AU2016256694A1 - Use of an S1P receptor agonist - Google Patents

Abstract

H:\dar\Intrwovn\NRPortbl\DCC\DAR\I 1906198_l.docx-7/1/2016 The present invention relates to new uses of S1 P receptor modulator or agonist such as fingolimod, for reducing or delaying the progression of brain damage, e.g. associated with

Description

Use of an S1P Receptor Agonist

This application is a divisional of Australian Patent Application No. 2015202061, the entire content of which is incorporated herein by reference.

The present invention relates to new uses of S1P receptor modulator or agonist such as fingolimod, for limiting brain tissue damage, in particular associated with Multiple Sclerosis (MS), by reducing the number of T1 hypointense lesions in the patient.

In Multiple Sclerosis, in particular Relapsing Remitting Multiple Sclerosis, the presence of gadoliniumenhancing (Gd+) T1 lesions on brain MRI reflects active focal inflammation. Gd+ lesions may evolve into persistent T1 hypointense lesions, which are considered as indicators of severe tissue damage. S1P receptor modulators or agonists are compounds which signal as agonists at one or more sphingosine-1 phosphate receptors, e.g. S1 P1 toS1P8. Agonist binding to a S1P receptor may e.g. result in dissociation of intracellular heterotrimeric G-proteins into Ga-GTP and GPy-GTP, and/or increased phosphorylation of the agonist-occupied receptor and activation of downstream signaling pathways/kinases. S1P receptor modulators are valuable compounds for the manufacture of medication for the treatment of various conditions in mammals, especially in human beings. For example, efficacy in transplantation has been demonstrated in rats (skin, heart, liver, small bowel), dogs (kidney), and monkeys (kidney) models. Due to their immune-modulating potency, S1P receptor modulators are also useful for the treatment of inflammatory and autoimmune diseases.

Fingolimod (FTY720) is currently being evaluated for the treatment of multiple sclerosis (MS). Evidence indicates that fingolimod acts by preventing lymphocyte egress from lymph nodes. This leads to a reduced infiltration of potentially autoaggressive lymphocytes into the central nervous system (CNS), in particular the number of activated lymphocytes reaching the brain is decreased, resulting in reduced inflammatory destruction. Preclinical evidence also suggests that fingolimod may promote neuroprotective and reparative processes within the CNS via modulation of sphingosine 1 -phophate receptors expressed on neural cells. FTY720 efficacy in the treatment of multiple sclerosis has been showed in humans (e.g. as described in “FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis”. Mehling M, et al., Neurology. 2008 Oct 14;71 (16):1261 -7; and Oral fingolimod (FTY720) for relapsing multiple sclerosis”. Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW; FTY720 D2201 Study Group. N Engl J Med. 2006 Sep 14;355(11):1124-40.).

The inventors of the present invention have shown that treating MS patients with fingolimod permits to significantly reduce the number of persistent T1 hypointense lesions, which are considered as indicators of severe tissue damage.

As herein defined, active inflammatory lesions are Gd+ lesions (gadolinium-enhancing lesions). T1 hypointense lesions may be Gd+ or not.

S1P receptor modulators or agonists according to the invention are typically sphingosine analogues, such as 2-substituted 2-amino- propane-1,3-diol or 2-amino-propanol derivatives, e. g. a compound comprising a group of formula X

wherein Z is H, Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, phenyl, phenyl substituted by OH, Ci_6alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C3-8cycloalkyl, phenyl and phenyl substituted by OH, or CH2-R4z wherein R4z is OH, acyloxy or a residue of formula (a)

wherein Z! is a direct bond or O, preferably O; each of R5z and R6z, independently, is H, or C^alkyl optionally substituted by 1,2 or 3 halogen atoms; R1z is OH, acyloxy or a residue of formula (a); and each of R2z and R3z independently, is H, 0^ 4alkyl or acyl.

The group of formula X is a functional group attached as a terminal group to a moiety which may be hydrophilic or lipophilic and comprise one or more aliphatic, alicyclic, aromatic and/or heterocyclic residues, to the extent that the resulting molecule wherein at least one of Z and Riz is or comprises a residue of formula (a), signals as an agonist at one of more sphingosine-1-phosphate receptor.

