NZ713051B2

NZ713051B2 - S-enantiomerically enriched compositions of beta blockers for treating amyotrophic lateral sclerosis

Info

Publication number: NZ713051B2
Application number: NZ713051A
Authority: NZ
Inventors: Stefan Anker; Andrew Js Coats; Jochen Springer
Original assignee: Andrew Js Coats
Priority date: 2013-03-14
Filing date: 2014-03-14
Publication date: 2021-01-06

Abstract

The present invention relates to S-enantiomerically enriched compositions of beta blockers and uses thereof, including uses of the beta blocker compositions for treating amyotrophic lateral sclerosis. The beta blocker compositions can also be used for preventing loss of lean mass, preventing body weight loss in subjects, improving quality of life in subjects, and prolonging survival in amyotrophic lateral sclerosis patients. The beta blocker can be oxprenolol or a pharmaceutically acceptable salt thereof. ight loss in subjects, improving quality of life in subjects, and prolonging survival in amyotrophic lateral sclerosis patients. The beta blocker can be oxprenolol or a pharmaceutically acceptable salt thereof.

Description

S-ENANTIOMERICALLY ENRICHED COMPOSITIONS OF BETA BLOCKERS FOR TREATING AMYOTROPHIC LATERAL SCLEROSIS CROSS—REFERENCE TO RELATED APPLICATIONS This application claims the ty hene lit ol‘ US. Provisional Patent Application Serial No. 61/786,235, filed March 14. 2013, which, is incorporated herein by reference in its entirety.

TECHNICAL FIELD The present invention relates to S—enantiomcrically enriched compositions of beta blockers or pharmaceutically acceptable salts thereof and uses thereof, ing uses of the beta blocker compositions for treating ophic lateral sclerosis. The beta blocker can be oxprenolol or a phannaceutically able salt thereof.

BACKGROUND Amyotrophic lateral sclerosis (ALS) covers a spectrum of neurodegenerative syndromes terized by progressive muscular paralysis reﬂecting degeneration of motor neurons in the brain and spinal cord. ALS is one of the most common neurodegenerative disorders, with an incidence of l to 2 per 100,000 and a prevalence 014 to 6 per 100,000; as many as 30,000 Americans have the disease at any given time (Worms PM. The epidemiology of motor neuron e: a review of recent studies. .1 Nenrol Sci 2001, 191 :3- 9). The incidence in males is higher than in females (1.6: 1). 5—10% of ts have a positive family history of ALS, most ly with an autosomal dominant inheritance pattern. ALS is a disease of mature . with a median age of onset ol‘55 years and its frequency increases with age until age 75. Overall 50% of patients die within the ﬁrst three years since the ﬁrst clinical manifestations. Apart from age or a positive family history, a number of factors and enviromnental toxins have been further studied as risk factors. A high relative risk was described in smokers, soccer players, al 1y Italians and veterans ofthe Gulf War.

Oxprenolol is a non-selective beta blocker which possesses some intrinsic sympathomimetic activity. e of its beta blocker function, oxprenolol has been used for the treatment of various diseases such as angina pectoris, abnormal heart rhythms. and high blood pressure. ()xprenolol is lipophilic and crosses the blood-brain barrier more easily than other more water soluble beta blockers. As a result, oxprenolol is associated with a bi0 er incidence of CNS—related side effects than other beta blockers‘ but also has more central CNS modes of action.

The disclosure of all publications, patents, patent applications, and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.

BRIEF SUMMARY OF THE INVENTION The present invention relates to tiomerically enriched compositions of beta blockers or pharmaceutically acceptable salts thereof and uses thereof. including uses of the beta blocker compositions for treating amyotrophic lateral sclerosis. The beta r can be oxprenolol or a pharmaceutically able salt thereof.

The present disclosure provides, in some embodiments, a method of treating amyotrophic lateral sclerosis in an dual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of a composition comprising a beta blocker or a pharrnaceutically acceptable salt thereof, wherein beta blocker has one chiral center and the composition is enantiomerically enriched for the tiomer.

The present disclosure es, in some embodiments, a method of prolonging survival of an individual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of a composition comprising a beta blocker or a pharmaceutically able salt thereof, wherein beta blocker has one chiral center and the composition is enantiomerically enriched for the S-enantiomer.

The present disclosure provides, in some embodiments. a method aying the development ofamyotrophic lateral sclerosis in an individual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of a composition comprising a beta blocker or a pharmaceutically acceptable salt thereof, wherein beta blocker has one chiral center and the ition is enantiomerieally enriched for the S-enantiomer.

The present disclosure provides, in some ments a method of preventing loss of lean mass of an dual having amyotrophic lateral sclerosis, comprising administering to the dual an effective amount ot‘a composition comprising a beta blocker or a pharmaceutically acceptable salt thereof. wherein beta blocker has one chiral center and the composition is cnantiomerically ed for the S-enantiomer.

Ix.) |0011| The t disclosure provides, in some embodiments, a method of preventing muscle wasting of an individual having amyotrophic lateral sclerosis, comprising administering to the individual an ive amount of a composition comprising a beta blocker or a phannaceutically acceptable salt thereof, wherein beta blocker has one chiral center and the composition is enantiomerieally enriched for the tiomen “1012] The present disclosure es, in some embodiments, a method of improving quality of life in an individual having amyotrophic lateral sclerosis, comprising administering to the dual an effective amount of a ition comprising a beta blocker or a pharmaceutically acceptable salt f, wherein beta r has one chiral center and the composition is enantiomerically enriched for the S~enantiomer In some embodiments, the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. In some embodiments, the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition is enantiomerieally enriched for S-oxprenolol. In some embodiments, the composition comprises an enantiomeric excess of at least about 50% of S—oxprenolol. in some embodiments, the composition comprises an enantiomerie excess of at least about 80% ofS-oxprenolol. In some embodiments, the composition comprises an enantiomeric excess of at least about 99% of S—oxprenolol. In some embodiments, the composition comprises an enantiomerie excess of at least 99.9% ol‘S-oxprenolol. In some embodiments, the amyotrophic lateral sclerosis is sporadic amyotrophic l sclerosis. in some embodiments, the ophic lateral sclerosis is al amyotrophic lateral sclerosis. In some embodiments, the amyotrophic lateral sclerosis is Western Paciﬁc amyotrophic lateral sis. In some ments, the amy‘otrophic lateral sis is juvenile amyotrophie lateral sclerosis. In some embodiments, the amyotrophic lateral sclerosis is Hiramaya Disease. In some embodiments, the amyotrophic lateral sclerosis is ssive bulbar palsy (PBP), progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), or ALS with multi—system involvement. In some embodiments, the composition is administered orally. In some embodiments, the amount of S—oxprenolol in the composition is about 80 to about 160 mg daily. In some embodiments, the composition is administered daily or twice daily.

The present disclosure provides, in some embodiments, a k it comprising a pharmaceutical composition comprising a composition comprising a beta blocker or a ceutieally acceptable salt thereof, wherein beta blocker has one chiral center and the composition is enantiomerical 1y enriched for the S-enantiomer; and a pharmaceutically acceptable carrier for treating amyotrophic lateral sclerosis. In some embodiments. the beta r is oxprenolol.

BRIEF DESCREPTION OF THE S Figure l is a diagram showing a clinical symptomatological evaluation of the BGSJL-'l‘g(SOl)l“‘G93A)lGur/.l ALS transgenic mouse.

Figure 2 is a graph showing the percent survival of mice tions that were stered with S—oxprenolol or a placebo (plac). The sample size in the population is indicated by “n." Figure 3 is a graph showing the percent survival of mice populations that were administered S—oxprenolol. S-pindolol, or a placebo. The sample size in the population is indicated by “n.” “HR” refers to hazard ratio. “CI” refers to conﬁdence interval. “95% CI” is 95% conﬁdence interval. “p” refers to p-value.

Figure 4 is a graph showing the percent survival of mice populations that were administered S—oxprenolol ), R-oxprenolol (roxlO). oxprenolol (0x20), riluzole (riluzole), propanolol (prop), or a o (plac). The sample size in the population is ted by “11.“ “HR” refers to hazard ratio. “CI” refers to conﬁdence interval. “95% CI” is 95% conﬁdence interval. “p” refers to p-value.

Figure 5 is a graph showing the change in body weight per survival day alter ALS onset of mice populations that were administered with various dosages of the S- oxprenolol, S-pindolol, or a placebo. The sample size in the population is indicated by “n.” Figure 6 is a graph showing the change in lean body mass (in grams (“g")) of mice populations that: were administered with S-oxprenolol or a o.

Figure 7 is a graph showing the change in lean body mass per survival day after Al..S onset of mice populations that were administered with S-oxprenolol, S-pindolol, or a placebo. The asterisk (*) indicates that the p value is less than 0.05 versus placebo.

Figure 8 is a graph showing the mass of gastrocnemius muscle (in grams ("‘g”)) in mice populations that were administered a placebo.

Figure 9 is a graph showing the mass of gastrocnemius muscle (in grams (“g”)) in, mice populations that were administered enolol.

Figure 10 is a graph showing the mass of tibialis or muscle (in grams (“g”)) in mice populations that were stered a placebo.

Figure 11 is a graph showing the mass of tibialis anterior muscle (in grams (“g“)) in mice populations that were administered S—oxprenolol.

Figure 12 is a graph showing the change in fat mass (in grams (“g”)') of mice populations that were administered S-oxprcnolol or a placebo.

Figure 13 is a graph showing the change in fat mass per al day alter ALS onset ol‘mice populations that were administered with S-oxprenolol, S-pindolol, or a placebo. The asterisk (*) tes that the p value is less than 0.05 versus placebo.

Figure 14 is a graph g the percent survival of mice populations that were administered with enolol, rilutek, propanolol, oxprenolol (racemic), or R- oxprenolol. The sample size in the population is indicated by “n.” Figure 15 is a graph showing the percent survival of male mice populations that were administered with S-oxprenolol, rilutek, propanolol. oxprenolol (racemic), or R oxprenolol. The sample size in the population is indicated by “n." Figure 16 is a graph showing the percent al of female mice populations that were administered with S-oxprenolol, Iilutek, propanolol, oxprenolol (racemic; or R- oxprenolol. The sample size in the population is indicated by “n.” Figure 17 is a graph showing the change in disease progression scored from score 1 to score 2 of mice populations that were administered with S—oxprenolol, rilutek, propanolol, oxprenolol icl, or R-oxprenolol.

Figure 18 is a graph g the change in disease progression scored from score 2 to score 3 of mice populations that were administered with S~oxprenoloh rilutek, propanolol, oxprenolol (racemic), or enolol.

Figure 19 is a graph showing the change in disease progression scored from score 1 to score 3 of mice populations that were stered with enolol, rilutek, propanolol, oxprenolol (racemic), or enoiol.

Figure 20A is a graph showing the change in body weight of mice populations that were administered with S-oxprcnolol, R-oxprenolo], or rilutck. Figure 208 is a graph showing the change in body weight of male mice populations that were administered with S— oxprenolol, R-oxprenolol, or rilutek. Figure 20C is a graph showing the change in body weight of female mice tions that were administered with S—oxprenolol, R-oxprenolol, or rilutek. Figure 20D is a graph showing the change in lean mass of mice populations that were administered with Svoxprenolol, R.~oxprenolol, or rilutelc Figure 20F. is a graph showing the change in lean mass of male mice populations that were administered with S- oxprenolol, R-oxprenolol. or k. Figure 20F is a graph showing the change in lean mass of female mice populations that were stered with S~oxprenolol. R-oxprenolol, or rilutek. Figure 200 is a graph showing the change in fat mass ofmice populations that were stered with S-oxprenolol, R-oxprenolol, or rilutek. Figure 20H is a graph showing the change in fat mass of male mice tions that were stered with S—oxprenolol, R- oxprenolol, or rilutek. Figure 201 is a graph showing the change in fat mass of female mice populations that were administered with S-oxprenolol. R-oxprenolol, or rilutek. The sample size in the population is indicated by “n.” Figure 2] A is a graph showing the heart mass of mice populations that. were administered with S-oxprenolol, R—oxprenoloL or rilutek at the end of the study. Figure 21B is a graph showing the heart mass of male mice tions that were administered with S- oxprenolol, R-oxprenolol, or rilutek at the end ol‘ the study. Figure 21C is a graph showing the heart mass of female mice tions that were administered with S-oxprenolol, R- oxprenolol, or rilutek at the end of the study. Figure 2lD is a graph showing gastrocnemius muscle weight of mice populations that were administered with S-oxprenolol, R-oxprenolol, or rilutek at the end ot‘the study. Figure 2113 is a graph showing gastroenemius muscle weight of male mice populations that were administered with S—oxprenolol. R—oxprenolol, or rilutek at the end of the study. Figure 21 F is a graph showing gastrocnemius muscle weight of female mice populations that were administered wilh S-oxprenolol. R-oxprenolol, or rilutek at the end of the study. Figure 216 is a graph showing tibialis muscle weight of mice populations that were administered with S—oxprenolol, R~oxprenoloL or rilutek at the end of the study. Figure 2111 is a graph showing tibialis muscle weight of male mice populations that were administered with S-oxprenolol, R—oxprenolol, or rilutek at the end of the study.

Figure 211 is a graph showing tihiulis muscle weight of female mice tions that were administered with S—oxprenolol, R—oxprenolol, or k at the end ol'the study. The sample size in. the population is indicated by “n.” ED DESCRIPTION OF THE INVENTION The present invention provides use of an S—enantiomerically enriched composition of a beta blocker for achieving beneﬁcial results in individuals having ophic lateral sclerosis, such as treating ophic lateral sclerosis, prolonging survival, preventing lean mass loss, improving quality of life, and/or treating muscle wasting.

In an S-enantiomerically enriched composition ot‘a beta blocker or a pharmaceutically acceptable salt thereof, the beta blocker or a pharmaceutically acceptable salt f has one chiral center and the composition is enantiomerically enriched for the S~enantiomer. Thus, as used herein, “S-enantiomerically enriched composition of a beta blocker” refers to a beta blocker having one chiral center and the composition is cnantiomerically ed for the S- enantiomer. in some embodiments. the beta r is oxprenolol or a pharmaceutically acceptable salt thereof.

The present invention is based on the surprising ﬁnding that S—oxprenolol signiﬁcantly improved survival in animals having amyotrophic lateral sclerosis in an experiment using an amyotrophic l sclerosis animal model. Other effects of the compositions were observed on preserving lean body mass and preventing body weight loss in the animals. At least. these effects suggest that S-oxprenolol is effective in treating amyotrophic l sis and prolonging al.

Thus, the present invention, in one aspect, provides methods of treating amyotrophic lateral sclerosis, prolonging survival, preventing lean mass loss, preventing and/or treating muscle wasting, or improving quality of life in an individual having amyotrophic lateral sis, comprising administering to the individual an effective amount ofan S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof. in some embodiments. the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. |0039l Also provided are kits, unit dosages, medicines, and articles ofinanufacture that are useful for methods described .

Definitions The following terms have the following meanings unless otherwise indicated.

Any undeﬁned terms have their ad ized meanings.

