WO2020191087A1

WO2020191087A1 - Therapeutic combinations for use in treating a muscular dystrophy

Info

Publication number: WO2020191087A1
Application number: PCT/US2020/023412
Authority: WO
Inventors: Stuart W. Peltz; Gregory O. VORONIN; Marla L. Weetall; Ellen Welch
Original assignee: Ptc Therapeutics, Inc.
Priority date: 2019-03-18
Filing date: 2020-03-18
Publication date: 2020-09-24

Abstract

Described herein are therapeutic combinations for use in treating a muscular dystrophy in a patient in need thereof. Specifically described herein is a therapeutically beneficial combination of a steroid therapeutic agent and a NF-_KB inhibitor for use in treating a muscular dystrophy in a patient in need thereof.

Description

THERAPEUTIC COMBINATIONS FOR USE IN TREATING A

MUSCULAR DYSTROPHY

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/819,750, filed on March 18, 2019, the contents of which are incorporated by reference herein.

FIELD

In one aspect described herein are therapeutic combinations for use in treating a muscular dystrophy in a patient in need thereof. In another aspect described herein is a therapeutically beneficial combination of a steroid therapeutic agent and a NF- kB inhibitor for use in treating a muscular dystrophy in a patient in need thereof.

INTRODUCTION

Steroid agents such as prednisone/prednisolone and deflazacort have been used for treating various diseases. Deflazacort is approved for use in treating Duchenne Muscular Dystrophy (DMD), providing therapeutic benefit by delaying loss of ambulation.

The small molecule N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide, having the generic name edasalonexent (International Publication WO2010/006085), is an orally bioavailable compound consisting of a polyunsaturated fatty acid conjugated to salicylic acid found to suppress the pathogenic NF-kB subunit p65/RelA in vitro and in vivo (JCI Insight. 2016 Dec 22; 1 (21 ): e90341 ).

Edasalonexent was tested in the Phase 1/2 MoveDMD clinical trial (see, Clinical Trials.gov Study NCT02439216) for treatment of Duchenne Muscular Dystrophy.

The NCT02439216 trial enrolled 31 boys, ages 4 to 7, with different DMD gene mutations excluding, as one of the enrollment criteria, use of corticosteroids within the 6 months prior to treatment initiation or planning to initiate steroid therapy within the 6 months prior to treatment initiation. Supported by preclinical results, the clinical biomarker data from the MoveDMD trial suggest that the therapy may be beneficial for preserving function of skeletal, diaphragm, and heart muscle. Results from the MoveDMD trial showed that boys treated with edasalonexent on average grew 2.1 inches and gained 2.9 pounds per year. Over 72 weeks of treatment, overall body mass index decreased from the 70th to the 55th percentile, closer to the average body mass index of unaffected boys in the same age range. Edasalonexent enabled normal growth, preserved muscle function and slowed disease progression compared with an off-treatment control period, as evaluated with the North Star Ambulatory Assessment and the time to stand, four-stair climb and 10-meter walk/run tests. (Lopes, J.M., Edasalonexent Leads to Normal Growth, Other Benefits in Boys with DMD, Phase 1/2 Trial Shows, Muscular Dystrophy News Today, February 22, 2019)(https://musculardystrophynews.com/2019/02/22/dmd- boys-improvements-edasalonexent-phase-1 -2-trial/).

The steroid (8S, 10S, 13S, 14S,16R, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12,14,15,16-hexahydro~6H-cyclopenta[a]phenanthren-3-one, having the generic name vamorolone (U.S. Patent 3,461 ,1 17 and U.S. Patent 9,198,921 ), is structurally similar to a glucocorticosteroid and has a similar mechanism of action, binding to the glucocorticoid receptor. Vamoroione is being developed as an alternative to certain glucocorticosteroids used as the current standard of care for treating DMD. (https://www.duchenneuk.org/vbp15#:~:text=).

The known therapeutic benefits provided by corticosteroids suggest that there still remains a great need for combinations with other agents that maintain or enhance the therapeutically beneficial activity of corticosteroids, have favorable and improved pharmaceutical properties resulting from combined administration, and are amenable to clinical evaluation for use in treating a muscular dystrophy in patients having high unmet medical need.

SUMMARY

In one aspect, described herein is a therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In one aspect, the steroid therapeutic agent is selected from the group consisting of prednisone, prednisolone, deflazacort, 21-desacetyl deflazacort (21-desDFZ). and vamoroione.

In another aspect, the steroid therapeutic agent is selected from the group consisting of deflazacort, 21 -desacetyl deflazacort (21-desDFZ), and vamoroione. In another aspect, the steroid therapeutic agent is selected from deflazacort.

In another aspect, the steroid therapeutic agent is selected from vamorolone.

In one aspect, the NF-kB inhibitor is selected from the group consisting of edasolonexent, and CAT-1041.

In another aspect, the NF-kB inhibitor is selected from edasolonexent.

In another aspect, the steroid therapeutic agent is prednisone, described as

(8S,9S, 10R, 13S, 14S, 17R)-17-hydroxy-17-(2-hydroxyacetyl )-10, 13-dimethyl- 7,8,9,10,12,13,14,15,16,17-decahydro-3FI-cyclopenta[a]phenanthrene-3, 11 (6H)- dione and hereinafter referred to as“Compound 1” or“Cpd 1", having the structure:

In another aspect, the steroid therapeutic agent is prednisolone, described as (8S,9S,10R,11 S,13S,14S,17R)-11 ,17-dihydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[a]phenanthren-3-one and hereinafter referred to as“Compound 2” or “Cpd 2”, having the structure:

In another aspect, the steroid therapeutic agent is defiazacort, described as 2- ((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trimethyl-4-oxo- 1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1:4,5]indeno[1 ,2- d]oxazol-8b-yl)-2-oxoethyl acetate, alternatively described as (11 b,16b)-21- (acetyloxy)-l 1-hydroxy-2 -methyl-5 H-pregna-1 ,4-dieno[17,16-d3oxazole-3,20-dione, and hereinafter referred to as“Compound 3” or“Cpd 3", having the structure:

In another aspect, the steroid therapeutic agent is 21 -hydroxy deflazacort, also referred to as 21-desacetyl deflazacort, described as

(6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a,10- trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-4-one and hereinafter referred to as

“Compound 4” or“Cpd 4”, having the structure:

In another aspect, the steroid therapeutic agent is vamorolone, described as

(8S,10S,13S,14S,16R,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl- 7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and hereinafter referred to as“Compound 7” or“Cpd 7”, having the structure:

In another aspect, the NF-kB inhibitor is edasalonexent, also referred to as“CAT- 1004”, described as N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide and hereinafter referred to as

“Compound 5” or“Cpd 5”, having the structure:

In another aspect, the NF-kB inhibitor is“CAT-1041", described as 2-hydroxy- N-(2- ((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17-pentaenamido)ethyl)benzamide and hereinafter referred to as“Compound 6” or“Cpd 6”, having the structure:

In one aspect, a therapeutic combination described herein for use in treating a muscular dystrophy in a patient in need thereof includes treating a muscular dystrophy selected from the group consisting of Becker muscular dystrophy,

Duchenne muscular dystrophy and Limb Girdle muscular dystrophy.

