WO2018129231A1

WO2018129231A1 - Method for treating multiple sclerosis

Info

Publication number: WO2018129231A1
Application number: PCT/US2018/012455
Authority: WO
Inventors: Charles A. Dinarello
Original assignee: Olatec Therapeutics Inc
Current assignee: Olatec Therapeutics Inc
Priority date: 2017-01-06
Filing date: 2018-01-05
Publication date: 2018-07-12
Anticipated expiration: 2019-07-06
Also published as: US20190321325A1; US10548870B2; EP3589370A1; EP3589370A4

Abstract

The present invention is directed to a method for treating multiple sclerosis by administering dapansutrile to a subject in need thereof. A preferred route of administration is oral administration.

Description

METHOD FOR TREATING MULTIPLE SCLEROSIS

FIELD OF THE INVENTION

The present invention relates to a method for treating multiple sclerosis using a pharmaceutical composition comprising dapansutrile.

Reference to Sequence Listing, Table or Computer program

The Sequence Listing is concurrently submitted herewith with the specification as an ASCII formatted text file via EFS-Web with a file name of Sequence Listing.txt with a creation date of December 29, 2017, and a size of 533 bytes. The Sequence Listing filed via EFS-Web is part of the specification and is hereby incorporated in its entirety by reference herein.

BACKGROUND OF THE INVENTION

Multiple sclerosis (MS) is an autoimmune disease with the autoimmune activity directed against central nervous system (CNS) antigens. MS is an inflammatory

demyelinating disease of the CNS, which results in damage to the protective covering (myelin sheath) that surrounds nerve fibers in the brain and spinal cord, leading to the loss of the myelin sheathing around neuronal axons (demyelination), axonal loss, and the eventual death of neurons, oligodendrocytes and glial cells.

When the myelin sheath is damaged, nerve impulses slow or even stop, causing neurological problems. MS is characterized clinically by relapses and remissions, often leading to progressive physical impairment. The cause of MS is unknown; however, pathologic, genetic, and immunologic features have been identified which suggest that the disease has an autoimmune basis. Although the antigenic target in MS is believed to be confined within the CNS, a systemic immunoregulatory defect may be present. T cells that were reactive to myelin basic protein (MBP) were detected in the blood of MS patients. Circulating blood cells of MS patients were also primed for enhanced cytokine synthesis. Exaggerated mitogen-inducible cytokine synthesis by peripheral monocytes was measured during the weeks immediately preceding the onset of episodes of relapsing MS. Thus, the exaggerated production of tumor necrosis factor (TNF), interleukin-1 (IL-1), and interferon - γ by circulating blood cells may serve as a peripheral trigger or marker for the induction of demyelinating inflammation in the CNS. An estimated 2,500,000 people in the world suffer from MS. It is one of the most common diseases of the CNS in young adults. MS is a chronic, progressing, disabling disease, which generally strikes its victims sometime after adolescence, with diagnosis generally made between 20 and 40 years of age, although onset may occur earlier. The disease is not directly hereditary, although genetic susceptibility plays a part in its development. MS is a complex disease with heterogeneous clinical, pathological and immunological phenotype.

BRIEF DESCRIPTION OF THE DRAWING FIG. 1 shows clinical course of animals treated with dapansutrile (OLT1177) or saline in an EAE model.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

"About," as used herein, is ± 10% of the recited value.

"An effective amount," as used herein, is the amount effective to treat a disease by ameliorating the pathological condition or reducing the symptoms of the disease.

"Pharmaceutically acceptable salts," as used herein, are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Pharmaceutically acceptable salt forms include various crystalline polymorphs as well as the amorphous form of the different salts. The pharmaceutically acceptable salts can be formed with metal or organic counterions and include, but are not limited to, alkali metal salts such as sodium or potassium; alkaline earth metal salts such as magnesium or calcium; and ammonium or tetraalkyl ammonium salts, i.e., X₄+ (wherein X is C_1-4).

Description

The inventors have discovered that dapansutrile, or the pharmaceutically acceptable salts thereof, is effective in treating multiple sclerosis. Dapansutrile (3- methanesulfonylpropionitrile), CAS#: 54863-37-5, has a formula weight of 133.17, and its structure is shown below.

The present invention provides methods for treating a subject having multiple sclerosis and for preserving and/or increasing myelin content in a subject having multiple sclerosis. The method comprises administering an effective amount of dapansutrile to a subject suffering from multiple sclerosis.