] As used herein, “treatment” or “treating” is an approach for obtaining beneﬁcial or desired results including clinical results. For purposes of this invention, beneﬁcial or desired clinical results include, but are not limited to. one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the e, stabilizing the disease (eg, preventing or delaying the ing of the disease), preventing or ng the spread (cg, metastasis) of the e, preventing or delayng the recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission al or total) of the disease, decreasing the dose ofone or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality oflife, and/or prolonging survival. Also encompassed by “treatment” is a reduction of ogical uence of amyotrophic lateral sclerosis. The methods of the invention contemplate any one or more of these aspects of treatment. “1042] The term idual” refers to a mammal and includes, but is not limited to, human, bovine. horse, feline, canine, rodent. or primate. In some embodiments. the individual is a human.

As used herein, an “at risk” individual is an individual who is at risk of developing amyotrophic lateral sclerosis. An individual “at risk" may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so called risk factors, which are measurable parameters that correlate with pment of amyotrophic lateral sclerosis. An individual having one or more of these risk factors has a higher probability of developing amyotrophic lateral sclerosis than an individual Without these risk factorts).

As used herein, “delaying“ the pment of a disease means to defer, hinder, slow, retard, stabilize, and/or ne development of the e. This delay can be of varying lengths oftime. ing on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufﬁcient or significant delay can, in effect, ass prevention, in that the individual does not develop the disease. A method that s” development ol’a disease is a method that reduces probability of disease development in a given time frame and/or reduces the extent of the disease in a given time Frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically cant number of subjects. [0045i As used , by “combination therapy" is meant that a ﬁrst agent be administered in conjunction with another agent. “In conjunction with” refers to administration of one treatment modality in addition to another treatment modality, such as administration of a nanoparticle composition described herein in addition to administration of the other agent to the same individual. As such, “in conjunction with” rei’e rs to stration of one treatment modality , . or after delivery of the other treatment modality to the individual. Such combinations are considered to be part ofa single treatment regimen or regime. 2014/000274 |0046| The term “effective amount” used herein refers to an amount of a compound or composition sufﬁcient to treat a ed disorder, condition or disease such as ameliorate, palliate, lessen. and/or delay one or more of its symptoms. in nce to ophic lateral sclerosis, an effective amount comprises an amount ent to prevent or delay other unwanted symptoms associated with amyotrophic lateral sclerosis. in some embodiments, an effective amount is an amount sufﬁcient to delay development. in some embodiments, an effective amount is an amount sufﬁcient to prevent or delay ence. An effective amount can be administered in one or more administrations.

The term “simultaneous administration,” as used herein, means that a ﬁrst therapy and second therapy in a combination therapy are administered with a time separation of no more than about i5 minutes, such as no more than about any of 10, 5, or 1 minutes.

When the ﬁrst and second therapies are administered simultaneously, the ﬁrst and second therapies may be contained in the same ition (ag, a composition comprising both a ﬁrst and second therapy) or in separate compositions (cg a ﬁrst therapy in one ition and a second therapy is contained in another composition).

As used herein, the term “sequential administration” means that the ﬁrst y and second therapy in a combination therapy are administered with a time separation of more than about [5 minutes, such as more than about any ot‘20. 30, 40, 50, ()0, or more minutes. Either the ﬁrst therapy or the second therapy may be administered ﬁrst. The ﬁrst and second therapies are contained in te compositions, which may be contained in the same or different packages or kits. [0049! As used herein, the term “concurrent administration” means that the administration of the ﬁrst y and that of a second therapy in a combination therapy p with each other.

As used herein, by “pharmaceutically acceptable“ or “pharmacologically compatible" is meant a material that is not biologically or otherwise undesirable, sag. , the material may be incorporated into a ceutical composition administered to an individual without causing any signiﬁcant undesirable biologicai effects or interacting in a deleterious manner with any ol‘the other components ofthe composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the inactive ient Guide prepared by the U.8. Food and Drug administration. [005” An "adverse event" or “AE’ as used herein refers to any untoward medical occurrence in an individual receiving a marketed pharmaceutical product or in an individual who is participating on a clinical trial who is receiving an investigational or non- investigational pharmaceutical agent The term “isomers” or “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

The term l” refers to molecules which have the property of non- superimposability ofthe mirror image partner, while the term “achiral” refers to les which are superimposable on their mirror image partner, The term “diastereomers” refers to stereoisomcrs with two or more centers of metry and whose molecules are not mirror images of one another.

The term “enantiomers” refers to two stereoisomers of a compound which are non—superimposable mirror images of one r. An equimolar mixture of two enantiomers is called a “racemic mixture” or a “racemate.” The term “enantiomerieally enriched" means that the racemic mixture (i.e., 50/50 e of the enantiorners) has been puriﬁed such that one enantiomer comprises greater than 50% of the total amount of the compound present. For example, a composition that is enantiomerically ed for S-oxprenolol is a composition wherein more than 50% of the oxprenolol is the S-enantiomer of oxprenolol (S-oxprenolol).

The degree of enantiomeric ment ot‘a composition can be determined by “enantiomeric excess,” or ee. “Enantiomeric excess” represents the percentage of one omer in excess of the other. For instance, a composition having a 75:25 mixture of S— oxprenolol and R-oxprenolol has a 75 3 50 % ee, while a 50:50 racemic mixture has a 50 — 25 — 50 = 0 % ee. The value ot'ee will be a number from 0 to 100, 0 being c and 100 being pure, single enantiomer.

The term “phannaceutically acceptable salt” means a salt which is acceptahie for stration to a subject, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from phannaceutically acceptable inorganic or organic bases and from pharniaeeutically acceptable inorganic or organic acids. “Pharmaceutically acceptable salt" refers to phannaceutically acceptable salts ot'a compound, which salts are derived from. a variety of organic and nic COLmter ions well known in the art and include: by way of example only, sodium. potassium, m. magnesium. ammonium, tetraalkylanunonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride. hydrobromide, formate. te, besylate. mesylate. e. maleate, oxalate, and the like.

The term “salt thereof” means a compound formed when a proton of an acid is replaced by a , such as a metal cation or an organic cation and the like. Where applicable. the salt is a phaimaceutically able salt, although this is not required for salts of intermediate compounds that are not intended for administration to the subject. By way of example, salts ofthe present nds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the ate base of the inorganic or organic acid as the anionic component of the salt.

“Solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can he an organic compound, an inorganic compound, or a mixture ofboth. Some examples of solvents include, but are not limited to, methanol. MN—dimethylformamide, tetrahydrofuran. dimethylsulfoxide, and water. When the solvent is water. the solvate formed is a hydrate. it will be iated that the term “or a salt or solvate thereof” is intended to include all permutations of salts and solvates, such as a solvate ot‘a phannaceutically acceptable salt ol’a subj eet compound. [0062[ As used herein, “in conjunction with” refers to administration of one treatment modality in addition to another treatment modality. As such, “in conjunction with” refers to administration of one treatment modality before, during or after administration of the other treatment modality to the individual.

As used herein and in the appended claims, the singular forms “a,” “an," and “the” e plural reference unless the context clearly indicates otherwise. [0064[ Reference to “about" a value or parameter herein includes (and describes) ments that are directed to that value or parameter per se. For example, ption referring to “about X” includes description of “X.” It is understood that aspects and variations of the invention described herein include sting” and/or sting essentially 0t” aspects and variations.

Methods of the present invention The present disclosure, in one aspect, provides methods of treating amyotrophic lateral sclerosis. In some embodiments, there is provided a method of treating amyotrophic lateral sclerosis in an individual having amyotrophic lateral sclerosis, comprising administering to the dual an effective amount of an S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (such as a composition having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ce). In some embodiments. the beta blocker is selected from the group consisting of acebutolol. atenolol, betaxolol. bisoprolol, carteolol. celeprolol, lol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, ol. propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol, bucindolol. levobunolol, metipranolol, celiprolol and enone or a pharmaceutically acceptable salt thereof. In some embodiments, the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. In some embodiments, the composition ses an enantiomeric excess of at least about 10% (such as at least about any one ot‘20%, 3t %, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) of S-oxprenolol. In some embodiments, there is provided a method ot‘treating amyotrophie lateral sclerosis in an individual having amyotrophic l sclerosis, comprising administering to the individual an ett‘ective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition comprises an omeric excess of at least. about 99% (for example at least about 99.9%) of enolol. In some embodiments, there is provided a method ting amyotrophic lateral sclerosis in an individual having ophic lateral sclerosis. comprising administering (such as orally administering) to the individual an effective amount of a composition comprising oxprcnolol or a pharmaceutically acceptable salt thereof, wherein the composition is enantiomerically enriched for S—oxprenolol. (for example comprises an enantiomeric excess of at least about 99% of S-oxprenolol), wherein the amount of S—oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for example about l00 mg to about 160 mg).

In some embodiments, there is ed a method of prolonging survival ofan individual having amyotrophic l sclerosis, comprising administering to the individual an effective amount of an tiomcrically enriched composition ofa beta blocker or a pharmaceutically acceptable salt f (such as a composition having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). in some embodiments, the beta blocker is selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, carteolol, celeprolol, lol. metoprolol. nadolol, ncbivolol, oxprenolol, penbutolol, pindolol, propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol, dolol, levobunolol, metipranolol, eeliprolol and propafenone. in some ments, the beta blocker is olol or a phannaceutieally acceptable salt thereof. In some embodiments, the composition comprises an enautiomeric excess of at least about 10% (such as at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%. or 99.9%) ol’S~oxprenololi in some embodiments, there is ed a method of prolonging survival in an individual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the ition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) ofS—oxprenolol. in some embodiments, there is provided a method of prolonging survival of an individual having ophic lateral sclerosis, comprising administering (such as orally stering) to the dual an effective amount ofa composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition is enantiomerically enriched for S~oxprenolol (for example comprises an enantiomeric excess of at least about 99% of enolol), wherein the amount of S-oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for example about 100 mg to about 160 mg). In some embodiments. the method prolongs the survival ol’the individual by at least any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, 12, 18, or 24 months.

In some embodiments, there is provided a method of prolonging progression- free survival in an individual with amyotrophic lateral sclerosis, comprising administering to the dual an effective amount of an S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (such as a ition having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% co). in some embodiments, the beta blocker is ed from the group consisting of aeebutolol, atenolol. betaxolol, bisoprolol, catteolol, celeprolol, labetalol, metoprolul, nadolol, nebivolol, oxprenolol, olol, pindolol, propanolol, sotalol, esmolol, caivedilol, timolol, bopindolol, mcdroxalol, bucindolol, lcvobunolol. metipranolol, olol and propafenone. in some embodiments. the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises an enantiomeric excess of at least about 10% (such as at least about any one of20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) ol‘S-oxprenolol. In some embodiments, there is provided a method of prolonging progression-tree survival in an individual with ophic lateral sclerosis, sing administering to the individual an effective amount ofa composition comprising oxprenolol or a pharmaceutical ly acceptable salt thereof, wherein the ition ses an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S-oxprenolol. In some embodiments, there is provided a method ot‘pt‘olonging progression—free suwival in an individual with amyotrophic lateral sclerosis. comprising administering (such as orally administering) to the individual an eftective amount ot‘a composition comprising oxprenolol or a pharmaceutically able salt thereof, wherein the composition is enantiomerically enriched for S—oxprenolol (for e ses an enantiomeric excess of at least about 9 % of S-oxprenolol), wherein the amount of S-oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for example about l00 mg to about 160 mg).