In another aspect described herein, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect described herein, the therapeutic combination for use in treating Becker muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect described herein, the therapeutic combination for use in treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor. In another aspect described herein, the therapeutic combination for use in treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In one or more of the foregoing aspects described herein, the therapeutic

combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor, wherein the effective amount of the steroid therapeutic agent and the effective amount of the NF-kB inhibitor may be administered alone or together.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the results of improved diaphragm specific force (in N/cm²) after treatment with the combination of Cpd 2 and Cpd 6 in comparison to Cpd 2 dosed alone once weekly and Cpd 6 dosed alone once weekly, wherein activity of Cpd 2 dosed alone once weekly is synergistically improved in the combination with Cpd 6 relative to use of Cpd 2 alone or treatment with vehicle alone.

Figure 2 shows the results of improved EDL (Extensor Digitorum Longus) specific force (in N/cm²) after treatment with the combination of Cpd 2 and Cpd 6 in comparison to Cpd 2 dosed alone once daily and Cpd 6 dosed alone once weekly, wherein activity of Cpd 2 and Cpd 6 dosed alone once daily and weekly,

respectively, are synergistically improved in the combination relative to each other and treatment with vehicle.

Figure 3 shows the results of improved EDL maximum force (in N/cm²) after treatment with the combination of Cpd 2 and Cpd 6 in comparison to Cpd 2 dosed alone once daily, wherein activity of Cpd 2 dosed alone once daily is synergistically improved in the combination relative to Cpd 2 alone and treatment with vehicle.

Figure 4 shows the results of improved EDL ECC (Excitation-Contraction Coupling) after treatment with the combination of Cpd 1 and Cpd 6 in comparison to Cpd 1 dosed alone once daily, as described in Example 1 , wherein contractile activity of Cpd 1 dosed alone once daily is synergistically improved in the combination relative to Cpd 1 alone and treatment with vehicle. Figure 5 shows the results of the 4-limb wire hang test holding impulse performed on all mice after treatment with vehicle (in wildtype [WT] and D2-mdx mice), with Cpd 3 alone and Cpd 5 alone (in D2-mdx mice only) and with the combination of Cpd 3 and Cpd 5 together (in active D2-mdx mice). Mice in the Sedentary [SED] Treatment Group were not exercised or treated with any Test or Control Article. The holding impulse is used to account for the confounding of animal bodyweight in the

performance of the test (Carlson G., The use of four limb hanging tests to monitor muscle strength and condition over time, TREAT-NMD SOP MDX-DMD_M.2.1.005. (https://treat-nmd.Org/wp-content/uploads/2016/08/MDX-DMD_M.2.1.005.pdf).

There were no statistically significant differences in the holding impulse across treatment groups.

Figure 6 shows creatinine kinase (CK) levels measured from plasma samples obtained at study termination resulting from treatment with vehicle (in WT and D2- mdx mice), with Cpd 3 alone and Cpd 5 alone (in D2-mdx mice only) and with the combination of Cpd 3 and Cpd 5 together (in active D2-mdx mice). Mice in the Sedentary [SED] Treatment Group were not exercised or treated with any Test or Control Article. A statistically significant decrease was observed in the combination therapy D2-mdx mice when compared to the vehicle treated D2-mdx mice.

Figure 7 shows cytokine levels measured from plasma samples obtained at study termination resulting from treatment with vehicle (in WT and D2-mdx mice), with Cpd 3 alone and Cpd 5 alone (in D2~mdx mice only) and with the combination of Cpd 3 and Cpd 5 together (in active D2-mdx mice). Mice in the Sedentary [SED] Treatment Group were not exercised or treated with any Test or Control Article. A statistically significant decrease was observed in plasma IL-6 (interleukin-6) in the combination therapy D2-mdx mice compared to the vehicle treated D2-mdx mice.

Figure 8 shows plasma MIG (Monokine induced by lnterferon-g) levels measured from plasma samples obtained at study termination resulting from treatment with vehicle (in WT and D2-mdx mice), with Cpd 3 alone and Cpd 5 alone (in D2-mdx mice only) and with the combination of Cpd 3 and Cpd 5 together (in active D2-mdx mice). Mice in the Sedentary [SED] Treatment Group were not exercised or treated with any Test or Control Article. A statistically significant decrease was observed in MiG in the combination therapy D2-mdx mice compared with the vehicle treated D2- mdx mice. Figure 9 shows the effects on myofiber diameter resulting from treatment with vehicle (in WT and D2-mdx mice), with Cpd 3 alone and Cpd 5 alone (in D2-mdx mice only) and with the combination of Cpd 3 and Cpd 5 together (in active D2-mdx mice). Mice in the Sedentary [SED] Treatment Group were not exercised or treated with any Test or Control Article. There was a statistically significant decrease in average myofiber diameter in the combination treated D2-mdx mice compared with the vehicle treated mice, the sedentary D2-mdx mice and the vehicle treated DBA/2J wildtype mice.

Figure 10 shows the effects on variance coefficient resulting from treatment with vehicle (in WT and D2-mdx mice), with Cpd 3 alone and Cpd 5 alone (in D2-mdx mice only) and with the combination of Cpd 3 and Cpd 5 together (in active D2~mdx mice). Mice in the Sedentary [SED] Treatment Group were not exercised or treated with any Test or Control Article. There was a statistically significant decrease in the variance coefficient for the combination treated D2-mdx mice compared to the vehicle treated, Cpd 5 treated and SED D2-mdx mice in contrast, there was a statistically significant increase in the variance coefficient for the combination treated D2-mdx mice compared with the vehicle treated DBA/2J wildtype mice.

Figure 11 shows the effects on centrally located nuclei in the quadriceps muscle resulting from treatment with vehicle (in WT and D2-mdx mice), with Cpd 3 alone and Cpd 5 alone (in D2-mdx mice only) and with the combination of Cpd 3 and Cpd 5 together (in active D2-mdx mice). Mice in the Sedentary [SED] Treatment Group were not exercised or treated with any Test or Control Article. There was a statistically significant decrease in the percent of centrally located nuclei in the quadriceps muscle for the combination treated D2-mdx mice compared with the Cpd 5 D2-mdx treated mice.

DETAILED DESCRIPTION

In one aspect, described herein is a therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent and a NF-kB inhibitor.

In one aspect, the steroid therapeutic agent is selected from the group consisting of prednisone, prednisolone, deflazacort, 21-desacetyl deflazacort (21-desDFZ), and vamorolone. In another aspect, the steroid therapeutic agent is selected from the group consisting of deflazacort, 21-desacetyl deflazacort (21-desDFZ), and vamorolone.

In another aspect, the steroid therapeutic agent is selected from deflazacort, and vamorolone.

In another aspect, the steroid therapeutic agent is selected from deflazacort.

In another aspect, the steroid therapeutic agent is selected from vamorolone.

In another aspect, the NF-kB inhibitor is selected from the group consisting of edasolonexent.

