WO2025231467A1 - Vamorolone composition to treat infants with bronchopulmonary dysplasia - Google Patents

Abstract

Methods for preventing and/or treating a chronic lung disease, e.g., bronchopulmonary dysplasia, in preterm infants using vamorolone are provided herein. Vamorolone reduces symptoms of bronchopulmonary dysplasia and yields reduced risk for adverse effects that are associated with other corticosteroids. The presently disclosed subject matter further relates to pharmaceutical compositions, e.g., aerosolized compositions, for administering vamorolone to preterm infants.

Description

VAMOROLONE COMPOSITION TO TREAT INFANTS WITH BRONCHOPULMONARY DYSPLASIA

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 63/642,314 filed May 3, 2024, the content of which is incorporated by reference in its entirety.

GRANT INFORMATION

This invention was made with government support under HD 104215 awarded by the National Institutes of Health. The government has certain rights in the invention.

FIELD OF THE INVENTION

The disclosed subject matter relates to methods for treating or preventing chronic lung disease in preterm infants. The disclosed subject matter further relates to methods for treating or preventing bronchopulmonary dysplasia.

BACKGROUND

Bronchopulmonary dysplasia (BPD) is deadly and highly debilitating disease that is prominent in low birth weight and premature infants. The world-wide incidence of BPD has been estimated to range from 11-50% of premature infants with the incidence increasing as birth weight and gestational age at birth decreases. Conventional treatment for preterm infants with BPD is administration with corticosteroids, e.g., dexamethasone, budesonide, or prednisolone. Although treatment of infants using these drugs may lead to improvements in lung function, these drugs are associated with adverse effects, e.g., growth suppression, neurodevelopmental defects, white matter loss, brain injury, hyperglycemia, and other metabolic or systemic dysfunction. There is need for new therapies for treating BPD in infants with reduced risk of adverse effects.

SUMMARY

The presently disclosed subject matter provides methods for preventing and/or treating a chronic lung disease in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising vamorolone, a derivative thereof, or a combination thereof. In certain embodiments, the composition comprises vamorolone. In certain embodiments, the subject is a preterm infant. In certain embodiments, the chronic lung disease is bronchopulmonary dysplasia. In certain embodiments, composition is an aerosolized composition. In certain embodiments, the composition comprises a dose of vamorolone ranging between about 80 pg and about 360 pg. In certain embodiments, the composition is formulated for oral administration. In certain embodiments, the composition comprises a dose of vamorolone ranging between about 2 mg/kg and about 50 mg/kg. In certain embodiments, the subject is an infant.

The presently disclosed subject matter further provides methods of reducing lung inflammation in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising vamorolone, a derivative thereof, or a combination thereof. In certain embodiments, the composition comprises vamorolone. In certain embodiments, the lung inflammation is associated with bronchopulmonary dysplasia. In certain embodiments, the composition is an aerosolized composition. In certain embodiments, the composition comprises a dose of vamorolone ranging between about 80 pg and about 360 pg. In certain embodiments, the composition is formulated for oral administration. In certain embodiments, the composition comprises a dose of vamorolone ranging between about 2 mg/kg and about 50 mg/kg. In certain embodiments, the subject is an infant. In certain embodiments, the subject is a preterm infant.

The presently disclosed subject matter further provides pharmaceutical compositions comprising vamorolone, a derivative thereof, or a combination thereof, wherein the pharmaceutical composition is suitable for administration by inhalation. In certain embodiments, the pharmaceutical composition comprises vamorolone. In certain embodiments, the pharmaceutical composition is an aerosolized composition. In certain embodiments, the pharmaceutical composition comprises a dose of vamorolone ranging between about 80 pg and about 360 pg. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition comprises a dose of vamorolone ranging between about 2 mg/kg and about 50 mg/kg. In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

DESCRIPTION OF DRAWINGS

The following figures are included to illustrate certain aspects of the present disclosure and should not be viewed as exclusive embodiments. The subject matter disclosed is capable of considerable modifications, alterations, combinations, and equivalents in form and function, without departing from the scope of this disclosure.

Figures 1A-1D show adverse effects of systemic budesonide (Bud) and deflazacort (Def) but not vamorolone (Vam) in neonatal rats. Figures 1A shows body weight measures from P1-P5 rats which were given vehicle (Veh), Bud, Def, or Vam daily s.c. for 5 days beginning on postnatal day 1 (Pl). Figure IB shows body weight measures at P5 measured 4 hours following final injection (*p<0.05; **p<0.01; n=3-4). Figure 1C shows brain weight measures atP5 measured 4 hours following final injection (**p<0.01; n=3-4). Figure ID shows blood glucose measured 4 hours after final injection at P5 (*p<0.05; ****p<0.0001; n=3-4).

Figures 2A-2C show gene expression changes in neonatal lung of rats which were given vehicle (Veh), Bud, Def, or Vam daily s.c. for 5 days beginning on postnatal day 1 (Pl). Figures 2A-2B shows induction of FK506 binding protein-5 (FKBP5) (Figure 2A) and glucocorticoid- induced leucine zipper (GILZ) (Figure 2B) mRNA by BUD and DEF but not VAM in lung tissue as assessed by qRT-PCR analysis (***p<0.001; ****p<0.0001; n=3-4). Figure 2C shows repression of turn or necrosis factor-a (TNFa) mRNA by all drugs tested (*p<0.05; ***p<0.001; n=3-4). Lung tissue was collected for RNA preparation 4 hours post final injection.

DETAILED DESCRIPTION

A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections:

1. Definitions;

2. Vamorolone;

3. Pharmaceutical Compositions; and

4. Methods of Treatment.

1. Definitions

The terms used in this specification generally have their ordinary meanings in the art, within the context of this disclosure and in the specific context where each term is used. Certain terms are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner in describing the compositions and methods of the disclosure and how to make and use them. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.

