also relates to a pharmaceutical composition, a medicament or a kit comprising an inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, for use in the method for treating non-aggressive or moderately aggressive ALS as defined in the present invention.

In one embodiment, the pharmaceutical composition, medicament or kit of the present invention further comprises at least one other active pharmaceutical ingredient, preferably an anti-glutamate compound, in particular riluzole, topiramate, gabapentin, lamotrigine, talampanel, ceftriaxone, or a glutamate carboxypeptidase II inhibitor. Preferably, the other active pharmaceutical ingredient is riluzole.

The present invention also relates to the use of a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament or pharmaceutical composition for the treatment of non-aggressive or moderately aggressive ALS, optionally in combination with at least one other active pharmaceutical ingredient. The tyrosine kinase inhibitor is preferably masitinib, and the other active pharmaceutical ingredient is preferably an anti-glutamate compound, in particular riluzole, topiramate, gabapentin, lamotrigine, talampanel, ceftriaxone, or a glutamate carboxypeptidase II inhibitor. Preferably, the other active pharmaceutical ingredient is riluzole, as defined herein.

The tyrosine kinase inhibitor and optionally at least one pharmaceutically active ingredient are administered in a dosage regimen comprising a therapeutically effective amount.

definition

In the present invention, the following terms have the following meanings:

As mentioned above, the expression "ALS patients whose rate of progression of ALSFRS-R score before the start of treatment is <1.1 points per month" as used in this application includes a subpopulation of patients from the entire ALS patient population.

The term "ALSFRS-R score" means the revised Amyotrophic Lateral Sclerosis Functional Rating Scale. The ALSFRS-R is a score of 0-48 that assesses disability. The ALSFRS-R consists of 12 questions, each scored on a 5-point scale, ranging from 0 = unable to complete to 4 = normal ability. The individual item scores are summed to produce a reported score of 0 = worst to 48 = best. The ALSFRS-R score is significantly correlated with quality of life as measured by the Sickness Impact Scale, which suggests that functional quality in ALS is an important determinant of quality of life [Cedarbaum JM, ALSFRS-R: A revised ALS Functional Rating Scale that includes an assessment of respiratory function, BDNF ALS Study Group (Phase III), J Neurol Sci 1999; 169: 13-21].

The term "progression of ALSFRS-R score" refers to the rate of change in the ALSFRS-R score before treatment initiation, expressed as a score per unit time (e.g., month). As the disease progresses, the ALSFRS-R score decreases, i.e., the rate of change in the ALSFRS-R score is the loss of points.

"Progression in ALSFRS-R score" (points/month) is defined as the time from the date of the first ALS-related symptom to the time of the first treatment (baseline). In other words, in one embodiment, the progression of ALSFRS-R score before the start of treatment corresponds to the rate of change in ALSFRS-R score from the date of the first ALS-related symptom to the time of the first treatment (baseline). If the ALSFRS-R score on the day of the first ALS-related symptom is unknown, an acceptable estimate will replace the upper limit of 48 (minimal disease burden).

The term "baseline" refers to the time before treatment initiation or randomization into a study.

The "progression of ALSFRS-R score" for a given ALS patient was calculated using the following formula: {(ALSFRS-R score on the day of the first ALS-related symptom) - (ALSFRS-R score at baseline)} divided by {(time between the first ALS-related symptom and baseline)}. If the ALSFRS-R score on the day of the first ALS-related symptom was unknown, an acceptable estimate was substituted for the upper limit of 48 (minimal disease burden).

The term "normal progressor" or "non-aggressive or moderately aggressive ALS" refers to a patient whose ALSFRS-R score progressed by less than 1.1 points per month before treatment initiation. Thus, a "normal progressor" or a patient with non-aggressive or moderately aggressive ALS has an ALSFRS-R score that decreases by less than 1.1 points per month. Among "normal progressors" or patients with non-aggressive or moderately aggressive ALS, a further distinction can be made:

- Patients with non-aggressive ALS who have an ALSFRS-R score decrease of less than 0.8 points per month (<0.8 points per month), and

- Patients with moderately aggressive ALS whose ALSFRS-R score decreases by less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month).

Both non-aggressive ALS patients and moderately aggressive ALS patients are ALS patients whose ALSFRS-R score progression rate is <1.1 points per month before treatment initiation. In other words, ALS patients whose ALSFRS-R score progression rate is <1.1 points per month before treatment initiation include both non-aggressive ALS patients and moderately aggressive ALS patients.

The term "non-aggressive ALS" refers to patients whose ALSFRS-R score progresses by less than 0.8 points per month before treatment initiation. Thus, a patient with non-aggressive ALS has an ALSFRS-R score that decreases by less than 0.8 points per month.

The term "moderately aggressive ALS" refers to a patient whose ALSFRS-R score progression before treatment initiation is less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month). Thus, a patient with moderately aggressive ALS has an ALSFRS-R score that decreases by less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points/month).

The term "rapid progressor" or "aggressive ALS" refers to a patient whose ALSFRS-R score progressed by 1.1 points or more per month before treatment was started. Thus, a "rapid progressor" or aggressive ALS patient has an ALSFRS-R score that decreases by 1.1 points or more per month.

The term "ALS patients whose ALSFRS-R progression is <1.1 points per month before treatment initiation" can be used interchangeably with the expression "ALS patients whose ALSFRS-R progression rate is <1.1 points per month before treatment initiation."

The term "FVC" stands for forced vital capacity. FVC (percent of predicted normal) is the vital capacity (VC) measured when a patient exhales at maximum speed and effort. VC can be measured using a conventional spirometer that has been calibrated before the test.

The term "CAFS" stands for Combined Assessment of Function and Survival (Berry JD et al. The Combined Assessment of Function and Survival (CAFS): a new endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener 2013 Apr;14(3):162-8).

The term “overall survival” is defined as the time from randomization of a clinical trial to the time of documented death.

The term “tracheotomy-free survival” was defined as the time from randomization of the clinical trial to the date of documented death or first tracheotomy.

The term "subject" refers to a mammal, preferably a human. In one embodiment, the subject can be a "patient," i.e., a warm-blooded animal, more preferably a human, who is awaiting or receiving medical care, or who was/is/will be the subject of a medical procedure, or who is being monitored for the development of ALS.

The term "treatment" refers to both therapeutic treatment and preventative measures; wherein the object is to prevent or slow (mitigate) non-aggressive or moderately aggressive ALS. Subjects in need of treatment include those already suffering from non-aggressive or moderately aggressive ALS, as well as those who are predisposed to developing non-aggressive or moderately aggressive ALS, or those who need prevention of non-aggressive or moderately aggressive ALS. A subject's non-aggressive or moderately aggressive ALS is successfully "treated" if, after receiving a therapeutic amount of a tyrosine kinase inhibitor according to the methods of the present invention, the subject shows, to some extent, observable and/or measurable relief of one or more symptoms associated with non-aggressive or moderately aggressive ALS, reduced morbidity and mortality, and improved quality of life issues. The above parameters for assessing successful treatment and disease improvement can be readily measured by routine procedures with which physicians are familiar.

The term "masitinib" also refers to acceptable salts or solvates thereof, in particular masitinib mesylate, even if not expressly stated.

The term "as defined according to the present invention" refers to any embodiment or aspect of the present invention, alone or in combination, without limitation, including any preferred embodiments and variations, including any embodiments and features involving tyrosine kinase inhibitors, preferably masitinib, methods of treating non-aggressive or moderately aggressive ALS, pharmaceutical compositions, and any combination with other pharmaceutically active ingredients, preferably riluzole.

The term "therapeutically effective amount" refers to a level or amount of an agent of interest that does not produce significant negative or adverse side effects on the target site and that: (1) delays or prevents the onset of non-aggressive or moderately aggressive ALS; (2) slows or stops the progression, exacerbation, or worsening of one or more symptoms of non-aggressive or moderately aggressive ALS; (3) ameliorates the symptoms of ALS; (4) reduces the severity or incidence of non-aggressive or moderately aggressive ALS; or (5) cures non-aggressive or moderately aggressive ALS. A therapeutically effective amount can be administered before the onset of non-aggressive or moderately aggressive ALS for a preventive effect. Alternatively, or in addition, a therapeutically effective amount can be administered after the onset of non-aggressive or moderately aggressive ALS for a therapeutic effect or maintenance of a therapeutic effect.

The term "pharmaceutically acceptable carrier or excipient" refers to an excipient or carrier that does not produce side effects, allergic reactions or other adverse reactions when administered to animals, preferably humans. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. For human administration, the injectable formulation should meet the sterility, pyrogenicity, general safety and purity standards required by regulatory agencies (such as FDA Office or EMA).

The term "solvate" as used herein describes a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules.

The term "about" preceding a number means ±10% of the stated number.

As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic group containing carbon atoms and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Aryl groups can be unsubstituted or substituted with one or more substituents. In one embodiment, an aryl group is a monocyclic ring wherein the ring contains 6 carbon atoms, referred to herein as a "(C ₆ )aryl group."

As used herein, the term "alkyl" refers to a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms. Representative saturated straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; while saturated branched-chain alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethyl Alkyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, etc. The alkyl groups included in the compounds of the present invention may be optionally substituted with one or more substituents.

As used herein, the term "alkoxy" refers to an alkyl group connected to another moiety through an oxygen atom. Examples of alkoxy groups include methoxy, isopropoxy, ethoxy, tert-butoxy, and the like. An alkoxy group may be optionally substituted with one or more substituents.

As used herein, the term "heteroaryl" or similar terms refers to a monocyclic or polycyclic aromatic heterocycle comprising carbon atom ring members or one or more heteroatom ring members (e.g., oxygen, sulfur, or nitrogen). Typically, heteroaryl has 1 to about 5 heteroatom ring members and 1 to about 14 carbon atom ring members. Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl, furyl, benzo [1,3] dioxol, benzo [1,4] dioxin, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolyl, indazolyl, benzo Oxazolyl, benzofuranyl, indolizinyl, imidazopyridinyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridinyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridinyl and benzo(b)thienyl. The heteroatoms may be substituted with protecting groups known to those of ordinary skill in the art, for example, the hydrogen on nitrogen may be substituted with tert-butyloxycarbonyl. The heteroaryl group may optionally be substituted with one or more substituents. In addition, the nitrogen or sulfur heteroatom ring members may be oxidized. In one embodiment, the aromatic heterocycle is selected from a 5-8 membered monocyclic heteroaryl ring. The connection site of the aromatic heterocycle or heteroaromatic ring to the other group may be a carbon atom or heteroatom of the aromatic heterocycle or heteroaromatic ring.