In some embodiments, there is provided a method of alleviating one or more symptoms associated with amyotrophic lateral sclerosis. sing administering to the individual an tive amount of an S~enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (such as a composition having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%. 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the beta blocker is selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, olol, pindolol, propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol. medroxalol. bucindolol, levobunolol, metipranolol, olol and propalenone. ln some embodiments, the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. In some embodiments. the composition comprises an omeric excess of at least about 10% (such as at least about any one 0f20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%. or 99.9%) of S—oxprenolol. In some embodiments, there is provided a method ofalleviating one or more symptoms associated with atnyotrophic lateral sclerosis, comprising stering to the individual an effective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S—oxprenolol. In some embodiments, there is provided a method of alleviating one or more symptoms associated with amyotrophic lateral sclerosis, comprising administering (such as orally administering) to the individual an ive amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition is enantiomerically enriched for S-oxprenolol (for example comprises an enantiomeric excess ofat least about 99% ol’S—oxprenolol), wherein the amount of S—oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for example about 100 mg to about 160 mg). in some embodiments, there is provided a method of delaying the development otrophic lateral sclerosis in an individual having amy‘otrophic lateral sclerosis. comprising administering to the individual an effective amount ofan S— enantinmerically enriched composition ot'a beta blocker or a pharmaceutical ly acceptable salt thereof (such as a composition having at least about any one of l0%, 20%. 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%. 99%, or 99.9% ee). in some embodiments, the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. In some embodiments, the beta blocker is selected from the group consisting utolol, atenolol, betaxolol, bisoprolol, carteolol, olol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol. sotalol, esmolol, ilol, timolol, bopindolol, medroxalol, olol, levobunolol, metipranolol, celiprolol and propafenone. in some embodiments, the ition comprises oxprenolol or a phannaceutically acceptable salt thereof. In some embodiments, the composition comprises oxprenolol or a pharmaceutically acceptable salt thereof, wherein the ition is enantiomerically enriched for S~ oxprenolol. in some embodiments, the ition comprises an enantiomeric excess of at least about 10% (such as at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) of S—oxprenolol. in some ments, there is provided a method aying the development of amyotrophic lateral sclerosis in. an individual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of a composition comprising oxprcnolol or a pharmaceutically acceptable salt f, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S-oxprenolol. In some embodiments, there is ed a method ot‘delaying the development of atnyotrophic lateral sclerosis in an individual having amyotrophic lateral sis, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein. the composition is enantiomerically enriched for S—oxprenolol (for example ses an enantiomeric excess of at least about 99% of S-oxprenolol), wherein the amount of S~oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for example about 100 mg to about l60 mg). In some embodiments, the method prolongs the survival of the individual by at least any of 1. 2, 3, 4, 5, 6, 7, 8,9, 10,11, 12,18, or 24 months. |007ll ln some embodiments, there is provided a method ofpreventing loss of lean body mass in an dual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of an S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt f (such as a composition having at least about any one of l0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 999% cc). In some embodiments, there is provided a method of ng loss of lean body mass in an individual having amyotrophic lateral sclerosis, comprising administering to the dual an effective amount of an S-enantiomerically enriched composition ot‘a beta blocker or a pharmaceutically acceptable salt thereof (such as a composition having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%. 98%, 99%, or 99.9% eye). In some embodiments, the method of treating loss of lean body mass is reversing muscle wasting or sing muscle weight. In some ments, the beta blocker is selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol, sotalol, l, carvedilol, timolol, bopindolol, medroxalol, bucindolol, levobunolol, metipranolol, celiprolol and enone. ln some embodiments, the beta blocker is oxprenolol or a phannaceutically acceptable salt thereof. ln some embodiments, the composition comprises an enantiomeric excess of at least about 10% (such as at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%. 98%, 99%, or 99.9%) ofS—oxprenolol. ln some embodiments, there is provided a method of preventing loss of lean body mass in an individual having amyotrophic lateral sclerosis. comprising administering to the individual an effective amount of a ition comprising oxprenolol or a ceutically acceptable salt thereof, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S- oxprenolol. in some embodiments, there is provided a method of preventing loss of lean body mass in an individual having amyotrophic lateral sclerosis, comprising administering (such as orally administering) to the individual an effective amount ot‘a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, n the composition 2014/000274 is enantiomerically enriched for S—oxprenolol (for example comprises an enantiomeric excess of at least about 99% of S—oxprenolol), wherein the amount of S—oxprenolol in the ition is about 50 mg to about l60 mg (such as about 80 to about 160 mg, for example about 100 mg to about 160 mg). In some embodiments, the loss oflcan body mass of the individual is no more than about 10% (for example no more than about any of 10%, 9%, 8%, 7%, 6%, or 5%) of the total lean body mass. in some embodiments, the loss of lean body mass is evaluated over a time period of about 1 month to 2 years (for example, about 1, 2, 3, 4, 5, 6, 7, 8, 910,11. 12,13, 14,15,16, l7, 20 or 24 months). , 21, 22, 23, In some embodiments, there is provided a method of treating muscle wasting in an individual having amyotrophic lateral sclerosis, sing stering to the individual an. effective amount of an S—enantiomcrically enriched composition ofa beta blocker or a pharmaceutically able salt thereof (such as a composition having at least about any one of 10%. 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% cc). In some embodiments. the beta blocker is selected from the group consisting ofacebutolol, atenolol. betaxolol, bisoprolol, carteolol, olol, labetalol, olol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol, alol, bucindolol, levobunolol, metipranolol, celiprolol and propafenone. In some embodiments, the beta blocker is oxprenolol or a phamtaceutieally acceptable salt thereof. In some embodiments, the composition comprises an enantiomeric excess of at least about 10% (such as at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) of S~oxprenolol. In some ments, there is provided a method ot‘treating muscle wasting in an individual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S—oxprenolol. In some embodiments, there is provided a method of treating muscle wasting in an individual having amyotrophic lateral sclerosis, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition is omerically enriched for S—oxptenolol (for example comprises an orneric excess of at least about 99% of S—oxprenolol), wherein the amount of Svoxprenolol in the compositi on is about 50 mg to about 160 mg (such as about 80 to about 160 mg, For e about 100 mg to about 160 mg). In some embodiments. the 2014/000274 muscle wasting of the individual is no more than about 10% (for e no more than about any of 10%, 9%, 8%, 7%, 6%, or 5%) of the total body weight. In some embodiments, the muscle wasting is evaluated over a time period of about 1 month to 2 years (for example, about 1,2, 3,4, 5, 6,7, 8, 9,10,11,12,13,14,15,16,17,18,19 ,20 or24 , 21, 22,23, months). In some embodiments. the method leads to a reduction of muscle wasting, i.e., a slow-down ol‘musele loss in the individual. ln some embodiments, the method leads to a reversal of muscle g, i.e., an increase in muscle weight in the individual. in some embodiments, there is provided a method of improving y of life of an individual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of an S-enantiomerically enriched composition ofa beta blocker or a pharmaceutical 1y acceptable salt thereof (such as a composition. having at least about any one of 10%, 20%. 30%, 4 %, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%. 99%, or 99.9% ea). In some embodiments, the beta blocker is selected from the group consisting of acebutolol, ol, betaxolol, bisoprolol, lol, celeprolol, labetalol, nietoprolol, nadolol, nebivolol, oxprenolol, olol, pindolol, propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol, bucindolol, levobunolol, metipranolol, celiprolol and propafenone. in some embodiments, the beta r is olol or a pharmaceutically acceptable salt thereof. in some embodiments. the composition comprises an enantiomeric excess of at least about 10% (such as at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) of S—oxprenolol. In some embodiments, there is provided a method of improving quality of life of an individual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of a composition sing oxprenolol or a pharmaceutically acceptable salt thereof, n the composition comprises an enantiomeric excess ol’at least about 9.9% (for example at least about 99.9%) of S-oxprenolol. In. some embodiments, there is provided a method of improving quality of life ofan individual having amyotrophic lateral sclerosis, comprising administering (such as orally stering) to the individual an effective amount of a composition comprising oxprenolol or a. pharmaceutically able salt thereof, n the composition is enantiomerieally enriched for S-oxprenolol (for example comprises an enantiomeric excess of at least about 99% ofS-oxprenolol), wherein the amount of S—oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for example about 100 mg to about l60 mg). improvement of'quality of life can be assessed, for example, by food intake, locomotive activity, improvement in fatigue or dyspnea or global patient assessment scores. in short physical performance battery scores, in standard clinical assessment of functional performance, muscle strength, gait speed, leg strength and hand grip th. 6-minute corridor walk test. stair climbing power, ability to tolerate courses of chemotherapy and other tests or instruments or questionnaires assessing patient quality oflife. “1074] ln some embodiments, there is provided a method of increasing food intake of an individual having amyotrophic lateral sclerosis. comprising stering to the individual an effective amount of an S-enantiomerically enriched composition of a beta blocker or a phannaceutically acceptable salt: thereof (such as a, composition having at least: about any one of l0%, 20%, 30%, 40%. 50%, 60%, 70%= 80%, 90%, 9 %, 96%., 97%, 98%” 999/ or 99.9% cc). In some embodiments, the beta blocker is selected from the group consisting of olol, atenolol, betaxolol. olol, carteolol. oiol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propanolol, sotalol, esmolol, carvcdilol, timolol, bopindolol, mcdroxaloL bucindolol, levobunolol, anolol, celiprolol and propafenone. in some embodiments, the beta blocker is oxprenolol or a pharmaceutically able salt thereof. In some embodiments, the composition ses an enantiomeric excess of at least about 10% (such as at least about any one of 20%, 30%, 40%, 50%, 60%, 70%. 80%, 90%, 95%, 96%, 97%, 98%. 9.9%, or 99.9%) ofS—oxprenolol. in some embodiments, there is provided a method of sing food intake of an individual having amyotrophic lateral sclerosis, comprising stering to the dual an effective amount ol'a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S—oxprenolol. In some embodiments, there is provided a method of increasing food intake of an individual having amyotrophic lateral sclerosis, comprising stering (such. as orally administering) to the individual an effective amount ofa composition comprising oxprenolol. or a pharmaceutically acceptable salt thereof, wherein the composition is enantiomerically enriched for cnolol (for example comprises an enantiomeric excess of at least about 99% of enolol), wherein the amount of S-oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for e about 100 mg to about 160 mg).

In some embodiments, there is provided a method of increasing locomotive activity of an individual having amyotrophic lateral sclerosis, comprising administering to the individual an ive amount of an S-enantiomerically enriched composition ofa beta WO 38814 blocker or a pharmaceutically acceptable salt f (such as a composition having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the beta blocker is selected from the group consisting ot‘acebutolol, atenolol, betaxolol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol. pindolol, propanolol, sotalol, esmoloi, carvedilol, timoiol, hopindolol, medroxalol, bucindolo], levobm‘nolol, metipranolol, celiprolol and propafenone. In some embodiments, the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises an enantiomerie excess of at least about 10% (such as at least. about any one of 20%, 30%, 40%, 50%, 60%. 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) ofS—oxprenolol. in some embodiments, there is provided a method of increasing locomotive activity of an individual having amyotrophic lateral sclerosis, comprising administering to the individual an ive amount of a composition comprising oxprenolol or a pharmaceutically able salt thereof, wherein the composition comprises an omeric excess of at least about 99% (for example at least about 99.9%) of enolol. ln some embodiments, there is provided a method of increasing locomotive activity of an individual having amyotrophic lateral sclerosis, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt f, wherein the ition is enantiomerically ed for S-oxprenoloi (for example comprises an enantiomeric excess of at least about 99% of S—oxprenolol), wherein the amount ol‘S—oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for example about 100 mg to about 160 mg). ln some embodiments, there is provided a method of improving fatigue or dyspnea in an individual having amyotrophic lateral sclerosis, comprising stering to the individual an effective amount: of an S-enantiomerically ed composition ol‘a beta blocker or a pharmaceutically acceptable salt thereof (such as a composition having at least about any one of l 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, the beta. blocker is selected from the group consisting ol’acebutolol, atenolol, lol, bisoprolol, carteolol, celeprolol, labetalol, metoprolol, l, nebivolol, oxprenolol, olol, pindolol, propanolol, sotalol. esmolol. ilol, timolol, bopindolol, medroxalol, hucindolol, levobunolol, metipranolol, celiprolol and propatenone. In some embodiments, the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises an enantiomeric excess of at least about 10% (such as at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) of enolol. In some embodiments, there is provided a method ofimproving fatigue or dyspnea in an individual having amyotrophic lateral sclerosis, comprising administering to the individual an cﬁ'ective amount of a composition comprising oxprenolol or a pharmaee‘utically acceptable salt thereof, wherein the composition comprises an meric excess of at least about 99% (for e at least about 99.9%) of S—oxprenolol. in some embodiments, there is ed a method of improving fatigue or dyspnea in an individual having amyotrophic lateral sis, comprising administering (such as orally administering.) to the individual an effective amount of a composition comprising oxprenolol or a ceutically acceptable salt thereof, wherein the composition is enantiomerically enriched for S-oxprenolol (for example comprises an enantiorneric excess of at least about 99% of S—oxprenolol), wherein the amount ofS—oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for example about 100 mg to about 160 mg). lo some embodiments, there is provided a method of preventing body weight loss of an individual having amyotrophic- lateral sclerosis, comprising stering to the individual an effective amount of an S—cnantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereot‘(such as a composition having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%. 96%, 97%, 98%, 99%, or 99.9% ea). In some embodiments, the beta r is selected from the group consisting ol‘acebutolol, atenolol, betaxolol, bisoprolol, carteolol, eeleprolol, labetalol, metoprolol, l, nebivolol, oxprenolol, penbutolol, pindolol, olol, sotalol, l, dilol, timolol, bopindolol, medroxalol, bucindolol, levobunolol, anolol, celiprolol and enone, In some embodiments, the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. ln some embodiments, the composition comprises an enantiomeric excess of at least about 10% (such as at least about any one 012096. 30%, 40%, 50%, 60%. 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) of S—oxprenolol. In some embodiments, there is provided a method ofpreventing body weightless in an individual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt: thereof, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S~oxprenoloL In some embodiments, there is ed a method 01‘ preventing body weight loss clan individual having amyotrophic lateral sclerosis, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition is enantiomerically enriched for S—oxprenolol (for example comprises an enantiomeric excess of at least about 99% ot'S-oxprenolol), wherein the amount of S~oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, For example about 100 mg to about 160 mg). In some embodiments, the body weight loss of the individual is no more than about 20% (for example no more than about any of 15%, 14%, 13%, 12%. 11%, 10%, 9%, 8%, 7%, 6%, or 5%) ofthe total body weight. In seine embodiments, the body weight loss is ted over a time period of about 1 month to 2 years (for example, about 1, 2, 3, 4, 5, 6, 7, 8,9. 10,11, 12,13,14, 15,16,17,18,19 20 , _. 21, 22, 23, or 24 months). in some embodiments, there is provided a method of ting loss of body fat in an individual having amyotrophic lateral sclerosis, comprising administering to the dual an effective amount of an S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (such as a composition having at least about any one of10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 9 %, 99%, or 99.9% ee). In some embodiments, the beta blocker is selected from the group consisting of olol, atenolol, betaxolol. bisoprolol, carteolol, celeprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, olol, pindolol, propanolol. sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol, bueindolol, levobunolol, anolol. celiprolol and propal‘enone. In some embodiments, the beta blocker is oxprenolol or a phannaceutically acceptable salt thereof. In some embodiments, the composition comprises an enantiomeric excess of at least about 10% (such as at least about any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%. or 99.9%,)01‘S-oxprenolol. In some embodiments, there is provided a method of ting loss ol'body lat in an individual having rophie lateral sclerosis, comprising administering to the individual an effective amount ot‘a composition comprising oxprenolol or a ceutically acceptable salt thereof, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S-oxprenolol. in some embodiments, there is provided a method of ting loss of body fat in an individual having amyotrophic lateral sclerosis, comprising administering (such as orally administering) to the individual an effective amount ot‘a composition comprising oxprenolol or a pharmaceutically able salt thereof, wherein the composition is omerically enriched for cnolol (for example comprises an enantiomeric excess of at least about 99% of S—oxprenolol), wherein the amount of S—oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about 160 mg, for example about 100 mg to about 160 mg). In some embodiments, the loss ofbody fat of the individual is no more than about 10% (for example no more than about any of 15%, 14%, 13%. 12%, 11%. 10%, 9%, 8%, 7%, 6%, or 5%) of the total body fat. In some embodiments, the loss 01‘ body fat is evaluated over a time period of about l month to 2 years (for example. about I, 2. 3. 4, 5, 6, 7, 8, 9,10,11,12,13,l4,15,16.17,18,19 20 , . 21, 22, 23, or 24 months).

In some ments, there is provided a method of providing cardioprotective effects in an dual having amyotrophic lateral sclerosis, comprising administering to the individual an effective amount of an S-enantiomerically enriched composition ofa beta blocker or a ceutically acceptable salt thereof (such as a composition having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%. 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some embodiments, there is ed a method of preventing wasting ofa heart muscle in an individual having arnyotrophic l sclerosis, comprising administering to the individual an effective amount ofan S— enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt ft such as a composition having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%. 97%, 98%, 99%, or 999% cc). In some embodiments, the beta blocker is selected from the group consisting of acebutolol, atenolo], betaxolol, bisoprolol, carteolol. celeprolol. lol, metoprolol, nadolol, nebivoloi. olol, penbutolol, pindolol. propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol. medroxalol, bucindolol, levobunolol, metipranolol, celiprolol and propafenone. In some embodiments, the beta blocker is oxprenolol or a phannaceutically acceptable salt thereof. In some embodiments, the composition comprises an enantiomeric excess of at least about 10% (such as at least about any one of 20%. 30%, 40%, 50%, 60%, 70%, 80%. 90%, 95%. 96%, 97%, 98%, 99%, or 99.9%) ot‘S-oxprenolol. In some embodiments, there is provided a method of providing cardioprotective effects in an individual having amyotrophic lateral sclerosis, sing administering to the dual an effective amount of a composition comprising olol or a pharmaceuticall y able salt thereof, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S~oxprenolol. In some embodiments, there is provided a method of preventing wasting ofa heart muscle in an individual having ophic lateral sclerosis, comprising administering 2014/000274 to the individual an effective amount of a composition comprising oxprenolol or a phartnaceutically acceptable salt thereof, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S-oxprenolol. In some embodiments, there is provided a method of providing cardioprotective effects in an individual having amyot‘rophic lateral sclerosis, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition is enantiotnerically enriched for S-oxprenolol (for e comprises an enantiomeric excess of at least about 99% ofS—oxprenolol), wherein the amount ol'S—oxprenolol in the composition is about 50 mg to about l60 mg (such as about 80 to about 160 mg, for example about lOO mg to about 160 mg). In some embodiments, there is provided a method of preventing g ofa heart muscle in an individual having amyotrophic lateral sclerosis, comprising stering (such as orally administering) to the individual an effective amount of a ition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein the composition is enantiomerically enriched for S-oxprenolol (for example comprises an enantiomeric excess of at least about 99% of S-oxprenolol), wherein the amount of S—oxprenolol in the composition is about 50 mg to about 160 mg (such as about 80 to about l60 mg. for example about 100 mg to about l60 mg). Cardioprotective effects include one or more of the following: preventing and treating atrial ﬁbrillation and ventricular ﬁbrillation. improving arrhythmias, improving diastolic function of :1 hearts and preventing and treating fibrosis of a heart. The methods described herein are ore useful for any one or more of these cardioprotective effects.