As used in this specification and the following claims, the terms “comprise” (as well as forms, derivatives, or variations thereof, such as “comprising” and “comprises”) and “include” (as well as forms, derivatives, or variations thereof, such as “including” and “includes”) are inclusive (i.e., open-ended) and do not exclude additional elements or steps. For example, the terms “comprise” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Other than where noted, all numbers expressing quantities of ingredients, reaction conditions, geometries, dimensions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches.

Accordingly, these terms are intended to not only cover the recited element(s) or step(s), but can also include other elements or steps not expressly recited. Furthermore, as used herein, the use of the terms “a”, “an”, and “the” when used in conjunction with an element can mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” Therefore, an element preceded by “a” or “an” does not, without more constraints, preclude the existence of additional identical elements.

As used herein, the term “about” or “approximately” are defined as follows. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. By “about” is meant within 5% of the value, e.g., within 4, 3, 2, or 1% of the value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. A range can be construed to include the start and the end of the range. For example, a range of 10% to 20% (i.e., range of 10%- 20%) can includes 10% and also includes 20%, and includes percentages in between 10% and 20%, unless explicitly stated otherwise herein.

It is understood that when combinations, subsets, groups, etc. of elements are disclosed (e.g., combinations of components in a composition, or combinations of steps in a method), that while specific reference of each of the various individual and collective combinations and permutations of these elements cannot be explicitly disclosed, each is specifically contemplated and described herein.

As used herein, “administration” to a subject includes any route of introducing or delivering to a subject an agent. Generally, administration of an agent can be carried out by any suitable route, including oral, topical, transcutaneous, transdermal, intra-joint, intra-arteriole, intradermal, intraventricular, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrastemal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injections or infusion techniques), and the like. The presently disclosed subject matter includes different modes of administration, including but not limited to, injection, subcutaneous injection, oral, and by inhalation.

“Concurrent administration”, “administration in combination”, “simultaneous administration” or “administered simultaneously” as used herein, means that the compounds are administered at the same point in time or essentially immediately following one another. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time.

“Systemic administration” refers to the introducing or delivering to a subject an agent via a route which introduces or delivers the agent to extensive areas of the subject’s body (e.g., greater than 50% of the body), for example through entrance into the circulatory or lymph systems. By contrast, “local administration” refers to the introducing or delivery to a subject an agent via a route which introduces or delivers the agent to the area or area immediately adjacent to the point of administration and does not introduce the agent systemically in a therapeutically significant amount. For example, locally administered agents are easily detectable in the local vicinity of the point of administration but are undetectable or detectable at negligible amounts in distal parts of the subject’s body. Administration includes selfadministration and the administration by another.

As used here, the terms “beneficial agent” and “active agent” are used interchangeably herein to refer to a chemical compound or composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, i.e., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, i.e., prevention of a disorder or other undesirable physiological condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, fragments, analogs, and the like. When the terms “beneficial agent” or “active agent” are used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, conjugates, active metabolites, isomers, fragments, analogs, etc.

A “decrease” can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. For example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant. Similarly, “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control.

“Inhibit,” “inhibiting,” and “inhibition” mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This can also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.

“Inactivate”, “inactivating” and “inactivation” means to decrease or eliminate an activity, response, condition, disease, or other biological parameter due to a chemical (covalent bond formation) between the ligand and a its biological target.

As used herein, the terms “treating” or “treatment” of a subject includes the administration of a drug to a subject with the purpose of preventing, curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, stabilizing or affecting a disease or disorder, or a symptom of a disease or disorder. The terms “treating” and “treatment” can also refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.

By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something can be reduced but not prevented, but something that is reduced can also be prevented. Likewise, something can be prevented but not reduced, but something that is prevented can also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. For example, the terms “prevent” or “suppress” can refer to a treatment that forestalls or slows the onset of a disease or condition or reduced the severity of the disease or condition. Thus, if a treatment can treat a disease in a subject having symptoms of the disease, it can also prevent or suppress that disease in a subject who has yet to suffer some or all of the symptoms. As used herein, the term “preventing” a disorder or unwanted physiological event in a subject refers specifically to the prevention of the occurrence of symptoms and/or their underlying cause, wherein the subject may or may not exhibit heightened susceptibility to the disorder or event.

By the term “effective amount” of a therapeutic agent or a “therapeutically effective amount” is meant a nontoxic but sufficient amount of a beneficial agent to provide the desired effect. The amount of beneficial agent that is “effective” will vary from subject to subject, depending on the age and general condition of the subject (such as gender or weight), the particular beneficial agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount”. However, an appropriate “effective’ amount in any subject case can be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of a beneficial can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts. For example, several divided doses can be administered daily or the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation. In certain embodiments, a therapeutically effective amount refers to an amount of a composition comprising vamolorone, a derivative thereof, or a combination thereof that is sufficient for improving lung function and/or reducing inflammation.

As used herein, the term “pharmaceutically acceptable” component can refer to a component that is not biologically or otherwise undesirable, i.e., the component can be incorporated into a pharmaceutical formulation of the disclosed subject matter and administered to a subject as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When the term “pharmaceutically acceptable” is used to refer to an excipient, it is generally implied that the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

As used herein, “prodrug” refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the disclosed subject matter include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of the disclosed subject matter include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the presently disclosed subject matter can be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, nontoxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, H00C-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts can be found, e.g., in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

Also, as used herein, the term “pharmacologically active” (or simply “active”), as in a “pharmacologically active” derivative or analog, can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be “positive” or “negative.”