Examples of appropriate S1P receptor agonists or modulators are, for example:

- Compounds as disclosed in EP627406A1, e.g. a compound of formula I

wherein R: is a straight- or branched (C12.22)chain - which may have in the chain a bond or a hetero atom selected from a double bond, a triple bond, O, S, NR6, wherein R6 is H, C1_4alkyl, aryl-C1_4alkyl, acyl or (C1.4alkoxy)carbonyl, and carbonyl, and/or - which may have as a substituent C^alkoxy, C2-4alkenyloxy, C2.4alkynyloxy, arylC^alkyl-oxy, acyl, C^alkylamino, C^alkylthio, acylamino, (C1.4alkoxy)carbonyl, (C^alkoxy)-carbonylamino, acyloxy, (C^alkyOcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy; or Ri is - a phenylalkyl wherein alkyl is a straight- or branched (C6-20)carbon chain; or - a phenylalkyl wherein alkyl is a straight- or branched (Ci-30)carbon chain wherein said phenylalkyl is substituted by - a straight- or branched (C6-20)carbon chain optionally substituted by halogen, - a straight- or branched (C6-20)alkoxy chain optionally substitued by halogen, - a straight- or branched (C6-20)alkenyloxy, - phenyl-Ci_i4alkoxy, halophenyl-Ci_4alkoxy, phenyl-Ci-i4alkoxy-CM4alkyl, phenoxy-Ci_4alkoxy or phenoxy-Ci_4alkyl, - cycloalkylalkyl substituted by C6.20alkyl, - heteroarylalkyl substituted by C6.20alkyl, - heterocyclic C6.20alkyl or - heterocyclic alkyl substituted by C2.20alkyl, and wherein the alkyl moiety may have - in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, 0, S, sulfinyl, sulfonyl, or NR6, wherein R6 is as defined above, and - as a substituent C^alkoxy, C2.4alkenyloxy, C2.4alkynyloxy, arylC^alkyloxy, acyl, C^alkyl-amino, Ci_4alkylthio, acylamino, (Ci_4alkoxy)carbonyl, (Ci-4alkoxy)carbonylamino, acyloxy, (Ci_ 4alkyl)carbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each of R2, R3, R4 and R5, independently, is H, Ci_4 alkyl or acyl or a pharmaceutically acceptable salt or hydrate thereof; benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane-diol or 2-amino-2-[4-(benzyloxyphenylthio)-2- chlorophenyl]propyl-1,3-propane-diol, or a pharmacological salt, solvate, hydrate or phosphate derivative thereof.

When the compound of formula I has one or more asymmetric centers in the molecule, the present invention is to be understood as embracing the various optical isomers, as well as racemates, diastereoisomers and mixtures thereof are embraced.

The compounds of formula I may exist in free or salt form. Examples of pharmaceutically acceptable salts of the compounds of the formula I include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, or, when appropriate, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine.

Acyl as indicated above may be a residue Ry-CO- wherein Ry is Ci_6alkyl, C3-6cycloalkyl, phenyl or phenyl-C^alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.

Aryl may be phenyl or naphthyl, preferably phenyl.

When in the compounds of formula I the carbon chain as R: is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.

Preferred compounds of formula I are those wherein Ri is Ci3-2oalkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein Ri is phenylalkyl substituted by C6_i4-alkyl chain optionally substituted by halogen and the alkyl moiety is a Ci_ 6alkyl optionally substituted by hydroxy. More preferably, Ri is phenyl-Ci-6alkyl substituted on the phenyl by a straight or branched, preferably straight, C6_i4alkyl chain. The C6-i4alkyl chain may be in ortho, meta or para, preferably in para.

Preferably each of R2 to R5 is H.

Preferred S1P receptor modulators of the invention are selected 2-amino-2-tetradecyl-1,3-propanediol, pharmacological salt thereof, prodrug, and phosphate thereof. An example of S1P receptor modulator is FTY720, Le. 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form (referred to hereinafter as Compound A), e.g. the hydrochloride, as shown:

Another preferred S1P receptor modulator is the phosphate derivative form (FTY720-phosphate), referred to hereinafter as Compound B, as shown:

In a specific embodiment of the invention, the S1P receptor modulator of the invention, e.g. fingolimod in free form, in a pharmaceutically acceptable salt form or fingolimod-phosphate, is administered orally.