There are four major clinical types of MS that the present invention is useful to treat: 1) relapsing-remitting MS, characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery; periods between disease relapses characterized by a lack of disease progression; 2) secondary progressive MS, characterized by initial relapsing remitting course followed by progression with or without occasional relapses, minor remissions, and plateaus; 3) primary progressive MS, characterized by disease progression from onset with occasional plateaus and temporary minor improvements allowed; and 4) progressive relapsing MS, characterized by progressive disease onset, with clear acute relapses, with or without full recovery; periods between relapses characterized by continuing progression.

In one embodiment, dapansutrile slows or prevents neurodegeneration including demyelination and neuronal death.

Pharmaceutical Compositions

The active compound dapansutrile, or its pharmaceutically acceptable salt or solvate in pharmaceutical compositions in general is in an amount of about 0.1-5% for an injectable formulation, about 1-90% for a tablet formulation, about 1-100% for a capsule formulation, about 0.1-5% for a patch formulation, about 0.01-20%, or 0.05-20%, or 0.1-20%, or 0.2-15%, or 0.5-10%), or 1-5%) (w/w) for a topical formulation.

Pharmaceutically acceptable carriers, which are inactive ingredients, can be selected by those skilled in the art using conventional criteria. Pharmaceutically acceptable carriers include, but are not limited to, non-aqueous based solutions, suspensions, emulsions, microemulsions, micellar solutions, gels, and ointments. The pharmaceutically acceptable carriers may also contain ingredients that include, but are not limited to, saline and aqueous electrolyte solutions; ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose; pH adjusters and buffers such as salts of hydroxide, phosphate, citrate, acetate, borate; and trolamine; antioxidants such as salts, acids and/or bases of bisulfite, sulfite, metabi sulfite, thiosulfite, ascorbic acid, acetyl cysteine, cystein, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherols, and ascorbyl palmitate; surfactants such as lecithin, phospholipids, including but not limited to

phosphatidylcholine, phosphatidylethanolamine and phosphatidyl inositiol; poloxamers and ploxamines, polysorbates such as polysorbate 80, polysorbate 60, and polysorbate 20, polyethers such as polyethylene glycols and polypropylene glycols; polyvinyls such as polyvinyl alcohol and povidone; cellulose derivatives such as methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and hydroxypropyl

methylcellulose and their salts; petroleum derivatives such as mineral oil and white petrolatum; fats such as lanolin, peanut oil, palm oil, soybean oil; mono-, di-, and

triglycerides; polymers of acrylic acid such as carboxypolymethylene gel, and

hydrophobically modified cross-linked acrylate copolymer; polysaccharides such as dextrans and glycosaminoglycans such as sodium hyaluronate. Such pharmaceutically acceptable carriers may be preserved against bacterial contamination using well-known preservatives, these include, but are not limited to, benzalkonium chloride, ethylene diamine tetra-acetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or may be formulated as a non-preserved formulation for either single or multiple use.

For example, a tablet formulation or a capsule formulation of dapansutrile may contain other excipients that have no bioactivity and no reaction with the active compound. Excipients of a tablet may include fillers, binders, lubricants and glidants, disintegrators, wetting agents, and release rate modifiers. Binders promote the adhesion of particles of the formulation and are important for a tablet formulation. Examples of binders include, but not limited to,

carboxymethylcellulose, cellulose, ethylcellulose, hydroxypropylmethylcellulose,

methylcellulose, karaya gum, starch, starch, and tragacanth gum, poly(acrylic acid), and polyvinylpyrrolidone.

For example, a patch formulation of dapansutrile may comprise some inactive ingredients such as 1,3-butylene glycol, dihydroxyaluminum aminoacetate, disodium edetate, D- sorbitol, gelatin, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. A patch formulation may also contain skin permeability enhancer such as lactate esters (e.g., lauryl lactate) or diethylene glycol monoethylether.

Topical formulations including dapansutrile can be in a form of gel, cream, lotion, liquid, emulsion, ointment, spray, solution, and suspension. The inactive ingredients in the topical formulations for example include, but not limited to, lauryl lactate (emollient/permeation enhancer), di ethylene glycol monoethyl ether (emollient/permeation enhancer), DMSO

(solubility enhancer), silicone elastomer (rheology/texture modifier), caprylic/capric

triglyceride, (emollient), octisalate, (emollient/UV filter), silicone fluid (emollient/diluent), squalene (emollient), sunflower oil (emollient), and silicone dioxide (thickening agent). In one embodiment, diethylene glycol monoethyl ether is included in the topical gel formulation.

Method of Use

The present invention is directed to a method of treating multiple sclerosis.