In another aspect, the steroid therapeutic agent is prednisone, described as

(8S ,9S, 10R, 13S, 14S, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl- 7,8,9,10,12,13,14,15,16,17-decahydro-3H-cyciopenta[a]phenanthrene-3, 11 (6H)- dione and hereinafter referred to as“Compound 1” or“Cpd 1", having the structure:

In another aspect, the steroid therapeutic agent is prednisolone, described as (8S,9S, 10R, 11 S, 13S, 14S, 17R)-11 , 17-dihydroxy-17-(2~hydroxyacetyl)-10,13- dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[a]phenanthren-3-one and hereinafter referred to as“Compound 2” or “Cpd 2”, having the structure:

In another aspect, the steroid therapeutic agent is deflazacort, described as 2- ((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trimethyl-4-oxo- 1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1’:4,5]indeno[1 ,2- d]oxazol-8b-yl)-2-oxoethyl acetate, alternatively described as (11 b,16b)-21- (acetyloxy)-11-hydroxy-2 -methyl-5 H-pregna-1 ,4-dieno[17,16-d]oxazole-3,20-dione, and hereinafter referred to as“Compound 3” or“Cpd 3”, having the structure:

“Compound 4" or“Cpd 4”, having the structure:

In another aspect, the steroid therapeutic agent is vamorolone, described as (8S, 10S, 13S,14S,16R,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl- 7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and hereinafter referred to as“Compound 7” or“Cpd 7”, having the structure:

“Compound 5” or“Cpd 5”, having the structure:

In another aspect, the NF-kB inhibitor is“CAT-1041”, described as 2-hydroxy-N-(2- ((5Z,8Z, 1 1 Z, 14Z, 17Z)-icosa-5,8, 1 1 ,14,17-pentaenamido)ethyl)benzamide and hereinafter referred to as“Compound 6” or“Cpd 6”, having the structure:

In one aspect, the therapeutic combinations described herein for use in treating a muscular dystrophy in a patient in need thereof include a muscular dystrophy selected from the group consisting of Becker muscular dystrophy, Duchenne muscular dystrophy and Limb Girdle muscular dystrophy.

In another aspect, the therapeutic combination for use in treating Becker muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the therapeutic combination for use in treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the therapeutic combination for use in treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In one aspect, described herein is a method of use for treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient a therapeutic combination of an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the method of use for treating Becker muscular dystrophy in a patient in need thereof comprises, administering to the patient a therapeutic combination of an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the method of use for treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient a therapeutic combination of an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the method of use for treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient a therapeutic combination of an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor. In one aspect, described herein is a therapeutic combination for use in the

manufacture of a medicament for treating a muscular dystrophy in a patient in need thereof comprising, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Becker muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In one aspect, described herein is a pharmaceutical composition for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In another aspect, the pharmaceutical composition for use in treating Becker muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In another aspect, the pharmaceutical composition for use in treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In another aspect, the pharmaceutical composition for use in treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In one or more of the foregoing aspects described herein, the therapeutic

combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor, wherein the effective amount of the steroid therapeutic agent and the effective amount of the NF-kB inhibitor may be administered alone or together. In one aspect, the steroid therapeutic agent is selected from the group consisting of:

In one aspect, the NF-kB inhibitor is selected from the group consisting of:

Cpd 6.

In one aspect, described herein is a therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the therapeutic combination for use in treating Becker muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the therapeutic combination for use in treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6. In another aspect, the therapeutic combination for use in treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In one aspect, described herein is a method of use for treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient a therapeutic combination of an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the method of use for treating Becker muscular dystrophy in a patient in need thereof comprises, administering to the patient a therapeutic combination of an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the method of use for treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient a therapeutic combination of an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the method of use for treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient a therapeutic combination of an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In one aspect, described herein is a therapeutic combination for use in the

manufacture of a medicament for treating a muscular dystrophy in a patient in need thereof comprising, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6. In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Becker muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In one aspect, described herein is a pharmaceutical composition for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In another aspect, the pharmaceutical composition for use in treating Becker muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients. In another aspect, the pharmaceutical composition for use in treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In another aspect, the a pharmaceutical composition for use in treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In one or more of the foregoing aspects described herein, the therapeutic

In one aspect, described herein is a therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of:

Cpd Name

1 (8S,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-7,8,9,10,12,13,14,15,16,17-decahydro-3H- cyclopenta[a]phenanthrene-3, 11 (6H)-dione

2 (8S,9S,1 OR, 11 S, 13S, 14S, 17R)-11 , 17-dihydroxy-17-(2-hydroxyacetyl)- 10,13-dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[aJphenanthren-3-one

3 2-((6aR,6bS,7S,8aS,8bS,11 aR, 12aS,12bS)-7-hydroxy-6a,8a, 10-trimethyl-4- oxo-1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate Cpd Name

4 (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-4-one, and

7 (8S,10S,13S,14S,16R,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12, 14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from the group consisting of:

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide, and

6 2-hydroxy-N~(2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide.

Cpd Name

3 2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trimethyl-4- oxo-1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1’:4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate, and

4 (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl~1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-4-one;

7 (8S, 10S, 13S, 14S, 16R, 17R)-17-hydroxy-17-(2~hydroxyacetyl)-10,13,16- trimethyl-7,8, 12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from the group consisting of:

Cpd Name

6 2-hydroxy-N-(2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide. In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of:

Cpd Name

1 (8S,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-

7.8.9.10.12.13.14.15.16.17-decahydro-3H-cyclopenta[a]phenanthrene- 3,11 (6H)-dione

2 (8S,9S,10R,11 S,13S,14S,17R)-11 ,17-dihydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[a]phenanthren-3-one

3 2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy~6a,8a,10-trimethyl-4- oxo-1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate

4 (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1’:4,5]indeno[1 ,2-d]oxazol-4-one, and

7 (8S,10S,13S,14S,16R,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12,14,15,16-hexahydro~6H~cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide. In one aspect, described herein a therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of:

Cpd Name

1 (8S,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-

7.8.9.10.12.13.14.15.16.17-decahydro-3H-cyclopenta[a3phenanthrene- 3,11 (6H)-dione

2 (8S,9S, 10R, 11 S, 13S, 14S, 17R)-11 , 17-dihydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[a]phenanthren-3-one

3 2-((6aR,6bS,7S,8aS,8bS,11 aR, 12aS,12bS)-7-hydroxy-6a,8a, 10-trimethyl-4- oxo-1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate

4 (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-4-one, and 7 (8S,10S,13S,14S,16R,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12, 14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

6 2-hydroxy-N-(2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide.