In some embodiments, there is provided a method ot'preventing sudden death and/or cardiovascular death in an individual having amyotrophic lateral sis, sing stering to the individual an effective amount ol'an S-enantiomerically enriched composition of a beta blocker or a phartnaceutically acceptable salt f (such as a composition having at least about, any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%” or 99.9% ee). In some embodiments. the beta r is selected from the group consisting utolol, atenolol, betaxolol, bisoprolol, carteolol, celeprolol, labelalol, olol, nadolol, nebivolol, oxpt‘enolol, pcnbutolol, pindolol, propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol, medroxalol, bucindolol, levobunolol, metipranolol, celiprolol and fenone. in some embodiments, the beta r is oxprcnolol or a phamiaceutically acceptable salt thereof. in some embodiments, the composition comprises an enantiomeric excess of at least about 10% (such as at least about any one of20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) of S—oxprenolol. In some embodiments, there is ed a method of preventing sudden death and/or cardiovascular death in an individual. having amyotrophic l sclerosis. comprising administering to the individual an effective amount oi’a composition comprising olol or a phamiaceutically acceptable salt thereof, wherein the composition comprises an enantiomeric excess of at least about 99% (for example at least about 99.9%) of S—oxprenolol. in some embodiments, there is provided a method of preventing sudden death and/or cardiovascular death in an individual having amyotrophic lateral sclerosis, sing administering (such as orally administering) to the individual an effective amount ofa composition comprising oxprcnolol or a pharmaceutically acceptable salt thereof, wherein the composition is enantiomerically enriched for S-oxprenolol (for example comprises an omeric excess of at least about 99% of enolol). wherein the amount ot‘S— oxprenolol in the ition is about 50 mg to about 160 mg (such as about 80 to about 160 mg. for example about 100 mg to about 160 mg).

The methods described herein may also be useful for any one or more of the following: 1) preventing loss of skeletal muscle associated with amyotrophic lateral sclerosis; 2) treating muscle weakness associated with amyotrophic lateral sclerosis; 3) strengthening skeletal muscle in an individual having ophic lateral sclerosis; 4) treatment ol‘muscle wasting associated with amyotrophic lateral sclerosis; 5) treating dyspnea associated with muscle changes in amyotrophic lateral sclerosis; and 6) ing fatigue resistance of muscle in amyotrophic lateral sclerosis. Skeletal muscle includes, but is not limited to, gastrocnemius muscle, is , soleus muscle, and extensor digitorum longus (EDL) muscle. quadriceps. hamstrings. al muscles. hand muscles. triceps, biceps, masseter and otherjaw muscles, and ostal and other respiratory muscles. The present application encompasses any of these methods. in some embodiments. the individual has been diagnosed with or is suspected of having ophic lateral sclerosis. in some ments, the individual exhibits one or more symptoms associated with amyotrophic lateral sclerosis. in some embodiments, the individual is a human. in some embodiments, the individual is at. least: about any of35: 40, 45. 50, 55, 60., 65, 70. 75, 80, or 85 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments. the individual has been previously d for amyotrophic lateral sclerosis. In some embodiments, the individual has not previously been treated for rophic lateral sis.

Amyotrophic lateral sclerosis covers a spectrum of egenerative syndromes characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the brain and spinal cord. It is a debilitating disease with varied etiology characterized by rapidly progressive weakness, muscle y and culations, muscle city, difficulty speaking (dysarthria), lty swallowing (dysphagia). and difﬁculty ing (dyspnea).

Amyotrophic l sclerosis can be diagnosed by observation of symptoms and signs. An individual may receive neurologic examinations at regular intervals to see whether symptoms are getting worse. Symptoms may include muscle weakness, muscle atrophy. hyperrellexia (overactive reﬂexes. including twitching and spastic movement), and spasticity (tightening and ction of muscles, muscle stiffening). Tests can be run to obtain deﬁnitive information to diagnose ALS or rule out es other than ALS. Such tests include electromyography (EMG), nerve conduction velocity (NCV) test. magnetic resonance imaging (MRI), spinal tap, x-rays, myelogram ofthe cervical spine, and muscle and/or nerve biopsy. ln some embodiments, the individual has early stage amyotrophic lateral sclerosis. In some embodiments, the individual has middle stage amyotrophic lateral sclerosis. In some embodiments, the individual has late stage amyotrophie lateral sclerosis. ln early stage ALS, the individual can have any of the following symptoms, Muscles Physical effects 0f the body, Mild symptoms may affect more than one region.

Muscles characterized by: May experience symptoms such as: Weak and so ft or stiff, tight and spastic Fatigue . l Cramping and twitching Poor balance Atrophy (loss of muscle mass) Slurred words Weak grip |0087| In middle stage ALS, the individual can have any of the following symptoms.

Muscles Physical effects Symptoms become more widespread. Some Unused muscles may cause contractures 7 muscles are paralyzed, while others are joints become rigid, l and may be weakened or unaffected. Twitching may deformed. As a result of weak muscles, an continue. individual with ALS may: < Require help to stand l Have difﬁculty eating and wing, causing g Have difficulty breathing, especially lying 1 down Some people with ALS experience bouts of uncontrolled and inappropriate laughing or crying (called pseudobulbar affect or PBA).

In late stage ALS, the individual can have any of the following symptoms.

Muscles. Physical s Most voluntary s are paralyzed. The Most people in the late stages of ALS have ability to move air in and out of the lungs is severely limited ty and are unable to severely compromised. care for their own needs.

Fatigue Fuzzy thinking Headaches l Susceptibility to pneumonia Speech may no longer be possible Eating and drinking by mouth may no longer be possible As used herein, “amyotrophie lateral sclerosis” or “‘ALS" includes the um ofneurodegcnerativc syndromes known under the names ot‘Classical (Chareot’ 3) ALS, Lou Gehrig’s disease, motor neuron disease (MND). progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), bulbar onset ALS.

WO 38814 spinal onset ALS and ALS with multi-system involvement ekera LC and Leigh PN.

Amyotrophic lateral sclerosis. Orphanet l of Rare Disease 2009, 4:3). Types ot‘ALS include sporadic ALS. familial ALS, Western Paciﬁc ALS, Juvenile ALS, and Hirayama Disease.

Types of ALS include sporadic ALS, familial ALS, and variants. including Western Paciﬁc ALS. Juvenile ALS. and H'irayama Disease. The present disclosure es a method for treating ALS. including sporadic ALS. familial ALS, and variants. including Western Pacific ALS. Juvenile ALS, and Hirayama Disease.

Approximately 10% ol’cases ol‘.ALS are familial. The remaining 90% are sporadic and though to be multifactorial, with both environmental and genetic components buting to disease susceptibility. The genetics of both FALS and SALS is complex.

About 20% ol‘cases with autosomal dominant FALS and 2% of patients with SALS show mutations in the copper/zinc superoxide dismutase (SODI) gene on chromosome 21.

Mutations in the gene are thought to cause disease through a toxic gain of function rather than causing impairment ofthe antioxidant function of the SOD l enzyme. gh genes different from other than SODl have been associated with familial ALS, including alsin , senataxin (ALS4) or Angiogenin, the genetic defect remains to be identiﬁed in the majority of cases.

Sporadic and familial ALS (SALS and FALS, respectively) are clinically and pathologically similar. suggesting a common pathogenesis. Both forms produce similar pathological hallmarks, including progressive muscle weakness, atrophy, and spasticity, each of which reflects the degeneration and death of upper and lower motor s. Denervation of the respiratory muscles and diaphragm is lly the fatal event. In current l practice. the terms “bulbar onset ALS” and “spinal onset ALS" have replaced the terms PBP and Charchot‘s ALS. Approximately two thirds of patients with typical ALS have a spinal Form of the disease (limb onset) and present symptoms related to focal muscle weakness and wasting. where the symptoms may start either distally or proximal ly in the upper and lower limbs. Gradually. spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset Al's-S y present with hria and dysphagia for solid or liquids, and limbs symptoms can, develop almost aneously with bulbar symptoms. and in the vast majority of cases will occur within 1—2 years. Paralysis is progressive and leads to death due to respiratory failure within ‘2-3 years for bulhar onset cases and 3-5 years for limb onset ALS cases. |0093| Western Paciﬁc ALS is a unique neurological disease initially identified among the Chamorro people of Guam and is terized by a combination of symptoms including stooped posture, a blank expressionless face, dementia. slow shuffling movement, a resting tremor that stops upon rate action, slow movements, and muscle atrophy that results in muscles dipping down in the hand. Some patients have Parkinsonism features combined with dementia (Parkinsonism Dementia Complex, PDC). in still others, only dementia is observed. Neuropathologically, all clinical forms of the disease result in a speciﬁc feature, neuroﬁbrillary tangles, found in the cortex and in the spinal cord. Because the disease has aspects that resemble amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer's e (AD), this disease is known as n Pacific ALS or amyotrophic l scierosis—Parkinsonism dementia complex of Guam. (ALS—PDC) and is also known as lytico-bodig.

Juvenile ALS is an adolescent motor neuron disease that is clinically indistinguishable from ALS. Onset is between ages of twelve and sixteen years and occurs below the age of 25 years.

In Hirayama e, there is localized atrophy of one arm associated with increased reﬂexes implicating the presence of upper and lower motor neuron damage.

However, Hirayama Disease involves a problem at the junction between the cervical spine and the. skull where there is pressure on the cervical spinal cord. In order to detect I-Iirayama Disease, an MRI of the neck needs to be performed in different ons including neck ﬂexion and extension. [0096! Other syndromes related to the ALS spectrum of disorders include ssive bulbar palsy (PBP), progressive ar atrophy (PMA), primary lateral sclerosis (PLS) and ALS with multi-system involvement. The t disclosure es a method for treating a syndrome related to the ALS spectrum of ers, such as progressive bulbar palsy (PEP), progressive muscular atrophy (PMA). primary lateral sclerosis (PLS), or ALS with multi— system involvement.

Progressive bulbar palsy (PBP) is a motor neuron disease. in which the nerves supplying the hulbar muscles are attacked. PBP is characterized by the ration of motor neurons in the cerebral cortex, spinal cord, brain stem. and pyramidal tracts.

Progressive bulbar palsy symptoms can include progressive difﬁculty with g, talking. and swallowing. Patients can also exhibit reduced gag reﬂexes. weak l movements, 2014/000274 fasciculations. and weak movement of the facial muscles and . In advanced cases of PBP, the patient may be unable to protrude their tongue or manipulate food in their mouth.

Progressive muscular atrophy (PMA, also Duchenne-Aran muscular atrophy or Duchenne-Aran disease) is motor neuron disease which affects the lower motor neurons.

Symptoms ofPMA include atrophy. fasciculation, and muscle weakness. Some patients have ms restricted to the arms or legs.

Primary lateral sclerosis (PLS) is a neurotnuscular disease characterized by progressive muscle weakness in the voluntary muscles. PLS affects upper motor neurons.

Symptoms include difficulty with balance and weakness and stillness in the legs. Other common symptoms are spasticity (involuntary muscle contraction due to the stretching of ). There may also be difﬁculty in breathing in the later stages ot‘the disease, causing those patients who develop ventilatory failure. Hyperrellexia is another feature of PLS as seen in patients presenting with the Babinski's sign. Some people present with nal lability and bladder urgency, and occasionally people with PLS experience mild cognitive changes detectable on neuropsychological testing, particularly on measures of ive function. in some ments, the beneﬁts of administering the compositions to alleviate the symptoms or treat ALS can be evaluated by the following tests: a reduction in the rate of decrease in the ALSFRS-R score, the Manual Muscle Testing (MMT) score, the Slow Vital Capacity (VC) percent predicted value, the ALE-Speciﬁc Quality of Life (ALSSQoL) score, and EuroQol~5 Dimensions (EQ—SD) Health Outcomes Scale score.

Another suitable test for evaluation includes a reduction in the rate of increase in the Zarit Burden Interview (ZBI) score. r suitable test for evaluation is the use of electrical nce phy as a ker (Rutkove et at, oph l Scler. 2012 Sep; l3(5):439—4). In some ments, the rate of decrease in, or the symptom measured by, the ALSFRS-R score is d by at least 15% as compared to an individual with AIS who is not administered S-oxprenolol.

Beta Blockers ] The methods described herein comprise administration of compositions comprising beta blockers. Beta blockers, which are used to treat hypertension, can be used for preventing the onset of amyotrophic lateral sclerosis and for treating amyotrophic lateral sclerosis. For example, the use ot‘a beta blocker in an individual with ALS has shown that the dual has prolonged al compared to an individual with ALS that did not receive a beta blocker. Other beneﬁts ofthe use ofa beta blocker include preservation of lean body mass and prevention of body weight loss. These eflects suggest that beta blockers can be used to treat AIS, delay the development of ALS, alleviate the symptoms of ALSﬁ and improve the quality of life for ALS patients. |0102] ln some embodiments the beta blocker has intrinsic homimetic ty (ISA). In some embodiments, the beta blocker does not have intrinsic sympathomimetic activity (lSA). Intrinsic sympathotnimetic activity is used to refer to beta blockers that can Show both agonism and antagonism at a, given beta receptor, ing on the concentration of the agent (beta blocker) and the concentration of the antagonized agent.

In some embodiments, where the beta blocker ns one chiral centeri the beta blocker is the enantiomerically enriched S-enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the beta blocker is selected from the group consisting ofacebutolol, atenolol, betaxolol, bisoprolol, carteolol, celeprolo]= labetaloL metoprolol, l. nebivolol. oxprenolol, penbutolol, pindolol, propanolol, sotalol, esmolol, earvediloh timolol, bopindolol, medroxalol, bucindololi levobunolol. metipranolol, celiprolol and propat‘enone. ln some embodiments, the beta blocker is oxprenolol. ()xprenolol is a non- selective beta blocker which possesses some sic sympathomiinetic activity. |0105] in some embodiments, the beta blocker also has partial 5-HT; A rn activity. The 5-HT, A receptor is a subtype of 5~HT receptor that binds the endogenous netu'otransmitter serotonin (5-hydroxytryptamine, 5-HT). Oxprenolol is a partial S-I-I‘I'la agonist. tiomerically enriched compositions of beta blockers 06] The methods described herein comprise administration ol’an S- enantiomerically ed composition of a beta r or a phamiaceutically acceptable salt f (for example comprising an enantiomeric excess of at least about 99% of a beta blocker). The present sure also provides such compositions which are useful for the methods disclosed herein.