As used herein, by a “subject” is meant an individual. Thus, the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds. “Subject” can also include a mammal, such as a primate or a human. Thus, the subj ect can be a human or veterinary patient.

As used herein, the term “patient” refers to a subject under the treatment of a clinician, e.g., physician, infant. In certain embodiments, the subject is a human patient. The human patient can be of any age. In a specific embodiment, the human patient can be a child or infant. More specifically, the infant can be a preterm infant. As used herein, the terms “preterm infant” or “premature infant” refer to a human subject born prior to 37 weeks gestation.

2. Vamorolone

The present disclosure demonstrates compositions and methods for bronchopulmonary dysplasia (BPD) therapy in infants, and more specifically in preterm infants. The bronchopulmonary dysplasia therapy comprises administering a therapeutically effective amount of vamorolone, or derivatives thereof.

Vamorolone is a compound having the following chemical structure:

Vamorolone, with the formula C22H28O4, is also known 17a, 21 -dihydroxy- 16a-methylpregna- 1,4, 9(1 l)-triene-3, 20-dione.

In certain embodiments, derivatives of vamorolone can include isomers, stereoisomers, epimers, and enantiomers. As used herein, the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. As used herein, the term “stereoisomer” refers to any of the various stereo isomeric configurations which can exist for a given compound of the presently disclosed subject matter and includes geometric isomers. As used herein, the term “epimer” refers to either of two stereoisomers that differ in the arrangement of groups on a single asymmetric carbon atom (such as the first chiral center of a sugar’ s carbon chain). As used herein, the terms “constitutional isomers” refers to different compounds which have the same numbers of, and types of, atoms but the atoms are connected differently. The term “optical isomers”, as used herein, refers two compounds which contain the same number and kinds of atoms, and bonds (i.e., the connectivity between atoms is the same), and different spatial arrangements of the atoms, but which have non-superimposable mirror images. Each non-superimposable mirror image structure is called an enantiomer.

Vamorolone is a corticosteroid which has received FDA approved as an oral suspension for long term treatment of children (over 2 years of age) with Duchene Muscular Dystrophy (DMD). Use of vamorolone as a treatment for DMD is discussed in U.S. Patents 8,207,151, 10,857,161, and 11,382,922, the disclosures of which are incorporated herein by reference. However, vamorolone has not previously been identified for use in infants with BPD. Other corticosteroids have been attempted, e.g., dexamethasone, budesonide, and prednisolone; however, these corticosteroids have been shown to cause adverse effects in preterm infants including growth suppression, neurodevelopmental defects, white matter loss, brain injury, hyperglycemia, and other metabolic or systemic dysfunction.

The present disclosure demonstrates vamorolone as a therapy for BPD in preterm infants with reduced adverse effects in comparison to alternative corticosteroid therapies.

3. Pharmaceutical Compositions

The present disclosure provides a pharmaceutical composition, comprising vamorolone, a derivative thereof, or a combination thereof. Vamorolone can be formulated as a pharmaceutical composition in combination with one or more pharmaceutically acceptable carriers or excipients appropriate for the form of administration. In certain embodiments, the composition is formulated for oral administration, for inhalation, or injection. However, formulations suitable for other routes of administration are also contemplated. In certain embodiments, the pharmaceutical composition is formulated for administration by inhalation.

As disclosed herein, vamorolone can be formulated in pharmaceutically acceptable compositions suitable for delivery to the lungs. Particular formulations include dry powders, liquid solutions or suspensions suitable for nebulization and propellant formulations suitable for use in metered dose inhalers. The preparation of such formulations is well-known to those skilled in the art and are described in U.S. Patent Nos. 5,814,607 and 5,654,007, the disclosures of which are incorporated herein by reference. As noted, the formulation can be administered by metered-dose inhalers, dry powder inhalers, nebulizers, or soft mist inhalers. Spacers can be used as necessary.

In certain embodiments, the composition is formulated in a dry powder or liquid form. Dry powder formulations will comprise vamorolone in a dry, lyophilized, form with a particle size within a preferred range for deposition within the lung. Typically, the particle size for deposition in the lung will range between 1 and 5 microns. When systemic delivery of the vamorolone via absorption from the lung into the bloodstream is desired the vamorolone particle size is generally between 0.1 and 2 microns in size. The preferred size range of particles can be produced using methods such as jet-milling, spray drying and solvent precipitation, for example.

Dry powder devices typically require a powder mass in the range from about 1 mg to 10 mg to produce an aerosolized dose. Thus, the vamorolone will typically be combined with a pharmaceutically acceptable dry bulking powder. In certain embodiments, dry bulking powders can include, but are not limited to, sucrose, lactose, trehalose, human serum albumin (HSA), glycine, or a combination thereof. Dry powders can be administered to the subject in conventional dry powder inhalers.

For liquid formulations, vamorolone can be dissolved in any recognized pharmaceutically acceptable carrier for use in delivery of aerosolized formulations. Such carriers, for example, include, but are not limited to, ethanol, propylene glycol and ethanolpropylene combinations.

In certain embodiments, vamorolone is formulated as a pharmaceutically acceptable composition for oral administration. In certain embodiments, the formulation is in the form of a liquid, a powder, a capsule, a tablet, or an orally disintegrating tablet. In certain embodiments, where the formulation is a liquid, said formulation can be a solution, an emulsion, or a suspension. In certain embodiments, where the formulation is a liquid, the formulation comprises a pharmaceutically suitable liquid such as, but not limited to, water, saline, or an emulsion formed between an aqueous solution and an oil or other liquid that is not substantially miscible with water.

As noted herein, pharmaceutical compositions suitable for use in the presently disclosed subject matter include vamorolone and a pharmaceutically acceptable carrier in an effective amount to achieve its intended purpose. More specifically an effective dose refers to that amount of vamorolone sufficient to decrease the inflammation associated with BPD.