Dapansutrile, or the pharmaceutically acceptable salts thereof, can be used as is, or it can be administered in the form of a pharmaceutical composition that additionally contains a pharmaceutically acceptable carrier. The method comprises the steps of first identifying a subject suffering from multiple sclerosis, and administering to the subject the active compound, in an amount effective to treat multiple sclerosis.

In one embodiment, the subject has multiple sclerosis, such as relapsing-remitting multiple sclerosis, and is administered an effective amount of dapansutrile for a period of time sufficient to achieve one or more of the following changes: (a) reduced frequency of relapse in the subject, (b) reduced probability of relapse in the subject, (c) reduced annualized relapse rate in the subject, (d) reduced risk of disability progression in the subject, (e) reduced number of new or newly enlarging T2 lesions in the subject, (f) reduced number of new non- enhancing Tl hypointense lesions in the subject, and (g) reduced number of gadolinium (Gd+) lesions in the subject, wherein the changes (a)-(g) are relative to a subject treated with placebo, or the subject prior to treatment.

In another embodiment, a subject having relapsing-remitting multiple sclerosis is administered an effective amount of dapansutrile for a period of time sufficient to achieve one or more of the following changes: (a) reduced annualized relapse rate of at least 30%; (b) reduced risk of disability progression of at least 30%; and (c) reduced number of new or newly enlarging T2 lesions of at least 65% in the subject, wherein the changes (a)-(c) are relative to a subject treated with placebo, or the subject prior to treatment.

The pharmaceutical composition of the present invention can be applied by local administration or systemic administration. Local administration includes topical

administration. Systemic administration includes oral, parenteral (such as intravenous, intramuscular, subcutaneous or rectal), and other systemic routes of administration. In systemic administration, the active compound first reaches plasma and then distributes into target tissues. Oral administration is a preferred route of administration for the present invention.

Dosing of the composition can vary based on the extent of the injury and each patient's individual response, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents. For systemic administration, plasma concentrations of the active compound delivered can vary; but are generally Ixl0^"10-lxl0^"4 moles/liter, and preferably Ixl0^"8-lxl0^"5 moles/liter.

In one embodiment, the pharmaceutical composition is administrated orally to a subject. The dosage for oral administration is generally 0.1-100, 0.1-20, or 1-50 mg/kg/day, depending on the subject's age and condition. For example, the dosage for oral

administration is 0.1-10, 0.5-10, 1-10, 1-5, or 5-50 mg/kg/day for a human subject. In one embodiment, the active compound can be applied orally to a human subject at 1-100, 10-50, 20-1000, 20-500, 100-800, or 200-600 mg/dosage, 1-4 times a day, depends on the patient's age and condition.

In one embodiment, the pharmaceutical composition is administrated intravenously to a subject. The dosage for intravenous bolus injection or intravenous infusion is generally 0.1- 10, 0.03 to 5, or 0.03 to 1 mg/kg/day.

In one embodiment, the pharmaceutical composition is administrated subcutaneously to the subject. The dosage for subcutaneous administration is generally 0.1-1, 0.3-20, 0.3-3, or 1-6 mg/kg/day.

In one embodiment, the composition is applied topically. The composition is topically applied at least 1 or 2 times a day, or 3 to 4 times per day, depending on the medical issue and the disease pathology. In general, the topical composition comprises about 0.01- 20%, or 0.05-20%, or 0.1-20%, or 0.2-15%, 0.5-10, or 1-5 % (w/w) of the active compound. Typically 0.2-10 mL of the topical composition is applied to the individual per dose.

The time period for which the subject is dosed with the dapansutrile in any of the methods described above can range, for example, every day, every 2-4 days, or every week, from about 1 week to the remaining lifespan of the subject. Dapansutrile can be dosed, for example, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50 weeks, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50 years.

Those of skill in the art will recognize that a wide variety of delivery mechanisms are also suitable for the present invention. The present invention is useful in treating a mammal subject, such as humans, horses, and dogs. The present invention is particularly useful in treating humans.

The following examples further illustrate the present invention. These examples are intended merely to be illustrative of the present invention and are not to be construed as being limiting.

EXAMPLES

Example 1. Rat Model for Treating Multiple Sclerosis (Prophetic Example)

The experiments are performed according to Marin et al (Experimental Neurology, 131 : 221-228 (1995)) with some modification; Marin et al is incorporated herein by reference.