When a compound has a chiral center, the compound can exist in optically active forms. Optically active compounds have the ability to rotate the plane of plane- polarized light. in describing an optically active compound, the preﬁxes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The preﬁxes “d” and “l” or (+) and (—) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is “levorotalory” and with (+) or 0. meaning that the compound is “dextrorotatory.” There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. For a given al structure, these compounds, called “stereoisomers,” are identical except that they are mirror images of one another. A c stereoisomer can also be referred to as an “enantiomer,” and a mixture of such isomers is often called an “enantiomerie” or “racemic” mixture. When a compound has one chiral center, there are two enantiiomers: the S- enantiomer and the R—enantiomer. [0.108] The compositions described herein are enantiomerically enriched for S— enantiomer. For example, in some embodiments, the composition comprises an enantiomeric excess of at least about 1%, %, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% ofS—enantiomer ofthe beta r. In some embodiments, the composition comprises an enantiomeric excess of at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% of S-enantiomer of the beta r.

In some embodiments, the composition comprises an enantiomeric excess of at least about 90%. 95%, 98%, 99%, or 100%, up to the detectable limit of purity, of S—enantiomer ot‘the beta r. In some embodiments, the composition comprises an enantiomeric excess of any t 1-4%, 5-9%, 10-11%, 20-29%, 30-39%, 40-49%, 50-59%, 60-69%, 70-79%, 80- 89%, 90—99, or 100% of tiomer of the beta blocker. In some ments, the composition comprises an enantiomeric excess of at least about 99% or 100% of S- enantiomer of the beta blocker (i.e., pure S—enantiomer of the beta blocker). In some embodiments, the composition comprises an enantiomeric excess ot‘al least 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 or 1.00% 01' S—enantiomer ot‘the beta blocker (i.e., pure S— enantiomer of the beta blocker). Methods of making enantiomerically enriched compositions of beta blockers are known in the art.

In some ments, the beta blocker is ed from the group consisting ofacebutolol, atenolol, lol, bisoprolol, lol, celeprolol, labctalol, metoprolol, nadolol, lol, oxprenolol, penbutolol, pindolol, propanolol, sotalol, esmolol. carvedilol, titnolol, bopindolol, medroxalol, bucindolol, levobunolol, metipranolol, celiprolol and propafcnone or a pharmaceuticahy acceptable salt thereof.

WO 38814 |0110| In some embodiments, the beta blocker is oxprenolol or a pharmaceutically acceptable salt thereof. Oxprenolol is l~[2—(allyloxy)phenoxy]~3—(isopropylamino)propan—2- 01. The structure ol‘oxprenolol is shown below.

@OWNYCMH/ OWV’CHZ CH3 Oxprenolol is a compound with one chiral . As a racemic mixture. there is a mixture of )-oxprenolol and (S)-(~)—oxprenolol. Analytical s. such as HPLC, can be used for separation and quantiﬁcation oi'(R)-(+)-oxprenolol and (S345)- oxprenolol in mixtures. The structures of )~oxprenolol and (S)—(i}0xprenolol are shown below.

CE WCHZf3O (R)- +( ) oxprenolol or R oxprenolol. - /H“Y\H (R)~1—(2—( allyloxy)phenoxy)-3~ O ‘ - N CH 3 (isopropylammo)propan—2—ol. 1 0H 1 1 lot S-ox renolol O.\/"l\/NH, H (8') (- ~ -) oxpreno o p (19-1—(2—(al1yloxy)phenoxy) (isopropylamino)propan~2~o1 The compositions described herein are enantiomerically enriched for S- oxpreno1ol. For example. in some ments, the composition comprises an enantiomeric excess ofat least about 1%, 5%, 10%. 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% ot‘S—oxprenolol. 1n some ments, the composition comprises an enantiomeric excess of at least about 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% of S—oxprenolol. in some embodiments, the composition comprises an enantiomeric excess of at least about 90%, 95%, 98%, 99%, or 100%, up to the detectable limit of purity, of enolol. 111 some embodiments, the composition comprises an enantiomeric excess of any of about 1-4%, 5—9%. 10-11%. 20- 29%. . 40-49%. 50—59%. 60—6. %. 70—79%, 80—89%, 90—99. or 100% of S—oxprenolol.

In some embodiments, the composition comprises an enantiomeﬁc excess of at least about 99% or 100% of S—oxprenolol (i.e.. pure S—oxprenolol). In some embodiments, the composition comprises an enantiomeric excess of at least 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 9.9.7, 9.9.8, 9.9.9 or 100% of Svoxprenolol (i.e., pure Svoxprenolol). Methods of making enantiomerically enriched compositions ofoxprenolol are known. in the art. 2014/000274 |0113| Two main routes are established for obtaining enantiomerically enriched compounds: (1) asymmetric syntheses and ('2) racemic resolutions. (R. A. n: The Industrial Syn/hens ofOptically Active Compounds, in Miklés Simonyi (editor). Problems and s ifChiraZ Molecules, Akadémiai Kiado, Budapest, 1990, S. 349—386). The syntheses give medium-high yields and excellent enantiomeric excess. but the resolutions are d by 50% yield. Both technologies involve techniques such as dynamic kinetic resolution (DKRV) and membrane-based extraction (Augustian J et al., s Biochemistry Volume 45, issue 10. October 20l0, Pages 1587—1604). One method describes enantiomer enrichment ot‘oxprenolol up to 68 % enantiomeric excess was achieved by using a cellulose tris(3,5~dimethylpbenylcarbamate) (CTPC)-coated rayon—belt. (Yashima E. et 2d,. edron: Asymmetry Volume 6, issue 8, August 1995, Pages l889ml 890).

The compositions described herein in some embodiments are present in pharmaceutical compositions. The phannaceutical itions may further comprise one or more pharmaceutically acceptable carrier (or cxcipicnts). A pharmaceutically-acceptable excipient is a nce that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds bed herein and are compatible with the active ingredient. Examples of pharmaceutically—acceptable excipients include stabilizers, lubricants, surfactants. diluents. anti-oxidants, binders, coloring agents, bulking agents, cmulsiﬁerst or taste-modifying agents. in some embodiments, the pharmaceutical composition is sterile.

Also provided here are unit dosage forms comprising a pharmaceutical compositions described herein. These unit dosage forms can be stored in a suitable ing in single or multiple unit dosages and may also be further sterilized and sealed. Unit dosage Forms can be provided, for example, in the form of tablets, capsules, vials, and any other forms described herein. [01161 In some embodiments. there is provided a compositioa (such as a pharmaceutical ition, for example a unit dosage) comprising oxprenolol or a phamtaceutically acceptable salt thereof. wherein the composition is enantiomerically enriched for S-oxprenolol (for example comprising an enantiomeric excess of at least about 99% ofS—oxprenolol), wherein the amount ol‘S—oxprenolol in the ition (such as pharmaceutical composition) is included in any of the following ranges: about 5 to about 10 mg. about 10 to about 20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40 to about 50 mg, about 50 to about 60 mg, about 60 to about 70 mg, about 70 to about 80 mg. 2014/000274 about 80 to about 90 mg, about 90 to about 100 mg, about 100 to about 110 mg, about 110 to about 120 mg, about 120 to about 130 mg, about 130 to about 140 mg, about 140 to about 150 mg, about 150 to about 160 mg. in some embodiments, the amount of S-oxprenolol in the composition is about 20 to about 160 mg, including for example about 50 to about l 50 mg. 80 to about 150 mg. about 90 to about 140 mg, about 100 to about 120 mg. In some embodiments, the composition is suitable for oral administration.

In some embodiments, the composition is provided in a slow release form.

For e, olol can be administered in slow release form. (Eur J Drug Metab Pharmacokinet. 1998 Apr—Jun:23(2):l78-84; t PN, Bennett J, Bradbrook 1, Francis J, John VA, Rogers H, Turner P, Wanington SJ. Br J Clin Pharmacol. 1985;19 Suppl 221718— 1758; and Woods KL, Jack DB, Kendall MJ, Halsey A, O’Donnell ML, gton. SJ, John VA. Br J Clin Pharmacol. 1985; I9 Suppl 741778-1848.) Also provided are articles of manufacture comprising the compositions, formulations, and unit dosages described herein in le packaging for use in the methods of treatment, methods of administration, and dosage regimens described herein. Suitable packaging for compositions described herein are known in the an, and include, for example, Vial (such as sealed , vessels (such as sealed vessels), ampules, bottles, jars, ﬂexible packaging (cg, sealed Mylar or plastic bags), and the like. These articles ofmanufacture may further be ized and/or sealed.

Dosages and Administration Route The dosage of the itions described herein stered to an individual (such as a human) may vary with the particular composition, the method of administration, and the particular stage of amyotrophic lateral sclerosis. The amount should be suﬂicient to produce a desirable response, such as a therapeutic or prophylactic response against amyotrophic lateral sclerosis. in some embodiments, the amount of the composition is a therapeutically effective amount. In some ments. that amount of the composition is a prophylactically effective amount. In some embodiments, the amount of total oxprenolol in the composition is below the level that induces a toxicological effect (1?. c an effect above a clinically able level of toxicity) or is at a level where a potential side effect can be controlled or tolerated when the composition is administered to the individual.

In some embodiments, the amount of an S—enantiomerically enriched composition ofa beta blocker or a pharmaceutical ly acceptable salt thereof (e.g., — oxprenolol) in the ition is included in any of the ing ranges: about 0.5 to about mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 to about 1.25 mg, about 125 to about 150 mg. about 150 to about 175 mg, about 175 to about 200 mg, In some embodiments, the amount ol" an S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (eg, S—oxprenolol) in the composition is included in any of the following ranges: about 5 to about 10 mg, about 10 to about 20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40 to about: 50 mg, about 50 to about 60 mg, about 60 to about 70 mg. about 70 to about 80 mg, about 80 to about 90 mg, about 90 to about 100 mg, about IOO to about [10 mg. about i 10 to about 1'20 mg, about 120 to about [30 mg, about 130 to about 140 mg, about 140 to about 150 mg, about l50 to about [60 mg. in smne embodiments, the amount of an S-enantiomerically enriched ition ofa beta blocker or a pharmaceutically acceptable salt thereof (cg. S—oxprenolol) in the composition is about 20 to about 160 mg, including for example about 50 to about 150 mg, 80 to about 150 mg, about 90 to about 140 mg, about 100 to about 120 mg. in some embodiments, the amount of an S—enantiomerically enriched composition ot‘a beta blocker or a phannaceutically acceptable salt thereof (eg, S— oxprenolol) in the composition includes at least about any ol‘0.1 , 0.5 mg/kg, 1 rug/kg. mg/kg. 5 mg/kg, 7.5 mg/kg, 10 tug/kg, l5 mg/kg, or 20 mg/kg. 111 some embodiments, the amount of an S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (_e.g., S-oxprenolol) in the composition es less than about any of35 mg/kg, 30 mg/kg, 25 mg/kg, 20 mg/kg, 15 rug/kg, 10 mg/kg, 5 mg/kg, 2.5 mg/kg, 2 mg/kg, 1 mg/kg, 0.5 mgkg, or 0.1 mg/kg.

Exemplary dosing frequencies include, but are not limited to, weekly without break; , three out of four weeks; once every three weeks; once every two weeks; weekly, two out e weeks. 111 some embodiments, the composition is administered about once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some embodiments, the composition is administered at least about any of 1x, 2X, 3x, 4x, 5x, 6x, or 7X (Ila, daily) a week. In some embodiments, the intervals between each administration are less than about any of 6 months, 3 months. 1 month, 20 days, 15, days, 12 days, 10 days, 9 days. 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. in some embodiments, the intervals n each administration are more than about any of 1 month. 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months.

In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each stration is no more than about a week. In some embodiments, the composition is administered daily. in some embodiments, the composition is administered twice daily. in some embodiments, the composition is stered at least once (such as at least any ol‘2x, 3x, or 4x) daily.

The administration of the composition can be extended over an extended period oftime. such as from about a month up to about seven years or life-long. In some embodiments, the composition is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, l 1, l2, 18, 24, 30, 36. 48, 60, 72, or 84 months or life-long. In some embodiments, the composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week.

The itions described herein can be administered to an dual (such as human) via various routes, including, for example, intravenous, ultra—arterial, intraperitoneal, intraportal, ulmonaiy. oral, inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, intraocular, intrathecal, transmucosai, and transdermal. In some embodiments. sustained continuous release formulation of the composition may be used.

Once improvement of the patients disease has occurred, the dose may be adjusted for preventative or nance treatment. For example. the dosage or the frequency of stration, or both, may be reduced as a function of the ms, to a level at which the desired therapeutic or prophylactic effect is maintained. Ol‘course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.

Pharmaceutical Formulations and stration The ceutical, compositions described herein may be formulated as solutions, emulsions, suspensions, dispersions, or inclusion complexes such as cyclodextrins in suitable pharmaceutical solvents or carriers, or as pills. tablets, lozenges. itories, sachets, dragees, granules, s, powders for reconstitution. or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions ofthe embodiments may be administered by a le route of delivery, such as oral, eral, rectal. nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

For oral administration, the compositions may be ed in a solid form. such as a tablet or capsule, or as a solution, emulsion, or suspension. Oral tablets may include the active ingredient(s) mixed with ible pharmaceutically acceptable excipients such as ts, disintegrating agents, binding agents, lubricating agents, sweetening , ng agents, coloring agents and preservative agents. Suitable inert ﬁllers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch. sugar, glucose, methyl cellulose, magnesium te, niannitol. sorbitol, and the like.

Exemplary liquid oral ents include l, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium. starch glycolatc, microcrystalline cellulose, and alginic acid are ary disintegrating agent's. Binding agents may include starch and gelatin.

The lubricating agent, it‘present, may be magnesium stearate, stearic acid, or talc. if desired, the tablets may be coated with a material such as glyceryl rnonostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. The oral formulations may be presented as discrete units such as capsules, cachets or tablets. each containing a ermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non—aqueous ; or as an oilvin—water liquid emulsion or a in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Capsules for oral administration include hard and soft gelatin capsules. To prepare hard n capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di— glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. [0129! A tablet may be made by compression or moulding, optionally with one or more accessory ients. Compressed tablets may he prepared by compressingr in a suitable machine the active ingredient in a free—ﬂowing form such as a powder or granules, optionally mixed with a binder (cg nc, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (cg sodium starch glycolate, cross-linked ne, cross—linked sodium carboxymethyl cellulose), surface—active or dispersing agent.

Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release proﬁle.

Liquids for oral administration may be in the form of sions, ons, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid itions may optionally contain: phannaceutiwily-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxynretliylcellulose, aluminum stearate gel and the like); non—aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene , ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired. ﬂavoring or ng agents.

] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or aneous routes, the itions may be ed in e aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium de, Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in niulti-dose forms such as Vials from which the appropriate dose may be withdrawn, or in a solid form or pres-concentrate that can be used to prepare an injeetable formulation Formulations le for parenteral including intravenous administration include aqueous and non~aqueous sterile injection solutions which may contain anti—oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze— dried ilised) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. red unit dosage 'l'ormulations are those containing a daily dose or unit, daily sub—dose or an riate on thereof, of an active ingredient.

Drug ations The methods of the embodiments comprise administering an effective amount of at least one compound of the embodiments; optionally the compound may be administered in combination with one or more onal therapeutic agents, particularly therapeutic agents known to be useful for treating a amyotrophic lateral sclerosis afflicting the subject.

The additional active ingredients may be administered in a. separate ceutical ition from a compound of the embodiments or may be included with a nd of the ments in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the embodiments.

In certain embodiments, the additional therapeutic agent is selected from the group consisting ofCK-2017357, olesoxime (TRO 19622), arimoclomol, riluzole, tretionin and tazone HC 1, AVP-923, memantine, talampanel. tauroursodeoxycholic acid (TUDCA), thalidomide, olanzapine, KNS—760704, lithium carbonate, NPOOI, ONO-2506PO, tamoxifen, creatine monohydrate, coenzymc Q l 0, YAMSO, sodium phenylbutyratc, pyrimethamine, R(+)pramipexole dihydrochloride monohydrate, vitamin E, minocycline, topiramate, gabapentin, Ol 50, stem cell injections, , autologous bone marrow—derived stem cells. ceftriaxone, E0302 (mecobalamin), MCL 186, glatiramer acetate, insulin-like growth factor- 1 (lGIi -1), 1518 333611, sNN 002‘), GSK1223249, brain—derived neurotrophic factor (BDNFL and anti-CD4OL antibody, Kits The present, application also provides kits, medicines, compositions, and unit dosage forms for use in any of the methods described herein‘ Kits provided herein include one or more containers comprising any one of the compositions described herein and/or other agent(s), and in sortie embodiments, further comprise ctions for use in accordance with any of the methods described herein The kit may further comprise a description of selection of individual suitable for treatment, Instructions supplied in the kits of the invention are typically n instructions on a label or package insert (e.g., a paper sheet ed in the kit). but machine—readable instructions ‘ ' . I . (e g v v I I v 3 x v ( » v . 1‘ L ‘9 ctions carried on a magnetic or optical stor igc disk) are also accept tbleg . |0138| For example. in some embodiments, the kit ses a) an S- enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereol‘(e.g.. S-oxprenolol) and a pharmaceutically able carrier and b) instructions for administering the composition for treatment ot'amyotrophic lateral sclerosis.

The kits of the invention are in suitable ing. Suitable packaging include, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Kits may ally provide additional components such as buffers and retative information. The present application thus also es articles of manufacture, which include vials (such as sealed vials), bottles, jars. ﬂexible packaging, and the like.

The instructions relating to the use of the compositions generally e information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e. g.. multi—dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of S— olol as disclosed herein to provide effective treatment ofan individual for an extended period, such as any ot‘a week, 8 days, 9 days, 10 days, 1 l days, 12 days, 13 days, 2 weeks, 3 weeks. 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the pharmaceutical itions and instructions for use and packaged in quantities ent for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.

Also provided are medicines, compositions, and unit dosage forms useful for the methods bed herein. For example, the present disclosure provides, in some embodiments, an tiomerically enriched composition of a beta blocker or a phatmaceutically able salt thereof (em, S—oxprenolol) for treating amyotrophic lateral sis in an individual having amyotrophic lateral sclerosis. The present disclosure provides, in some embodiments, an S—enantiornerically enriched composition of a beta blocker or a phannaceutically acceptable salt thereof (e.g., S-oxprenolol) for prolonging survival of an individual having atnyotrophic lateral sclerosis. The t disclosure provides, in some embodiments, an S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (e.g., enolol) for delaying the development of amyotrophic lateral sclerosis in an individual having amyotrophic lateral sclerosis. The present disclosure provides, in some embodiments, an tiomerically enriched composition ot‘a beta blocker or a pharrnaeeutically acceptable salt thereof (e.g., S- oxprenolol) for ting lean mass loss of an individual having amyotrophie lateral sclerosis. The t disclosure provides“ in some embodiments, an S-enantioinerically enriched ition ol‘a beta blocker or a phannaceutically acceptable salt f (egt, S- oxprenolol) for preventing muscle g of an individual having amyotrophic lateral sclerosis. The present disclosure provides in some embodiments, an S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt f (e.g., S— oxprenolol) for improving quality of life in an individual having amyotrophic lateral sclerosis.

For example. the t disclosure es, in some embodiments, an S- enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (e.g., S-oxprenolol) for the manufacture of a medicament for treating amyotrophie lateral sclerosis in an individual having amyotrophic lateral sclerosis. The present disclosure provides, in some embodiments, an S-enantiomerically enriched composition ofa beta blocker or a pharmaceutically acceptable salt thereof (cg. S—oxprenolol) for the manufacture of a medicament for prolonging survival of an individual having ophic lateral sclerosis. The present disclosure provides, in some ments, an S—enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (emg S- oxprenolol) for the manufacture of a medicament for ng the development of amyotrophic lateral sclerosis in an individual having amyotrophic lateral sclerosis. The present disclosure provides, in some embodiments, an S—enantiomerically enriched ition of a beta blocker or a ceutically able salt thereof (e.g S- oxprenolol) for the manufacture of a medicament for preventing lean mass loss of an individual having amyotrophic lateral sclerosis. The present disclosure provides. in some embodiments, an S-enantiomerically enriched composition of a beta blocker or a pharmaceutically acceptable salt f (e.g., S—oxprenolol) for the manufacture ofa medicament for preventing muscle wasting ofan individual having amyotrophic lateral sclerosis. The present disclosure provides, in some ments, an timnerically enriched composition of a beta blocker or a pharmaceutically acceptable salt thereof (egq — oxprenolol) for the manufacture of a medicament for improving quality of life in an individual having amyotrophic lateral sclerosis.

Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of this invention. The ion will now he described in greater detail by reference to the following non-limiting examples. The following examples further illustrate the invention but. of course, should not be construed as in any way limiting its scope.

Examples e 1. Synthesis renolol The synthesis of S—oxprenolol is shown in Scheme 1. 9 ma 0 /ﬂ_§‘(\/ﬂ7 ”\vox/\ L> I n O L \ @OH _, @O‘VR 3 / /\o/\/\ﬁ’k OH OH OH iPrNH2 (S)—0xpre nolol 1 2 Scheme 1 Preparation of2—(aZ/.)zlo.ryi{)plzenol To a solution of ol (1) (40.0 g, 0.364 mol) in acetone (160 mL) was added potassium carbonate (50.0 g, 0.363 mol) portion-wise at room temperature, over a period of 30 minutes. After the addition was complete the e was d at room temperature for l hour. Ally] bromide (31 .0 ml... 0.358 mol) was then added over a period of minutes. and the reaction heated to 60—70 0C for 6 hours. The reaction was allowed to cool. then water and ethyl acetate were added and the mixture was separated. The organic layer was dried (MgSO4) and the solvent evaporated to give 2~(allyloxy)phenol. (2) (46.2 g) as a 7:3 mixture of mono and his alkylated al.

'H NMR (300 MHZ, CDCl3)(56.93'-6.77(1’U, 4H), 6.05 (m. 1H), 5.41 (dd. 1H), .30 (in. Ill), 4.61 (d, 211). LCMS: Rt 0.70 min, [Mill]f 148.9. 70%.

Preparation QfS—oxprermlol CsF (22.8 g. 0.150 mol) was added to a solution of2~(allyloxy)phenot (7.50 g, 0.050 mol) in DMF (100 mL) and stirred for 1 hour at room temperature. (S)-Glycidyl nosylate (13.0 g, 0.050 mol) was added and the reaction stirred for ‘72 hours at room temperature, then added dropwise to iPrNHg ('97 mL, 1.26 mol) and stirred overnight. The reaction mixture was diluted with EtOAe (150 mL) and water (200 mL) and the solids removed by ﬁltration. The phases were separated and the organic layer washed with water (100 ml.) then brine (100 ml). dried over MgSO4 and concentrated. Puriﬁcation by column chromatography (5—10% /DCM then 5% (17% NI—h/MeOI-l) in DCM) gave (S)— oxprenolol (4.67 g. 20%) as a brown solid. |0148| '11 NMR 1300 M112, c1103) 0‘ 6.92-6.89 (m, 211), 6.82-6.79 (m, 211), 5.99 (111. 111), 5.37 (d, 1H), 5.21 (d, 11114870» 3, 1H), 4.51 (d, 2H), 3.85 ((1,211), 3.80011. 1H), 2.69-2.61 (m, 2H), 2.47 (m. 1H), 1.48 (b;- s. 1H),, 0.93 (d, 6H). [01.4.9] LCMS: R1 1.78 min, [M+H]" 266.1, 100%.

Example 2. Synthesis qu—Oxprenolol The synthesis of S—oxprenolol is shown in Scheme 2.

[N02 1) o '59 / Ml“ (3)4 b _—::J/ /\ /O‘\/§~ a Cfov\/ . ‘ J\ O H OH 2119mm2 2 (m-oxprenolol Scheme 2 ation Qf'R—oxprenolol CsF (2.95 g, 19.4 11111101) and K3C03 (17.3 g, 125 11111101) were added to a solution ot‘2-(allyloxy)phenol (14.4 g, 96.2 mmol) in DMF (250 mL) and stirred for 30 minutes at room temperature. (R)—Glycidyl11osylate (25.0 g, 96.4 11111101) was added and the reaction d for 48 hours at room temperature. iPrNHg (190 mL, 2.2] mol) was added in one portion and the reaction stirred for 72 hours. The reaction mixture was diluted with water (1.0 L) and ted with EtOAc (3 x 300 mL). The combined organics were washed with HCl (2.0 M, 3 x 300 mL). The aqueous layer was pH adjusted to pH 12 with NaOH (2.0 M) and extracted into EtOAc (2 x 500 . This was washed with 1 :1 water/brine (3 x 500 1111.), then with brine (500 ml), dried over NaZSO4 and concentrated. The crude solid was triturated from heptanes, ﬁltered and dried under vacuum at 40 °C overnight to give (R)— oxprenolol (24.5 g, 69%) as a brown solid. 1H NMR (300 MHZ. CDC13)5 6.92-6.89 (m, 2H), 6.82-6.79 (m, 2H), 5.99 (111., 1H), 5.57 (d, 1H), 5.21 (d, 1H), 4.87 (br s, 1H), 4.51 (d, 2H). 3.85 (d, 2H), 3.80 (m, 1H), 2.69—2.6l (in, 2H), 2.47 (m, 1H), 1.48 (br s. 1H). 0.93 (d, 6H).

LCMS: Rt 179 min, [MHLJI]f 266.1, 99%.

Example 3. Study ol with B6SJL~Tg(SODI *G93A)IGur/JALS .Mouse diode! Transgenic mice xpressing a high copy number (25 copies) of mutated human SOD] gene with a G93A point mutation. i.e., B6SJL-TgN [SOD l -G93A] lGur ((3 1H- 2014/000274 693A transgenic mice. JR2726; Hemizygote) y M E, et al., Science, 264, 1772-1775. 1994) (“‘G93A SODl B6SJL hybrid (G93A) model”), were used. As shown in a diagram in Figure 1, the transgenic mice display muscle weakness and atrophy by 90 to 100 days of age. and typically die near 130 days ot‘age.

An intervention study was performed with S‘oxprenolol (l Omg/kg/day) in the G93A SOD] BéSJL hybrid (G93A) model after onset ol’ALS. Onset ease was deﬁned as peak body weight as well as the beam walk and splay neurological scores as suggested by Ludolph et al. 2007. (Ludolph AC, Bendotti C, Blaugrund E, Hengerer B, Lofﬂer JP, Martin J Moussaoui S. Robberech’t W Scott: S, Silani V5 Van Den Be rg LH , Meininger V.) Meyer T. , (ENMC Group For The ishment Of Guidelines For The Conduct OfPreclinical And Proof Ot‘Concept Studies in ALS/MND ). 2007. Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: Report on the 142nd ENMC international workshop. Arrzyotmphic Lateral Sclerosis 8: 217—223.) There were 15 mice in the placebo group. There were 16 mice in the S-oxprenolol group.

The primary endpoint was survival, humanely deﬁned as the ability of the animal to right itself in 30 s after being laid on its side. Secondary endpoints were body weight, body ition, spontameous activity and food intake. Body weight of the animals was assessed weekly until onset of disease. Additionally, body composition (fat mass and lean body mass) was assessed using NMR scans (EchoMRl-lOO. Echo Medical Systems, Houston, USA) every 4 days. After onset of disease, body weight and body composition were assessed every two days until the end of the study. All personal handling the s was strictly blinded to the randomized treatment tion.

Example 4. Effect qu—Oxprenolol on Survival To study the effect of S—oxprenolol on survival. survival was monitored over time. Figure 2 shows the percent survival of mice that were administered with S—oxprenolol at dosages of 10 day. As shown in Figure 2, mice re‘eiving S-oxprenolol had longer survival than those in the o group. Treatment of G93A mice with 10 mg/kg/day ot‘S- oxprenolol after onset of ALS signiﬁcantly improved survival by about 33% compared to placebo treated mice (56 vs 42 days after onset, respectively. HR: 0.39, 95%Cl: 0.l7l—0.88. p= 0.0241, Figure 2). Median survival was improved from 28 days (placebo) to 37 days (S~ oxprenolol, ratio: 1.32, 95%Cl: 0.83-1.81). |0158] Figure 3 shows the percent survival of mice that were administered S— oxprenolol at a dosage of 10 mg/kg/day. One control group received S-pindolol at its red dosage of 3 mg/kg/day. As shown in Figure 3. S-oxprenolol was signiﬁcantly superior to either placebo or S—pindolol at its preferred dose. The median survival after onset ofALS symptoms was 28 days for the placebo group; 3] days for the S—pindolol group; and 37 days for the S-oxprenolol group.

Figure 4 shows the t survival of mice that were administered S— oxprenolol at a dosage of 10 mg/kg/day, R-oxprenolol at a dosage of H) mg/kg/day, oxprenolol at a dosage ol‘20 mg/kg/day, le at a dosage of 30 mg/kg/day, or propanolol at a dosage of l0 mg/kg/day. There was also a o group. As shown in Figure 4, - oxprenolol was signiﬁcantly superior to either placebo or the other nds.

Example 5. Effect ofS—Oxprenolol on Body Weight To study the effect of S—oxprenolol on body weight, body weight was monitored over time. |0161] Figure 5 shows the change of body weight (in grams per day alive after onset ofALS symptoms) per survival day after ALS onset in mice administered S-oxprenolol at a dosage of 10 mg/kg/day or S—pindolol at red dosage of 3 mgr'ltg/day. As shown in Figure 5, mice receiving S—oxprenolol had body weight loss that was close to those administered S-pindolol. Mice receiving S-oxprenolol had less body weight loss than those in the placebo group. e 6. Effects ofS—Oxprenolol an ving Lean Body Mass To study the effect of the test compounds on lean body mass, lean mass was determined at the end of the study.