According to the invention, there is provided: 1.1 A S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, e.g. Compound A or Compound B, e.g. hydrochloride salt of FTY720, for use in reducing the number of persistent T1 hypointense lesions in the brain, e.g. in MS patients, in particular RRMS patients. 1.2 A S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, e.g. Compound A or Compound B, e.g. hydrochloride salt of FTY720, for use in preventing or reducing the formation of T1 hypointense lesions in the brain, e.g. in MS patients, in particular RRMS patients. 1.3 A S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, e.g. Compound A or Compound B, e.g. hydrochloride salt of FTY720, for use in preventing inflammatory lesions in the brain, e.g. preexisting active inflammatory lesions, to evolve into T1 hypointense lesions, or for reducing the number of active inflammatory lesions in the brain, e.g. preexisting active inflammatory lesions, that evolve into T1 hypointense lesions. E.g. in MS patients, in particular RRMS patients. 1.4 A S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, for use in preventing, limiting or stopping brain tissue damage or in reducing the progression of brain tissue damage that arises from active inflammatory lesions in the brain. 1.5 A S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, for use in preventing, limiting or stopping brain tissue damage or in reducing the progression of brain tissue damage, by reducing the number of active inflammatory lesions in the brain. 1.6 A S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, for use in preventing, limiting or stopping brain tissue damage, or in reducing the progression of brain tissue damage, by reducing the formation of T1 hypointense lesions in the brain. 1.7 A S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, for use in preventing, limiting or stopping brain tissue damage or in reducing the progression of brain tissue damage, by reducing the number of T1 hypointense lesions the brain. 1.8 A S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, for use in treating MS by reducing the formation of T1 hypointense lesions in the brain. 1.9 A S1P receptor modulator or agonist as defined above wherein the brain tissue damage results from an autoimmune disease e.g. multiple sclerosis, e.g. Relapsing-remitting RRMS Secondary-progressive (SPMS), Primary-progressive (PPMS) or Progressiverelapsing (PRMS). 1.10 A S1P receptor modulator or agonist as defined above wherein the brain tissue damage results from an autoimmune disease with CNS involvement, e.g. Neuromyelitis Optica (NMO), Systemic Lupus Erythematosus (SLE), optic neuritis (ON). 1.11 A S1P receptor modulator or agonist as defined above wherein the brain tissue damage results from Amyotrophic Lateral Sclerosis (ALS). 1.12 FTY720 for use as defined above under 1.1 to 1.9, whereby FTY720 is administered at a daily dosage of 0.5 mg. 2.1 A method for preventing, limiting or stopping brain tissue damage or for reducing the progression of brain tissue damage that arises from active inflammatory lesions in the brain in a subject in need thereof, comprising administering to the subject a S1P receptor modulator or agonist, e.g. FTY720 or a pharmaceutically acceptable salt thereof, or Compound B. 3.1 Use of a S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, e.g. Compound A or Compound B, e.g. hydrochloride salt of FTY720, in the manufacture of a medication for reducing the number of persistent T1 hypointense lesions in the brain, e.g. in MS patients, in particular RRMS patients. 3.2 Use of a S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, e.g. Compound A or Compound B, e.g. hydrochloride salt of FTY720, in the manufacture of a medication, for preventing or reducing the formation of T1 hypointense lesions in the brain, e.g. in MS patients, in particular RRMS patients. 3.3 Use of a S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, e.g. Compound A or Compound B, e.g. hydrochloride salt of FTY720, in the manufacture of a medication for preventing inflammatory lesions in the brain, e.g. preexisting active inflammatory lesions, to evolve into T1 hypointense lesions, or for reducing the number of active inflammatory lesions in the brain, e.g. preexisting active inflammatory lesions, that evolve into T1 hypointense lesions, e.g. in MS patients, in particular RRMS patients. 3.4 Use of a S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, in the manufacture of a medication for preventing, limiting or stopping brain tissue damage or for reducing the progression of brain tissue damage that arises from active inflammatory lesions in the brain. 3.5 The use of a S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, in the manufacture of a medication for preventing, limiting or stopping brain tissue damage or for reducing the progression of brain tissue damage, by reducing the number of active inflammatory lesions in the brain. 3.6 Use of a S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, in the manufacture of a medication for preventing, limiting or stopping brain tissue damage, or for reducing the progression of brain tissue damage, by reducing the formation of T1 hypointense lesions in the brain. 3.7 Use of a S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, in the manufacture of a medication for preventing, limiting or stopping brain tissue damage, or for reducing the progression of brain tissue damage, by reducing the formation of T1 hypointense lesions in the brain. 3.8 Use of a S1P receptor modulator or agonist, e.g. FTY720, a salt or phosphate thereof, in the manufacture of a medication for preventing or treating MS by reducing the formation of T1 hypointense lesions in the brain, or by reducing the number of active inflammatory lesions in the brain, e.g. preexisting active inflammatory lesions, that evolve into T1 hypointense lesions. 3.9 Use of a S1P receptor modulator or agonist as defined above wherein the brain tissue damage results from an autoimmune disease e.g. multiple sclerosis, e.g. Relapsing-remitting RRMS Secondary-progressive (SPMS), Primary-progressive (PPMS) or Progressive-relapsing (PRMS). 3.10 Use of a S1P receptor modulator or agonist as defined above wherein the brain tissue damage results from an autoimmune disease with CNS involvement, e.g. Neuromyelitis Optica (NMO), Systemic Lupus Erythematosus (SLE), optic neuritis (ON). 3.11 Use of a S1P receptor modulator or agonist as defined above wherein the brain tissue damage results from Amyotrophic Lateral Sclerosis (ALS). 3.12 The use of FTY720 in the manufacture of a medication as defined above, whereby said medication is administered at a daily dosage of 0.5 mg or 1.25 mg.