The mouse experimental allergic encephalomyelitis (EAE) is an induced autoimmune demyelinating disease with many similarities to human MS in its clinical manifestations. In both EAE and MS, clinical disease is associated with blood-brain barrier dysfunction, infiltration of central nervous system by mononuclear cells (mainly macrophages and T lymphocytes, and serum products), and demyelination (Baker et al. J. Neuroimmunol., 1990, 28:261; Butter et al., J. Neurol. Sci., 1991, 104:9; Harris et al., Ann. Neurol., 1991, 29:548; Kermonde et al., Brain, 1990, 113: 1477). The ability of dapansutrile to slow or prevent neurodegeneration including demyelination and neuronal death can be assessed in an EAE model.

Experimental Allergic Encephalomyelitis (EAE) induction.

Rats are anesthetized with 2% isoflurane + 0₂ and immunized on Day 0 in the footpad of the left hind limb with 0.1 ml of an emulsion containing myelin basic protein (MBP) at one of the following doses: 0, 1, 3, 10 or 30 μg (fragment 68-84). The MBP is dissolved in phosphate-buffered saline (PBS) and emulsified with an equal volume of complete Freund's adjuvant (CFA) containing 5 mg/ml of Mycobacterium tuberculosis H37Ra. Control rats receive 0.1 ml of the PBS/CFA emulsion with no MBP in the footpad of the left hind limb.

Clinical scoring of EAE.

Evaluation of clinical disease is performed on a daily basis using a standard 0-5 scoring system. The spectrum of rating is 0, normal; 0.5, partial loss of tail tone; 1, complete loss of tail tone; 2, dragging of one hind limb; 3, paralysis of both hind limbs; 4, moribund; and 5, death. Daily weights are recorded for individual rats and weight loss/gain is expressed relative to initial weight. Treatment of EAE.

Dapansutrile is diluted in about 200 μΙ_, of an oral vehicle such as Ora-Plus^® and is given orally to rats at 1-500 or 10-100 mg/kg/day. Treatment with active compound begins at Day 0 or Day 9 after immunization with MBP and continued until 21 days post- immunization. The efficacy of four different dosing regimens is compared over that time period. In each experiment, the control rats received the same amounts of vehicle as the active compound- treated groups. Cyclosporin A is used as a positive control in some studies.

Cyclosporin A (4 mg/kg) or vehicle (PBS) is administered subcutaneously on alternate days for 22 days beginning at the day of immunization. CNS pathology.

In a separate study, the effects of treatment with the active compound is determined on CNS pathology induced by immunization with MBP (0, 10, or 30 μg). Dapansutrile at 1- 100 or 10-100 mg/kg/day is administered every other day beginning on Day 9 post-MBP. Animals are killed (via C0₂) on Days 9, 14, or 20 post-MBP injection. The brain and spinal cord from each rat are removed and placed in 10% neutral -buffered formalin. Following fixation for at least 72 h, cross sections of the brain are made at the optic chiasm caudal to the attachment of the pituitary and at the transverse fibers of the pons. The spinal cord is examined by making 4 to 6 cross sections through the cervical, thoracic, lumbar, and sacral portions. The sacral segment with attached caudal nerves is embedded longitudinally.

Tissues are processed for paraffin embedding and stained with hematoxylin and eosin.

Histologic evaluations are performed without knowledge of the treatment groups. Each slide is assigned a numerical score ranging from 1 to 4 to indicate the intensity of inflammation and demyelination. Scoring criteria are as follows: 1, minimal with small perivascular cuffs of inflammatory cells surrounding one to two vessels; 2, mild with small perivascular cuffs of inflammatory cells surrounding three or more vessels with little if any extension of inflammation into parenchyma; 3, moderate with prominent perivascular cuffs of inflammatory cells with three or more vessels and moderate extension of the inflammation into the surrounding parenchyma; and 4, marked with the majority of vessels with prominent perivascular cuffs of inflammatory cells with extensive involvement of the neuropil in the inflammatory process.

A composite inflammatory score is determined for each rat for each CNS region. Means ± SEM score values are computed for each portion of the CNS for each time point and compared against the vehicle-treated animals.

Statistical analyses.

Values of clinical and histopathologic scoring are expressed as means ± SEM. The integrated clinical score for each rat over the entire course of the disease is calculated as the area under the curve of daily clinical score versus time (units arbitrary). The values of the treated groups for integrated clinical scoring are compared statistically against those of the control group using the Mann— Whitney test. Student's t test is used to ascertain whether disease duration is reduced by the active compound. Example 2. Effect of Dapansutrile for Treating Multiple Sclerosis in Mice

EAE induction and dapansutrile treatment

Active immunization was done in female adult (8 weeks old) C57B1/6 mice.