4. Methods of Treatment

Lung Disease

The present disclosure provides a method of preventing and/or treating and/or reducing a lung disease in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising vamorolone, a derivative thereof, or a combination thereof. In certain embodiments, the lung disease can be chronic lung disease. Lung disease (or chronic lung disease), as used herein, refers to conditions causing impaired lung function, and can comprise bronchopulmonary dysplasia (BPD) and/or lung inflammation. In certain embodiments, the lung disease can also comprise lung injury, airway injury, pulmonary fibrosis, asthma, obstructive lung disease, or a combination thereof. The methods of the presently disclosed subject matter can prevent, treat, or reduce one or more of the various conditions associated with lung disease. In certain embodiments, the present disclosure provides a method of preventing, treating, or reducing chronic lung disease in a subject in need thereof, comprising the administration of vamorolone, a derivative thereof, or a combination thereof. In certain embodiments, the present disclosure provides a method of preventing, treating, or reducing lung inflammation in a subject in need thereof, comprising the administration of vamorolone, a derivative thereof, or a combination thereof. In certain embodiments, the present disclosure provides a method of preventing, treating, or reducing BPD in a subject in need thereof, comprising the administration of vamorolone, a derivative thereof, or a combination thereof.

In certain embodiments, chronic lung disease can comprise lung inflammation. In certain embodiments, the lung inflammation is induced by tumor necrosis factor-a (TNFa). In other embodiments, the chronic lung disease can comprise BPD.

BPD is a chronic lung disease that occurs primarily in low birth weight and premature infants. The lungs of low birth weight and premature infants can exhibit impaired or delayed development leading to poor lung function, fibrosis, and/or inflammation. Low birth weight and premature infants with BPD require prolonged treatment with supplemental oxygen. BPD can be caused or aggravated by the use of mechanical ventilation due to the susceptibility of the developing lungs to injury.

One form of pharmacotherapy for preterm infants with BPD is administration with corticosteroids, e.g., dexamethasone, budesonide, prednisolone, or hydrocortisone. Although these drugs can improve lung function, these treatments are associated with adverse effects, e.g., growth suppression, neurodevelopmental defects, white matter loss, brain injury, hyperglycemia, and other metabolic or systemic dysfunction.

The data presented herein demonstrate that vamorolone does not trigger adverse effects observed with the noted alternative corticosteroid drugs used to prevent or treat BPD. Specifically, vamorolone 1) does not reduce whole body growth or brain growth; 2) does not increase blood glucose (i.e., hyperglycemia); and 3) does not increase expression of tissue stress markers. In addition, vamorolone can reduce basal expression of the proinflammatory cytokine TNFa, thereby producing anti-inflammatory effects, which is a desirable outcome essential for resolving BPD in infants that develop this condition following premature birth.

Patent population

In the disclosed methods, the subject is an infant. In certain embodiments, the subject is a preterm infant. In certain embodiments, the subject is a preterm infant born prior to about 37 weeks gestation.

In certain embodiments, the subject is an infant born at about 25 weeks gestation, about 26 weeks gestation, about 27 weeks gestation, about 28 weeks gestation, about 29 weeks gestation, about 30 weeks gestation, about 31 weeks gestation, about 32 weeks gestation, about 33 weeks gestation, about 34 weeks gestation, about 35 weeks gestation, about 36 weeks gestation, about 37 weeks gestation, about 38 weeks gestation, about 39 weeks gestation, or about 40 weeks gestation. In certain embodiments, the subject is an infant born prior to about 25 weeks gestation, prior to about 26 weeks gestation, prior to about 27 weeks gestation, prior to about 28 weeks gestation, prior to about 29 weeks gestation, prior to about 30 weeks gestation, prior to about 31 weeks gestation, prior to about 32 weeks gestation, prior to about 33 weeks gestation, prior to about 34 weeks gestation, prior to about 35 weeks gestation, prior to about 36 weeks gestation, prior to about 37 weeks gestation, prior to about 38 weeks gestation, prior to about 39 weeks gestation, or prior to about 40 weeks gestation. In certain embodiments, the subject is an infant bom after about 25 weeks gestation, after about 26 weeks gestation, after about 27 weeks gestation, after about 28 weeks gestation, after about 29 weeks gestation, after about 30 weeks gestation, after about 31 weeks gestation, after about 32 weeks gestation, after about 33 weeks gestation, after about 34 weeks gestation, after about 35 weeks gestation, after about 36 weeks gestation, after about 37 weeks gestation, after about 38 weeks gestation, after about 39 weeks gestation, or after about 40 weeks gestation.

Administration

In any of the disclosed methods, the pharmaceutical composition comprises vamorolone and is in the form of an aerosolized composition. The vamorolone is delivered to the lung of the subject by inhalation of vamorolone in the form of an aerosol spray using, for example, pressurized delivery devices or nebulizers. The vamorolone can be formulated in either a dry powder or liquid form.

Additionally or alternatively, in any of the disclosed methods, the compositions of the present disclosure can be delivered in the form of an aerosol spray administered via pressurized packs, a metered-dose inhaler, a pressurized metered-dose inhaler, or a nebulizer, with the use of a propellant, e.g., dichlorodifluoromethane, dichlorotetrafluoroethane or other suitable gas. Preferably, for incorporation into the aerosol propellant, the vamorolone of the present disclosure is processed into respirable particles as described above for the dry powder formulations. The particles are then suspended in the propellant, typically being coated with a surfactant to enhance their disbursement. In the use of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount.