As used herein, the term "heterocycle" refers collectively to heterocycloalkyl and heteroaryl groups.

As used herein, the term "heterocycloalkyl" refers to a monocyclic or polycyclic group having 2 to 11 carbon atoms and at least one heteroatom selected from O, N, and S, which may be saturated or unsaturated but is not aromatic. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, ethylene oxide, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiopyranyl sulfone, tetrahydrothiopyranyl sulfoxide, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, tetrahydrofuranyl, dihydrofuranyl-2-one, tetrahydrothiophenyl, and tetrahydro-1,1-dioxothiphenyl. Typically, monocyclic heterocycloalkyl groups are 3 to 7 members. Preferred 3 to 7 membered monocyclic heterocycloalkyl groups are those with 5 or 6 ring atoms. Heteroatoms can be substituted with protecting groups known to those skilled in the art, for example, the hydrogen on the nitrogen can be substituted with tert-butyloxycarbonyl. In addition, heterocycloalkyl groups can optionally be substituted with one or more substituents. Additionally, the point of attachment of the heterocycle to the other group can be a carbon atom or a heteroatom of the heterocycle. Only stable isomers of such substituted heterocyclic groups are considered in this definition.

As used herein, the term "substituent" or "substituted" refers to a hydrogen radical on a compound or group that is replaced with any desired group that is substantially stable to the reaction conditions in its unprotected form or when protected with a protecting group. Examples of preferred substituents are those that appear in the exemplary compounds and embodiments disclosed herein, as well as halogen (chlorine, iodine, bromine or fluorine); alkyl; alkenyl; alkynyl; hydroxyl; alkoxy; nitro; mercapto; thioether; imine; cyano; amino; phosphonic acid; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl, which can be a monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocycloalkyl, which can be a monocyclic or non-fused polycyclic. cyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl); amino (primary, secondary or tertiary); _CO2CH3 ; _CONH2 ; _OCH2CONH2 ; _NH2 ; _SO2NH2 ; _OCHF2 ; _{CF3 ; OCF3} ; these moieties may also be optionally substituted _with fused _ring structures or bridges, such as _-OCH2O- . These substituents may be optionally further substituted with substituents selected from these groups. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a group selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, -C(O) _NR11R12 , _-NR13C (O) _R14 , halogen, _-OR13 , cyano, nitro, _haloalkoxy , -C(O) _{R13 , -NR11R12, -SR13, -C(O)OR13, -OC(O)R13, -NR13C(O)NR11R12, -OC(O)NR11R12 , -NR13C ( O ) OR14 , -S ( O ) rR13 , -NR13S} (O) _{rR14 , -OS} (O) _rR14 wherein _{R 11 and} R 12 are independently _H , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; or R ₁₁ and R ₁₂ , together with the nitrogen to which they are attached, are optionally substituted heterocycloalkyl or optionally substituted heteroaryl; R ₁₃ and R ₁₄ are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl _{; Each} occurrence of R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a solubilizing group.

The term "solubilizing group" refers to any group that can substantially ionize and dissolve a compound in a desired solvent, such as water or an aqueous solvent. Additionally, a solubilizing group can be a group that increases the lipophilicity of the compound or complex. Typically, the solubilizing group is selected from an alkyl group substituted with one or more heteroatoms such as N, O, S, each of which is optionally substituted with an alkyl group that is independently substituted with an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a cyano group, or a cycloheteroalkyl group or a heteroaryl group, or a phosphate group, or a sulfate group, or a carboxylic acid group. For example, a "solubilizing group" in this article refers to one of the following:

- an alkyl, cycloalkyl, aryl, or heteroaryl group containing at least one nitrogen or oxygen heteroatom or substituted or substituted with at least one amino group;

- amino group, which may be a saturated cyclic amino group which may be substituted by a group selected from an alkyl group, an alkoxycarbonyl group, a halogen, a haloalkyl group, a hydroxyalkyl group, an amino group, a monoalkylamino group, a dialkylamino group, a carbamoyl group, a monoalkylcarbamoyl group and a dialkylcarbamoyl group;

- one of the structures a) to i) shown below, wherein the wavy lines and arrow lines correspond to the points of attachment of the core structure of formula [A].

The term "cycloalkyl" refers to a saturated cyclic alkyl group having 3 to 10 carbon atoms. Representative cycloalkyl groups include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. A cycloalkyl group may be optionally substituted with one or more substituents.

The term "halogen" refers to -F, -Cl, -Br or -I.

DETAILED DESCRIPTION

Thus, the present invention relates to a method for treating non-aggressive or moderately aggressive amyotrophic lateral sclerosis (ALS) in a subject, preferably a human patient, comprising administering to the subject or patient in need thereof a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof. Preferably, a therapeutically effective amount of a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject.

In one embodiment, non-aggressive or moderately aggressive ALS is diagnosed in a patient by calculating the ALSFRS-R score for the patient. The "progression of ALSFRS-R score" for a given ALS patient is calculated using the following formula: {(ALSFRS-R score on the day of the first ALS-related symptom) - (ALSFRS-R score at baseline)} divided by {(time between the first ALS-related symptom and baseline)}. If the ALSFRS-R score on the day of the first ALS-related symptom is unknown, an acceptable estimate will replace the upper limit of 48 (minimal disease burden).

Thus, in one embodiment, the progression of the ALSFRS-R score before the start of treatment corresponds to the rate of change in the ALSFRS-R score from the date of the first ALS-related symptom to the time of the first treatment (baseline).

Patients whose ALSFRS-R score progressed by less than 1.1 points per month before treatment initiation had non-aggressive or moderately aggressive ALS and were defined as "normal progressors." Thus, "normal progressors," i.e., patients whose ALSFRS-R score progressed by less than 1.1 points per month (<1.1 points per month) before treatment initiation, included:

- Patients with non-aggressive ALS whose ALSFRS-R score decreased by less than 0.8 points per month (<0.8 points per month) before treatment initiation, and

- Patients with moderately aggressive ALS whose ALSFRS-R score decreased by less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 points to <1.1 points per month) before the start of treatment.

Thus, in one embodiment, non-aggressive or moderately aggressive ALS is defined as an ALSFRS-R score of less than 1.1 points per month before the start of treatment. In another embodiment, non-aggressive or moderately aggressive (ALS) is defined as a rate of change in ALSFRS-R score of less than 1.1 points per month from the date of the first ALS-related symptom to the first treatment time (baseline).

In one embodiment, non-aggressive ALS is defined as a progression of less than 0.8 points per month in ALSFRS-R score before the start of treatment. In another embodiment, non-aggressive ALS is defined as a rate of change of less than 0.8 points per month in ALSFRS-R score from the date of the first ALS-related symptom to the time of first treatment (baseline).

In one embodiment, moderately aggressive ALS is defined as a progression of the ALSFRS-R score of less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points/month) before the start of treatment. In another embodiment, moderately aggressive ALS is defined as a rate of change of the ALSFRS-R score from the date of the first ALS-related symptom to the time of first treatment (baseline) of less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month).

If the ALSFRS-R score on the date of the first ALS-related symptom was unknown, an acceptable estimate was substituted for the upper limit of 48 (minimal disease burden).

The ALSFRS-R is a scale of 0 to 48 that assesses disability. The ALSFRS-R consists of 12 questions, each scored on a 5-point scale, ranging from 0 = unable to complete to 4 = normal ability. The individual item scores are summed to produce a reported score of 0 = worst to 48 = best. ALSFRS-R scores are significantly correlated with quality of life as measured by the Sickness Impact Scale, indicating that functional quality is an important determinant of quality of life in ALS [Cedarbaum JM, J Neurol Sci 1999;169:13-21].

The ALSFRS-R is a rapidly administered (5-minute) ordinal rating scale (rating 0-4) that is used to determine a subject's assessment of ability and independence in 12 functional activities/problems. All 12 activities are relevant to ALS. Initial validity was established by documenting changes in ALSFRS-R scores over time in patients with ALS, which were associated with changes in strength, and correlated well with quality of life measures and predicted survival [Traynor B et al., Neurology, 2004. 63: 1933-35]. The test-retest reliability for all test items was greater than 0.88. The advantages of the ALSFRS-R are that the categories are relevant to ALS, the instrument is a sensitive and reliable tool for assessing functional activities of daily living in patients with ALS, and it can be performed more quickly. With appropriate training, the ALSFRS-R can be performed with high inter-rater reliability and test/retest reliability.

The 12 ALSFRS-R questions and their rating scales are described below:

ALSFRS-R instrument

1. Language

The subject was asked if he/she had noticed any changes in speech. The subject compared his/her current function with that before any symptoms of ALS.

4Normal speech process

Speech as before the onset of illness; 4 if the subject records completely normal speech

3. Noticeable speech disturbances

Some noticeable changes in speech

2. Understandable in case of repetition

Needs some repetition to understand speech

1. Combining verbal and non-verbal communication

Communication requires a combination of speech and gestures, including hand gestures or nodding, or communication aids, including low-tech and high-tech devices

0 Lost useful words

Verbal communication with the subject is impossible

2. Drooling

Regardless of whether the subject is currently taking medication for sialorrhea, the current status of sialorrhea was assessed compared to the pre-ALS onset period. Current status included all medications or therapies used.

4Normal

3. Slight but definite excess saliva in the mouth; may have nocturnal drooling

2 Moderate hypersalivation; minimal drooling may occur

1. Significant excess saliva with some drooling

0 Significant salivation

Constantly needing tissues or handkerchiefs

3. Swallowing

4Normal eating habits

Have no difficulty swallowing and can eat any food or liquid of their choice

3 Early feeding problems - occasional choking

Ask if the subject avoids any food because it gets stuck in his/her throat; can still eat all selected foods but occasionally chokes

2. Changes in diet consistency

Avoiding certain foods or requesting a change in food consistency

1. Need to supplement tube feeding diet

0 NPO

Parenteral or enteral feeding only

4. Writing

The question asks about writing with the dominant hand before the onset of ALS without any assistive devices (such as the use of a foam tube and/or mechanical assistive device due to hand or finger weakness).

