JP2023530681A - Methods and compositions for preventing and treating myopia using fingolimod, sphingosine-1-phosphate receptor modulators, and derivatives thereof - Google Patents

Abstract

The present disclosure relates to methods and compositions for preventing and/or treating eye diseases. In particular, the present disclosure relates to the prevention and/or treatment of myopia by systemic or local administration of the sphingosine-1-phosphate receptor modulator fingolimodolinic acid, or a derivative thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to US Patent Application No. 63/037,910, filed Jun. 11, 2020, which is hereby incorporated by reference in its entirety.

The present disclosure relates to methods and compositions for preventing and/or treating eye diseases. In particular, the present disclosure relates to the prevention and/or treatment of myopia by systemic or local administration of the sphingosine-1-phosphate receptor modulator fingolimod (FTY720) phosphate and its derivatives.

Myopia (nearsightedness) is the most common eye disorder in the world. The prevalence of myopia in the United States has increased from 25% to 48% over the past 40 years. ^1,2 In parts of Asia, over 80% of the population suffers from myopia. ³ The global prevalence of myopia is projected to increase from 25% in 2020 to 50% by 2050. ⁴ Myopia causes $250 billion in lost productivity worldwide annually.

Myopia leads to serious pathological complications such as retinochoroidal atrophy, retinoschisis, retinal tears, retinal detachment, and myopic macular degeneration, which often lead to blindness. ^5,6 It also represents a major risk factor for many other serious eye diseases, such as cataracts and glaucoma, which often lead to vision impairment and loss. Due to ^its increasing prevalence, myopia is rapidly becoming one of the leading causes of vision loss, and the World Health Organization has designated myopia as one of five priority health conditions. ^{5, 9}

The development of myopia is controlled by both environmental and genetic factors. ¹⁰ Human population studies suggest that the major environmental factors that cause myopia in humans are precision work and reading, ^11-13 and these are associated with delayed accommodation, i.e., when subjects perform precision tasks. It is associated with hyperopic defocus caused by an insufficiently strong accommodative response to near objects. ^14,15 The optical blur produced by hyperopic defocus is thought to be the signal that drives excessive eye growth and causes myopia. ^16,17 For example, an analysis of the incidence of myopia in orthodox Jewish students (who spent most of their day reading) and secular Jewish students (who spent less time reading) showed that orthodox Diligent students were found to have a much higher incidence and degree of myopia compared to secular students ¹⁸ , suggesting that reading is a factor causing myopia. Additionally, there are numerous epidemiological studies showing that myopia is more common in urban areas among professionals, educated patients, computer users, and college students, and is associated with increased intelligence. ^19-23 myopia also increases in individuals who perform tasks requiring increased use of the eye, such as microscopists. ²⁴ The association between optical defocus and myopia suggests that resolution of visual input using either diffuse or negative lenses is excessive in diverse species such as fish, chickens, tree shrews, monkeys, guinea pigs and mice. supported by numerous animal studies that have been found to cause abnormal eye growth and myopia. ²⁵

Although the increase in the prevalence of myopia in recent decades is primarily due to the rapidly increasing exposure of young children to precision work, ²⁶ genetic factors contribute 60%-80% to the development of myopia. % ²⁷ . The incidence of myopia increases when both parents are myopic. ²⁰ Numerous studies have shown that parental refractive error is the most important predictor of the development of myopia. ^28,29 Strong support for the role of genetic factors in the development of myopia also comes from studies comparing monozygotic ^twins30 and dizygotic twins. ^{31, 32} . Myopia is a complex genetic disease controlled by hundreds of genes, similar to height and weight ^27,33 . Genetic studies have suggested over 900 genes for the development of human myopia. ^{27, 33}

Thus, both environmental and genetic factors have been shown to contribute to the development of myopia. ¹⁰ Furthermore, recent studies have demonstrated the existence of genes that regulate the effects of myopiagenic environmental factors on refractive eye development. ³⁴ Further support for the gene-environment interaction in the development of myopia comes from gene expression profiling studies that revealed that the development of myopia is accompanied by large-scale changes in gene expression in the eye, which is the subject of precision work. suggest that it activates molecular signaling pathways in the eye that stimulate excessive eye growth, leading to the development of myopia. ^{33, 35-37} Several studies have shown that the eye responds to regional changes in optical defocus that accompany regional changes in growth rate, thus information about optical defocus is distributed over the entire surface of the retina. suggesting that the integrated signal, summed over, regulates eye growth. ^38,39 Importantly, the eye can respond to myopiagenic optical defocus even when the optic nerve is severed, ³⁹ the signaling cascade that regulates refractive eye development Located within the eye itself, it demonstrates no need for feedback from the brain.