Clinicians usually categorize patients having MS into four types of disease patterns: • Relapsing-remitting (RR-MS): Discrete motor, sensory, cerebellar or visual attacks that occur over 1 -2 weeks and often resolve over 1 -2 months. Some patients accrue disability with each episode, yet remain clinically stable between relapses. About 85% of patients initially experience the RR form of MS, but within 10 years about half will develop the secondary progressive form. • Secondary-progressive (SP-MS): Initially RR followed by gradually increasing disability, with or without relapses. Major irreversible disabilities appear most often during SP. • Primary-progressive (PP-MS): Progression disease course from onset without any relapses or remissions, affecting about 15% of MS patients. • Progressive-relapsing (PR-MS): Progressive disease from onset with clear acute relapses; periods between relapses characterized by continuing progression.

Accordingly, the patient to be treated with the S1P receptor modulator or agonist, e.g. FTY720, a pharmaceutically acceptable salt thereof, or Compound B, may be affected by one or more of Relapsing-remitting (RRMS), Secondary-progressive (SPMS), Primary-progressive (PPMS) and Progressive-relapsing (PRMS) forms of MS.

According to the invention, multiple sclerosis refers to Relapsing-remitting (RRMS), Secondary-progressive (SPMS), Primary-progressive (PPMS) or Progressive-relapsing (PRMS), for example to RRMS.

Daily dosages required in practicing the method of the present invention when a S1P receptor modulator or agonist is used will vary depending upon, for example, the compound used, the host, the mode of administration and the severity of the condition to be treated. A preferred daily dosage range is about from 0.1 to 100 mg as a single dose or in divided doses. Suitable daily dosages for patients are on the order of from e.g. 0.1 to 50 mg p.o.

The S1P receptor modulator or agonist may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions. In a specific embodiment the S1P receptor modulator or agonist, e.g. FTY720 or a salt thereof, or Compound B, is administered orally. Oral formulation may be in the form of a powder, granule or pellets or a unit dosage form, for example a tablet or capsule. In a specific embodiment, FTY720 or a pharmaceutically acceptable salt thereof is administered in the form of a unit dosage, e.g. a capsule, each unit dosage suitably containing 0.5 to 10 mg of FTY720, e.g. 0.5 mg.