4Normal

3 Slow or Scrawl: All text is legible

2Not all text is legible

1No text is clearly visible, but the pen can still be held

0Unable to hold a pen

5a. Cutting food and handling utensils

In patients without gastrostomy

NOTE: If >50% of nutrition is via g-tube, use 5b

If the subject chooses not to cut food or feed themselves for any reason, he/she will be scored as unable to cut food or feed themselves. Unable to cut food or feed themselves is scored as 0.

4Normal

No difficulty cutting or handling utensils as before the onset of illness

3 is a bit slow and clunky, but doesn't need help

Some difficulty cutting or manipulating utensils as before the onset of illness, but the subject continues to do so independently.

2 Can cut most foods (>50%), though slowly and clumsily; needs some help

Some difficulty cutting food or handling utensils using pre-onset methods; subject requires assistance but still attempts to cut some food, successfully completing >50% of tasks

1. The food must be cut by someone else, but can still be eaten slowly

People are unable to cut food using methods they used before the onset of the disorder but still try to feed themselves and are at least occasionally successful

0 Needs to be fed

5b. Cutting food and handling utensils

In patients with gastrostomy

NOTE: If the subject has a gastrostomy and only if it is the primary method of feeding, use option 5b. If the subject has an active gastrostomy but consumes most nutrients orally (more than 50%), use option 5a until option 5b is appropriate. The answer to question 5b addresses tube feeding procedures and procedures.

4Normal

3 Clumsy, but able to perform all operations independently

2 Closure and fastening need some help

1Provide minimal assistance to caregivers

0 Unable to perform any work

6. Clothing and Hygiene

If the subject chooses not to dress or bathe themselves for any reason, they are scored as unable to dress or bathe themselves. Unable to dress or bathe themselves is scored as 0.

4Normal function

The patient has no difficulty and remains completely independent in dressing and maintaining hygiene using the same methods as before the onset of the disease

3. Independent; can complete self-care with effort or reduced efficiency

The patient remains completely independent in dressing but requires more effort to do so; there are no alternative methods for dressing

2Intermittent auxiliary or alternative methods

Patients occasionally require assistance or use assistive devices or alternative methods (eg, pull-on garments, Velcro closures or shoes, pre-buttoned shirts, dressing while lying down, use of shower chairs or benches) for dressing and hygiene. The methods used now differ from those used before the onset of the disease.

1. Self-care requires a caregiver

The subject needs daily assistance from a caregiver to dress, but has a certain degree of function

0 Fully dependent

7. Turning over in bed and adjusting bedding

If the subject chooses not to turn over in bed or adjust bedding for any reason, he or she is scored as unable to turn over in bed or adjust bedding. Being able to perform two activities, turning over and adjusting bedding, is scored as a 3 or 4. Performing one activity is scored as a 2.

4Normal function

3 is a bit slow and clunky, but doesn't need help

Patients can use bed rails, headboards, or motorized beds.

2 Can turn over on his own and adjust the sheets, but it is difficult

The patient can turn over or adjust bed linens independently but has difficulty completing tasks; assistance is not required.

Patients can use bed rails, headboards, or motorized beds.

1 Can start, but cannot turn over or adjust the sheets on their own

0Incompetence

8. Walking

The definition of walking is as defined by the subject.

4Normal

3. Early difficulty walking

Notices some difficulty but walks without assistance

2 Help walking

Includes AFO, cane, walker, or caregiver

1 Functional movements other than walking only

Patients are able to partially move their lower extremities for functional movement; they are able to stand and bear shifted weight but are unable to walk.

0Unintentional leg movements

9. Climb stairs

If the subject chose not to climb the stairs for whatever reason, he/she was scored as “0-unable to do so.”

4Normal

3. Slow

2. Mild instability or fatigue

The patient needs to rest between steps or feels unsteady but does not need a handrail

1 Need assistance

Patient requires assistance, including handrails or a caregiver; requires assistance to ensure stability and safety 0 Unable to do so

ALSFRS-R respiratory system subscale

10. Difficulty breathing

4 No

3 Occurs while walking

2 Occurs when one or more of the following occurs: eating, bathing, dressing

1 Occurs while resting: difficulty breathing when sitting or lying down

0 Significant difficulty: Consider using mechanical respiratory support

11. Orthopnea

If a nighttime BiPAP is used and the subject is unable to sleep without the device, score 0. If the subject uses a BiPAP but sometimes sleeps without it (able to sleep without it), select the number that best describes the subject's orthopnea while sleeping without the device.

4 No

3. Difficulty sleeping at night due to shortness of breath and usually not using more than two pillows

2. Need extra pillows to sleep (more than two)

1. Can only sleep sitting up

0Unable to sleep without mechanical assistance

12. Respiratory insufficiency

4 No

3. Intermittent use of BiPAP

2. Continuous use of BiPAP at night

1. Use BiPAP continuously throughout the day and night

0Invasive mechanical ventilation via intubation or tracheostomy

Thus, within the overall ALS population, there are at least two highly distinct subgroups of ALS patients that can be distinguished from each other in terms of "rapid progressors" (also called "aggressive ALS"), whose ALSFRS-R score progresses by 1.1 points or more per month before treatment initiation, and "normal progressors" (also called "non-aggressive or moderately aggressive ALS"), whose ALSFRS-R score progresses by less than 1.1 points per month before treatment initiation. The former subgroup represents a more aggressive and differentiated form of the disease, with patients at higher risk of death (with a significantly shorter median survival time) or tracheostomy [Kimura F et al., Neurology 2006; 66: 265-267]. Among "normal progressors," or patients with non-aggressive or moderately aggressive ALS, further distinctions can be made:

- Patients with non-aggressive ALS who have a decrease in ALSFRS-R score of less than 0.8 points per month (<0.8 points/month),

- Patients with moderately aggressive ALS who have a decrease in ALSFRS-R score of less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points/month).

Tyrosine kinases are receptor- or non-receptor-type proteins that transfer the terminal phosphate of ATP to tyrosine residues in proteins, thereby activating or inactivating signal transduction pathways. These proteins are known to be involved in many cellular mechanisms, which, when disrupted, can lead to diseases such as abnormal cell proliferation and migration, as well as inflammation. Therefore, within the meaning of the present invention, "tyrosine kinase inhibitors" are drugs that inhibit tyrosine kinases, thereby interfering with the signaling processes within cells. Blocking these processes can prevent cell growth and division.

In one embodiment, the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, used in the method of treating non-aggressive or moderately aggressive ALS in a subject of the invention is an inhibitor of the kinase activity of wild-type c-Kit, Lyn, Fyn, PDGFR, and CSF1R, or any combination thereof. In another embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, inhibits wild-type c-Kit, Lyn, Fyn, PDGFR, and/or CSF1R without inhibiting kinases associated with known toxicity (i.e., those tyrosine kinases or tyrosine kinase receptors that contribute to potential tyrosine kinase inhibitor cardiotoxicity, including ABL, KDR, and Src) at therapeutic doses [Dubreuil et al., 2009, PLoS ONE 2009. 4(9):e7258] [Davis et al., Nat Biotechnol 2011, 29(11):1046-51].

In one embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof used in the methods of the present invention is thus capable of inducing cell cycle arrest and apoptosis in cell lines that are dependent on c-Kit signaling [Dubreuil et al., 2009, PLoS ONE, 4(9): e7258]. Stem cell factor is a ligand for the c-Kit receptor, a key growth factor for mast cells; therefore, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof used in the methods of the present invention is a potent anti-mastocyte substance that exerts direct anti-proliferative and pro-apoptotic effects on mast cells by inhibiting c-Kit signaling. Similarly, Lyn and Fyn kinases are known to act on key components of the transduction pathway that leads to IgE-induced mast cell degranulation; therefore, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof used in the methods of the present invention also modulates mast cell activation by targeting Lyn and Fyn.

Mast cells themselves play an important role in maintaining the inflammatory network in the central nervous system, and mast cell-microglia crosstalk further promotes the continuation of the inflammatory response.

Mast cells are characterized by their heterogeneity, not only in terms of tissue location and structure, but also in terms of function and histochemistry. Upon activation, mast cells release a variety of mediators that are essential for the defense of the organism against invading pathogens. Mast cells produce a large number of mediators, which are divided into three groups:

- Preformed granule-associated mediators (histamine, proteoglycans, and neutral proteases);

- lipid-derived mediators (prostaglandins, thromboxanes, and leukotrienes);

- Various cytokines (including interleukins: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and tumor necrosis factor α TNF-α, GM-CSF, MIP-1α, MIP-1β and IFN-γ).

Human mast cells structurally express the receptors of many different biomolecules. Among these receptors, receptor connection induces mast cell activation, the most widely known is the IgE receptor (FcεRI) of high affinity. The combination of IgE-multivalent antigen complex and FcεRI causes receptor aggregation and internalization, signal transduction and degranulation. This may be accompanied by the transcription of cytokine genes, so that inflammatory response persists. In addition, triggering mast cells causes secretion of various preformed and/or de novo synthesized mediators, such as vasoactive amines (histamine, serotonin), sulfated proteoglycans, lipid mediators (prostaglandin D2, leukotrienes), growth factors, proteases, cytokines and chemokines, which are as previously described. These mediators can be individually, or synergistic with macrophage-derived cytokines and T cell-derived cytokines, produce complex inflammatory response and induce inflammatory cells to replenish and activate to the site of degranulation.

Mast cells are present on both sides of the BBB and also have the ability to rapidly cross the BBB, thereby increasing their number in response to physiological stimuli [Nautiyal K et al., Proc Natl Acad Sci USA, 2008 Nov; 18: 105(46): 18053-18057] [Theoharides TC et al., J Neuroimmunol. 2004 Jan; 146(1-2): 1-12] [Silverman AJ et al., J Neurosci 2000, 20: 401-408]. The release of these proinflammatory mediators into the central nervous system can alter the function of both neural and vascular elements [Skaper SD et al., Immunol 2014; 141: 314-327]. Stem cell factor is a ligand for the c-Kit receptor and is a key growth factor for mast cells. Similarly, Lyn and Fyn kinases are known to act on key components of the transduction pathway leading to IgE-induced mast cell degranulation; therefore, c-Kit, Lyn, and Fyn are targets for modulating mast cell activity.