Commercially available jet nebulizers are available and can be used to deliver aerosolized vamorolone to a subject. Such jet nebulizers include, but are not limited to, those supplied by AeroTech II (CIS-US, Bedford, Mass.). In addition, for delivery of aerosolized vamorolone to the lungs of a subject, an oxygen source can be attached to the nebulizer providing a flow rate of, for example, about 10 L/min. In general, inhalation is performed over a time interval of approximately 30 to approximately 40 minutes through a mouthpiece during spontaneous respiration.

The presently disclosed subject matter further provides novel compositions comprising a suitable carrier and aerosolized vamorolone in doses sufficient to reduce or ameliorate chronic lung disease, e.g., bronchopulmonary dysplasia. Determination of effective amounts is well within the capability of those skilled in the art and can be readily ascertained. The amount of composition administered is also dependent on the subject to whom the aerosolized vamorolone is administered, the pulmonary disorder the subject has, the severity of the disorder's symptoms and the judgement of the overseeing physician. In some instances, it can be necessary to terminate, interrupt or adjust the treatment to a lower dose due to toxicity as well as adjusting the treatment to higher levels a suitable beneficial response is not obtained.

In any of the disclosed methods, vamorolone is formulated in a pharmaceutically acceptable composition for administration by inhalation. In certain embodiments, the dose of vamorolone delivered by inhalation ranges between about 50 pg and about 1000 pg, between about 50 pg and about 500 pg, between about 50 pg and about 250 pg, between about 50 pg and about 100 pg, between about 100 pg and about 1000 pg, between about 100 pg and about 500 pg, between about 100 pg and about 250 pg, between about 250 pg and about 1000 pg, between about 250 pg and about 500 pg, or between about 500 pg and about 1000 pg. In certain embodiments, the dose of vamorolone delivered by inhalation ranges between about 80 pg and about 720 pg, between about 80 pg and about 360 pg, between about 80 pg and about 160 pg, between about 160 pg and about 720 pg, between about 160 pg and about 360 pg, or between about 360 pg and about 720 pg. In certain embodiments, the dose of vamorolone delivered by inhalation ranges between about 80 pg and about 160 pg. In certain embodiments, the dose of vamorolone delivered by inhalation ranges between about 80 pg and about 360 pg. In certain embodiments, the dose of vamorolone delivered by inhalation ranges between about 160 pg and about 720 pg. In certain embodiments, the dose of vamorolone delivered by inhalation is about 50 pg, about 80 pg, about 100 pg, about 160 pg, about 250 pg, about 360 pg, about 500 pg, about 720 pg, or about 1000 pg. In certain embodiments, vamorolone is administered by inhalation once daily, or twice daily. In certain embodiments, vamorolone delivered by inhalation for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months.

Additionally or alternatively, in any of the disclosed methods, vamorolone is formulated as a pharmaceutically acceptable composition for oral administration. In certain embodiments, the dose of vamorolone in a composition for oral administration ranges between about 0.5 mg/kg and about 10 mg/kg, between about 0.5 mg/kg and about 8 mg/kg, between about 0.5 mg/kg and about 6 mg/kg, between about 0.5 mg/kg and about 4 mg/kg, between about 0.5 mg/kg and about 2 mg/kg, between about 0.5 mg/kg and about 1 mg/kg, between about 1 mg/kg and about 10 mg/kg, between about 1 mg/kg and about 8 mg/kg, between about 1 mg/kg and about 6 mg/kg, between about 1 mg/kg and about 4 mg/kg, between about 1 mg/kg and about 2 mg/kg, between about 2 mg/kg and about 10 mg/kg, between about 2 mg/kg and about 8 mg/kg, between about 2 mg/kg and about 6 mg/kg, between about 2 mg/kg and about 4 mg/kg, between about 4 mg/kg and about 10 mg/kg, between about 4 mg/kg and about 8 mg/kg, between about 4 mg/kg and about 6 mg/kg, between about 6 mg/kg and about 10 mg/kg, between about 6 mg/kg and about 8 mg/kg, between about 8 mg/kg and about 10 mg/kg. In certain embodiments, the dose of vamorolone in a composition for oral administration ranges between about 0.5 mg/kg and about 1 mg/kg. In certain embodiments, the dose of vamorolone in a composition for oral administration ranges between about 2 mg/kg and about 6 mg/kg. In certain embodiments, the dose of vamorolone in a composition for oral administration is about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg, about 10 mg/kg. In certain embodiments, the dose of vamorolone in a composition for oral administration ranges between about 2 mg/kg and about 50 mg/kg, between about 2 mg/kg and about 40 mg/kg, between about 2 mg/kg and about 30 mg/kg, between about 2 mg/kg and about 20 mg/kg, between about 2 mg/kg and about 10 mg/kg, between about 10 mg/kg and about 50 mg/kg, between about 10 mg/kg and about 40 mg/kg, between about 10 mg/kg and about 30 mg/kg, between about 10 mg/kg and about 20 mg/kg, between about 20 mg/kg and about 50 mg/kg, between about 20 mg/kg and about 40 mg/kg, between about 20 mg/kg and about 30 mg/kg, between about 30 mg/kg and about 50 mg/kg, between about 30 mg/kg and about 40 mg/kg, or between about 40 mg/kg and about 50 mg/kg. In certain embodiments, the dose of vamorolone in a composition for oral administration is about 2 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg. In certain embodiments, vamorolone is administered in a composition for oral administration once daily, or twice daily. In certain embodiments, vamorolone is administered in a composition for oral administration for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months.