Suitable unit dosage forms for oral administration comprise from ca. 0.1 to 30 mg, usually 0.25 to 30 mg S1P receptor modulator or agonist, together with one or more pharmaceutically acceptable diluents or carriers therefore. The S1P receptor modulator or agonist, e.g. FTY720 or a pharmaceutically acceptable salt thereof, may be administered at a dose of 0.5 mg or 1,25mg, e.g. 0.5mg.

Utility of an S1P receptor modulator or agonist in treating diseases and conditions as hereinabove specified may be demonstrated in standard animal or clinical tests, e.g. in accordance with the methods described hereinafter.

Example

Patients with Relapsing Remitting Multiple Sclerosis received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo (Pbo), in a 24-month, double-blind, randomized study. The patients were from 18 to 55 years of age, with a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years.

The effect of fingolimod therapy on the evolution of preexisting Gd+ lesions to persistent T1 hypointense lesions in RRMS patients was evaluated. Gd+ lesions detected in the screening MRI were followed at each post baseline scan to evaluate the evolution of such lesions into persistent T1 hypointense lesions. Summary statistics were generated at both the patient and lesion level by treatment group (fingolimod 0.5mg, 1.25mg and Pbo). The proportion of Gd+ lesions (%) that evolved into T1 hypointense lesions and patients (%) in whom this was observed was estimated at Months (M) 6, 12 and 24 by a logistic Generalized Estimating Equation (GEE) method and a logistic regression model adjusted for treatment and baseline number of Gd+ lesions.

Results

Of the 1270 patients with available scans at screening, 38% of the fingolimod 0.5 mg group and 36.8% of the Pbo group had >1 Gd+ lesion. Groups were balanced except for lower mean number (SD) of Gd+ lesions/patient at screening in the Pbo (3.4[4j) vs. the fingolimod groups (0.5 mg: 4.3[8.4]; 1.25 mg: 4.6[6.5]). The mean % Gd+ lesions at screening that evolved into T1 hypointense lesions was lower in the fingolimod 0.5 mg group vs. Pbo, at all-time points (M6, 39% vs 53% [odds ratio, OR] 0.61 ,p=0.006, M12: 30% vs.43% [OR 0.62,p=0.012] and M 24, 29% vs. 38% [OR:0.63,p=0.018]). The % patients who had any Gd+ lesion at screening that evolved to a T1 hypointense lesion was lower at M 6, 12 and 24 for fingolimod 0.5 mg vs. Pbo (MO-6:63% vs 75%, p=0.014; M0-12:65% vs.76%,p=0.031; MO-24:66% vs.76%,p=0.042). Data for fingolimod 1.25 mg/day were comparable after correction for imbalances at screening.

These results show that fingolimod 0.5 mg significantly reduces the proportion of Gd+ lesions at screening that evolve into persistent T1 hypointense lesions at M6, M12 and M24, versus placebo. In addition, the data shows that the proportion of patients in whom any Gd+ lesions evolve to persistent T1 hypointense lesions is also reduced by S1P receptor modulator compared to placebo. These findings indicate that fingolimod reduces the permanent damage caused by acute inflammatory lesions already present before starting treatment.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (6)

1. THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1 A method for reducing the number of persistent T1 hypointense lesions in the brain, in a subject in need thereof, comprising administering to the subject a S1P receptor modulator or agonist, e.g. FTY720 or a pharmaceutically acceptable salt thereof, or Compound B.
2. 2. A method for preventing, limiting or stopping brain tissue damage or for reducing the progression of brain tissue damage that arises from active inflammatory lesions in the brain in a subject in need thereof, comprising administering to the subject a S1P receptor modulator or agonist, e.g. FTY720 or a pharmaceutically acceptable salt thereof, or Compound B.
3. 3. The method of claim 2 wherein the brain tissue damage results from an autoimmune disease, e.g. multiple sclerosis.
4. 4. The method of claim 1 or 2 wherein the subject to be treated is affected by an autoimmune disease, e.g. multiple sclerosis.
5. 5. The method according to any preceding claim wherein the S1P receptor modulator or agonist is FTY720, a pharmaceutically acceptable salt or a phosphate thereof, e.g. FTY720 hydrochloride salt.
6. 6. The method according to any preceding claim comprising administering to the subject a daily dosage of FTY720 or a pharmaceutically acceptable salt thereof of about 0.5mg.