Thus, in one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of mast cell activity.

In one embodiment, the mast cell activity inhibitor is imatinib (STI571, Novartis), more preferably imatinib mesylate. Therefore, in a specific embodiment, the present invention relates to a method for treating non-aggressive or moderately aggressive ALS in a mammal, especially a human patient, comprising administering an effective amount of a compound known in the art, such as imatinib. (STI571, CGP57148B): 4-[(4-methyl-1-piperazinyl)methyl]-N-(4-methyl-3-{[4-(3-pyridinyl)-2-pyrimidinyl]amino}phenyl)benzamide. The preparation of this compound is described in Example 21 of EP564409, and a particularly useful form is described in WO 99/03854.

In another embodiment, the mast cell activity inhibitor can be selected from the group consisting of midostaurin (PKC412; Novartis), dasatinib (BMS354825; Bristol-Myers Squibb), sunitinib (SU11248; Pfizer), nilotinib (AMN107; Novartis), axitinib (AG013736; Pfizer), pazopanib (GlaxoSmithKline), tocitanib (SU11654; Pfizer), BLU-285 (Blueprint Medicines), bosutinib (SKI-606; Pfizer), ibrutinib (PCI-32765; Pharmacyclics), LAS189386 (Almirall R&D Center), DP-2618 (Deciphera Pharmaceuticals), formamyl (R788; Rigel), and sodium cromolyn.

In another embodiment, the mast cell activity inhibitor may be selected from the group consisting of: masitinib, imatinib, sodium cromoglycate, midostaurin, BLU-285, bosutinib, ibrutinib, LAS189386, DP-2618, formamex, nilotinib, dasatinib, sunitinib, axitinib, pazopanib, and tocinib.

CSF-1, which is derived from neurons via CSF-1R, has been suggested as a mechanism for triggering microglial proliferation in the spinal cord. It has been observed that damaged motor neurons induce the expansion of spinal microglia by expressing CSF-1 [Guan Z et al. (2016) Nature Neuroscience 19(1): 94-101]; therefore, CSF-1R is a target for regulating microglial activity. In addition, microglia respond to proinflammatory signals released from non-neuronal cells (mainly immunogenic cells, such as mast cells). There is evidence that there is extensive communication between the immune system and the central nervous system, and proinflammatory cytokines play a key role in this communication [Skaper SD et al., Immunol 2014; 141: 314-327]. Therefore, this mast cell-microglia crosstalk further exacerbates and prolongs the effects of chronic neuroinflammation.

The tyrosine kinase inhibitors used in the methods of the present invention, or pharmaceutically acceptable salts or solvates thereof, also regulate microglial activation by targeting CSF-1R.

Thus, in one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of microglial activity.

In one embodiment, the microglial activity inhibitor can be selected from the group consisting of: GW2580 (GlaxoSmithKline), paxidartinib (PLX3397; Plexxikon), BLZ945 (Novartis), linifanib (ABT-869; Abbott), OSI-930 (OSI Pharmaceuticals Inc), imatinib (STI571, Novartis), sunitinib (SU11248; Pfizer), nilotinib (AMN107; Novartis), pazopanib (GlaxoSmithKline), imatinib (RG7155; Roche), FPA008 (Five Prime Therapeutics, Inc), quizartinib (AC220; Daiichi Sankyo), axitinib (AG-013736; Pfizer), motesanib (AMG-706; Takeda), cediranib (AZD-2171; AstraZeneca), JNJ-28312141 (Johnson & Johnson), Ki-20227 (Kirin Pharma Company Limited), MLN-518 (Millennium), sorafenib (Bayer), and SU-14813 (Pfizer).

In another embodiment, the microglial activity inhibitor can be selected from the group consisting of: masitinib, GW2580, pasidatinib, BLZ945, linifanib, OSI-930, imatinib, sunitinib, nilotinib, pazopanib, imatuzumab, FPA008, quizartinib, axitinib, motesanib, cediranib, JNJ-28312141, Ki-20227, MLN-518, sorafenib and SU-14813.

In addition, there is extensive communication between the immune system (e.g., through mast cells) and the central nervous system, and proinflammatory cytokines play a key role in this communication [Skaper SD et al., Immunol 2014; 141: 314-327]. The resulting mast cell-microglia crosstalk further exacerbates and prolongs the effects of chronic neuroinflammation; therefore, the tyrosine kinase inhibitors or pharmaceutically acceptable salts or solvates thereof used in the methods of the present invention also regulate neuroinflammation by inhibiting mast cell-microglia crosstalk.

In one embodiment, the tyrosine kinase inhibitor of the invention, or a pharmaceutically acceptable salt or solvate thereof, is an inhibitor of mast cell activity and microglial activity.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is a 2-aminoarylthiazole derivative.

In one embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof is a 2-aminoarylthiazole derivative of formula [A]. In another embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof is a 2-aminoarylthiazole derivative of formula [B].

In one embodiment, the tyrosine kinase inhibitor of the present invention for use in the method of treating non-aggressive or moderately aggressive ALS in a subject (i.e., a human patient with ALS whose ALSFRS-R score progresses by less than 1.1 points per month before the start of treatment) has the following formula [A], or a pharmaceutically acceptable salt or solvate thereof:

in,

R ₁ and R ₂ are independently selected from hydrogen, halogen, linear or branched alkyl, cycloalkyl containing 1 to 10 carbon atoms, trifluoromethyl, alkoxy, cyano, dialkylamino, and solubilizing groups, m is 0 to 5 and n is 0 to 4;

The group _R3 is one of the following:

(i) aryl, such as phenyl, or substituted variants thereof, carrying one or more substituents in any combination at any ring position, such as halogen, alkyl containing 1 to 10 carbon atoms, trifluoromethyl, cyano and alkoxy;

(ii) heteroaryl, such as 2-pyridyl, 3-pyridyl or 4-pyridyl, which may additionally carry one or more substituents in any combination, such as halogen, alkyl containing 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(iii) a five-membered aromatic heterocyclic group, such as 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may further carry any combination of one or more substituents, such as halogen, alkyl having 1 to 10 carbon atoms, trifluoromethyl and alkoxy.

In one embodiment, the tyrosine kinase inhibitor of the present invention for use in the method of treating non-aggressive ALS in a subject (i.e., a human patient with ALS whose ALSFRS-R score progresses by less than 0.8 points per month before the start of treatment) has formula [A] as defined above.

In one embodiment, the tyrosine kinase inhibitor of the present invention for use in the method of treating moderately aggressive ALS in a subject (i.e., a human patient with ALS whose ALSFRS-R score progresses from ≥0.8 to <1.1 points per month before the start of treatment) has formula [A] as defined above.

In a specific embodiment, the tyrosine kinase inhibitor of the present invention for use in the method of treating non-aggressive or moderately aggressive ALS in a subject (i.e., a human patient with ALS whose ALSFRS-R score progresses by less than 1.1 points per month before the start of treatment) has the general formula [B], or a pharmaceutically acceptable salt or solvate thereof:

in,

R ₁ is independently selected from hydrogen, halogen, linear or branched alkyl, cycloalkyl containing 1 to 10 carbon atoms, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizing groups, and

m is 0 to 5.

In a specific embodiment, the tyrosine kinase inhibitor of the present invention for use in the method of treating non-aggressive ALS in a subject (i.e., a human patient with ALS whose ALSFRS-R score progresses by less than 0.8 points per month before the start of treatment) has the general formula [B] as defined above.

In a specific embodiment, the tyrosine kinase inhibitor of the present invention for use in the method of treating moderately aggressive ALS in a subject (i.e., a human patient with ALS whose ALSFRS-R score progresses from ≥0.8 to <1.1 points per month before the start of treatment) has the general formula [B] as defined above.

Pharmaceutically acceptable salts are preferably pharmaceutically acceptable acid addition salts, for example acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic acids or sulfonic acids, for example aliphatic mono- or dicarboxylic acids such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid or 2-hydroxyethanesulfonic acid, in particular methanesulfonic acid, or aromatic sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid.

Unless otherwise indicated, "mesylate" as used herein refers to the salt of methanesulfonic acid and the drug (e.g., compound of formula [A] or [B]). The use of mesilate rather than mesylate complies with the INNM (International Nonproprietary Names Modified) published by the WHO (e.g., World Health Organization (February 2006). International Nonproprietary Names Modified. INN Working Document 05.167/3. WHO.). For example, masitinib mesylate or imatinib mesylate refers to the mesylate salt of masitinib and imatinib, respectively.

In a highly preferred embodiment, the tyrosine kinase inhibitor of formula [B] used in the method of the present invention is masitinib or a pharmaceutically acceptable salt or solvate thereof, more preferably masitinib mesylate.

Preferably, "masitinib mesylate" refers to the orally bioavailable mesylate salt of masitinib - CAS 1048007-93-7 (MsOH); C ₂₈ H ₃₀ N ₆ OS·CH ₃ SO ₃ H; MW 594.76:

The chemical name of masitinib is 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylthiazol-2-ylamino)phenyl]benzamide - CAS number 790299-79-5.

Masitinib is described in US Pat. No. 7,423,055 and EP 1,525,200 Bl. Detailed procedures for the synthesis of masitinib mesylate are given in WO 2008/098949.

Tyrosine kinase inhibitors, preferably formula [A] or [B] or masitinib mesylate, can be preferably used as inhibitors of wild-type c-Kit, Lyn, Fyn, PDGFR, and CSF1R kinase activity, or any combination thereof.

In the context of the present invention, without wishing to be bound by theory, molecules capable of inhibiting the c-Kit/SCF signaling pathway and thereby inhibiting mast cell survival and/or activation, or molecules capable of modulating mast cell degranulation and thereby modulating mast cell-microglia crosstalk, or molecules capable of inhibiting the CSF-1/CSF-1R signaling pathway and thereby inhibiting microglial proliferation, or any combination thereof, are capable of controlling the symptoms and progression of ALS. In the context of the present invention, tyrosine kinase inhibitors, particularly tyrosine kinase inhibitors as defined above, particularly masitinib, exert this effect in the treatment of non-aggressive or moderately aggressive ALS by inhibiting the tyrosine kinase activity of wild-type c-Kit, Lyn, Fyn, PDGFR, and CSF1R, in particular, by, but not limited to, reducing the total mast cell burden, inhibiting overall mast cell activity, inhibiting mast cell-microglia crosstalk, and inhibiting microglial proliferation, thereby affecting the overall inflammatory cascade, and this effect is exerted in patients whose ALSFRS-R score progression is less than 1.1 points per month before the start of treatment. Surprisingly, without wishing to be bound by theory, it is through this multifaceted mechanism of action that the use of tyrosine kinase inhibitors according to the present invention can elicit a response in patients with non-aggressive or moderately aggressive ALS.

