CN-111902188-B - Treatment of demyelinating diseases

Abstract

Described herein are methods of promoting remyelination in a subject suffering from a demyelinating disease by administering to the subject a combination of a steroid hormone and a hedgehog signaling pathway modulator. Methods of administering a combination of drugs in a form suitable for nasal administration are also described.

Inventors

• C. Matten
• E. Trevor
• M. SCHUMACHER

Assignees

• 马特恩制药股份公司

Dates

Publication Date

20260505

Application Date

20190110

Priority Date

20180111

Claims (13)

1. 1. Use of an androgen receptor ligand and a Smo agonist in the manufacture of a medicament for promoting remyelination in a subject suffering from multiple sclerosis, wherein the use comprises administering to the subject an effective amount of an androgen receptor ligand and Smo agonist, wherein the androgen receptor ligand is testosterone, and wherein the Smo agonist is 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide (SAG).
2. 2. The use of claim 1, wherein the androgen receptor ligand and Smo agonist are administered substantially simultaneously or sequentially in separate compositions.
3. 3. The use of claim 1 or 2, wherein the androgen receptor ligand and Smo agonist are administered in the form of the same composition.
4. 4. The use of any one of the preceding claims, wherein one or both of the androgen receptor ligand and the Smo agonist are administered intranasally in the form of an intranasal pharmaceutical composition further comprising (a) at least one lipophilic or partially lipophilic carrier present in an amount of about 60% to about 98% by weight of the formulation, (b) at least one compound having surface tension reducing activity present in an amount of about 1% to about 20% by weight of the formulation, and (c) at least one viscosity modifier present in an amount of about 0.5% to about 10% by weight of the formulation.
5. 5. The use of claim 4, wherein the intranasal pharmaceutical composition comprises the androgen receptor ligand.
6. 6. The use of claim 4, wherein the intranasal pharmaceutical composition comprises the Smo agonist.
7. 7. The use of claim 4, wherein the intranasal pharmaceutical composition comprises the androgen receptor ligand and the Smo agonist.
8. 8. The use of any one of claims 1 to 7, wherein the androgen receptor ligand and Smo agonist are administered intranasally in the form of an intranasal pharmaceutical composition comprising a porous excipient, wherein the androgen receptor ligand and/or Smo agonist is loaded onto a surface of the porous excipient that is located inside a pore of the porous excipient.
9. 9. The use of claim 8, wherein the androgen receptor ligand is loaded onto a surface of the porous excipient that is inside a pore of the porous excipient.
10. 10. The use of claim 8, wherein the Smo agonist is loaded onto a surface of the porous excipient that is inside a pore of the porous excipient.
11. 11. The use of claim 8, wherein both the androgen receptor ligand and the Smo agonist are loaded onto a surface of the porous excipient that is inside a pore of the porous excipient.
12. 12. The use of any one of the preceding claims, wherein the subject is a human, non-human primate, dog, cat, cow, sheep, horse, rabbit, mouse or rat.
13. 13. Use of an androgen receptor ligand and a Smo agonist in the manufacture of a medicament for treating demyelination in a subject suffering from multiple sclerosis, wherein the use comprises administering the androgen receptor ligand and the Smo agonist to the subject, wherein the androgen receptor ligand is testosterone, and wherein the Smo agonist is 3-chloro-N- [ trans-4- (methylamino) cyclohexyl ] -N- [ [3- (4-pyridinyl) phenyl ] methyl ] benzo [ b ] thiophene-2-carboxamide (SAG).

Description

Treatment of demyelinating diseases Cross Reference to Related Applications The present application claims priority from U.S. c. ≡119 U.S. provisional application 62/616,173 filed on date 11 at 1/2018, the entire contents of which are incorporated herein by reference. Technical Field Described herein are compositions and methods for treating demyelinating diseases using steroid hormones and sonic hedgehog signaling pathway modulators. Background Myelin is a fat white substance that surrounds the axons of certain nerve cells, forming an electrical isolation layer. In humans, approximately 40% of the brain contains white matter, which includes densely packed fibers, with myelin being the main component (50-60% dry weight of white matter). Myelin is synthesized and maintained by Oligodendrocytes (OL) in the Central Nervous System (CNS). Oligodendrocytes are a type of glial cell that serves to support and isolate axons in the CNS. Oligodendrocytes are produced from Oligodendrocyte Precursor Cells (OPC) and are found only in the CNS. In demyelinating diseases, the myelin sheath of neurons of the nervous system is damaged. This disruption may impair the conduction of signals in the affected nerves, resulting in, for example, a lack of sensation, movement, cognition and other functions, which depend on the nerves involved. Among the various demyelinating diseases, multiple Sclerosis (MS) is the disabling neurological condition most prevalent in young adults worldwide. The multiple sclerosis foundation (Multiple Sclerosis Foundation) estimates that more than 400,000 people in the united states and about 250 tens of thousands of people worldwide have MS. In the united states, about 200 new cases are diagnosed weekly. It is a therapeutically expensive disease and in the united states, direct and indirect medical costs range from $ 8528 to $ 54244 per patient per year. Multiple sclerosis can disrupt the ability of part of the nervous system to communicate, leading to a range of physiological, psychological and sometimes mental problems. There is no known treatment for MS, but current treatments attempt to improve post-seizure function and prevent new episodes. Most drugs used to treat MS may be effective in the relapsing remitting form of the disease, but are generally ineffective in the progressive form of chronic demyelination characterized by axons. While the immunomodulatory agent orelizumab (Ocrelizumab) has recently been shown to be effective in the progressive form, orelizumab is associated with major potential side effects and is poorly tolerated. See Montalban x et al, "orey Zhu Shankang in primary progressive multiple sclerosis versus placebo", "new england journal of medicine (NEW ENGLAND Journal of Medicine) 376 209-220 (2017). In another approach, US 2013/0226133 describes a method of recovering myelin sheath of nerve fibers using stephanine sulfate. In another approach, US 2004/0141947 discloses a method for treating demyelinating CNS disorders using a colony stimulating factor or a colony stimulating factor-like ligand, such as, for example, a saxagliptin (sargramostim) (type 1 interferon homolog) and at least one additional therapeutic agent. In another approach, US 2004/0053850 describes a method of treating demyelinating diseases of the CNS by co-administration of the tripeptides gly-pro-glu and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainic acid antagonist compounds. In another approach, U.S. patent No. 4,760,092 claims a method of treating demyelinating diseases such as multiple sclerosis using colchicine or colchicine. In another approach, US 2013/0302410 describes a method of neuroprotection using dimethyl fumarate or monomethyl fumarate in demyelinating diseases. In another approach, US 2013/0108643 describes a method of treating autoimmune or inflammatory diseases using inhibitors of macrophage scavenger receptor class 1 MSR 1. In another approach, EP 0423943 describes the use of inhibitors of members of the collagenase family of mammals to treat demyelinating diseases. Despite these proposed methods, there remains a need for methods of promoting remyelination in subjects suffering from demyelinating diseases such as MS. Disclosure of Invention According to some embodiments, there is provided a method of promoting remyelination in a subject in need thereof, the method comprising administering to the subject an effective amount of a steroid hormone and a hedgehog signaling pathway modulator. In some embodiments, the steroid hormone is an androgen receptor ligand such as testosterone, a progesterone receptor ligand such as progesterone or allopregnanolone, an estrogen receptor ligand such as estradiol, or is dehydroepiandrosterone, or is a selective hormone receptor modulator, such as a selective androgen receptor modulator, a selective estrogen receptor modulator, or a selective progesterone receptor modulator. In some embodiments, the hedgehog signaling pathway modulator