In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

1 (8S,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl- 7,8,9,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a3phenanthrene-

3,11 (6H)-dione

and an effective amount of a NF-kB inhibitor selected from the group consisting of:

Cpd Name

6 2-hydroxy-N-(2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide. In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

3 2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trimethyl-4- oxo-1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1 ':4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4 ,7, 10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide, and

6 2-hydroxy-N-(2-((5Z,8Z,11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide. In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

4 (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-4-one

Cpd Name

In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

7 (8S, 10S, 13S, 14S, 16R, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from the group consisting of:

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide, and Cpd Name

Cpd Name

1 (8S,9S, 10R, 13S, 14S , 17R)-17-hydroxy- 17-(2-hydroxyacetyl)-10,13-dimethyl- 7,8,9,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene-

3,11 (6H)-dione

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4 ,7, 10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide. In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

2 (8S,9S, 10R, 11 S, 13S , 14S, 17R)-11 , 17-dihydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[a]phenanthren-3-one

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4 ,7, 10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide.

Cpd Name

3 2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trimethyl-4- oxo-1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1’:4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide.

Cpd Name

⁴ (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro~4H~ naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-4-one

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

7 (8S, 10S,13S,14S,16R, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10, 13,16- trimethyl-7,8, 12,14,15,16-hexahydro~6H~cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide. In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

1 (8S,9S, 10R, 13S, 14S, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-

7,8,9,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene- 3,11 (6H)-dione and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

3 2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trimethyl-4- oxo-1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1’:4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

6 2-hydroxy-N~(2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide. In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

4 (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro~4H~ naphtho[2',1’:4,5]indeno[1 ,2-d]oxazol-4-one and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

Definitions

As used herein, the term“about” means a range around a given value wherein the resulting value is substantially the same as the expressly recited value. In one aspect,“about” means within 25% of a given value or range. For example, the phrase“about 70% by weight” comprises at least all values from 52% to 88% by weight. In another aspect, the term“about” means within 10% of a given value or range. For example, the phrase“about 70% by weight” comprises at least all values from 63% to 77% by weight. In another aspect, the term“about” means within 7% of a given value or range. For example, the phrase“about 70% by weight” comprises at least all values from 65% to 75% by weight.

Concentrations, amounts, cell counts, percentages and other numerical values may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.

As used herein, the term“patient” refers to an individual being administered a therapy as described herein. In a specific aspect, the individual is a human. As used herein, the term“effective amount” in the context of administering the agent combinations described herein to a patient having a muscular dystrophy refers to the dose of each agent used in the combinations described herein that results in a beneficial or therapeutic effect.

As used herein, the term“in a 24 hour period” refers to a period of time over which a condition is maintained; for example, the effective amount of the therapeutic agent combinations described herein is identified when the mean plasma concentration of the therapeutic agent combinations described herein is achieved and maintained for a certain time, usually a plurality of 24 hour periods. In other words, the mean plasma concentration of the therapeutic agent combinations described herein may be reached in a suitable time, which may be more or less than 24 hours.

As used herein, the term“pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base; see, for example,

Remington’s Pharmaceutical Sciences, 18^th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 ^th eds., Mack Publishing, Easton PA (1995).

Method of Use

In one aspect, the steroid therapeutic agent is selected from the group consisting of prednisone, prednisolone, defiazacort, 21-desacetyl deflazacort (21-desDFZ), and vamorolone.

In another aspect, the steroid therapeutic agent is selected from the group consisting of deflazacort, 21-desacetyl deflazacort (21-desDFZ), and vamorolone.

In another aspect, the steroid therapeutic agent is selected from deflazacort.

In another aspect, the steroid therapeutic agent is selected from vamorolone. In one aspect, the NF-kB inhibitor is selected from the group consisting of edasolonexent, and CAT-1041.

In another aspect, the steroid therapeutic agent is prednisone, described as

In another aspect, the steroid therapeutic agent is prednisolone, described as (8S,9S,10R,11 S, 13S, 14S, 17R)-11 , 17-dihydroxy-17-(2-hydroxyacetyl)-10, 13- dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[a]phenanthren-3-one and hereinafter referred to as“Compound 2” or “Cpd 2”, having the structure:

In another aspect, the steroid therapeutic agent is deflazacort, described as 2- ((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trimethyl-4-oxo- 1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro~8bFI-naphtho[2',T:4,5]indeno[1 ,2- d]oxazol-8b-yl)-2-oxoethyl acetate, alternatively described as (11 b,16b)-21- (acetyloxy)-l 1-hydroxy-2 -methyl-5 H-pregna-1 ,4-dieno[17,16-d3oxazole-3,20-dione, and hereinafter referred to as“Compound 3” or“Cpd 3", having the structure:

“Compound 4” or“Cpd 4”, having the structure:

In another aspect, the steroid therapeutic agent is vamorolone, described as

“Compound 5” or“Cpd 5”, having the structure:

In one aspect, the therapeutic combination described herein for use in treating a muscular dystrophy in a patient in need thereof includes a use in treating a muscular dystrophy selected from Becker muscular dystrophy, Duchenne muscular dystrophy or Limb Girdle muscular dystrophy

In another aspect, the therapeutic combination described herein for use in treating a muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the therapeutic combination described herein for use in treating Becker muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the therapeutic combination described herein for use in treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor. In another aspect, the therapeutic combination described herein for use in treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In another aspect, the method of use for treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient a therapeutic combination of an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In one aspect, described herein is a therapeutic combination for use in the

In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Becker muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor. In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

In one or more of the foregoing aspects described herein, the therapeutic

In one aspect, the steroid therapeutic agent is selected from the group consisting of:

In one aspect, the NF-kB inhibitor is selected from the group consisting of:

Cpd 5, and

In another aspect, the therapeutic combination for use in treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the therapeutic combination for use in treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In one aspect, described herein is a therapeutic combination for use in the

manufacture of a medicament for treating a muscular dystrophy in a patient in need thereof comprising, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Becker muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6. In another aspect, the therapeutic combination for use in the manufacture of a medicament for treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering the medicament to the patient, wherein the therapeutic combination is an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6.

In another aspect, the pharmaceutical composition for use in treating Becker muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In another aspect, the pharmaceutical composition for use in treating Duchenne muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In another aspect, the pharmaceutical composition for use in treating Limb Girdle muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of Compounds 1-4 and 7 and an effective amount of a NF-kB inhibitor selected from the group consisting of Compounds 5 and 6, wherein the steroid therapeutic agent and the NF-kB inhibitor are in admixture with one or more pharmaceutically acceptable excipients.