In one embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 0.8 points per month. In another embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points/month).

The present invention relates to a method for treating non-aggressive or moderately aggressive ALS in a human patient, wherein the method comprises administering to a human patient in need thereof a tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, in particular masitinib or a pharmaceutically acceptable salt or solvate thereof.

In connection with the present invention, non-aggressive or moderately aggressive ALS in a human patient is defined as a progression of less than 1.1 points per month in the ALSFRS-R score before the start of treatment. According to the present invention, non-aggressive ALS in a human patient is further defined as a progression of less than 0.8 points per month in the ALSFRS-R score before the start of treatment. According to the present invention, moderately aggressive ALS in a human patient is further defined as a progression of less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month) in the ALSFRS-R score before the start of treatment.

Thus, the present invention relates to methods of treating patients suffering from amyotrophic lateral sclerosis (ALS) who have a progression of less than 1.1 points per month in ALSFRS-R score prior to initiation of treatment.

The present invention also relates to an inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, for treating patients with amyotrophic lateral sclerosis (ALS) whose ALSFRS-R score progresses by less than 1.1 points per month before the start of treatment.

The present invention also relates to the use of an inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR and CSF1R, or any combination thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for treating patients with amyotrophic lateral sclerosis (ALS) whose ALSFRS-R score progresses by less than 1.1 points per month before the start of treatment.

In one embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 0.8 points per month. In another embodiment, the patient's ALSFRS-R score progression before the start of treatment is less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month).

With respect to the present invention, the term "treat" (and its various grammatical forms) refers to preventing, curing, reversing, alleviating, relieving, minimizing, inhibiting, or stopping the deleterious effects of a disease state, disease progression, disease-causing agent (e.g., bacteria or virus), or other abnormal condition. For example, treatment may involve alleviating the symptoms of a disease (i.e., not necessarily all symptoms) or slowing the progression of a disease.

The inventors unexpectedly showed that masitinib provides therapeutic benefit to highly diverse subpopulations of ALS patients, with progression of ALSFRS-R scores before treatment initiation serving as an independent predictor of treatment efficacy.

A randomized, placebo-controlled Phase 3 study (AB10015) was conducted to compare the efficacy and safety of masitinib plus riluzole versus placebo plus riluzole in patients with ALS (see Example 1).

Following an interim analysis of the forward-looking AB10015 study, the inventors unexpectedly demonstrated that masitinib produced a clinical advantage compared to placebo in a subpopulation of ALS (see Example 2). This subpopulation, defined by restrictive eligibility criteria, consisted of ALS patients whose ALSFRS-R score progressed by less than 1.1 points per month before the start of treatment; collectively referred to as the non-aggressive or moderately aggressive ALS subpopulation or the "normal progressor" subpopulation within the overall ALS population, included patients with non-aggressive ALS or moderately aggressive ALS as defined above. This result represents new knowledge that could not have been predicted by the teachings of the prior art.

Masitinib showed an improvement over placebo in its primary endpoint (P = 0.0032, Table 4), with a statistically significant delay in the rate of disease progression. This positive treatment effect was unexpectedly driven by a subpopulation of non-aggressive or moderately aggressive ALS (normal progressors) compared to placebo (P = 0.0004, Table 5), while masitinib had limited or no effect on patients with aggressive ALS (faster progressors, or rapid progressors as defined above) (P = 0.4327, Table 6). In summary, these data suggest that masitinib produces a clinical advantage in a restricted population of non-aggressive or moderately aggressive ALS (normal progressors), which is unexpectedly superior to other patient groups. These findings support the use of progression of ALSFRS-R scores before treatment initiation (threshold less than 1.1 points per month) as an independent predictor of the treatment effect of masitinib and for selecting patients from the entire ALS population.

Thus, the inventors unexpectedly showed that different subpopulations responded to masitinib treatment, differentiated according to the aggressiveness of the disease, calculated by a rate of change in ALSFRS-R score of less than 1.1 points per month from the date of first ALS-related symptoms to the time of randomization into the study (baseline) (including non-aggressive ALS and moderately aggressive ALS subpopulations as defined above); this can be summarized as the progression of ALSFRS-R score before treatment initiation, expressed as points per unit time.

The methods of the present invention advantageously have been shown to provide significant beneficial effects in patients with non-aggressive or moderately aggressive ALS (normal progressors). In one embodiment, the expression "normal progressor" or "non-aggressive or moderately aggressive" is considered to refer to a clinical situation in which the ALS patient receiving treatment exhibits a history of disease progression expressed as less than 1.1 points per month according to the ALSFRS-R score.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with at least one pharmaceutically active ingredient. The pharmaceutically active ingredient is preferably active in the treatment of ALS.

Examples of such active pharmaceutical ingredients include, but are not limited to, anti-glutamate compounds, in particular riluzole (6-(trifluoromethoxy)benzothiazol-2-amine), topiramate (2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranosylsulfamate), gabapentin (2-[1-(aminomethyl)cyclohexyl]acetic acid), lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine), talampanel ((8R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro- 8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine), ceftriaxone ((6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfonylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid), an inhibitor of glutamate carboxypeptidase II.

In one embodiment, a tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with an anti-glutamate compound.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with riluzole.

In one embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof is an inhibitor of at least one tyrosine kinase selected from c-Kit, Lyn, Fyn, PDGFR, and CSF1R, or any combination thereof, and is administered in combination with riluzole.

In one embodiment, the mast cell activity inhibitor of the present invention is administered in combination with riluzole. In one embodiment, the microglia activity inhibitor of the present invention is administered in combination with riluzole.

The present invention also relates to a method for treating non-aggressive or moderately aggressive ALS in a subject, preferably a human patient, comprising administering to a subject or patient in need thereof masitinib or a pharmaceutically acceptable salt or solvate thereof in combination with riluzole.

In one embodiment, the methods of the present invention are used to treat patients whose ALSFRS-R score progression is less than 0.8 points per month before the start of treatment. In another embodiment, the methods of the present invention are used to treat patients whose ALSFRS-R score progression is less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month) before the start of treatment.

Riluzole can be administered at a dose of 50 mg/day to 200 mg/day, for example, 50 mg/day, 100 mg/day, or 200 mg/day, preferably 50 mg twice a day.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with topiramate.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with gabapentin.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with lamotrigine.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with talampanel.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with ceftriaxone sodium.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a glutamate carboxypeptidase II inhibitor.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered simultaneously, separately or sequentially with at least one pharmaceutically active ingredient.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is co-administered with the at least one pharmaceutically active ingredient in a combined preparation for simultaneous, separate or sequential use.

Regarding the optimal dosage regimen, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, particularly masitinib or a pharmaceutically acceptable salt or solvate thereof, used in the method of the present invention is administered at a daily dose of about 1.0 mg/kg/day to about 9.0 mg/kg/day (mg/kg body weight/day). In one embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, more preferably masitinib mesylate, is administered at a daily dose of about 1.5 mg/kg/day to about 7.5 mg/kg/day, for example, about 1.5 mg/kg/day, about 3.0 mg/kg/day, about 4.5 mg/kg/day, about 6.0 mg/kg/day, or about 7.5 mg/kg/day, more preferably about 3.0 mg/kg/day, about 4.5 mg/kg/day, or 6.0 mg/kg/day (mg/kg body weight/day).

Nevertheless, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, in particular masitinib or a pharmaceutically acceptable salt or solvate thereof, can be administered in low-responder patients in incremental doses of about 1.5 mg/kg/day, up to a maximum of about 7.5 mg/kg/day, more preferably about 4.5 mg/kg/day or about 6.0 mg/kg/day, with each dose increase being controlled for toxicity, and no dose-escalating toxic events being allowed to occur.

In one embodiment, the dose escalation of the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, occurs at any time point after at least 4 weeks after the initial dose and before 26 weeks after the initial dose; for example, at week 4, week 8, week 12, week 16, week 20, or week 24. Each dose escalation is subject to toxicity control, including but not limited to: no suspected serious adverse events reported during the first 4 weeks of treatment at a constant dose of study treatment, no suspected adverse events leading to treatment discontinuation, and no suspected adverse events, regardless of severity, occurring during the dose increase. In the absence of any of the above toxic events, scheduled dose escalation can occur. In the event of a non-serious suspected adverse event during dose escalation, or in the case of a treatment interruption without dose reduction when treatment is resumed, any dose increase is delayed until after an additional 4-week treatment period. Dose escalation will not be permitted for patients whose dose is reduced for safety reasons.

In one embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, is initially administered orally, preferably twice daily, at a dose of 3 mg/kg/day for 6 weeks, followed by 4.5 mg/kg/day for 6 weeks, and then 4.5 mg/kg/day. In another embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, is initially administered orally, preferably twice daily, at a dose of 3.0 mg/kg/day for 12 weeks, and then 4.5 mg/kg/day.

In another example, masitinib or a pharmaceutically acceptable salt or solvate thereof is initially administered orally, preferably twice daily, at a dose of 3 mg/kg/day for four weeks, then 4.5 mg/kg/day for four weeks, and then 6 mg/kg/day, with toxicity controls performed at each increasing dose.

In one embodiment, the tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, more preferably masitinib mesylate, is administered at an initial dose of 4.5 mg/kg/day for at least 6 weeks, followed by 6.0 mg/kg/day for at least 6 weeks, and thereafter at 6.0 mg/kg/day, with toxicity controls performed at each increasing dose.

Any dosage indicated herein refers to the amount of the active ingredient itself, not its salt form.

Considering that the dosage of masitinib in mg/kg/day used in the dosage regimen refers to the amount of the active ingredient masitinib, changes in the composition of the pharmaceutically acceptable salt of masitinib mesylate will not alter the dosage regimen.