In this experiment. all mice were killed using the 30 seconds endpoint and hence all mice were equally diseased at the end of the study. Figure 6 shows the change in lean body mass (in grams) of mice that were administered S—oxprenolol at a dosage of 10 mg’kg/day. As shown in Figure 6, rats receiving S—oxprenolol had less change in lean body mass than those receiving a placebo. Wasting of lean mass was reduced by about 40% by active treatment compared to placebo (p=0.18, Figure 6). This effect shows that S-oxprenolol is effective in preserving lean body mass. |0164| Figure 7 shows the change in lean body mass (in grams per day alive after onset ofALS symptoms) per survival day after ALS onset of mice that were administered S~ oxprenolol at a dosage of 10 mg/kg/day or S-pindolol at preferred dosage of 3 mg/kg/day. As shown in Figure 6, rats receiving S-oxprenolol had less change in lean body mass than those receiving olol.

Example 7. Efjécts Q/‘S-OxpreIwIOI on Skeletal Muscle Atrophy To study the effect of the test compounds on al muscle atrophy. the skeletal muscle mass were determined at the end of the study.

Figures 8—1 1 show the mass ofvarious types of skeletal muscle (in grams) of mice populations that were administered S-oxprenolol at a dosage of 10 mg/kg/day or a placebo. Figure 8 shows results for gastroenemius muscle weight plotted with days after onset for the placebo group. A trend for a correlation of days after onset (=survival) and gastrocnemius weight was seen in placebo-treated mice. (R:-0.5(i, p=().18) Figure 9 shows results for gastroenemius muscle weight plotted with days after onset for the S—oxprenolol group. Figure 9 shows that with stration of enolol. the gastrocnemius weight in the G93A ALS model is steady. There is no correlation ot'days after onset ival) for gastrocnemius weight. 03, p-"~~O.94) Figure 10 shows results for tibialis or muscle weight plotted with days after onset for the placebo group. A trend for a correlation olidays after onset (=survival) and tibialis anterior muscle weight was seen in placebo—treated mice. (R:-0.67, p=().097) Figure 1 l shows s for tibialis anterior muscle weight plotted with days after onset for the S— oxprenolol group. Figure 11 shows that with administration of S-oxprenolol, the tibialis anterior muscle weight in the G93A ALS model is steady. There is no correlation of days after onset (=survival) for is anterior muscle. (R1015, p=0.72) The loss of mass ol’the ﬁber type muscle gastroenemius showed a trend for a correlation of survival (:4 days after onset oldisease‘ Figure 8), while mice treated with S-oxprenolol (Figure 9) showed no correlation, indicating a muscle protective role ot‘S- oxprenolol. The loss of mass of the mixed-ﬁber type muscle tibialis showed a strong trend for a correlation of survival (= days after onset of disease, Figure 10), while mice treated with S—oxprenolol showed no correlation e l I)? again indicating a muscle protective role of S-oxprenolol.

Example 8. Effects ofS—Oxprenolol on Preserving Fat Mass To study the effect of the test compounds on fat mass, the fat mass were determined at the end of the study.

Figure [2 shows the change in fat mass (in grams) of mice administered S- oxprenolol. As shown in Figure 12, rats receiving S-oxprenolol had no reduction in fat mass than those in the placebo group. S-oxprenoloi had no effect on the loss offat: mass ('p>0.5, Figure 12). [0.171] Figure 13 shows the change in fat mass (in grams per day alive after onset of ALS symptoms) per al day after ALS onset ofmiee that were administered S— oxprenolol at a dosage of 10 day or S-pindolol at preferred dosage of 3 mg/kg/day. As shown in Figure 13, rats receiving S-oxprenolol had less change in fat mass than those receiving olol.

The ence between Figures 12 and 13 is explained by the survival. The overall loss of fat mass is equal on the day the animals are euthanized. But mice treated with S—oxprcnolol lived longer and therefore the loss of fat mass per day alive after onset of ALS symptoms is lower (=overall fat loss divided by number of days alive after ALS onset).

Example 9. s QfS—Oxprenolol on improving outcome QfALS ed to R~ Orprenolol and Rilutek |0173] To study the effect of S-oxprenolol on survival compared to R—oxprenolol and rilutek, survival was monitored over time. Rilutek (leuzole. structure shown below) is used for ng ALS. 0 3(Ri1utek) |0174] Figure 14 shows the percent survivai of mice that were administered with S- oxprenolol at dosages of 10 mg/kg/day or 20 mg/kg/day. Other groups of mice were administered riluteh at a dosage of 30 mg/kg/day; propanolol at a dosage of 10 mg/kg/day; olol (racemic) at a dosage of20 mg/kg/day; R—oxprenolol at a dosage of 10 mg/kg/day or 20 mg/kg/day: or a placebo. The number of mice in each population is indicated as “n" in Figure 14. As shown in Figure 14, mice receiving S-oxprenolol at a dosage of 20 mg/kg/day had longer survival than other groups. 2014/000274 |0175| The statistical data for Figure 14 is shown below. “HR” refers to hazard ratio. “95% Cl" is conﬁdence interval. “p" refers to p value.

Table 1: Statistical data for Figure 14 (for all mice) Comparison (dosage in mg/kg/day) 95% C1 p value Rilutek (30) vs. placebo . 0.55-l .46 Propanolol (10) vs. placebo l 0.73 045—! .18 0.20 Oxprenolol (20) vs. o 0.66 040—1 .07 0.09 R-Oxprenolol (lOWs. placebo . 0.35—0.93 0.0227 iTiiEiBFEEBiBi‘Eiii‘jV;Eli-5555"“WW 73757? 0310880013 S~Oxprenol0l (10) vs. o I 0.71 0464.10 0.13 enolol (20) vs. placebo ! 0.45 0.27—0.73 0.0014 Rilutek (30) vs. enolol (20) 2.07 l.l7—3.67 0.0129 Propanolol (10) vs. S—Oxprcnolol (10) 1.06 0.65—1.74 0.83 Propanolol (10) vs. S-Oxprcnolol (20) 1.77 0.99—3.15 0.0532 R-Oxprenolol (20) vs. S-Oxprenolol 1.32 0.77—2.28 0.3 (20) I S-Oxprenolol (20) vs. placebo 0.45 0.27-0.73 0.0014 Figure 15 shows the percent survival of male mice that were stered with S~oxprenolol at dosages of 10 day or 20 mg/kg/day. Other groups of male mice were administered rilutek at a dosage of30 mg/kg/day; propanolol at a dosage of 10 mg/kg/day; oxprenolol (racemie) at a dosage of 20 mg/kg/day; R—oxprenolol at a dosage of 10 mg/kg/day or 20 mg/kg/day; or a placebo. The number of male mice in each population is indicated as “n” in Figure 15. As shown in Figure 15. male mice receiving S—oxprenolol at a dosage of20 mg/kg/day had longer survival than other groups. |01 77] The statistical data for Figure 15 is shown below. “HR” refers to hazard ratio. “95% CI” is conﬁdence interval. “p” refers to p value.

Tabie 2: Statistical data for Figure 15 (for male mice) ison (dosage in mg/kg/day) p value Rilutek (30) vs. placebo 1 0.30-1.29 "ii'r'iiiiii'riiiiiiiiiﬁiiﬂéfﬁiéééiﬁ """"""""""" 1"""""""""""""""""""" Oxprenoiol (20) vs. placebo I 0.38 0.18-0.80 0.0114 R-Oxprenolol (10)Vs.pla.cebo I 0.49 0.23—0.99 0.0492 R-Oxprenolol (20) vs. placebo I 0.41 0.19—0.86 0.0176 S—Oxpreno'lol (10) vs. placebo I 0.46 0.23—0.92 0.0289 S-Oxprenolol (20) vs. placebo 0.39 0.19—0.83 0.0139 Rilutek (30) vs. S—Oxprenolol (20) Propanolol (10) vs. S—Oxprenolol (10) . 0.75—3.48 olol (10) vs. S—Oxprenoloi (20) 1 1.98 0.88—4.49 0.099 R-Oxprenolol (20) vs. enoiol 1.24 0.57—2.69 0.58 (20) i S—Oxprenolol (20) vs. placebo (1.39 0.19—0.83 0.0139 |0178] Figure 16 shows the percent survival of female mice that were administered with S-oxprenolol at dosages of 10 mg/kglday or 20 mgl'kg/day. Other groups of female mice were administered rilutek at a dosage of30 mg/kg/day; propanolol at a dosage of 10 mg/kg/day; oxprenolol (racemic) at a dosage of 20 mg/kg/day; R~oxprenolol at a dosage of mg/kg/day or 20 mg/kg/day; or a placebo. The number of female mice in each population is indicated as “n” in Figure 16. As shown in Figure 16, female mice ing S~oxprenolol at a dosage of 20 mg/kg/day had longer survival than other .

The statistical data for Figure 16 is shown below. “HR” refers to hazard ratio. “95% CI” is conﬁdence interval. “p” refers to p value.

Table 3: Statistical data for Figure 16 (for female mice) Comparison (dosage in Ing/kg/day) HR 95% CI p value Rilutck (30) vs. o 0.55-2.15 éiiiii'riliiiiii'i'iij'iié'fBiéiééiié'""""""""""' 'i'J'ﬁ'i """""""""""6363'1'23'9'""""""""""6333 """"""""""""""" Oxprenolol (20) vs. placebo 1.03 0.52-2.02 0.94 R-Oxprenolol (l0) vs. placebo 0.60 i 0.31—1.15 0.13 enolol (20) vs. placebo 0‘41 0.31—1.16 0.13 enolol (10) vs. placebo 0.96 0.53—1.73 0.8.9 S-Oxprenolol (20) vs. placebo 0.53 0227-] .02 0.058 Rilutek (30) vs. S—Oxprenolol (20) 0.92—4.5I Propanolol (10) vs. S—Oxprenolol (l0) 0.38—1.46 0.39 Propanolol (10) vs. S—Oxprenolol (20) L49 0.67—3.34 1 0.32 enolol (20) vs. S—Oxprenolol 1.26 0.59—2.72 0.55 (30) S—Oxprenolol (20) vs. placebo 0.53 0.27-1.02 i 0.058 |0180] Figures l7-l9 show changes in disease progression of scores in tested mice.

The disease progression score is based on the JAX SOP (Ludolph AC. Bendotti C. Blaugiund E, er B, Loffler JP, Martin J, Meininger V, Meyer T, Moussaoui S. Robbereelit W, Scott S. Silani V, Van Den Berg LH (ENMC Group For The Establishment Of Guidelines For The Conduct Of Preclinical And Proof Of Concept Studies In ALS/MND Models). 2007, which is incorporated by reference).

Figure 17 shows the t ofmice that improved from disease progression ofscore l to score 2 that were administered with S-oxprenolol at dosages of 10 mg/kg/day or mg/kg/day. Other groups of mice were administered rilutek at a dosage of 30 mg/lrg/day; propanolol at a dosage of 10 mg/kglday; oxprenolol ic) at a dosage of 20 mg/kg/day; R-oxprenolol at a dosage of 10 mg/kg/day or 20 mg/kg/day; or a. placebo.

The statistical data for Figure 17 is shown below. "HR" refers to hazard ratio. “95% CI” is conﬁdence interval. “p” refers to p value.

Table 4: Statistical data for Figure 17 (Progression from score 1 to score 2) ison e in mg/kg/day) p value Rilutek vs. placebo 0.48-1.40 "ii'r'iiiiiihliiiii'Jé'fiéi'éfééiiii"""""""""""""""""10.64""""""""""" 03631.66"""""""""""6586'""""""""""""" Oxprenolol vs. placebo I 0.60 0.36-1.01 0.053 R-Oxprenolol (10)Vs.pla.cebo I 0.47 0.28—0.79 0.0047 R-Oxprenolol (20) vs. o I 0.54 0.32—0.90 0.0176 S—Oxpreno'lol (10) vs. placebo I 0.56 0.35—0.91 0.0189 S-Oxprcnolol (20) vs. placebo 0.5] 0.31—0.87 0.0128 Rilutek \«s, S-Oxprenolol (10) . 0.92—3.08 Rilutek \«s. S—Oxprenoloi (20) . 0.913.29 Propanolol vs. S-Oxprenolol (_ 10) i 1.27 0.73—2.21 0.3 Propanolol vs. S—Oxprenolol (20) 1.49 0.82—2.69 0.19 ..........s R-Oxprenolol (10) vs. S—Oxprenolol 0.73 0.42—1.27 0.27 (10) S-Oxprenolol s. S-Oxprcnolol 1.17 0.65-2.09 0.60 (20) Figure 18 shows the percent of mice that improved from disease progression ofscore 2 to score 3 that were stered with S-oxprenolol at s of 10 mg/kg/day or mg/kg/day. Other groups of mice were administered rilulek at a dosage 01‘30 mg/kg/day; propanolol at a dosage of 10 mg/kg/day; oxprenolol (tacemicl) at a dosage of 20 mg/kg/day; R-oxprcnolol at a dosage of 10 mg/kgx’day or 20 day; or a placebo.

The statistical data for Figure 18 is shown below. “HR” refers to hazard ratio. “95% CI“ is conﬁdence interval. "1)" refers to p value.

Table 5: Statistical data for Figure 18 (Progression from score 2 to score 3) Comparison (dosage in mg/kg/day) 95% CI p value Rilutek vs. placebo 0.37-l .24 Propanolol vs. placebo 0 58-} .69 0 97 Oxprenolol vs. placebo 0.44-l .33 0.35 R-Oxprenolol (l0) vs. placebo 0.59—l .82 0.91 R-Oxprenolol (20) vs. placebo 0.74 0.43—1.27 0.27 S—Oxpreno'lol (10) vs. placebo 1.07 0.64—1.79 0.79 enolol (20) vs. placebo 0.64 0.37-1.12 0.12 Rilutek vs, S-Oxprenolol (l0) Rilutek vs, S—Oxprenoloi (20) 0.54—2.06 Propanolol vs. S-Oxprenolol (_ l0) 0.48—1.46 0.54 Propanolol vs. S—Oxprenolol (20) 0.81—2.64 0.21 _._...._... enolol (10) vs. S—Oxprenolol 9 0.87 (10) S-Oxprenolol (20) vs. S-Oxprcnolol 0.66-2.19 0.55 (20) Figure [9 shows the percent of mice that improved from disease progression ofscore 1 to score 3 that were administered with S-oxprenolol at s of 10 mg/kg/day or day. Other groups of mice were administered rilulek at a dosage ol‘30 mg/kg/day; propanolol at a dosage of 10 day; oxprenolol (tacemicl) at a dosage of 20 mg/kg/day; R-oxprcnolol at a dosage of 10 mg/kgx’day or 20 mg/kg/day; or a placebo.

The statistical data for Figure 19 is shown below. “HR” refers to hazard ratio. “95% CI“ is conﬁdence interval. "1)" refers to p value.