In one or more of the foregoing aspects described herein, the therapeutic

Cpd Name

1 (8S,9S, 10R, 13S, 14S, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl- 7,8,9,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a3phenanthrene~

3,11 (6H)-dione

2 (8S,9S , 10R, 11 S, 13S, 14S, 17R)-11 , 17-dihydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[a]phenanthren-3-one

3 2-((6aR,6bS,7S,8aS,8bS, 11 aR, 12aS, 12bS)-7-hydroxy-6a,8a, 10-trimethyl-4- oxo-1 ,2, 4, 6a, 6b, 7, 8, 8a, 11 a, 12, 12a, 12b-dodecahydro-8bH- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate

7 (8S, 10S, 13S, 14S, 16R, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12, 14, 15,16-hexahydro-6H-cyclopenta[a3phenanthren-3~one and an effective amount of a NF-kB inhibitor selected from the group consisting of:

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19- hexaenamido)ethyl)-2~hydroxybenzamide, and

Cpd Name

3 2-((6aR,6bS,7S,8aS,8bS,11 aR, 12aS,12bS)-7-hydroxy-6a,8a, 10-trimethyl-4- oxo-1 , 2, 4, 6a, 6b, 7, 8, 8a, 11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate, and

4 (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1 ':4,5]indeno[1 ,2-d]oxazol-4-one;

7 (8S,10S,13S,14S,16R,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from the group consisting of:

Cpd Name

In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from the group consisting of:

Cpd Name

1 (8S,9S,1 OR, 13S, 14S, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10, 13- dimethyl-7,8,9,10,12,13,14,15,16,17-decahydro-3H- cyclopenta[aJphenanthrene-3,11 (6H)-dione

2 (8S,9S,10R,11 S,13S,14S,17R)-11 ,17-dihydroxy-17-(2-hydroxyacetyl)- 10,13~dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17~dodecahydro-3H- cyclopenta[a]phenanthren-3-one

3 2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trimethyl-4- oxo-1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate

4 (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy~8b~(2-hydroxyacetyl)~ 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-4-one, and

7 (8S,10S,13S,14S,16R,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12, 14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

1 (8S.9S.10R,13S, 14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-

2 (8S,9S,10R,11S,13S,14S,17R)-11 ,17-dihydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[a]phenanthren-3~one

3 2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trinnethyl-4- oxo-1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro~8bH- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-8b-yl)-2-oxoethyl acetate

⁴ (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy~8b~(2-hydroxyacetyl)~ 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1':4,5]indeno[1 ,2-d]oxazol-4-one, and

7 (8S, 10S,13S,14S,16R, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10, 13,16- trimethyl-7,8, 12, 14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

1 (8S,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-

Cpd Name

6 2-hydroxy-N~(2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide. In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprises, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

2 (8S.9S, 10R, 11 S, 13S , 14S, 17R)-11 , 17-dihydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-6, 7,8, 9,10,11 ,12, 13,14, 15,16, 17-dodecahydro-3H- cyclopenta[a]phenanthren-3-one

Cpd Name

⁴ (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1’:4,5]indeno[1 ,2-d]oxazol-4-one and an effective amount of a NF-kB inhibitor selected from the group consisting of:

Cpd Name

7 (8S, 10S, 13S, 14S, 16R, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12, 14, 15,16-hexahydro-6H-cyclopenta[a3phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from the group consisting of:

Cpd Name

1 (8S,9S, 10R, 13S, 14S, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-

7,8,9,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene- 3,11 (6H)-dione

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

2 (8S,9S, 10R, 11 S, 13S , 14S, 17R)-11 , 17-dihydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-6, 7,8, 9,10,11 ,12, 13,14, 15,16, 17-dodecahydro-3H- cyclopenta[a]phenanthren-3-one

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

4 (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1’:4,5]indeno[1 ,2-d]oxazol-4-one

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

7 (8S, 10S, 13S, 14S, 16R, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-7,8, 12, 14, 15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one and an effective amount of a NF-kB inhibitor selected from the group consisting of:

Cpd Name

5 N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19- hexaenamido)ethyl)-2-hydroxybenzamide, In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

1 (8S,9S,10R,13S, 14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl- 7,8,9,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene-

3,11 (6H)-dione

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

2 (8S,9S,1 OR, 11 S, 13S, 14S, 17R)-11 , 17-dihydroxy-17-(2-hydroxyacetyl)- 10,13-dimethy!-6,7,8,9,10,11 ,12,13,14,15,16,17-dodecahydro-3H- cyclopenta[aJphenanthren-3-one

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

6 2-hydroxy-N-(2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide. In another aspect, the therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent selected from:

Cpd Name

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

⁴ (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',1 ':4,5]indeno[1 ,2-d]oxazol-4-one

and an effective amount of a NF-kB inhibitor selected from:

Cpd Name

6 2-hydroxy-N-(2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide. Effective Amount

In a phase III, double-blind, randomized, placebo-controlled, multicenter study to assess the safety and efficacy of deflazacort (Dfz)(Compound 3, herein) and prednisone (Prd)(Compound 2, herein) vs placebo in Duchenne muscular dystrophy (DMD), muscle strength was evaluated among 196 boys aged 5-15 years with DMD during a 52-week period (Griggs, et al., Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy, Neurology. 2016 Nov 15; 87(20): 2123-2131 ). in the first phase of the study, participants were randomly assigned to receive treatment with Dfz 0.9 mg/kg/d, Dfz 1.2 mg/kg/d, Prd 0.75 mg/kg/d, or placebo for 12 weeks (Griggs, et al.). In the second phase of the study, placebo participants were randomly assigned to 1 of the 3 active treatment groups (Griggs, et al.). Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks (Griggs, et al.). The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo (Griggs, et al.). The study was completed in 1995 (Griggs, et al.). All treatment groups (Dfz 0.9 mg/kg/d, Dfz 1.2 mg/kg/d, and Prd 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks (Griggs, et al.). Participants taking Prd had significantly more weight gain than placebo or both doses of Dfz at 12 weeks; at 52 weeks, participants taking Prd had significantly more weight gain than both Dfz doses (Griggs, et al.). The most frequent adverse events in all three active treatment arms were Cushingoid appearance, erythema, hirsutism, increased weight, headache, and nasopharyngitis (Griggs, et al.).

Deflazacort, also known as (11b ,16b)-21-(acetyloxy)-11-hydroxy-2^'-methyl-5^'H- pregna-1 ,4-dieno[17,16-d]oxazole-3,20-dione, is a glucocorticoid (GC) used as an anti-inflammatory and immunosuppressive agent. Pharmacologically, it is a pro-drug which is metabolized rapidly and completely in the plasma by esterases to the active drug 21-desacetyldeflazacort (21-desDFZ). After oral administration, GCs such as deflazacort or prednisone are readily absorbed into the bloodstream. GCs diffuse through cell membranes to the cytoplasm to bind soluble steroid hormone receptors that dimerize and translocate to the nucleus. In the nucleus, the receptor complex directly binds promoter elements that modulate gene transcription. The intracellular GC receptor (GR) binds GC Response Elements (GREs) in target gene promoters that can activate or inhibit transcription of a variety of genes. Downstream effects of GCs include increase in myoblast growth and stabilization of muscle fiber

membranes, followed by reduction in muscle necrosis. GCs can also suppress the inflammatory process by inhibiting production of inflammatory mediators, such as arachidonic acid metabolites, cytokines, interleukins, adhesion molecules, and enzymes, and by affecting B cell activity.

The American Academy of Neurology (AAN) and Center for Disease Control (CDC) guidelines recommend glucocorticoids including prednisone or deflazacort as first line therapy at the time of DMD diagnosis, typically ages 4-5. Treatment is generally aimed at controlling the symptoms and modifying certain aspects of the disease to sustain and maximize muscle function and improve quality of life. Results from multiple studies showed that glucocorticoids improve muscle strength, which was maximal at 3 months and maintained up to 18 months (Manzur et al., 2008).