In a specific embodiment, masitinib or a pharmaceutically acceptable salt or solvate thereof can also be administered by different routes of administration, but oral administration is preferred. In one embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof is administered orally. In one embodiment, the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof is administered by twice daily intake. Therefore, in another preferred embodiment, in the above-mentioned use or method, masitinib or a salt or solvate thereof is administered orally; preferably twice a day for a long period of time, for example for more than 6 months, preferably for more than 12 months. Masitinib or a pharmaceutically acceptable salt or solvate thereof can be administered in the form of 100 mg and 200 mg tablets.

In one embodiment, the tyrosine kinase inhibitor or a pharmaceutically acceptable salt or solvate thereof, preferably masitinib or a pharmaceutically acceptable salt or solvate thereof, more preferably masitinib mesylate, is contained in the pharmaceutical composition in an amount of at least 50 mg and less than 600 mg, preferably at least 100 mg and less than 400 mg.

The present invention also relates to a pharmaceutical composition comprising the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to a medicament comprising the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to a kit comprising the tyrosine kinase inhibitor of the present invention or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the pharmaceutical composition, medicament or kit of the present invention comprises masitinib or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the pharmaceutical composition, medicament or kit of the present invention comprises a tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one other pharmaceutically active ingredient. In one embodiment, the pharmaceutical composition, medicament or kit of the present invention comprises a tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one other pharmaceutically active ingredient, preferably an anti-glutamate compound, in particular riluzole, topiramate, gabapentin, lamotrigine, talampanel, ceftriaxone, or a glutamate carboxypeptidase II inhibitor. Preferably, the other pharmaceutically active ingredient is riluzole.

In one embodiment, the pharmaceutical composition, medicament, or kit of the present invention comprises a tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one anti-glutamate compound and/or glutamate carboxypeptidase II inhibitor. In one embodiment, the pharmaceutical composition, medicament, or kit of the present invention comprises a tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one other pharmaceutically active ingredient selected from riluzole, topiramate, gabapentin, lamotrigine, talampanel, and ceftriaxone.

In one embodiment, the pharmaceutical composition, medicament, or kit of the present invention comprises a combination of a tyrosine kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and riluzole. In a preferred embodiment, the medicament or kit of the present invention comprises a combination of masitinib, or a pharmaceutically acceptable salt or solvate thereof, and riluzole.

According to a specific embodiment, the pharmaceutical composition or medicament of the present invention is therefore an oral composition.

As known to those skilled in the art, excipients may be used in a variety of forms to suit the mode of administration, and some of them may enhance the effectiveness of the active molecule, for example, by enhancing the release profile, making the active molecule more effective overall for the desired treatment.

Thus, the pharmaceutical compositions, medicaments or compositions used in the methods of the present invention can be administered in various forms, more particularly, for example, in injectable, disintegrable or digestible forms, for example, by intramuscular, intravenous, subcutaneous, intradermal, oral, topical, rectal, vaginal, ophthalmic, nasal, transdermal or parenteral routes of administration. The preferred route is oral administration.

The present invention particularly encompasses the use of a compound according to the invention for the preparation of a pharmaceutical composition or medicament.

Such medicament or pharmaceutical composition can take the form of medicament or pharmaceutical composition suitable for oral administration, and it can use pharmaceutically acceptable carrier well known in the art to prepare with suitable dosage.These carriers enable pharmaceutical composition to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, syrups, suspensions etc. for patient intake.In addition to active ingredient, these pharmaceutical compositions can comprise suitable pharmaceutically acceptable carriers, which comprise excipients and adjuvants that promote the active compound to be processed into pharmaceutically usable preparations.Other details for formulation and administration techniques can be found in the latest version of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

Example

The present invention is further illustrated by the following examples.

Example 1

AB10015 study

design:

The AB10015 study is a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2/3 study comparing the efficacy and safety of masitinib plus riluzole versus placebo plus riluzole in patients with amyotrophic lateral sclerosis (ALS).

Randomization:

381 patients were randomly divided into 3 groups:

- Group 1: 127 patients received 4.5 mg/kg/day of masitinib plus riluzole

- Group 2: 127 patients received 3 mg/kg/day of masitinib plus riluzole

- Group 3: 127 patients received placebo + riluzole

Subgroup analysis (ALS patient subpopulations):

There are two distinct populations of ALS patients: the "normal progressor" subpopulation and the "faster progressor" subpopulation. The primary analysis focused on the "normal progressor" subpopulation.

Normal progressors:

Normal progressors were defined as ALS patients whose ALSFRS-R score progressed by less than 1.1 points per month before randomization. This group should represent approximately 80% of ALS patients.

“Normal progressors + faster progressors” group:

The "normal progressor + faster progressor" population included all ALS patients, "normal progressor" ALS patients, or "faster progressor" ALS patients. "Faster progressors" were defined as ALS patients whose ALSFRS-R score progressed by greater than or equal to 1.1 points per month before randomization.

Main inclusion criteria:

- Female or male patients aged 18 to 75 years, weighing >50 kg, with a body mass index between 18 kg/ ^m² and 35 kg/ ^m² ;

- Familial or sporadic ALS;

- Patients with a laboratory-supported diagnosis of clinically probable or definite ALS according to the El Escorial criteria revised by the World Federation of Neurology [Brooks BR, Journal of the Neurological Sciences 1994; 124(Suppl): 96-107];

- Duration of disease from symptom onset no more than 36 months at the screening visit;

- Patients have been treated with a stable dose of riluzole (100 mg/day) for at least 30 days prior to screening;

- FVC (forced vital capacity) equal to or greater than 60% of the predicted normal value for sex, height, and age at the screening visit;

- Patients have adequate organ function at screening and baseline.

Main exclusion criteria:

- Patients with tracheostomy and/or gastrostomy.

Treatment administration

As shown in Tables 2 and 3 below, enrolled subjects received a total daily dose of 4.5 mg/kg or 3 mg/kg masitinib or matching placebo during meals. For the morning dose, the tablets were taken with breakfast. If nausea occurred, the dose was administered during lunch. For the evening dose, the tablets were taken with dinner.

The study treatment daily dose was 4.5 mg/kg, administered in divided doses as shown in Table 2.

Table 2: Study treatment dose (mg) based on patient weight (4.5 mg/kg/day)

The study treatment daily dose was 3 mg/kg, administered in divided doses as shown in Table 3.

Table 3: Study treatment dose (mg) based on patient weight (3 mg/kg/day)

Analyze the dataset:

Intention-to-treat (ITT) Dataset - The ITT population was defined as all randomized patients, regardless of whether they received study treatment, who had at least one post-baseline efficacy assessment.

Modified Intention-to-Treat (mITT) Dataset - The mITT population will include all ITT patients with probable or confirmed ALS who have received at least one dose of study treatment (masitinib or placebo).

Per-Protocol (PP) Dataset - The PP population consists of all patients in the mITT population without any major protocol deviations. This is the group of patients who participated in the study as intended. Patients who prematurely terminated the study without protocol deviations will be included in the PP population. The exact reasons for excluding patients from the PP population will be fully defined and documented by the Data Review Committee before the database is locked.

Safety Population - The safety population (SAF) consisted of all enrolled patients who received at least one dose of study drug (masitinib or placebo).

Statistical methods

Primary endpoint:

Change from Baseline to Week 48 on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)

Secondary endpoints:

Secondary analyses included the following endpoints:

- Progression-free survival (PFS), defined as worsening of ALSFRS-R by more than 9 points or death;

-Comprehensive Assessment of Function and Survival (CAFS);

- Survival was defined as the time from randomization to the date of documented death or first tracheotomy;

- Time to first tracheostomy defined as the time from randomization to first tracheostomy;

- Change in forced vital capacity (FVC) from baseline to each time point (weeks 4, 8, 12, 24, 36, 48);

- Change in ALSFRS-R from baseline to each time point (weeks 4, 8, 12, 24, and 36);

- Survival was defined as the percentage of patients alive without tracheostomy at each time point (weeks 12, 24, 36, and 48).

Interim analysis

An interim analysis was planned involving approximately 50% of the randomized patients.

The interim analysis was conducted without unblinding. An independent contract research organization (CRO) was authorized to perform the analysis. The results were sent directly to members of the Independent Data Monitoring Committee (IDMC).

The IDMC concluded that the AB10015 study met its primary objective based on a pre-planned interim analysis. A small, three-person team, independent of the study and not included in the patient randomization list, was established to collect top-line data.

Example 2

Clinical data showed that masitinib provided therapeutic benefit in a highly diverse subset of ALS patients, identified as having non-aggressive or moderately aggressive ALS ("normal progressors"), defined as those with an ALSFRS-R score progression of less than 1.1 points per month before treatment initiation.

Interim Analysis of the AB10015 Study

method:

The study protocol and statistical analysis plan included provisions for analysis of two subgroups of patients: “normal progressors” (patients whose ALSFRS-R score progressed by less than 1.1 points per month before randomization; also referred to as patients with nonaggressive or moderately aggressive ALS) and “faster progressors” (patients whose ALSFRS-R score progressed by greater than or equal to 1.1 points per month before randomization; also referred to as patients with aggressive ALS).

According to the AB10015 study protocol, an interim analysis was planned after approximately 50% of the information was available for analysis. At the time of the interim analysis, 192 (50%) of the 381 patients randomized before February 12, 2015, could have reached the 48-week visit. This interim ITT population consisted of 65, 64, and 63 patients randomized to the placebo, masitinib 4.5 mg/kg/day, and masitinib 3.0 mg/kg/day groups, respectively. Of the 192 patients, 161 (85%) were "normal progressors," consisting of 54, 53, and 54 patients randomized to the placebo, masitinib 4.5 mg/kg/day, and masitinib 3.0 mg/kg/day groups, respectively. The randomization ratio according to dose (3 mg/kg/day versus 4.5 mg/kg/day) was 1:1 (50%); thus, the number of patients required for the interim analysis was achieved with respect to overall patient numbers, subpopulation status, and treatment dose.