Additionally or alternatively, in any of the disclosed methods, vamorolone is formulated as a pharmaceutically acceptable composition for intravenous, intraarterial, intraperitoneal, intramuscular, or subcutaneous administration. In certain embodiments, the dose of vamorolone ranges between about 0.01 mg/kg and about 1 mg/kg, between about 0.01 mg/kg and about 0.5 mg/kg, between about 0.01 mg/kg and about 0.25 mg/kg, between about 0.01 mg/kg and about 0.1 mg/kg, between about 0.01 mg/kg and about 0.075 mg/kg, between about 0.01 mg/kg and about 0.05 mg/kg, between about 0.01 mg/kg and about 0.025 mg/kg, between about 0.025 mg/kg and about 1 mg/kg, between about 0.025 mg/kg and about 0.5 mg/kg, between about 0.025 mg/kg and about 0.25 mg/kg, between about 0.025 mg/kg and about 0.1 mg/kg, between about 0.025 mg/kg and about 0.075 mg/kg, between about 0.025 mg/kg and about 0.05 mg/kg, between about 0.05 mg/kg and about 1 mg/kg, between about 0.05 mg/kg and about 0.5 mg/kg, between about 0.05 mg/kg and about 0.25 mg/kg, between about 0.05 mg/kg and about 0.1 mg/kg, between about 0.05 mg/kg and about 0.075 mg/kg, between about 0.05 mg/kg and about 0.05 mg/kg, between about 0.075 mg/kg and about 1 mg/kg, between about 0.075 mg/kg and about 0.5 mg/kg, between about 0.075 mg/kg and about 0.25 mg/kg, between about 0.075 mg/kg and about 0.1 mg/kg, between about 0.1 mg/kg and about 1 mg/kg, between about 0.1 mg/kg and about 0.5 mg/kg, between about 0.1 mg/kg and about 0.25 mg/kg, between about 0.25 mg/kg and about 1 mg/kg, between about 0.25 mg/kg and about 0.5 mg/kg, or between about 0.5 mg/kg and about 1 mg/kg. In certain embodiments, the dose of vamorolone is about 0.01 mg/kg, about 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg, about 0.1 mg/kg, about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, or about 0.1 mg/kg. In certain embodiments, the dose of vamorolone ranges between about 0.5 mg/kg and about 10 mg/kg, between about 0.5 mg/kg and about 8 mg/kg, between about 0.5 mg/kg and about 6 mg/kg, between about 0.5 mg/kg and about 4 mg/kg, between about 0.5 mg/kg and about 2 mg/kg, between about 0.5 mg/kg and about 1 mg/kg, between about 1 mg/kg and about 10 mg/kg, between about 1 mg/kg and about 8 mg/kg, between about 1 mg/kg and about 6 mg/kg, between about 1 mg/kg and about 4 mg/kg, between about 1 mg/kg and about 2 mg/kg, between about 2 mg/kg and about 10 mg/kg, between about 2 mg/kg and about 8 mg/kg, between about 2 mg/kg and about 6 mg/kg, between about 2 mg/kg and about 4 mg/kg, between about 4 mg/kg and about 10 mg/kg, between about 4 mg/kg and about 8 mg/kg, between about 4 mg/kg and about 6 mg/kg, between about 6 mg/kg and about 10 mg/kg, between about 6 mg/kg and about 8 mg/kg, between about 8 mg/kg and about 10 mg/kg. In certain embodiments, the dose of vamorolone ranges between about 0.5 mg/kg and about 1 mg/kg. In certain embodiments, the dose of vamorolone in a composition for oral administration ranges between about 2 mg/kg and about 6 mg/kg. In certain embodiments, the dose of vamorolone is about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg, about 10 mg/kg. In certain embodiments, vamorolone is administered once daily, or twice daily. In certain embodiments, vamorolone is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months.

Overall, doses of vamorolone can vary depending on the type and extent of lung disease. Vamorolone can be administered several times per day in small doses to ameliorate relatively mild airway inflammation. Higher doses, given less frequently, can be required to ameliorate more serious.

In a non-limiting embodiment, the present disclosure provides methods of preventing, treating, and/or reducing chronic lung disease in a preterm infant in need thereof, comprising the administration of a composition comprising vamorolone. In certain embodiments, the composition is formulated as an aerosolized composition and comprises between about 80 pg and about 360 pg vamorolone. In certain embodiments, the composition is formulated for oral administration and comprises between about 2 mg/kg and about 50 mg/kg vamorolone.

In another non-limiting embodiment, the present disclosure provides methods of preventing, treating, or reducing lung inflammation in a preterm infant in need thereof, comprising the administration of an aerosolized composition comprising vamorolone. In certain embodiments, the composition is formulated as an aerosolized composition and comprises between about 80 pg and about 360 pg vamorolone. In certain embodiments, the composition is formulated for oral administration and comprises between about 2 mg/kg and about 50 mg/kg vamorolone.

In another non-limiting embodiment, the present disclosure provides a method of preventing, treating, and/or reducing BPD in a preterm infant in need thereof, comprising the administration of an aerosolized composition comprising vamorolone. In certain embodiments, the composition is formulated as an aerosolized composition and comprises between about 80 pg and about 360 pg vamorolone. In certain embodiments, the composition is formulated for oral administration and comprises between about 2 mg/kg and about 50 mg/kg vamorolone.

EXAMPLES

The present disclosure will be better understood by reference to the following Examples, which are provided as exemplary of the presently disclosed subject matter, and not by way of limitation.

EXAMPLE 1: Vamorolone treatment in a rat model of bronchopulmonary dysplasia.

The present example demonstrates that vamorolone suppresses the inflammatory component of BPD while reducing adverse side effects. Vamorolone, budesonide, and deflazacort were administered to separate groups of neonatal rats (n=3 or 4 per group) daily via subcutaneous injection from postnatal day 1 (Pl) through P5 at 5 mg/kg. A vehicle-only treatment was administered as a control.