Increases in muscle strength were paralleled by significant improvements in functional testing and muscle mass, as measured by urinary creatinine excretion.

Applicants observed that deflazacort improves muscle strength in both ambulatory and non-ambulatory patients as early as six weeks after treatment initiation, that improvements in muscle strength are preserved during long-term treatment up to 24- months, that increases in muscle strength are paralleled by significant improvements in functional testing and muscle mass (as measured by urinary creatinine excretion), and also by improvements in pulmonary function testing.

Standard of Care (SOC) dosing of corticosteroids to DMD patients has been based on patient weight (mg/kg), regardless of the dosing schedule (daily; alternate day; 10 days on, 10 days off; high-dose weekends only; etc.), age, ambulatory status, use of CYP inducers or inhibitors and the like. The recommended SOC dose of deflazacort in DMD patients has been selected from 0.75 mg/kg, 0.9 mg/kg or 1.2 mg/kg. In various aspects, the therapeutically effective amount is 0.9 mg/kg/day. in various aspects described herein, the therapeutically effective amount is other than 0.75 mg/kg, 0.9 mg/kg or 1.2 mg/kg. The recommended dose is based on clinical data from randomized, blinded, placebo-controlled trials with additional supportive evidence obtained from the global literature, as well as clinical standard of care guidelines for treatment. The widespread adoption and acceptance of weight-based (mg/kg) dosing is based on published findings from long-term observational, natural history studies of boys with DMD treated with prednisone/prednisolone or deflazacort (Bello, et al., 2015).

As used herein, the term“effective amount” in the context of administering the agent combinations described herein to a patient having a muscular dystrophy refers to the dose of each agent used in the combinations described herein that results in a beneficial or therapeutic effect.

In the various aspects described herein, the therapeutically effective amount of the steroid therapeutic agent is other than 0.75 mg/kg, 0.9 mg/kg or 1.2 mg/kg. The therapeutic combinations described herein provide a surprisingly low therapeutically effective amount of the steroid therapeutic agent when combined with a NF-kB inhibitor for use in treating a muscular dystrophy in a patient in need thereof. In one aspect, the therapeutically effective amount of the steroid therapeutic agent is in a range from about 0.15 mg/kg to about 0.30 mg/kg. In another aspect, the

therapeutically effective amount of the steroid therapeutic agent is selected from the group consisting of 0.15 mg/kg, 0.16 mg/kg, 0.17 mg/kg, 0.18 mg/kg, 0.19 mg/kg, 0.20 mg/kg, 0.21 mg/kg, 0.22 mg/kg, 0.23 mg/kg, 0.24 mg/kg, 0.25 mg/kg, 0.26 mg/kg, 0.27 mg/kg, 0.28 mg/kg, 0.29 mg/kg, and 0.30 mg/kg. In another aspect, the therapeutically effective amount of the steroid therapeutic agent is selected from the group consisting of 0.18 mg/kg, 0.21 mg/kg, 0.22 mg/kg, 0.28 mg/kg, and 0.29 mg/kg. In another aspect, the therapeutically effective amount of the steroid therapeutic agent is selected from the group consisting of 0.18 mg/kg, 0.22 mg/kg, and 0.29 mg/kg. In another aspect, the therapeutically effective amount of the steroid therapeutic agent is 0.18 mg/kg. In another aspect, the therapeutically effective amount of the steroid therapeutic agent is 0.21 mg/kg. In another aspect, the therapeutically effective amount of the steroid therapeutic agent is 0.22 mg/kg.

In another aspect, the therapeutically effective amount of the steroid therapeutic agent is 0.28 mg/kg. In another aspect, the therapeutically effective amount of the steroid therapeutic agent is 0.29 mg/kg.

In one aspect, the steroid therapeutic agent is selected from the group consisting of prednisone, prednisolone, deflazacort, 21-desacetyl deflazacort (21-desDFZ), and vamorolone.

In another aspect, the steroid therapeutic agent is selected from the group consisting of deflazacort, and vamorolone.

In another aspect, the steroid therapeutic agent is selected from deflazacort.

In another aspect, the steroid therapeutic agent is selected from vamorolone.

In one aspect, the steroid therapeutic agent is selected from deflazacort and the effective amount of the steroid therapeutic agent is in a range from about 0.15 mg/kg to about 0.30 mg/kg.

In another aspect, the steroid therapeutic agent is selected from deflazacort and the effective amount of the steroid therapeutic agent is selected from the group consisting of 0.18 mg/kg, 0.21 mg/kg, 0.22 mg/kg, 0.28 mg/kg, and 0.29 mg/kg.

In another aspect, the steroid therapeutic agent is selected from deflazacort and the effective amount of the steroid therapeutic agent is selected from the group consisting of 0.18 mg/kg, 0.22 mg/kg, and 0.29 mg/kg.

In another aspect, the steroid therapeutic agent is selected from deflazacort and the effective amount of the steroid therapeutic agent is 0.18 mg/kg.

In another aspect, the steroid therapeutic agent is selected from deflazacort and the effective amount of the steroid therapeutic agent is 0.22 mg/kg.

In another aspect, the steroid therapeutic agent is selected from deflazacort and the effective amount of the steroid therapeutic agent is 0.29 mg/kg.

Kits

Provided herein is a pharmaceutical pack or kit comprising one or more containers filled with the therapeutic agent combinations described herein. Additionally, one or more other therapies useful for the treatment of Duchenne muscular dystrophy, or other relevant agents can also be included in the pharmaceutical pack or kit. Also provided herein is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein. Optionally associated with such kits can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

Examples

Example 1

ECC Patient Sample Testing: Samples of patient EDL were prepared and treated with Cpd 2 (5 mg/kg) once daily or once weekly, Cpd 6 (5 mg/kg) once daily and a combination of Cpd 2 and Cpd 6 (each 5 mg/kg) once weekly.

Results: Measurements of Bodyweight (BW, in grams) and ECC in Quadriceps (Quad, in mg), Gastrocnemius (Gastro, in mg), Tibealis Anterior (TA, in mg) and Heart (in mg) muscle after treatment with Cpd 2 once daily (^QDCpd 2), Cpd 2 once weekly (^QWCpd 2), Cpd 6 once daily (^QDCpd 6) and a combination of Cpd 6 once daily (^QDCpd 6) and Cpd 2 once weekly (^QDCpd 6/^QWCpd 2) are shown in Table 1.

Table 1 : ECC Test Results

As shown in Figure 4, successive ECC sessions for tested tissues suggest that the combination of Cpd 6 once daily and Cpd 2 once weekly maintain muscle cell contraction potential at least as well as Cpd 6 alone once daily and Cpd 2 alone once weekly relative to Cpd 2 alone once daily and treatment with vehicle.