The primary endpoint of the interim analysis was based on the change in ALSFRS-R from baseline to Week 48. The primary analysis was conducted in the mITT "normal progressor" subpopulation (i.e., non-aggressive or moderately aggressive ALS). This analysis was performed on patients who received an initial dose of 4.5 mg/kg/day of masitinib (Group 1, n=52) versus patients who received placebo (Group 3, n=46), with an alpha level of 3.11%. Missing values for the ALSFRS-R at the study visit were replaced based on the Modified Last Observation Carried Forward (mLOCF) method.

The absolute change in ALSFRS-R from baseline to week 48 was estimated with the use of analysis of covariance (ANCOVA) models adjusted for treatment (masitinib or placebo) and stratification criteria: ALS patient subpopulation, progression of ALSFRS-R score (points/month) from the date of first symptom onset to baseline, ALSFRS-R score at baseline, site of disease onset (bulbar vs. other), age at baseline, and geographic region.

A two-sided (1-α) confidence interval for the difference in mean change from baseline to week 48 between the groups was calculated. The primary analysis used a multiple randomization test. A multiple randomization test, also known as a randomization test or permutation test, is a statistical significance test in which the distribution of the test statistic under the null hypothesis is obtained by calculating all possible values of the test statistic under rearrangements of the labels on the observed data points. The proportion of replicates for which the p-value for the treatment factor is at least as small as the p-value for the treatment factor for the original data is calculated. In this proportion, the observed p-value for the treatment factor also accounts for one replicate in the numerator and denominator. This proportion is the p-value for the randomization test. If the randomization p-value is less than or equal to 3.11%, the hypothesis of no treatment difference is rejected at the 3.11% significance level.

In order to control the overall family-wise type I error rate at the study level, a power analysis was performed in a stepwise manner (fixed sequence method). The fixed sequence method ensured that the population was divided and treated with the selected dose by controlling the overall family-wise error rate of the primary analysis at the 0.0311 level. Sequence 1 was implemented for the 4.5 mg/kg/day randomized "normal progressor" patient population. The primary analysis was the absolute change in ALSFRS-R score from baseline to week 48 (calculated by the "least squares" method). At the 0.0311 significance level, the analysis was considered decisive.

result:

In general, patient demographics and baseline characteristics were well matched between treatment groups and subgroups. To analyze the effect of masitinib treatment, the following cohorts were compared based on progression of ALSFRS-R scores in the different subgroups of non-aggressive or moderately aggressive ALS (i.e., normal progressors) versus aggressive ALS (i.e., faster progressors).

i) Change from baseline to Week 48 in the ALSFRS-R (primary endpoint) in the group of patients randomized to 4.5 mg/kg/day "normal progressors" according to treatment group (masitinib vs. placebo). This corresponds to the primary analysis of the interim analysis, i.e., sequence 1 of the stepwise fixed-sequence approach.

A total of 98 patients were evaluable for the first sequence of the primary endpoints of the interim analysis, i.e., patients with evaluable baseline and 48-week data who were randomized to either 4.5 mg/kg/day of masitinib (n=46) or placebo (n=52) in the "normal progressor" subgroup. The mean exposure to masitinib (4.5 mg/kg/day) or placebo was 9.5±2.8 months (range, 1.7 to 11.5 months) and 9.3±3.2 months (range, 0.2 to 13.3 months), respectively.

Masitinib showed a significant improvement over placebo in its primary endpoint, with a mean reduction of 14.51 points in ALSFRS-R scores in placebo-treated patients and a reduction of 9.02 points in masitinib-treated patients, P = 0.0032 (Table 4). Thus, masitinib administered at 4.5 mg/kg/day produced a statistically significant delay in disease progression as measured by ALSFRS-R scores in the ALS "normal progressor" subpopulation.

Table 4: Primary analysis comparing the “normal progressor” subpopulation (ALSFRS-R score progression <1.1 points/month) of patients randomized to 4.5 mg/kg/day of masitinib versus placebo (interim AB10015)

For patients evaluable for the primary efficacy analysis. *P-values are based on repeated randomization. The significance level for the interim analysis was set at <0.0311. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). Masitinib (4.5) = randomized group 1, which received 4.5 mg/kg/day of masitinib plus riluzole. [CI] = mITT population (1-α) confidence interval.

ii) Changes in ALSFRS-R from baseline to Week 48 in the 4.5 mg/kg/day randomized patient cohort directly compared treatment efficacy between the masitinib-treated “normal progressors” and masitinib-treated “faster progressors” subpopulations.

Masitinib treatment of patients with normal progressors (non-aggressive or moderately aggressive ALS) showed a strong statistically significant improvement in ALSFRS-R scores compared to patients with faster progressors (aggressive ALS), with an average decrease of 5.57 points and 17.9 points, respectively, (P=0.0004) (Table 5). Thus, when compared to the ALS "faster progressor" subpopulation, masitinib administered at 4.5 mg/kg/day produced an unexpectedly strong delay in disease progression as measured by ALSFRS-R scores in the ALS "normal progressor" subpopulation.

Unexpectedly, these data suggest that in the primary analysis, the positive treatment effect of masitinib compared to placebo was strongly driven by the "normal progressor" subpopulation. Thus, masitinib was highly effective in the subpopulation of patients with non-aggressive or moderately aggressive ALS (normal progressors), while being less effective or having limited effect in patients with aggressive ALS (faster progressors).

Table 5: Comparison of the “normal progressor” subpopulation (ALSFRS-R score <1.1 points/month) with the “faster progressor” subpopulation (ALSFRS-R score ≥1.1 points/month progression), analysis of patients treated with masitinib (4.5 mg/kg/day) (interim AB10015)

For patients evaluable for the primary efficacy analysis, the interim analysis significance level was set at <0.0311. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). [CI] = mITT population (1-α) confidence interval.

iii) Change from baseline to Week 48 in the ALSFRS-R in the randomized “faster progressor” group of patients at 4.5 mg/kg/day according to treatment group (masitinib vs. placebo).

The observation of limited effect of masitinib in patients with aggressive ALS was confirmed by analyzing the change in ALSFRS-R from baseline to Week 48 in the randomized "faster progressor" group of patients at 4.5 mg/kg/day according to treatment group (masitinib vs. placebo) (see Table 5 above).

In the "faster progressors" subgroup, there were no significant differences between the treatment groups. In fact, there was no trend towards slower disease progression in this patient subgroup (masitinib-treated patients showed a greater mean reduction in ALSFRS-R scores compared with placebo-treated patients) (Table 6). This observation supports the unexpected finding that masitinib was only effective in patients with non-aggressive or moderately aggressive ALS (normal progressors), supporting the hypothesis that different mechanisms of disease progression in the entire ALS population are partly responsible for the survival differences.

Table 6: Analysis of the “faster progressor” subpopulation (ALSFRS-R score <1.1 points/month) comparing patients randomized to 4.5 mg/kg/day of masitinib with those randomized to placebo (interim analysis AB10015)

Patients evaluable for the primary efficacy analysis. The interim analysis significance level was set at <0.0311. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). Masitinib (4.5) = randomized group 1, who received 4.5 mg/kg/day of masitinib plus riluzole. [CI] = mITT population (1-α) confidence interval.

In summary, these data suggest that masitinib produces a clinical advantage in a limited population of patients with nonaggressive or moderately aggressive ALS (i.e., progression of ALSFRS-R score of less than 1.1 points per month before randomization), which unexpectedly outperforms other groups of patients with aggressive ALS (i.e., patients with progression of ALSFRS-R score of ≥1.1 points per month before randomization). These findings support the use of a threshold of progression of ALSFRS-R score of less than 1.1 points per month before treatment initiation as an independent predictor of masitinib treatment efficacy and for selecting patients from the general ALS population.

Example 3

When 100% of the information was available, the final analysis of the AB10015 study was performed. Clinical data from this final analysis confirmed the results of the AB10015 interim analysis, indicating that masitinib provides therapeutic benefit for highly diverse subpopulations of ALS patients. These patients were identified as normal progressors, defined as ALS patients whose ALSFRS-R score progressed by less than 1.1 points per month before the start of treatment (including patients with non-aggressive and moderately aggressive ALS as defined above).

Final Analysis of Study AB10015

The database cutoff date was March 16, 2017. The data shown in this example were derived in part from a preliminary analysis and therefore represent a fairly accurate approximation of the final validated dataset.

To determine the effect of masitinib administration in different subgroups of the overall ALS patient population according to progression of ALSFRS-R scores, the following analyses were performed.

i) Change from baseline to Week 48 in the ALSFRS-R (primary endpoint) in the group of patients randomized to 4.5 mg/kg/day according to treatment group (masitinib vs. placebo). This corresponds to the primary endpoint in the final analysis.

Masitinib administered at 4.5 mg/kg/day produced a statistically significant delay in disease progression, as measured by the ALSFRS-R score in the ALS "normal progressor" subpopulation (<1.1 points per month). Masitinib showed a significant improvement over placebo in its primary endpoint (P=0.0142), with an average reduction in ALSFRS-R scores of -8.7 points and -12.1 points for masitinib and placebo, respectively (equivalent to a difference of 3.4 points) (Table 7).

Table 7: Primary analysis of the “normal progressor” subpopulation (ALSFRS-R score less than 1.1 points per month) comparing patients randomized to 4.5 mg/kg/day of masitinib with those randomized to placebo (final B10015)

Patients evaluable for the primary efficacy analysis. The significance level for the final analysis was set at <0.05. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). Masitinib (4.5) = randomized group 1, which received 4.5 mg/kg/day of masitinib plus riluzole. [CI] = mITT population (1-α) confidence interval.

For the subgroup of patients with “non-aggressive ALS” (<0.8 points per month), masitinib produced a delay in ALSFRS-R scores equivalent to a difference of 3.4 points (-8.3 points for masitinib vs. -11.7 points for placebo, respectively) (Table 8).

Table 8: Primary analysis comparing the “non-aggressive” ALS subpopulation (ALSFRS-R score less than 0.8 points per month) of patients randomized to 4.5 mg/kg/day of masitinib versus placebo (final B10015)

For patients evaluable for efficacy analysis, the significance level for the final analysis was set at <0.05. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). Masitinib (4.5) = randomized group 1, which received 4.5 mg/kg/day of masitinib plus riluzole. [CI] = mITT population (1-α) confidence interval.