Briefly, m i c e w e r e subcutaneously injected with 30C^g of myelin oligodendrocyte glycoprotein (MOG)35-55 peptide (ME VGW YRSPF SRVYHLYRNGK, SEQ ID NO: 1) emulsified in complete Freund's Adjuvant (Sigma Aldrich) supplemented with 4 mg of micobacterioum tuberculosis H37RA (DIFCO Laboratories). On day 0 and 2 post- immunization, mice were also injected intraperitoneally (i.p.) with 500 ng of pertussis toxin (List Biological Laboratories). Starting on day 0, mice were injected intraperitoneally twice daily with dapansutrile (OLT1177, 60 mg/kg) or saline. Each group had 10 mice.

Functional assessment

Animals were monitored daily for signs of EAE and the scoring system is as follows: 0 = no clinical symptoms; 0.5 = partial floppy tail, 1 = floppy tail; 2 = mild hind- limb weakness (quick righting reflex); 3= severe hind-limb weakness (slow righting reflex); 3.5 = weakness in hind limbs or paralysis of one hind limb; 4 = paralysis of both hind limbs, 4.5 = weakness in front limbs; 5 = paralysis of front limbs; 6= moribund. At day 21 post- immunization, mice were perfused with 4% paraformaldehyde solution, spinal cords removed for histopathological studies if required. Results

The onset of clinical signs of EAE was observed between day 9 and 12 post- immunization in mice injected with saline. From this time point, mice underwent progressive functional disabilities, reaching a plateau of maximal disease outcomes by day 18-19 post- immunization (Fig 1). Mice treated with dapansutrile displayed

significant lower disease scores. Statistical analysis revealed significant differences in clinical score starting at day 11 post-immunization and remaining significantly reduced until the end of the study at day 21 (FIG. 1). The results show that in an animal model of multiple sclerosis, dapansutrile treated group ameliorated clinical signs of disease at days 11-21 comparing with the saline-treated group. Two-way ANOVA with Bonferroni's post hoc test shows *p<0.05 for multiple comparisons, n=10 for both groups.

Example 3. Treating Multiple Sclerosis in Humans (Prophetic Example)

A study is conducted to evaluate the efficacy and safety of dapansutrile over 2 years in human subjects with relapsing-remitting multiple sclerosis ("RR-MS").

Subjects 18-55 years of age with McDonald criteria diagnosis of RR-MS and an Expanded Disability Status Scale score of 0.0-5.0 (EDSS, see Definition in US2014/0163100, which is incorporated herein by reference) are eligible for enrolment. Subjects are randomly assigned in a 1 : 1 : 1 ratio to placebo, dapansutrile PO twice daily (BID), or dapansutrile three times daily (TID), in an amount of 10-300 mg per dosage. Safety and tolerability are assessed by continuous adverse event monitoring and laboratory tests at all monthly visits.

Additionally, physical examination, vital signs, and 12-lead ECG are evaluated.

The primary endpoint of the study is the proportion of subjects relapsing at 2 years, with relapses confirmed by an independent neurology evaluation committee to ensure consistent and accurate reporting across sites. Secondary clinical efficacy endpoints at 2 years are the annualized relapse rate (ARR) and disability progression using EDSS.

It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the scope of the present invention as set forth in the claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating multiple sclerosis, comprising the step of administering to a subject suffering from multiple sclerosis an effective amount of dapansutrile.

2. The method according to Claim 1, wherein said compound is administered by systemic administration.

3. The method according to Claim 1, wherein said compound is administered by oral administration.

4. The method according to Claim 1, wherein said multiple sclerosis is relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, or progressive relapsing multiple sclerosis.

5. The method according to Claim 4, wherein said multiple sclerosis is relapsing-remitting multiple sclerosis.

6. The method according to Claim 5, wherein dapansutrile is administered for a period of time sufficient to achieve one or more of changes selected from the group consisting of: (a) reduced frequency of relapse in the subject, (b) reduced probability of relapse in the subject, (c) reduced annualized relapse rate in the subject, (d) reduced risk of disability progression in the subject, (e) reduced number of new or newly enlarging T2 lesions in the subject, (f) reduced number of new non-enhancing Tl hypointense lesions in the subject, and (g) reduced number of gadolinium (Gd+) lesions in the subject.

7. The method according to Claim 5, wherein dapansutrile is administered for a period of time sufficient to achieve one or more of changes selected from the group consisting of:

(a) reduced annualized relapse rate of at least 30%; (b) reduced risk of disability progression of at least 30%; and (c) reduced number of new or newly enlarging T2 lesions of at least 65% in the subject.