Table 6: tical data for Figure 19 (Progression from score 1 to score 3) Comparison e in day) p value Rilutek vs. placebo éiiiii'riliiiii'Js'fiiiéfééiiii""""""""""""""" l"""""""""""""""""" "631'""""""""""""""" Oxprenolol vs. placebo I 0.60 0.35-1.01 0.055 R-Oxprenolol (10)Vs.pla.cebo I 0.60 0354.02 0.060 enolol (20) vs. placebo I 0.63 0.37—1.07 0.086 S—Oxprenolol (10) vs. placebo I 0.73 0.45—1.20 0.22 S-Oxprenolol (20) vs. placebo 0.47 0.28—0.81 0.006] Rilutek \«s. S-Oxprenolol (10) . 0.59—2.14 Rilutek \«s, S—Oxprenoloi (20) . 0.94—4.08 olol vs. S-Oxprenolol (10) i 0.92 0.53—I .57 0.75 Propanolol vs. S—Oxprenolol (20) 1.67 0.91—3.06 0.099 R-Oxprenolol(10)vs. S—Oxprenolol 0.7 0.45—1.36 0.17 (10) j S-Oxprenolol s. S-Oxprenolol L48 0.79-2.75 0.22 (20) Example I0. Effects ofS-Oxprenolol compared to enolol and Rilutek To study the effect of S—oxprenolol on body weight, body weight was monitored over time. Figure ZOA-ZOC show the change of body weight. in mice administered S-oxprenolol at a dosage of 20 mg/kg’day or 10 mg/kg/day; R-oxprenolol at a dosage of20 mg/kg/day; rilutek at a dosage of 30 mg/kg/day; or placebo. Figure 20A shows results for all mice. Figure BOB shows results for male mice. Figure 20C shows results for female mice.

The number of all mice in the population is indicated as “n“ in at the bottom of Figures 20A- 20C.

To study the effect ofthe test compounds on lean body mass, lean mass was determined at the end of the study. In this experiment. all mice were killed using the 30 seconds endpoint and hence all mice were equally diseased at the end of the study. Figures 20D-20F Show the change in lean body mass (in grams) of mice that were administered S— oxprenolol at a dosage of20 mg/kg’day or 10 mgkg/day; R—oxprenolol at a dosage of20 mg/kg/day; rilutek at a dosage of 30 mg/kgr’day; or placebo. Figure 20D shows results for all mice. Figure 2013 shows results for male mice. Figure 20F shows results for female mice.

The number of all mice in the population is indicated as “n” in at the bottom of Figures 20D- 20F.

To study the effect ol‘ the test compounds on fat mass, the fat mass were determined at the end of the study. Figures 2OG-20l show the change in fat mass (in. grams) of mice administered S-oxprenolol at a dosage of 20 mg/kg/day or 10 day; R- oxprenolol at a dosage of 20 mg’kg/day; rilutek at a dosage of3l) mg/kg/day; or placebo.

Figure 20G shows results for all mice. Figure 20H shows results for male mice. Figure 20l shows results for female mice. The number of all mice in the population is indicated as “n" in at the bottom ofFigures I.

Figures 2lA—21 C show results for heart weight at the end of the study.

Figures 21 A—Zl C show the heart weight (in rams) of mice administered S-oxprcnolol at a dosage of 20 mg/kg/day or 10 mg/kg/day; R—oxprenolol at a dosage of20 mg/kg/day; rilutek at a dosage of3() mg/kg/day; or placebo. Figure 21 A shows results for all mice.

Figure 21B shows results for male mice. Figure 21C shows results for female mice. The number of all mice in the population is ted as “n” in at the bottom of Figures 2lA-21C.

Figures ‘2lD-21F show results for gastrocnemius muscle weight at the end of the study. Figures 21D-21F show the gastrocnemius muscle weight (in milligrams) of mice administered S-oxprenolol at a dosage of2l) rug/kg/day or l0 rug/kg/day; R—oxprenolol at a dosage of 20 mg/ltg/day; rilutek at a dosage ol‘30 mg/kg/day; or placebo. Figure 21D shows s for all mice. Figure 21E shows results for male mice. Figure 21F shows results for female mice. The number of all mice in the population is indicated as “n" in at the bottom of Figures 20D-20F. s l Show results for tibialis muscle weight at the end of the study. Figures 210-2” show the tibialis muscle weight (in milligrams) ofmice stered S—oxprenolol at a dosage ol'20 mg/kg/day or 10 mg/kg/day; R—oxprenolol at a dosage ol’20 mg/kg/day: rilutek at a dosage of 30 mg/kg/day; or placebo. Figure 21 G shows s for all mice. Figure 21 H shows results for male mice. Figure 21 I shows results for female mice.

The number of all mice in the population is indicated as “n” in at the bottom of Figures 2lG- 2] I.

The following tables show results for mice administered with S—oxprenolol at a dosage of 20 mg/kg/day or 10 mg/kg/day; R—oxprenolol at a dosage of 20 mg/kg/day or 10 mg/kg/day; rilutck at a dosage of 30 mg/kgz’day; propanolol at a dosage of 10 mgdx’g/day; oxprenolol (racemic) at a dosage of 20 mg/kg/day; or placebo. The results for delta body weight, delta lean mass, delta fat mass, average delta body weight, e delta lean mass, average delta fat mass, heart mass, gastrocnemius mass, soleus mass, EDL, and BAT were obtained with tests according the examples herein.

Table 7: Data for all mice administered with S-oxprenolol, R—oxprenolol. rilutek, propanolol, oxprenolol (racemic), or placebo. placebo 30 mg/kg’d l0 mg/kg/d 20 m g’kg/ rilutek propanolol oxprenolol A body wcight [g] 5.51i0.34 -5.10i0.35 0.42 -5.59i0.48 A lean mass [g] -3.7l.+.0.27* -4.S9$—0.26 -4.67.Jc0.42 A fat mass [g] .15 -l.91i0.l5 4.8212025 -l.493c0.l2 Average A body - l 53 72522.2 :‘rl5.2 ~127.6i:10.6 -lZ3.6aEl2.3 weight [mg/day] Average A lean 435.91195 —92.31i15.84 —l L74 —l()2.()il0.7 mass [mg/day] Average A fat -35.6t3.8 -50.li6.l* -43.9i5r5 -33.li2.6 mass [mg/day] Heart [mg] l 005:3.4 23 104.0% ,2 l 00.25 .2 gastroenemius 477:3,0 55.2i3.() 52.4233 52.2223 [mg] soleus [mg] 5.851022 39 5.60:0.28 4.99;;036" EDL [mg] 6.94:”.025 6.7li0.32 7rlli0.37 7.24:0.41 BAT [mg] 41 212.4 53.7:2.9** 45. li2.9 40.63623 Table 7 (cont): Data for all mice stered with S-oxprenolol. R-oxprenolol, rilutek, propanolol, oxprcnolol (raccmic), or placebo. ““““““““““““““““““““““i Omgkbd 20makgd 10mgkgdzommd R-oxprenolol enolol S—oxprenolol S—oxprenolol A body weight [g] ‘:0.39 5.211039 5.401043 -5.561:0.47 A lean mass [g] 032 460120.28 —313 1 210.33W l:0.4l A {at mass [g] 0. l5 -l.59_L0.15 4.261.014 ~l .56i0.13 Average A body -146.lill.l 411.0194 43:11.6 -99.4:9.7""‘°-°64 weight [mg/day] Average A lean -125.8il2.7 06616.4 —89.6i9.l * -93.3:7.5* mass y] Average A fat mass ~38.3:£:4.2 -32.61:3.0 0.9.413] —29.8:l:3.6 [mg/day] Heart [mg] 101.32.? lOO.7::3.8 108.6:53 lO4.li3.5 gash‘ocnemius [mg] SO.8:3.3 47.0i2.6 55.1i4.0 50.]:29 soleus [mg] 4.49:0.36** 5.49i034 5.89i035 6.42:0.39 EDL [mg] .47 5.89.+0,31* 7..18+0.34 7.791029%“ BAT [mg] 44.5.7 . 43,314.! 46.885 43.7133 ASHEiiéfiiiiééiiéé’A'[{{{g7li.1y]. air'é'r'é'gé'aé'lfai'ﬁé‘r‘ﬁé‘i?Ell—1753053 diEéEsE'55&3;EEC?Eﬁé‘ﬁéér"éigiiﬁﬂﬁi'iiiﬁéiﬁ,‘""" BAT: brown adipose tissue, *rp<’0.05, ”t p'L‘Oﬂl vs placebo, ##1'11 p<.0.00l vs lOmg/kg/d propanolol, $1 p<10.05 vs wing/kg/d R-oxprcnolol. *+--=-+: p<0.00] vs 30 mg/kg/d rilutck Table 8: Data for male mice administered with S-oxprenolol, R-oxprenolol, rilutek, propanolol, oxprenolol (racemic), or placebo. placebo 30 mg/kgfd tilulek l0 mg’kg/d 20 d propanolol oxpi‘enolol _______._______4 A body weight [g] —6.81:0.54 0.43 —6.l l::0,54 -5.94::0.77 _______A________+._______._______,________ A lean mass [g] 6.4454139 ~4. .38* 6.0632037 -5.64:E0.68 mm?“ A fat mass [g] -l.66:i:0.27 2.0932022 —l.99: 20.26 433120.13 ————.—.

Average A body “2158:2364 ﬂ7.9* ~l42.7i15.9 —124.8d:20.7 weight [mg/day] Average A lean -l78. 1261.9 —S7.4:&:2 [ * . l 41861106 —1 19.421: 17.7 mass [mg-’day] Average A fat mass -40.5:6.8 -57.5=l 1.3 —Sl.9::6.9 -28.3::3.l 1mg/da11 I-lean [mg] ll7.9i3.4 115.6314 ll3.5i4.6 110.2i2.9 gastrocncmius [mg] .3 585:4.9 63.3i3.6 54.7139 soleus [mg] 6.03L0.32 5-72;0.64 5.63i038 5.2 H051 EDL [mg] 7.83:0.32 7.20i0.5l 7.941055 7.49i0.72 BAT [mg] 449:3!) 54.8:39 48.7i5.l 45.7::3.6 Table 8 (cont): Data for male mice administered with S~oxpreuoloL enolol. rilutek. olol, oxprenolol (racemic), or placebo.

'JI \l d 20 g/d 10 mg/kg/d 20 mgﬂkg/d R-oxprenolol R—oxprenolol S—oxprenolol S-oxprenolol A body weight [g] —6.515:0.65 -5.53::0.57 65710.57 —6.36:£.67 A lean mass [g] -5 55i0.47 -5.12i0.38 -3.67::O.49**" 6.34:0.56 A fat mass [g] —l 5720.21 -l.4&:0.16 ~1.44:,0.19 -l.78t0.28 e A body ~153.5:t 16 1 ~116.0:‘::l3,7* 450312145 ~115l7:112.6* weight [mg/day] Average A lean ~129.7i9.9 :1:8.5 :d:13.9 853:1 1015* mass y] Average A [at mass -37.4:‘:6 4 49.9135 43.615 7 ~32.l:15 4 [mg/day] ; Heart [mg] 107.4L3.4* 112.0:411 '12216i8.8 4115 gastrocnemius [mg] 538:5.1 49.91330 59.1:6.6 53.l::4.3 soleus [mg] 4.74:0.51* 5.84:0.45 604:0.53 6.58i0.61 EDL [mg] 6.5920161 5.31:0.42*** 7.23:0.47 39W BAT [mg] 467:4.9 53916.8 532:5.0 46.5281) A: delta, average A [mg/day]: average delta per day alive after disease onset. EDL: cxteusor digiionlm longus, BAT: brown adipose tissue. *:p<0.05, **: p<:0.0l, ***: p<0.001 vs placebo. #: p<0.05 vs lOmg/kgr’d propanelol, $$$z p<0.001 vs 20mg/kgd R—oxpx'enolol Table 9: Data for female mice administered with S-oxprenolol, R—oxprenolol, riluIek, propanolol, exprenolol (racemic). or placebo. placebo 30 mg/k‘g/d rilutek 10 mg/‘kg/d 2O mg/kg/d propauolol oxprenelol A body weight [g] -4v55i0.32 -4.49i0.46 -5.66:t0.66 '5.27i0.6l A lean mass [g] -3.42i0.25 -3.3 li0.37 -4.70i0.37** -3.76:t0.42 A fat mass [2,] ~1161i0.15 -l.76i0.21 -l.65i0.44 -1 .6421:0.2.l Average A body 20.6 -l'22,9::25.7 -l l 1.3i.l3.2 -122.5il4.7 weight [mg/day] Average A lean —84.3 1:119 -96.9i:24.2 ~91.2:18 “a -85.81:11.6 mass [mg/day] Average A ("at mass —“7"5.2:4.6 «12.216 1 ~30.9i8.3 3775i”: 7 [mg/day] -‘- —-4 Heart [mg] 86.1il.5 91.4:23 7" 895:2 4 ocnemius [mg] 21.2i2.9 5415.8“ 40.653 49.5:2 l soleus [mg] 5.721.030 5.26:&:().48 5571:1143 4.76: O 52 EDL [mg] 6291:0128 6 28¢ 39 ::O.37 6973:036 BAT [mg] 38.853!) 53 7&45’L 41212.2 35224.1 U! DO A definition of a specific embodiment of the ion as claimed herein follows.

According to an embodiment of the invention, there is provided use of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein oxprenolol has one chiral center and the ition comprises an enantiomeric excess of at least 60% of S-oxprenolol, in the manufacture of a medicament for treating amyotrophic lateral sclerosis in an dual having amyotrophic lateral sclerosis.

Claims

1. Use of a composition comprising oxprenolol or a pharmaceutically acceptable salt thereof, wherein oxprenolol has one chiral center and the ition ses an enantiomeric excess of at least 60% of S-oxprenolol, in the cture of a medicament for treating amyotrophic lateral sclerosis in an individual having amyotrophic lateral sclerosis.

2. The use of claim 1, wherein survival is prolonged, pment of amyotrophic lateral sclerosis is delayed, loss of lean mass is prevented, quality of life is improved and/or muscle wasting is prevented.

3. The use of claim 1 or 2, wherein the composition ses an enantiomeric excess of at least 80% of S-oxprenolol.

4. The use of claim 1 or 2, wherein the composition comprises an enantiomeric excess of at least 99% of S-oxprenolol.

5. The use of claim 1 or 2, wherein the composition comprises an enantiomeric excess of at least 99.9% of S-oxprenolol.

6. The use of any one of claims 1 to 5, wherein the amyotrophic lateral sclerosis is sporadic amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, Western Pacific amyotrophic lateral sclerosis, juvenile amyotrophic lateral sclerosis, or ya Disease.

7. The use of any one of claims 1 to 5, wherein the amyotrophic lateral sclerosis is progressive bulbar palsy (PBP), ssive muscular atrophy (PMA), primary lateral sclerosis (PLS), or ALS with multi-system involvement.

8. The use of any one of claims 1 to 7, wherein the composition is formulated to be administered orally.

9. The use of any one of claims 1 to 8, wherein the amount of S-oxprenolol in the ition is 80 to 160 mg daily.

10. The use of any one of claims 1 to 9, wherein the composition is formulated to be administered daily or twice daily.