Whole body weight was measured each day Pl through P5. Four hours following the final injection at P5, rats were sacrificed, and brain weight was measured. Whole body weight was significantly reduced in rats given budesonide or deflazacort in comparison to the vehicle control at P2 through P5 (Figures 1 A and IB). However, body weight was not reduced in rats given vamorolone; at P5, whole body weight for rats given vamorolone was not significantly different from rats given the vehicle control. Similar observations were made for brain weight at P5: brain weight was reduced in rats given budesonide or deflazacort versus rats given the vehicle control; but brain weight was not reduced for rats given vamorolone (Figure 1C).

Blood glucose was also measured four hours following the final injection on P5. Blood glucose was significantly increased in rats given budesonide or deflazacort versus rats given the vehicle control or vamorolone. However, blood glucose was not increased in rats given vamorolone; blood glucose for rats given vamorolone was not significantly different from rats given the vehicle control (Figure ID).

The impact of vamorolone, budesonide, or deflazacort treatment was evaluated on whole lung tissue collected at P5. Expression of FK506 binding protein-5 (FKBP5) and glucocorticoid-induced leucine zipper (GILZ) were measured by quantitative reverse transcription PCR (qRT-PCR) as indicators of tissue stress. FKBP5 and GILZ expression were significantly increased in rats given budesonide or deflazacort in comparison to the vehicle control (Figure 2A and 2B). However, FKBP5 and GILZ expression were not increased in rats given vamorolone. These results support that treatment with budesonide and deflazacort increased tissue stress; however, tissue stress was not increased following treatment with vamorolone.

In addition, expression of tumor necrosis factor-a (TNFa) was measured as an indicator of inflammation. Expression of TNFa was reduced in rats given vamorolone, budesonide, or deflazacort versus rats given the vehicle control (Figure 2C). These results show that vamorolone decreased inflammation following treatment.

EXAMPLE 2: Impact of long-term treatment using vamorolone

The present example tests the long-term outcomes of vamorolone treatment. Experiments are conducted using models of BPM. A first model involves induing lung injury using bleomycin: about 1 mg/kg bleomycin is administered to newborn rats injected intraperitoneally (i.p.) from Pl-Pl 1. A separate model involves inducing lung injury by exposing neonatal rats to hyperoxia: newborn rats are exposed to 65% O2 daily from Pl- P14. These models induce inflammation, fibrosis, and impaired lung function as observed in BPM.

Using the bleomycin-induced BPM model, vamorolone solution comprising about 1.25 mg/kg or about 2.5 mg/kg is administered by subcutaneous (s.c.) injection daily from about Pl- Pl 1. In a separate experiment using the bleomycin-induced BPM model, vamorolone solution comprising about 5 mg/kg, about 15 mg/kg, or about 30 mg/kg are administered orally; oral administration of vamorolone is initiated at Pl or P5. Lungs are collected 4 hours following the final vamorolone injection for both histological analysis and qRT-PCR analysis of mRNA expression of pro-inflammatory genes.

Similar experiments are conducted using the hyperoxia-induced BPM model. Neonatal rats are administered vamorolone orally or by intraperitoneal injection (i.p.) on about Pl, P3, and P5.A vehicle-only treatment is administered as a control. Histological analysis and qRT- PCR analysis of mRNA expression of pro-inflammatory genes are performed as described.

To evaluate the long-term effects of treatment, newborn rats are exposed to inducers of lung injury (bleomycin or hyperoxia) and treated with vamorolone as described above, and then are allowed to recover to about 2 months of age. The rats are then assessed for lung injury (i.e. including fibrosis) by histology and susceptibility to inducers of allergic asthma and pulmonary hypertension. The long-term impacts of vamorolone on metabolic health is additionally evaluated. For example, blood glucose levels are monitored as indicators of glucose metabolism or insulin resistance. Lipid metabolism and fat accumulation are measured as indicators of metabolic health. In addition, bone scans are used to identify adverse effects on skeletal growth as the rats transition to young adults. In a separate experiment, vamorolone treatment is continued daily as the rats age to about 2 months of age. References

1. Thebaud B., K.N. Goss, M. Laughon, J. A. Whitsett, S.H. Abman, R.H. Steinhorn, J.L. Aschner, P.G. Davis, S.A. McGrath-Morrow, R.F. Soil, A.H. Jobe. 2019. Bronchopulmonary dysplasia. Nature Reviews Disease Primers, 5:78; D01https://doi.org/10.1038/s41572-019- 0127-7.

2. Linafelter, A., A. Cuna, C. Liu, A. Quigley, et al. 2019. Extended course of prednisolone in infants with severe bronchopulmonary dysplasia. Early Human Development. 136: 1-6.

3. Guglieri, M., P.R. Clemens, S.J. Perlman, E.C. Smith, et al. 2022. Efficacy and safety of vamorolone vs placebo and prednisone among boys with Duchenne Muscular Dystrophy. JAMA Neurology. 79(10): 1005-1014.

4. Heier, C.R., J.M. Damsker, Q. Yu, B.C. Dillingham, et al. 2013. BP15, a novel antiinflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med. 5: 1569-1585.

5. Heier CR, Yu Q, Fiorillo AA, Tully CB, Tucker A, Mazala DA, Uaesoontrachoon K, Srinivassane S, Damsker JM, Hoffman EP, Nagaraju K, Spurney CF. Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy. Life Sci Alliance. 2019 Feb l l;2(l):e201800186. doi: 10.26508/lsa.201800186. PMID: 30745312; PMCID: PMC6371196.