Myopia appears to progress most during the vulnerable period between the ages of 6 and 16, after which it begins to slow down. In generations ^{40 and 41} and earlier, it was assumed that myopia progression ended around the age of 20. However, this is changing as more students enter graduate school, followed by jobs requiring eight hours of sustained computer work. ⁴² This speculation was recently studied in a post-college cohort with a mean age of 35 years. ⁴³ Myopia was found to progress in about 10% of the cohort who spent most of their time in front of a computer. Subjects who did not spend time in front of the computer did not progress as much.

Currently approved treatment options for myopia are limited to optical correction using spectacles or contact lenses. Optical correction using monofocal corrective lenses, the most widely used treatment option for myopia, does not halt myopia progression or prevent pathological complications of disease-related blindness. Several experimental optical-based clinical interventions for slowing the progression of myopia, such as spectacles with ^44, 45 bifocal lenses, multifocals, and Ortho-K contact lenses, have shown some promise, but These treatment options have low efficacy. ⁴⁶

Spectacles with bifocal lenses were first used to control the progression of myopia. A multicenter COMET study designed to determine whether bifocals can slow the progression of myopia compared to monofocal spectacle lenses found that bifocals slowed myopia progression by 20% in the first year. Although delayed, the effect decreased significantly from 2 to 4 years. ⁴⁷

Two separate meta-analyses analyzed the ability of Ortho-K lenses to slow myopia progression and found that they could reduce myopia progression by about 45%, ^48,49 although one study found that Ortho-K lenses could reduce myopia progression by approximately 45%. We have found that there is a significant rebound effect when K lenses are discontinued. ⁵⁰

Recently, there has been increasing interest in the use of soft multifocal contact lenses to replicate Ortho-K optics. ^51-53 A meta-analysis that included 587 subjects from eight studies found that concentric rings and distance-centered multifocal contact lenses slowed the progression of myopia by 30-38% over 24 months. ⁵⁴

Currently available pharmacological options for myopia control are essentially limited to two drugs, atropine and 7-methylxanthine, with significant side effects and/or relatively low efficacy.

Atropine, a non-selective muscarinic antagonist, is an alkaloid produced by Atropa belladonna that is traditionally used as a mydriatic and cycloplegic agent in ophthalmic practice. Several clinical trials have evaluated the effects of different concentrations of atropine on myopia progression and its long-term effects on visual function in children. The first study, atropine for the treatment of myopia 1 (ATOM1), revealed that 1% atropine eye drops slowed the progression of myopia by approximately 76% over a two-year treatment period. ⁵⁵ However, follow-up studies showed that discontinuation of treatment produced a strong rebound effect, resulting in a 300% increase in the rate of myopia progression compared to placebo in the first 12 months after discontinuation of atropine, and a 2-year reduction in treatment effect. We found that about 60% were excluded. ⁵⁶ In addition, 1% atropine caused unpleasant side effects such as photophobia, reduced accommodative amplitude, and blurred vision. The follow-up study ATOM2 evaluated the effects of 0.5%, 0.1%, and 0.01% atropine on myopia progression in children, with 0.5% atropine inhibiting myopia progression by 75%, We found that 0.1% and 0.01% atropine slowed progression by 68% and 59%, respectively. ⁵⁷ Withdrawal of treatment caused a 218% rebound increase in progression rate compared to placebo in the group treated with 0.5% atropine during the first 12 months after discontinuation of drug administration, with a rebound increase of 0.1 The group treated with % atropine caused a 170% increase. ⁵⁸ However, the rate of progression was reduced by approximately 30% in the group treated with 0.01% atropine. ⁵⁸ These findings were reinforced by a recent 5-year follow-up study, which revealed that higher initial atropine doses predisposed children to greater myopia progression after cessation of treatment, with 0.01% It was suggested that atropine provided the best long-term outcome with a suppressive effect of approximately 30%. ⁵⁹ These findings were ^refined by a recent study, the Low-Concentration Atropine for Myopia Control (LAMP) trial, which suggested that low-dose atropine has a dose-dependent inhibitory effect on myopia progression. This study found that 0.01% atropine slowed the progression of myopia by 27% over one year compared to 43% and 67% achieved with 0.025% and 0.05% atropine, respectively. . However, recent studies found that the use of atropine in young primates has long-term adverse effects on the development and normalization of ocular components, which may undermine atropine's utility as an anti-myopia drug. question. ⁶¹