These test results suggest in all muscles measured that:

• Once daily Cpd 6 gives similar benefits to once weekly Cpd 2 in the D2.mdx mouse • The combination of Cpd 6 once daily and Cpd 2 once weekly provides at least as much benefit than either treatment alone

Example 2

Effect of Combination of Cpd 3 and Cpd 6 in mdx mice on a DBA background:

This study is designed to assess the combination activity of the steroid Cpd 3 and NF-kB inhibitor Cpd 6 in the D2.mdx mouse on a DBA background (mice with dystrophin-deficiency due to a premature stop codon in exon 23).

Mice at 4 weeks of age (15 per treatment group) are treated with Cpd 3 (oral, QD,

5 mg/kg as 0.2 mg/mL or 1 mg/kg as 0.1 mg/mL) alone, Cpd 6 (oral, 0.75% w/w in chow) alone ad libitum and the combination of Cpd 3 and Cpd 6, each dosed as indicated.

Mice are allowed exercise ad libitum, with wheel time quantified. Upon sacrifice:

• Ex vivo muscle function of the diaphragm and EDL are performed

• Skeletal and heart muscle tissues (quadriceps, gastrocnemius, soleus,

diaphragm and EDL) are weighed to determine the ratio of muscle to body weight

• Histologic analysis of muscle tissues (quadriceps, diaphragm and EDL) is used to determine degree of intramuscular fibrosis

• Expression of NF-kB components (p65, p105, p50, RelB and p100), level of inflammatory biomarkers (osteopontin, IL-6, IL-4 and MMP2) and fibrosis biomarkers (FSP-1 and fibronectin) are assessed

Example 3

Proposed MR and Functional Testing for a Ciinicai Study:

Three groups of 20 patients are assessed with functional and MR testing over 48 weeks, where Group 1 includes patients receiving daily corticosteroid therapy, Group 2 includes patients receiving weekend only corticosteroid therapy at the daily dose, Group 3 includes patients receiving a combination of weekend only corticosteroid therapy and Cpd 5, each at the daily dose.

Statistical Analysis. Data are given as the mean ± SD or SEM where indicated for quantitative experiments. For statistical analysis, p-values may be derived using unpaired Student’s i-tests for studies with only two groups presented. Otherwise, comparisons of groups were performed on log-transformed data using a one-way ANOVA test. Where applicable, analyses were made using GraphPad Prism

Software.

Example 4

Effect of Combination of Cpd 3 and Cpd 5 in an Inflammatory mdx Mouse Model

Background. The D2.B10-Dmdmdx/J (D2-mdx) mouse model of DMD is

considered a more inflammatory mouse model with a more severe course than the traditional mdx mouse model having a C57BL/10 background (Coley WD, Bogdanik L, Vila MC, Yu Q, Van Der Meulen JH, Rayavarapu S, Novak JS, Nearing M, Quinn JL, Saunders A, Dolan C, Andrews W, Lammert C, Austin A, Partridge TA, Cox GA, Lutz C, Nagaraju K. Effect of genetic background on the dystrophic phenotype in mdx mice. Hum Mol Genet. 2016 Jan 1 ;25(1 ): 130-45) and therefore may better represent the effect of treatment in a human patient having a muscular dystrophy, in particular Duchenne muscular dystrophy.

The purpose of this study was to characterize the effect of a combination therapy administering Cpd 3 at 1.2 mg/kg and 1 % Cpd 5 compared to monotherapy with either agent in D2~mdx and DBA/2J mice. The standard of care treatment dose of Cpd 3 for a human patient is 0.9 mg/kg, equivalent to a dose of 5 mg/kg in a mouse. The Cpd 3 dose of 1.2 mg/kg administered to mice as the Test Article in the

Treatment Groups indicated in Table 2 of the present example corresponds to a human patient dose of about 0.22 mg/kg, representing a surprising reduction of the human dose for Cpd 3 to about 25% of the standard of care dose.

Methods

Cpd 3 was suspended in 0.1 % HPMC/0.5% Tween 80 in water, pH 4 and dosed at 1.2 mg/kg by oral gavage.

Cpd 5 was formulated 1% w/w in Purina LabDiet 5058 and provided ad libitum to the selected Treatment Group shown in Table 2.

Vehicle diet was formulated 1 % w/w in Purina LabDiet 5058 and provided ad libitum to the selected Treatment Group shown in Table 2. Mice used in the study were divided into 2 cohorts with mice from each cohort randomized across all study groups. The first cohort contained 50 male D2.B10- Dmdmdx/J (D2-mdx) mice (Jackson Laboratory, Stock No: 013141 ). The second cohort contained 10 male DBA/2J wildtype (WT) mice (Jackson Laboratory, Stock No: 000671 ).

Table 2 provides an overview of the Treatment Groups shown in the Group column, where Test Articles (active agents) include Treatment Group 2 (Cpd 3 alone), Treatment Group 3 (Cpd 5 alone), and Treatment Group 4 (Combination of Cpd 3 and Cpd 5 alone); and Control Articles include Treatment Group 1 (mdx-vehicle), Treatment Group 5 (Sedentary), and Treatment Group 6 (WT-vehicle); the

Test/Control Article column lists the composition of the Test and Control Articles administered, where HPMC refers to hydroxypropyl methylceilulose; the Dose column, where the indicated amounts were administered according to study protocol; the Route column, where PO refers to administration of Test or Control Article according to the indicated Schedule, or ad libitum oral dosing of Test Article in Control Diet, or ad libitum consumption of Control Diet without Test Article, and PO(g) refers to oral administration of Test Article by gavage; the Schedule column, where qd refers to once-per-day dosing, ad libitum refers to free access to Control Diet with or without Test Article; and, the Strain column, showing the number of mice treated in and the designated strain in each Treatment Group: wildtype mice

(DBA/2J) and D2-mdx mice (mdx-dba D2.B10-Dmdmdx/J mice). All mice received Purina LabDiet 5058 ad libitum as the Control Diet in addition to the Test/Control article indicated in Table 2.

Table 2. Group Designation and Study Design

Treatment Groups 1 , 2, 3, 4 and 6 were exercised on a treadmill once a week for 5 weeks to ensure uniform advancement of muscle pathology. Treatment Group 5 received no exercise. Mice from all Treatment Groups were assessed for muscle function by means of the 4-limb wire hang test 24 hours prior to the last treadmill exercise session.

At 6 weeks after study initiation, plasma was harvested from all Treatment Groups to measure creatinine kinase, a muscle enzyme associated with muscle damage and muscle membrane fragility. Plasma cytokines relevant to an inflammatory state were also measured. Body tissues from all Treatment Groups were obtained, weighed, and prepared for histological analysis. Histopathological markers of inflammation, fibrosis, necrosis and muscle degeneration and regeneration were then evaluated.

Study Conduct

Mice were weighed prior to initiating the study on Day 0 and twice weekly for each week thereafter.

Mice were 6-weeks of age when dosing was initiated. Prior to initiation of dosing, there were no significant differences in body weights across the D2-mdx mouse groups. In contrast, age-matched DBA/2J wild type control mice weighed

significantly more than D2-mdx mice at 6-weeks of age (ANOVA, multiple

comparisons vs D2~mdx vehicle) (see, Coley 2016).