In the subgroup of patients with "moderately aggressive ALS" (≥0.8 to <1.1 points per month), masitinib produced a delay in ALSFRS-R scores equivalent to a 2.2-point difference (-11 points to 13.2 points for masitinib and placebo, respectively) (Table 9). Notably, the group of patients with moderately aggressive ALS (ALSFRS-R score ≥0.8 to <1.1 points per month) was smaller than the group of patients with non-aggressive ALS (progression in ALSFRS-R score <0.8 points per month).

Table 9: Primary analysis comparing patients randomized to 4.5 mg/kg/day of masitinib versus placebo in the “moderately aggressive” ALS subpopulation (progression in ALSFRS-R score ≥0.8 to <1.1 points per month)

For patients evaluable for efficacy analysis, the significance level for the final analysis was set at <0.05. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). Masitinib (4.5) = randomized group 1, which received 4.5 mg/kg/day of masitinib plus riluzole. [CI] = mITT population (1-α) confidence interval.

There were no significant differences between treatment groups in the "faster progressor" subgroup (≥1.1 points per month), confirming that masitinib (4.5 mg/kg/day) has limited efficacy in ALS patients who are faster progressors and is not applicable to the overall ALS population (see Table 10). In fact, there was no trend towards slowing disease progression in this patient subgroup. This observation supports the unexpected finding that masitinib is only effective in ALS patients who are normal progressors (including the non-aggressive ALS and moderately aggressive ALS subgroups as defined above).

Table 10: Primary analysis of the “faster progressor” subpopulation (progression in ALSFRS-R score ≥1.1 points per month) comparing patients randomized to 4.5 mg/kg/day of masitinib versus placebo (final B10015)

Patients evaluable for the primary efficacy analysis. The significance level for the final analysis was set at <0.05. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). Masitinib (4.5) = randomized group 1, which received 4.5 mg/kg/day of masitinib plus riluzole. [CI] = mITT population (1-α) confidence interval.

Importantly, the study showed no significant differences between the treatment groups in the entire study population (P = 0.11) (i.e., the group that included both normal progressors and faster progressors, regardless of the progression of ALSFRS-R scores before treatment initiation) (Table 11). Therefore, any study design based on treating the entire ALS population would result in a failure to demonstrate a treatment effect. This observation supports the unexpected finding that masitinib is only effective in a limited subset of ALS patients, and the identification of responding patients represents new knowledge and could not be predicted by the teachings of the prior art.

Table 11: Primary analysis of the entire study population of “normal progressors and faster progressors” (regardless of ALSFRS-R score progression) comparing patients randomized to 4.5 mg/kg/day of masitinib to placebo (Final AB10015)

Patients evaluable for the primary efficacy analysis. The significance level for the final analysis was set at <0.05. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). Masitinib (4.5) = randomized group 1, which received 4.5 mg/kg/day of masitinib plus riluzole. [CI] = mITT population (1-α) confidence interval.

ii) Change in ALSFRS-R from baseline to Week 48 in the randomized group of patients receiving 4.5 mg/kg/day of masitinib to directly compare the efficacy of masitinib treatment between ALS subgroups.

Masitinib treatment of normal progressor ALS patients showed a strong statistically significant treatment effect in terms of ALSFRS-R scores compared to faster progressor (aggressive ALS) patients (P < 0.001), with an average decrease in ALSFRS-R scores of 8.4 points and 19.6 points in normal progressors and faster progressors, respectively (corresponding to a difference of 11.2 points) (Table 12). Thus, as measured by ALSFRS-R scores in the ALS "normal progressor" subpopulation, administration of masitinib at 4.5 mg/kg/day produced an unexpectedly strong delay in disease progression when compared to the ALS "faster progressor" subpopulation. Thus, masitinib is very effective in the "normal progressor" subpopulation (including non-aggressive ALS and moderately aggressive ALS subpopulations as defined above), but is ineffective or has limited effect in faster progressor ALS patients.

Table 12: Analysis of patients treated with masitinib (4.5 mg/kg/day) comparing the subpopulations of "normal progressors" and "faster progressors"

Primary efficacy analysis was performed in evaluable patients. The significance level for the final analysis was set at <0.05. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). [CI] = mITT population (1-α) confidence interval.

Similar statistically significant results were shown for patients with non-aggressive ALS (<0.8 points per month) compared to patients with aggressive ALS (≥1.1 points per month) (see Table 13), and for patients with non-aggressive ALS (<0.8 points per month) compared to patients with moderately aggressive and aggressive ALS (≥0.8 points per month) (see Table 14).

Table 13: Analysis of patients treated with masitinib (4.5 mg/kg/day) comparing the "non-aggressive" and "faster progressors (aggressive)" subpopulations (Final AB10015)

Primary efficacy analysis was performed in evaluable patients. The significance level for the final analysis was set at <0.05. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). [CI] = mITT population (1-α) confidence interval.

Table 14: Analysis of patients treated with masitinib (4.5 mg/kg/day) comparing "non-aggressive" and "moderately aggressive + aggressive" subpopulations (Final AB10015)

Patients evaluable for the primary efficacy analysis. The significance level for the final analysis was set at <0.05. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). [CI] = mITT population (1-α) confidence interval.

Masitinib treatment showed a trend toward better treatment efficacy in patients with moderately aggressive ALS (≥0.8 to <1.1 points per month) compared with patients with aggressive ALS (≥1.1 points per month) in terms of ALSFRS-R scores (see Table 15).

Table 15: Analysis of patients treated with masitinib (4.5 mg/kg/day) comparing the "moderately aggressive" and "faster progressors (aggressive)" subpopulations (Final AB10015)

Primary efficacy analysis was performed in evaluable patients. The significance level for the final analysis was set at <0.05. ΔALSFRS-R = change in ALSFRS-R score from baseline to Week 48 (least squares mean). [CI] = mITT population (1-α) confidence interval.

In summary, the final analysis data from the AB10015 study demonstrated the following:

- Masitinib is an effective treatment for ALS patients whose ALSFRS-R score progresses by less than 1.1 points per month before treatment initiation (this subgroup is collectively referred to as non-aggressive or moderately aggressive ALS).

- Masitinib was most effective in patients whose ALSFRS-R score progressed by less than 0.8 points per month before treatment initiation (this subgroup is collectively referred to as non-aggressive ALS).

- Masitinib was effective in treating patients whose ALSFRS-R score progressed by ≥0.8 to <1.1 points per month before treatment initiation (this subgroup is collectively referred to as moderately aggressive ALS), although to a lesser extent than in the non-aggressive subgroup.

Masitinib is an ineffective treatment for ALS patients whose ALSFRS-R score progresses by at least 1.1 points per month before treatment initiation (this subgroup is collectively referred to as aggressive ALS).

Claims (21)

1. The use of masitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicine for the treatment of non-invasive or moderately invasive amyotrophic lateral sclerosis (ALS) in patients in need, wherein non-invasive or moderately invasive ALS is defined as a progression of less than 1.1 points per month on the Amyotrophic Lateral Sclerosis Functional Rating Scale-R (ALSFRS-R) prior to the initiation of treatment. 2. The use according to claim 1, wherein the drug is used to treat non-invasive amyotrophic lateral sclerosis (ALS) defined as a progression of less than 0.8 points per month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS FRA) prior to the start of treatment. 3. The use according to claim 1, wherein the drug is used to treat moderately aggressive amyotrophic lateral sclerosis (ALS) defined as a progression of less than 1.1 points per month and equal to or greater than 0.8 points per month (≥0.8 to <1.1 points per month) on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS FRA) prior to the start of treatment. 4. The use according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of masitinib is masitinib mesylate. 5. The use according to any one of claims 1 to 3, wherein the masitinib or a pharmaceutically acceptable salt thereof is administered at a dose of 1.0 mg/kg/day to 9.0 mg/kg/day (mg/kg body weight/day). 6. The use according to claim 5, wherein the pharmaceutically acceptable salt of masitinib is masitinib mesylate. 7. The use according to claim 5, wherein the masitinib or a pharmaceutically acceptable salt thereof is administered at an initial dose of 3.0 mg/kg/day for at least 4 weeks, followed by administration at 4.5 mg/kg/day for at least 4 weeks, and then at 6.0 mg/kg/day, with toxicity controls performed for each dose escalation. 8. The use according to claim 5, wherein the masitinib or a pharmaceutically acceptable salt thereof is administered at a dose of 4.5 mg/kg/day. 9. The use according to claim 8, wherein the pharmaceutically acceptable salt of masitinib is masitinib mesylate. 10. The use according to claim 5, wherein the masitinib or a pharmaceutically acceptable salt thereof is administered at a dose of 6 mg/kg/day. 11. The use according to claim 10, wherein the pharmaceutically acceptable salt of masitinib is masitinib mesylate. 12. The use according to any one of claims 1 to 3, wherein the masitinib or a pharmaceutically acceptable salt thereof is administered by ingestion twice daily. 13. The use according to claim 12, wherein the pharmaceutically acceptable salt of masitinib is masitinib mesylate. 14. The use according to any one of claims 1 to 3, wherein the masitinib or a pharmaceutically acceptable salt thereof is administered orally. 15. The use according to claim 14, wherein the pharmaceutically acceptable salt of masitinib is masitinib mesylate. 16. The use according to any one of claims 1 to 3, wherein the masitinib or a pharmaceutically acceptable salt thereof is administered in combination with at least one other pharmaceutically active ingredient. 17. The use according to claim 16, wherein the other pharmaceutically active ingredient is an anti-glutamate compound. 18. The use according to claim 17, wherein the anti-glutamate compound is riluzole, topiramate, gabapentin, lamotrigine, talapane, ceftriaxone, or a glutamate carboxypeptidase II inhibitor. 19. The use according to claim 16, wherein the other pharmaceutically active ingredient is riluzole. 20. Use of a pharmaceutical composition, agent, or kit comprising masitinib or a pharmaceutically acceptable salt thereof for the preparation of an agent for the treatment of non-invasive or moderately invasive amyotrophic lateral sclerosis (ALS) in patients in need, wherein non-invasive or moderately invasive ALS is defined as a progression of less than 1.1 points per month on the Amyotrophic Lateral Sclerosis Functional Rating Scale-R (ALSFRS-R) prior to the initiation of treatment. 21. The use according to claim 20, wherein the pharmaceutically acceptable salt of masitinib is masitinib mesylate.