6. AGAMREE (vamorolone) [package insert], Santhera Pharmaceuticals (USA), Inc. 2023.

7. Gladyshev VN, Anderson B, Barlit H, Barre B, Beck S, Behrouz B, Belsky DW, Chaix A, Chamoli M, Chen BH, Cheng K, Chuprin J, Churchill GA, Cipriano A, Colville A, Deelen J, Deigin Y, Edmonds KK, English BW, Fang R, Florea M, Gershteyn IM, Gill D, Goetz LH, Gorbunova V, Griffin PT, Horvath S, Borch Jensen M, Jin X, Jovanovska S, Kajderowicz KM, Kasahara T, Kerepesi C, Kulkami S, Labunskyy VM, Levine ME, Libert S, Lu JY, Lu YR, Marioni RE, McCoy BM, Mitchell W, Moqri M, Nasirian F, Niimi P, Oh HS, Okundaye B, Parkhitko AA, Peshkin L, Petljak M, Poganik JR, Pridham G, Promislow DEL, Prusisz W, Quiniou M, Raj K, Richard D, Ricon JL, Rutledge J, Scheibye-Knudsen M, Schork NJ, Seluanov A, Shadpour M, Shindyapina AV, Shuken SR, Sivakumar S, Stoeger T, Sugiura A, Sutton NR, Suvorov A, Tarkhov AE, Teeling EC, Trapp A, Tyshkovskiy A, Unfried M, Ward- Caviness CK, Yim SH, Ying K, Yunes J, Zhang B, Zhavoronkov A. Disagreement on foundational principles of biological aging. PNAS Nexus. 2024 Dec 3;3(12):pgae499. doi: 10.1093/pnasnexus/pgae499. PMID: 39660064; PMCID: PMC11630784. 8. Li DB, Xu XX, Hu YQ, Cui Q, Xiao YY, Sun SJ, Chen LJ, Ye LC, Sun Q. Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms. Am J Physiol Lung Cell Mol Physiol. 2023 Feb l;324(2):L89-L101. doi: 10.1152/ajplung.00195.2022. Epub 2022 Dec 6. PMID: 36472329; PMCID: PMC9925164.

9. Gong, Z., Dixit, M., He, Z. et al. Deletion of absent in melanoma-2 (AIM2) drives bone marrow adipogenesis and impairs bone microarchitecture. GeroScience 47, 795-807 (2025).

10. Koestenberger M, Bogaard HJ, Hansmann G. Getting to the bottom of right heart failure. Cardiovasc Diagn Ther. 2020 Oct;10(5):1517-1521. doi: 10.21037/cdt-20-565. PMID: 33224771; PMCID: PMC7666963.

11. Heinrich VA, Uvalle C, Manni ML, Li K, Mullett SJ, Donepudi SR, Clader J, Fitch A, Ellgass M, Cechova V, Qin S, Holguin F, Freeman BA, Methe BA, Morris A, Gelhaus SL. Meta-omics profiling of the gut-lung axis illuminates metabolic networks and host-microbial interactions associated with elevated lung elastance in a murine model of obese allergic asthma. Front Microbiomes. 2023;2: 1153691. doi: 10.3389/frmbi.2023.1153691. Epub 2023 May 5. PMID: 37293566; PMCID: PMC10249466.

* * *

Although the presently disclosed subject matter and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the present disclosure. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, and compositions of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the present disclosure of the presently disclosed subject matter, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein can be utilized according to the presently disclosed subject matter. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps. Various patents, patent applications, publications, product descriptions, protocols, and sequence accession numbers are cited throughout this application, this present disclosures of which are incorporated herein by reference in their entireties for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A method of preventing, treating, and/or reducing a chronic lung disease in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising vamorolone, a derivative thereof, or a combination thereof.

2. The method of claim 1, wherein the composition comprises vamorolone.

3. The method of any one of claims 1-2, wherein the chronic lung disease is bronchopulmonary dysplasia.

4. The method of any one of claims 1-3, wherein the composition is formulated as an aerosolized composition.

5. The method of claim 4, wherein the composition comprises a dose of vamorolone ranging between about 80 pg and about 360 pg.

6. The method of any one of claims 1-3, wherein the composition is formulated for oral administration.

7. The method of claim 6, wherein the composition comprises a dose of vamorolone ranging between about 2 mg/kg and about 50 mg/kg.

8. The method of any one of claims 1-7, wherein the subject is an infant.

9. The method of any one of claims 1-7, wherein the subject is a preterm infant.

10. A method of preventing, treating, and/or reducing lung inflammation in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising vamorolone, a derivative thereof, or a combination thereof.

11. The method of claim 10, wherein the composition comprises vamorolone.

12. The method of claim 10 or claim 11, wherein the lung inflammation is associated with bronchopulmonary dysplasia.

13. The method of any one of claims 10-12 wherein the composition is an aerosolized composition.

14. The method of claim 13, wherein the composition comprises a dose of vamorolone ranging between about 80 pg and about 360 pg.

15. The method of any one of claims 10-12, wherein the composition is formulated for oral administration.

16. The method of claim 15, wherein the composition comprises a dose of vamorolone ranging between about 2 mg/kg and about 50 mg/kg.

17. The method of any one of claims 10-16, wherein the subject is an infant.

18. The method of any one of claims 10-16, wherein the subject is a preterm infant.

19. A pharmaceutical composition comprising vamorolone, a derivative thereof, or a combination thereof, wherein the pharmaceutical composition is suitable for administration by inhalation.

20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition comprises vamorolone.

21. The pharmaceutical composition of claim 19 or claim 20, wherein the pharmaceutical composition is an aerosolized composition.

22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition comprises a dose of vamorolone ranging between about 80 pg and about 360 pg.

23. The pharmaceutical composition of any one of claims 19-22, wherein the pharmaceutical composition is formulated for oral administration.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition comprises a dose of vamorolone ranging between about 2 mg/kg and about 50 mg/kg.

25. The pharmaceutical composition of any one of claims 19-24, further comprising a pharmaceutically acceptable carrier.