7-Methylxanthine (7-MX), a non-selective adenosine receptor antagonist, is produced by several plant species and is a natural derivative of caffeine and theobromine, two alkaloids that are major components of cocoa, coffee and tea. It is a metabolite. The first indication that 7-MX could be a potential drug for myopia control came from the observation that 7-MX causes scleral thickening and an increase in the diameter of scleral collagen fibrils, ⁶² That is, it causes scleral changes opposite to those observed in myopic eyes. A small follow-up clinical trial analyzed the effect of daily oral intake of 400 mg (approximately 15 mg/kg) 7-MX on the progression of myopia in children, and 7-MX reduced myopia in subjects with slow-progressing myopia. was found to have the potential to suppress the myopia progression by about 22%, but not to affect the progression of myopia in fast-progressing subjects. In ⁶³ guinea pigs, a 300 mg/kg dose of 7-MX was shown to reduce myopia by 49%. ⁶⁴ Similarly, a 30 mg/kg dose of 7-MX reduced the degree of myopia induced in rabbits by about 67%. Recent data from a study in ⁶⁵ monkeys also suggested that 7-MX can suppress myopia in primates, but the effect strongly depends on the genetic background of the particular subject. ⁶⁶ Preliminary data therefore suggest that 7-MX has therapeutic potential for myopia control in subjects with slowly progressive myopia, although the question of effective dose and efficacy in humans remains not made clear. The safety profile and long-term effects of daily oral intake of 7-MX in children are currently unknown.

Several other compounds have been suggested to inhibit myopia to varying degrees. The muscarinic receptor antagonists pirenzepine and himbacine have been shown to inhibit the development of experimental myopia in tree shrews, rhesus monkeys and chickens. ^67,68 Pirenzepine was found to inhibit the progression of myopia in children by 40%, but clinical trials were eventually stopped due to severe side effects. ⁶⁹ Some GABA _B and GABA such as (1,2,5,6-tetrahydropyridin-4yl)methylphosphinic acid (TPMPA), CGP46381 and (3-aminocyclopentanyl)butylphosphinic acid (3-ACPBPA) _C- receptor antagonists have been shown to suppress the development of myopia in chickens and guinea pigs. ^70-72 In addition, α-adrenergic agonists such as clonidine and guanfacine were shown to inhibit experimentally induced myopia in chickens, while ⁷³ brimonidine suppressed myopia in ^chickens73 and guinea ^pigs74 . In addition, the dopamine receptor agonist apomorphine was found to inhibit the development of myopia in several animal models such as chickens, mice and non-human primates, ^{75,76 and} the intraocular pressure-lowering drug latanoprost in guinea pigs. It was found to reduce the progression of myopia. ⁷⁷ Finally, a recent drug screen in a mouse model of myopia identified crocetin, a natural carotenoid found in crocus flowers and fruits of Gardenia jasminoides, as a potential anti-myopia agent. ⁷⁸

The prevalence of myopia has increased exponentially in recent years worldwide and has already reached epidemic proportions in many countries. The prevalence of myopia is projected to increase to 50% of the world's population by 2050, with 8% of those with low to moderate myopia and 29% of those with high myopia developing myopic macular degeneration, which reduces vision. The world will soon face a public health crisis of vision loss because of the loss. ⁷⁹ Currently available optical-based treatment options for myopia are ineffective and only slow the progression of myopia, not stop it. Currently available pharmacological options have either low efficacy and/or severe adverse effects. Clearly, there is an urgent medical need to develop products for myopia control that can achieve far greater efficacy than currently available products and that can be safely used in children. .

The present disclosure provides oral compositions, sustained drug release formulations or compositions, sustained drug delivery through contact lenses, or eye drops comprising drug compounds or agents identified using the pharmacogenomic pipeline for anti-myopia drug development. to prevent and/or treat myopia in a subject in need thereof by inhibiting ocular signaling pathways that underlie the development of myopia.

Accordingly, one embodiment is a method of preventing and/or treating myopia in a subject in need thereof, using a therapeutically effective amount of a pharmacogenomic pipeline for anti-myopia drug development. administering to the subject a composition comprising the active drug compound identified in the method.

又はその誘導体である。 In one embodiment, the active drug compound is fingolimod (FTY720) phosphate, a sphingosine-1-phosphate receptor modulator having the structure

or a derivative thereof.

In some embodiments, the present disclosure provides a therapeutically effective amount of fingolimodolic acid or a derivative thereof in oral compositions, sustained drug release formulations or compositions, sustained drug delivery by contact lenses during the susceptibility period of myopia onset. , or in the form of eye drops to a subject to prevent and/or treat myopia.

In some embodiments, the present disclosure provides repeated doses of a therapeutically effective amount of fingolimodonic acid or a derivative thereof via oral compositions, sustained drug release formulations or compositions, contact lenses during a susceptible period of myopia onset. Methods of preventing and/or treating myopia are provided by sustained drug delivery or administration to a subject in the form of eye drops.

In further embodiments, the active drug compound is a sphingosine-1-phosphate receptor modulator.

In some embodiments, sphingosine-1-phosphate receptor modulators include, but are not limited to, ONO-4641, ozanimod, siponimod, ponesimod, and derivatives thereof.

Accordingly, in a further embodiment, the present disclosure provides a therapeutically effective amount of a sphingosine-1-phosphate receptor modulator in oral compositions, sustained drug release formulations or compositions, contact lenses during the susceptibility period of myopia onset. Provided is a method of preventing and/or treating myopia by sustained drug delivery via or by administering to a subject in the form of eye drops.

In some embodiments, the present disclosure provides repeated doses of a therapeutically effective amount of a sphingosine-1-phosphate receptor modulator in oral compositions, sustained drug release formulations or compositions, during a susceptible period of myopia onset. Methods of preventing and/or treating myopia are provided by sustained drug delivery through contact lenses or administration to a subject in the form of eye drops.

In some embodiments, the composition is administered to the subject once daily. In some embodiments, the composition is administered once weekly. In some embodiments, the composition is administered twice weekly. In some embodiments, the composition is administered three times weekly. In some embodiments, the composition is administered to the subject continuously or intermittently for about 5 to about 10 years.

In some embodiments, the subject is a young adult, ie under the age of 30. In some embodiments, the subject is a child, ie, under the age of 18. In some embodiments, the subject is between about 4 years old and about 30 years old. In some embodiments, the subject is between about 6 years old and about 20 years old. In some embodiments, the subject is between about 8 and about 15 years old. In some embodiments, the subject is between about 10 and about 12 years old.

In some embodiments, the subject has myopia. In some embodiments, the subject is at risk for myopia. In some embodiments, the subject is prone to myopia.

In some embodiments, the subject is monitored for myopia suppression, and the therapeutically effective amount and/or frequency of administration of the drug compound is adjusted according to the degree of suppression. Suppression of myopia can be monitored using methods known in the art.

A further embodiment of the present disclosure is a kit comprising compositions and agents for practicing the disclosed methods.

For purposes of illustrating the invention, specific embodiments of the invention are shown in the drawings. However, the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

Experimentally induced myopia in mice has characteristics of human myopia. FIG. 2 shows a mouse induced to myopia with −25D lenses. FIG. 10 is a graph showing the statistically significant myopic shift in refraction observed in mouse eyes treated with −25D lenses for 21 days. FIG. 4 shows that lens-induced myopia in mice, like human myopia, results from a statistically significant increase in vitreous cavity depth. FIG. 11 shows power simulations demonstrating the relationship between statistical power and number of animals for induced myopia experiments. ACD, anterior chamber depth; CRC, corneal radius of curvature; LT, lens thickness; VCD, vitreous cavity depth; OD, right (myopia) eye; OS, left (control) eye. Error bars, S.D. P, significant value. FIG. 4 shows that systemic administration of 0.3 mg/kg fingolimodonic acid completely inhibited the development of myopia in experimentally induced myopic mice.

DEFINITIONS The following definitions and explanations take precedence in any construction unless explicitly and explicitly changed in the examples below or unless the application of meaning renders any construction meaningless or essentially meaningless. means and intends to Where the construction of a term renders it nonsensical or essentially nonsensical, definitions are to be taken from Webster's Dictionary or dictionaries known to those skilled in the art, such as the Oxford Dictionary of Biochemistry and Molecular Biology or the like. should.

The contents of patents, patent applications, and references cited throughout this specification are hereby incorporated by reference in their entireties.

As used herein, unless otherwise indicated, the terms "a" and "an" shall be taken to mean "one," "at least one," or "one or more." Unless otherwise required by context, singular terms used herein shall include pluralities and plural terms shall include the singular.

The terms "myopia" or "myopic" mean an ocular disease state in which the posterior portion of the eye is too large for the refractive power of the eye and the focal point is located in front of the retina, thus resulting in blurred distant vision. and

The terms "hyperopia" or "hyperopic" refer to an eye condition in which the back of the eye is too small for the refractive power of the eye and the focal point is located behind the retina, thus resulting in blurred near vision. shall be

The term "negative lens" shall mean a lens that shifts the focal point of the eye to the back of the eye, thus making the eye hyperopic.

The term "gene network" shall mean a network of interconnected genes that regulate a physiological or biological process.

The term "differentially expressed" shall mean changes in gene expression levels induced by environmental factors, changes in genetic background, or other internal or external injury or influence.

The term "experimentally induced myopia" is used herein to describe myopia induced in animal models by experimental manipulations such as application of negative lenses to the eye.

The term "genome-wide gene expression profiling" refers to methods that analyze differential gene expression at the genome-wide level, thus providing information on the expression of all genes encoded by the genome.

The term "gene-based genome-wide association studies" refers to the level of genetic variation and specific genes in the genome previously found to be involved in disease processes by other experimental approaches such as whole-genome gene expression profiling. A genetic study that analyzes statistical associations between diseases in

The term "positive optical defocus" shall mean the condition when the focal point of the eye is in front of the retina.

The term "negative optical defocus" shall mean the condition when the focal point of the eye is behind the retina.

The term "derivative" refers to a structural analogue of a compound derived from the compound by a chemical reaction. A structural analog is a compound that has a similar structure to another compound, but differs with respect to certain components. It may differ in one or more atoms, functional groups, or substructures replaced by other atoms, groups, or substructures. A structural analog can also differ from another compound by one or more atoms, functional groups, or substructures added to or subtracted from another compound. Structural analogs can be assumed, at least in theory, to be formed from other compounds by those skilled in the art.

The term "subject" as used in this application means a human subject. In some embodiments of the invention, the "subject" has myopia, is at risk for myopia, or is prone to myopia.

The terms "treat," "treatment," and the like refer to means of slowing, reducing, ameliorating or alleviating at least one of the symptoms of a disease, or reversing the disease after its onset.

The terms "prevent," "prevention," and the like, refer to actions that act before overt disease onset, prevent the onset of disease, minimize the extent of disease, or prevent the onset of disease. It refers to delaying the course of onset.

The term "in need of" is a subject known or suspected to be suffering from myopia.

A subject in need of treatment may be one who has already developed a disease or condition. A subject in need of prophylaxis may be a subject with risk factors for a disease or condition.

As used herein, the term "drug" means a substance that produces or is capable of producing an effect and includes chemicals, pharmaceuticals, biologicals, small organic molecules, antibodies, nucleic acids, peptides, , and proteins.

The phrase "therapeutically effective amount," as used herein, is an amount sufficient to cause a clinically significant improvement in condition in a subject, or to delay or minimize or alleviate one or more symptoms associated with the disease. or an amount sufficient to effect the desired beneficial physiological change in a subject.

Identification of Anti-Myopia Drugs Using a Pharmacogenomic Pipeline Presented herein are the results of the use of a pharmacogenomic pipeline developed by the inventors to identify drug compounds that can inhibit the development of myopia. . ^{An 80-} systems genetics approach was used to identify the genes, genetic networks, and signaling pathways that underlie refractive eye development and the development of myopia. A systems genetics approach has been used to identify differentially expressed genes in the eyes of animals with experimentally induced myopia using genome-wide gene expression profiling, and in humans using gene-based genome-wide association studies. included the identification of genes associated with myopia in humans. An example of our research is positive optical defocus (to suppress myopia) and negative We found that the signaling pathways underlying the ocular response to optical defocus propagate through two very different signaling cascades.

We extended this observation to several vertebrate species and demonstrated that the signaling cascades underlying myopia development are highly evolutionarily conserved across vertebrate species, including humans. . We then used Tkatchenko et al. 2019, using a vast myopia-related gene dataset (comprising over 3,500 genes) and computational tools to reconstruct the genetic networks that control ^myopia development and drive myopia development. Drug compounds have been identified that can inhibit signaling pathways and stimulate pathways that inhibit the development of myopia.

A total of 138 drug compounds with anti-myopia potential were identified. Using gene pathways and z-scores, these drug compounds were identified as top 10, top 20, top 40, top 80, based on their predicted potential to suppress myopia and known or predicted side effects. and assigned to the low priority category. These drug compounds were then tested in a mouse model of myopia (Example 1).

Methods and compositions for the prevention and/or treatment of myopia using fingolimod, sphingosine-1-phosphate receptor modulators, and derivatives thereof ) A method for preventing and/or treating myopia comprising administering phosphoric acid or a derivative thereof to a subject in need thereof.

In certain embodiments, the fingolimodolinic acid or derivative is administered systemically. In certain embodiments, the fingolimodolinic acid or derivative is administered orally. In certain embodiments, the fingolimodolinic acid or derivative is administered topically. In some embodiments, the fingolimodolic acid or derivative is administered directly or intraocularly to the eye. In some embodiments, the fingolimodolinic acid or derivative is administered by injection. In other embodiments, the fingolimodonic acid or derivative is administered as a sustained drug release formulation or composition, sustained drug delivery through contact lenses, or eye drops.

In certain embodiments, fingolimodolic acid is used directly as an active ingredient in a medicament. In other embodiments, fingolimodonic acid is chemically modified to improve its efficacy, reduce side effects, improve ocular tissue penetration, increase stability, or improve bioavailability. can do.

In certain embodiments, fingolimodolic acid (or a derivative thereof) is the only component of the drug. In other embodiments, the methods and compositions described herein comprise the use of pharmaceutical formulations comprising fingolimodonic acid (or derivatives thereof).

The term "pharmaceutical formulation" includes fingolimodonic acid (or a derivative thereof) and additional ingredients such as other drugs or excipients (vehicles, additives, preservatives, buffers) capable of suppressing myopia. Refers to a formulation comprising, which can be rationally administered to a subject to improve the efficacy of the active ingredient(s) or to increase the stability of the active ingredient(s). The active ingredient(s) will exhibit their physical and/or chemical properties and/or biological activity at room temperature (15-30°C) for at least 1 week or at 2-8°C for 3-1 months. A formulation is stable if it is essentially retained for years.

Fingolimodonic acid (or a derivative thereof) is degraded and/or aggregated, and/or it is considered to retain its physical properties in the pharmaceutical formulation if it meets the prescribed specifications for precipitation.

Fingolimodonic acid (or a derivative thereof) is believed to retain its chemical stability in pharmaceutical formulations provided the active ingredient content is within about 90% of the amount at which the pharmaceutical formulation is prepared. Some types of chemical degradation include oxidation and hydrolysis, which can be assessed by, for example, LC-MS/MS based methods.

Fingolimodonic acid (or a derivative thereof) exhibits about 90% of the biological activity exhibited at the time the pharmaceutical formulation was prepared, as the active ingredient at a given time is determined, for example, by in vivo testing. within, it is considered to retain its biostability in a pharmaceutical formulation.

In the context of the present disclosure, a therapeutically effective dose of fingolimodonic acid (or derivative thereof) is an amount sufficient to at least partially prevent and/or treat myopia. A therapeutically effective dose is sufficient if even gradual changes in disease-related symptoms or conditions can occur. A therapeutically effective dose need not completely cure the disease or eliminate the symptoms completely. Preferably, a therapeutically effective dose can significantly slow the progression of myopia in a subject suffering from the disease. The dose and frequency of drug administration effective for this use will depend, among other factors, on the severity of the disease (i.e., low-progressive vs. high-progressive myopia), the type of myopia (i.e., symptomatic vs. general myopia), It depends on the age of the subject, the weight of the subject and the route of administration. The dose and frequency of drug administration can be adjusted using state of the art techniques well understood and commonly used in optometric and ophthalmic practice.

Fingolimodolic acid as described herein can be co-administered with other agents, including additional agents for the prevention and/or treatment of myopia. Co-administration of agents can be by any administration described herein. Additionally, the additional agent may be of the same composition as fingolimodolic acid. The additional agent may be a separate composition from fingolimodonic acid. Administration of two or more compositions can be simultaneous, concurrent or sequential.

The present disclosure, in some aspects, further provides a method of preventing and/or treating myopia, comprising administering a therapeutically effective amount of a sphingosine-1-phosphate receptor modulator to a subject in need thereof. including.

In some embodiments, sphingosine-1-phosphate receptor modulators include, but are not limited to, ONO-4641, ozanimod, siponimod, ponesimod, or derivatives thereof.

In certain embodiments, the sphingosine-1-phosphate receptor modulator is administered systemically. In certain embodiments, the sphingosine-1-phosphate receptor modulator is administered orally. In certain embodiments, a sphingosine-1-phosphate receptor modulator is administered topically. In some embodiments, the sphingosine-1-phosphate receptor modulator is administered directly or intraocularly to the eye. In some embodiments, the sphingosine-1-phosphate receptor modulator is administered by injection. In other embodiments, the sphingosine-1-phosphate receptor modulator is administered as a sustained drug release formulation or composition, sustained drug delivery through contact lenses, or eye drops.

In further embodiments, sphingosine-1-phosphate receptor modulators are used directly as active ingredients in medicaments. In other embodiments, the sphingosine-1-phosphate receptor modulator is chemically modified to improve its efficacy, reduce side effects, improve ocular tissue penetration, and increase stability. , or improved bioavailability.

In certain embodiments, the sphingosine-1-phosphate receptor modulator is the sole component of the drug. In other embodiments, the methods and compositions described herein involve the use of pharmaceutical formulations comprising sphingosine-1-phosphate receptor modulators.

The term "pharmaceutical formulation" includes a sphingosine-1-phosphate receptor modulator and additional ingredients such as other drugs or excipients (vehicles, additives, preservatives, buffers) capable of suppressing myopia. and can be rationally administered to a subject to improve the efficacy of the active ingredient(s) or to increase the stability of the active ingredient(s). The active ingredient(s) will exhibit their physical and/or chemical properties and/or biological activity at room temperature (15-30°C) for at least 1 week or at 2-8°C for 3-1 months. A formulation is stable if it is essentially retained for years.

A sphingosine-1-phosphate receptor modulator may degrade and/or aggregate upon visual inspection for color and/or clarity or as measured by light scattering or other suitable art-recognized method. and/or meet prescribed specifications for precipitation, it is considered to retain its physical properties in the pharmaceutical formulation.

A sphingosine-1-phosphate receptor modulator is believed to retain its chemical stability in a pharmaceutical formulation if the active ingredient content is within about 90% of the amount at which the pharmaceutical formulation is prepared. Some types of chemical degradation include oxidation and hydrolysis, which can be assessed by, for example, LC-MS/MS based methods.

A sphingosine-1-phosphate receptor modulator has about 90% of the biological activity exhibited at the time the pharmaceutical formulation was prepared, as the active ingredient at a given time is determined, for example, by in vivo testing. %, it is considered to retain its biostability in pharmaceutical formulations.

In the context of the present disclosure, a therapeutically effective dose of a sphingosine-1-phosphate receptor modulator is an amount sufficient to at least partially prevent and/or treat myopia. A therapeutically effective dose is sufficient if even gradual changes in disease-related symptoms or conditions can occur. A therapeutically effective dose need not completely cure the disease or eliminate the symptoms completely. Preferably, a therapeutically effective dose can significantly slow the progression of myopia in a subject suffering from the disease. The dose and frequency of drug administration effective for this use will depend, among other factors, on the severity of the disease (i.e., low-progressive vs. high-progressive myopia), the type of myopia (i.e., symptomatic vs. general myopia), It depends on the age of the subject, the weight of the subject and the route of administration. The dose and frequency of drug administration can be adjusted using state of the art techniques well understood and commonly used in optometric and ophthalmic practice.

The sphingosine-1-phosphate receptor modulators described herein can be co-administered with other agents, including additional agents for the reduction, prevention and/or treatment of myopia. Co-administration of agents can be by any administration described herein. Additionally, the additional agent can be of the same composition as the sphingosine-1-phosphate receptor modulator. The additional agent can be a separate composition from the sphingosine-1-phosphate receptor modulator. Administration of two or more compositions can be simultaneous, concurrent or sequential.

Oral compositions of drugs can be in the form of capsules, tablets, powders, granules, solutions, syrups, suspensions (in non-aqueous or aqueous liquids), or emulsions. Tablets or hard gelatin capsules may contain lactose, starch or derivatives thereof, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, stearic acid or salts thereof. Soft gelatin capsules may contain vegetable oils, waxes, fats, semi-solid, or liquid polyols. Solutions and syrups may contain water, polyols, and sugars. Active agents intended for oral administration can be coated or mixed with a material that delays disintegration and/or absorption of the active agent in the gastrointestinal tract. Sustained release can thus be achieved over an extended period of time and, if desired, the active agent can be protected from degradation in the stomach. Pharmaceutical compositions for oral administration may be formulated to facilitate release of the active agent at specific gastrointestinal locations resulting from specific pH or enzymatic conditions.

In addition to the ingredients specifically mentioned above, the compositions may contain other agents customary in the art having regard to the type of formulation in question, for example those suitable for oral administration may contain flavoring agents. It should be understood.

Sustained drug release formulations or compositions can be in the form of nanosponges, patches, gels or other devices capable of slowly releasing drug over an extended period of time, which are injected into the anterior or posterior eye. or administered or applied to the anterior or posterior surface of the eye.

Sustained drug delivery through contact lenses is in the form of plano contact lenses, monofocal corrective contact lenses, or multifocal contact lenses, in which the inner surface of the lens is coated with drug or the entire volume of the lens is filled with drug. could be.

Eye drops are well known to those of skill in the art and can be in the form of commonly used conventional eye drops or in the form of microdose devices that deliver tightly controlled amounts of drug to the eye.

In some embodiments, the composition is administered to the subject once daily. In some embodiments, the composition is administered once weekly. In some embodiments, the composition is administered twice weekly. In some embodiments, the composition is administered three times weekly. In some embodiments, the composition is administered to the subject continuously or intermittently for about 5 to about 10 years.

In some embodiments, the composition is administered more than once.

Treatment using the methods and compositions of the invention can be continued as long as necessary.

In one embodiment, the efficacy of treatment in a myopic subject is evaluated every 3-6 months and the dose and/or frequency of drug administration is adjusted according to the degree of myopia suppression. If the subject does not show any further progression of myopia, treatment is discontinued, which means that treatment is temporarily discontinued and changes in refractive error are monitored over a period of 1-6 months according to a well-understood current It can be evaluated by measuring it in optometry and ophthalmology practice using technology.

In some embodiments, the subject is a child, ie, under the age of 18. In some embodiments, the subject is a young adult, ie under the age of 30. In some embodiments, the subject is between about 4 years old and about 30 years old. In some embodiments, the subject is between about 6 years old and about 20 years old. In some embodiments, the subject is between about 8 and about 15 years old. In some embodiments, the subject is between about 10 and about 12 years old.

In some embodiments, the subject has myopia. In some embodiments, the subject is at risk for myopia. In some embodiments, the subject is prone to myopia.

Risk factors for myopia may include, but are not limited to, having one or more parents with myopia.

Kits Also within the scope of this disclosure are kits for practicing the disclosed methods.

In some embodiments, kits can include instructions for use in any of the methods described herein. Included instructions can include instructions for administering an agent to a subject to achieve its intended activity in the subject. The kit can further include instructions for selecting a subject suitable for treatment based on identifying whether the subject is in need of treatment.

Instructions for use of the drugs described herein generally include information regarding dosages, dosing schedules, and routes of administration for the intended treatment. The containers may be unit doses, bulk packages (eg, multi-dose packages) or sub-unit doses. The instructions provided with the kits of the disclosure are typically those on the label or package insert. The label or package insert indicates that the pharmaceutical composition is used for treating, delaying onset of and/or ameliorating the disease or disorder in question.

The kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like.

Kits can optionally provide additional components such as buffers and interpretive information. The kit typically includes a container and a label or package insert on or associated with the container. In some embodiments, the disclosure provides an article of manufacture comprising the contents of the kits described above.

The following examples are included to demonstrate preferred embodiments of the invention. In light of this disclosure, those skilled in the art will appreciate that many changes can be made in the particular embodiments disclosed and the same or similar results can still be obtained without departing from the spirit and scope of the invention. should be understood by

Myopia can be induced in mammals using negative spectacle lenses Myopia was induced in 24-day-old C57BL/6J (B6) mice with −25 diopters placed in a plastic 3D-printed frame over the right eye. (D) Induced by mounting the lens. The contralateral eye served as a control. Mice were kept with lenses for 3 weeks. After 3 weeks, the lenses were removed and the refractive error of the lens-treated eye and the contralateral control eye were compared. Lens treatment produced myopia in lens-treated eyes (mean refractive error = -14.6 ± 0.3D) compared to control eyes (mean refractive error = +0.6 ± 0.6D) (Figure 1); The interocular difference in refractive error (−15.2±0.7D) was highly significant (P<0.0001). High-resolution MRI revealed enlargement of the eye and vitreous cavity in the treated eyes. The diameter of the lens-treated eyes was on average 65±8 μm larger (P<0.0001; FIG. 1C), and the vitreous chamber depth of the lens-treated eyes was 61±4 μm greater than that of the control fellow eye. longer (P<0.0001; FIG. 1D). No significant interocular differences in anterior chamber depth, corneal radius of curvature and lens thickness were observed (Fig. 1D), suggesting that changes induced in negative lens-treated mouse eyes were primarily ocular, similar to human myopia. suggests that it is confined to the rear of the Statistical power analysis revealed that a difference as small as 0.5 diopters in refractive error between eyes could be discriminated with 90% statistical power in a sample size of 22 mice.

Fingolimodonic acid suppresses myopia in subjects with lens-induced myopia Fingolimodonic acid was identified as one of the top 10 drug candidates using the pharmacogenomic pipeline for antimyopia drug development. rice field. Systemic oral administration of fingolimodolic acid was found to inhibit myopia by approximately 100% (Figure 2).

An experimental group of B6 mice were housed on a diet supplemented with 0.3 mg/kg fingolimodonic acid for 3 weeks with a −25D lens over the right eye, while B6 mice with a −25D lens over the right eye were maintained. A control group of mice was fed a normal, non-medicated diet. The interocular refractive error difference between lens-treated and control eyes in fingolimod-treated animals after 3 weeks of lens treatment was −0.02±1.58D versus −10.47±3.02D in the control group. and P=4.63×10 ⁻⁹ . Please refer to FIG.

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Claims (15)

A method of preventing or treating myopia in a subject in need thereof, comprising administering to said subject a composition comprising a therapeutically effective amount of fingolimodonic acid or a derivative thereof. or a method of preventing or treating myopia in a subject in need thereof. 2. The method of claim 1, wherein the subject is between about 4 years old and about 30 years old. 2. The method of claim 1, wherein the subject is between about 6 years old and about 20 years old. 2. The method of claim 1, comprising administering said composition to said subject once daily. 2. The method of claim 1, comprising administering said composition to said subject about once, twice or three times a week. 2. The method of claim 1, comprising administering said composition to said subject continuously or intermittently for about 5 years to about 10 years. 2. The method of claim 1, wherein the subject is monitored for suppression of myopia, and the therapeutically effective amount or frequency of administration is adjusted according to the degree of suppression. 2. The method of claim 1, wherein the composition is administered orally, eye drops, injection, patch or through contact lenses. 2. The method of claim 1, wherein said composition is in sustained release form. 9. The method of claim 8, wherein the contact lens is selected from the group consisting of plano contact lenses, monofocal contact lenses and multifocal contact lenses. 9. The method of claim 8, wherein the composition fills the inner surface of the lens or the entire volume of the contact lens. 2. The method of claim 1, wherein said composition is a sustained drug release formulation or composition. 13. The method of claim 12, wherein said sustained drug release formulation or composition is selected from the group consisting of nanosponges, patches, and gels. 2. The method of claim 1, wherein the composition further comprises an excipient or additional agent that reduces, prevents or treats myopia. 2. The fingolimodonic acid or derivative thereof according to claim 1, wherein said fingolimodolinic acid or derivative thereof is modified to improve its efficacy, ocular tissue penetration, stability and/or bioavailability and/or to reduce side effects. the method of.

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