Study Endpoints shown in Table 3 indicate that mice in Groups 1 , 2, 3, 4, and 6 were exercised on a treadmill for 1 session/week at Weeks 2, 3, 4, 5, and 6. Table 3 also indicates that an assessment of muscular function for mice in all groups was made by means of the four limb wire test 24 hours prior to the final treadmill exercise session for Groups 1 , 2, 3, 4, and 6 at Week 6.

Table 3 indicates that a weekly assessment of body weight gain showed that mice in all Treatment Groups gained weight. The vehicle-dosed D2-mdx mice subject to forced exercise weighed less than the sedentary D2-mdx mice. Treatment with Cpd 3 alone reduced weight gain and treatment with Cpd 5 alone reduced weight gain in the D2-mdx mice subject to forced exercise. Treatment with the combination of Cpd 3 and Cpd 5 led to the greatest reduction in weight gain. Table 3. Study Endpoints

After 6 weeks on study, blood was collected and plasma harvested for subsequent CK and cytokine analysis.

Table 4 shows the mean (standard deviation) value for the indicated cytokine measured for each Treatment Group, including IFNy (interferon gamma), IL

(interleukin), M-CSF (macrophage colony-stimulating factor), MCP-1 (monocyte chemoattractant protein-1 ) and TNFa (tumor necrosis factor alpha).

Table 4. Cytokine Results

Histopathology

Semi-quantitative and quantitative histopathological analyses were performed on samples of the heart, diaphragm, tibialis anterior, and quadriceps.

Semi-quantitative analysis of necrosis, fibrosis, and mineralization of the heart was performed. Semi-quantitative analysis of necrosis, regeneration, and fibrosis was performed on the diaphragm, tibialis anterior, and quadriceps.

Quantitative image analysis was performed on sections of quadriceps muscle to determine the average myofiber area, variance coefficient of myofiber diameter, and the central nuclei percent. This quantitative analysis is referred to as the‘Feret’s diameter’. Quantitative image analysis using this technique accounts for variable muscle cross-sectioning, allows for an assessment of regenerative state and differentiates dystrophic from normal muscle (Erb, M. Quantitative determination of muscle fibre diameter (minimal Feret’s diameter) and percentage of centralized nuclei. TREAT-NMD SOP MDX-DMD_M.1.2.001-24. (https://treat-nmd.org/wp- content/uploads/2016/08/MDX-DMD_M.1.2.001 -24.pdf)).

Figure 8 shows that significant differences were observed in histological parameters measured by quantitative image analysis.

Results

Although all Treatment Groups demonstrated weight gain during the study, the combination D2-mdx mice demonstrated the lowest percentage weight gain, had a significantly lower concentration of terminal plasma creatinine kinase when compared to vehicle treated D2-mdx mice, demonstrated overall lower terminal plasma cytokine concentrations of both IL-6 and MIG, with similar terminal plasma CK activity, IL-6 and MIG concentrations to the non-treadmill exercised sedentary D2-mdx group and demonstrated a significantly decreased percentage of central nuclei in the quadriceps muscle by quantitative immunohistopathology compared to Cpd 5 treatment alone and sedentary D2~mdx mice.

Taken as a whole, these data suggest that a combination of Cpd 3 and Cpd 5 may be therapeutically beneficial for treating a muscular dystrophy in a patient in need thereof, retaining the known therapeutic benefits provided by a corticosteroid therapy, and having favorable pharmaceutical properties such as a surprisingly lower therapeutically effective amount of the corticosteroid agent resulting from combined administration with an effective amount of a NF-kB inhibitor.

Without regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein.

Having now fully described the subject matter of the claims, it will be understood by those having ordinary skill in the art that the same can be performed within a wide range of equivalents without affecting the scope of the subject matter or aspects described herein. It is intended that the appended claims be interpreted to include all such equivalents.

Claims

What is claimed is:

1. A therapeutic combination for use in treating a muscular dystrophy in a patient in need thereof comprising, administering to the patient an effective amount of a steroid therapeutic agent and an effective amount of a NF-kB inhibitor.

2. The use of claim 1 , wherein the steroid therapeutic agent is selected from the group consisting of prednisone, prednisolone, deflazacort, 21-desacetyl deflazacort (21-desDFZ), and vamorolone..

3. The use of claim 1 , wherein the steroid therapeutic agent is selected from the group consisting of deflazacort, 21-desacetyl deflazacort (21-desDFZ), and vamorolone.

4. The use of claim 1 , wherein the steroid therapeutic agent is selected from deflazacort.

5. The use of claim 4, wherein the effective amount of the steroid therapeutic agent is in a range from about 0.15 mg/kg to about 0.30 mg/kg.

6. The use of claim 1 , wherein the steroid therapeutic agent is selected from vamorolone.

7. The use of claim 1 , wherein the NF-kB inhibitor is selected from the group consisting of edasoionexent, and CAT-1041.

8. The use of claim 1 , wherein the NF-kB inhibitor is selected from

edasoionexent.

9. The use of claim 1 , wherein the muscular dystrophy is selected from Becker muscular dystrophy, Duchenne muscular dystrophy or Limb Girdle muscular dystrophy.

10. The use of claim 1 , wherein the steroid therapeutic agent is selected from the group consisting of:

2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a,10-trimethyl-4-oxo- 1 ,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',T:4,5]indeno[1 ,2- d]oxazol-8b-yl)-2-oxoethyl acetate

(6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a,10-trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4FI- naphtho[2',T:4,5]indeno[1 ,2-d]oxazol-4-one, and (8S, 10S, 13S, 14S, 16R, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl- 7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one

and the NF-kB inhibitor is selected from the group consisting of:

N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19-hexaenamido)ethyl)-2- hydroxybenzamide, and

2-hydroxy-N-(2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5,8, 11 ,14,17- pentaenamido)ethyl)benzamide.

11. The use of claim 1 , wherein the steroid therapeutic agent is:

and the NF-kB inhibitor is:

N-(2-((4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19-hexaenamido)ethyl)-2- hydroxybenzamide.

12. The use of claim 1 , wherein the steroid therapeutic agent is:

(6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a,10- trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',T:4,5]indeno[1 ,2-d]oxazo!-4-one

and the NF-kB inhibitor is:

13. The use of claim 1 , wherein the steroid therapeutic agent is:

(8S, 10S, 13S, 14S, 16R, 17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl- 7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one

and the NF-kB inhibitor is:

N-(2-((4Z,7Z,10Z, 13Z, 16Z, 19Z)-docosa-4 ,7, 10,13,16,19-hexaenamido)ethyl)-2- hydroxybenzamide.

14. The use of claim 1 , wherein the steroid therapeutic agent is:

and the NF-kB inhibitor is:

15. The use of claim 1 , wherein the steroid therapeutic agent is:

(6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a,10- trimethyl-1 ,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H- naphtho[2',T:4,5]indeno[1 ,2-d]oxazol-4-one

and the NF-kB inhibitor is:

16. The use of claim 1 , wherein the steroid therapeutic agent is:

and the NF-kB inhibitor is: