Methods and compositions for treating glaucoma

Abstract

Provided herein are methods of identifying an individual having an increased likelihood of responding with an increased visual field functional outcome after treatment with a glaucoma therapy and methods of treating glaucoma in the eye of an individual having an increased likelihood of responding with an increased visual field functional outcome with a glaucoma therapy. For example, provided herein are methods of identifying an individual having an increased likelihood of responding with an increased visual field functional outcome after treatment with a glaucoma therapy, the method comprising: determining a historical visual field rate of loss for an eye of the individual having glaucoma; and identifying the historical visual field rate of loss as being between about -0.5 dB / year or less.

Description

METHODS AND COMPOSITIONS FOR TREATING GLAUCOMACROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 559, 129, filed February 28, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Vision is generally dependent on maintaining the anatomical and histological integrity of the structures within the eye. Changes in anatomical and histological homeostasis can provide the basis for a decrease and / or loss in vision. Glaucoma is a progressive eye condition characterized by damage to the optic nerve, often resulting in irreversible vision loss. Photoreceptor loss within the eye constitute abnormal changes in the structure of the eye (e.g., retina) that can contribute to a decrease and / or loss in vision.SUMMARY

[0003] In some embodiments, provided herein are methods of identifying an individual having an increased likelihood of responding with an increased visual field functional outcome after treatment with a glaucoma therapy, the methods comprising: (a) determining a historical visual field rate of loss for an eye of the individual having glaucoma; and (b) identifying the historical visual field rate of loss as being between about -3 and about -1 dB / year. In certain embodiments, the method further comprises: (c) administering the glaucoma therapy to the individual having the historical visual field rate of loss as being between about -3 and about -1 dB / year. In certain embodiments, the glaucoma therapy comprises a Fas inhibitor. In certain embodiments, the Fas inhibitor is a peptide comprising an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

[0004] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual, the methods comprising: (a) identifying the individual as having a historical visual field rate of loss as being about -0.5 dB / year or less (e.g., about -1 dB / year or less or between about -3 and about -1 dB / year); and (b) administering a peptide to the eye, wherein the peptide comprises an amino acid sequenceHHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

[0005] In certain embodiments, provided herein is a method of identifying an individual having an increased likelihood of responding with an increased visual field functional outcome after treatment with a glaucoma therapy comprising determining a historical visual field rate of loss for an eye of the individual having glaucoma, and identifying the historical visual field rate of loss as being between about -1 dB / year or less.

[0006] In some embodiments, the individual is identified as having a moderate baseline loss of sensitivity in at least one point of a visual field of the eye. In some embodiment, the moderate baseline loss of sensitivity in at least one point in the visual field is about -20 to about -5 dB.

[0007] In some embodiments, the method further comprises administering the glaucoma therapy to the individual having the historical visual field rate of loss as being between about -1 dB / year or less. In some embodiments, the historical visual field rate of loss is about -3 to about -1 dB / year. In some embodiments, the glaucoma therapy comprises a Fas inhibitor. In some embodiments, the Fas inhibitor is a peptide comprising an amino acid sequence HHIYLGAVNYIY or variant sequence thereof.

[0008] In certain embodiments, provided herein is a method of identifying an individual having an increased likelihood of responding with an increased visual field functional outcome after treatment with a glaucoma therapy, the method comprising: determining a baseline loss of sensitivity in at least one point in a visual field in an eye of the individual having glaucoma; and identifying the baseline loss of sensitivity in at least one point in the visual field as being a moderate baseline loss of sensitivity in at least one point in the visual field of about -3 dB or less. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -20 to about -5 dB.

[0009] In some embodiments, the individual is identified as having a historical visual field rate of loss of -1 dB / year or less. In some embodiments, the individual is identified as having a historical visual field rate of loss of about -3 to about -1 dB / year.

[0010] In some embodiments, the method further comprises administering the glaucoma therapy to the individual having the moderate baseline of sensitivity of about -3 dB or less. In some embodiments, the glaucoma therapy comprises a Fasinhibitor. In some embodiments, the Fas inhibitor is a peptide comprising an amino acid sequence HHIYLGAVNYIY or variant sequence thereof.

[0011] In certain embodiments, provided herein is a method of treating glaucoma in an eye of an individual comprising identifying the individual as having a historical visual field rate of loss as being between -3 and about -1 dB / year, and administering a peptide to the eye or a pharmaceutically acceptable salt of the peptide.

[0012] In some embodiments, identifying the individual as having a historical visual field rate of loss as being between about -3 and about -1 dB / year comprises selecting the individual having the historical visual field rate of loss as being between about -3 and about -1 dB / year for treatment with the peptide.

[0013] In some embodiments, the individual is identified as having a moderate baseline loss of sensitivity in at least one point in a visual field of the eye of the individual. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is -3 dB or less. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -20 to about -5 dB.

[0014] In certain embodiments, provided herein is a method of treating glaucoma in an eye of an individual comprising identifying the individual as having a moderate baseline loss of sensitivity in at least one point in a visual field of the eye of the individual of about -20 to about -5 dB; and administering a peptide to the eye or a pharmaceutically acceptable salt of the peptide.

[0015] In some embodiments, identifying the individual as having a moderate baseline loss of sensitivity in at least one point in the visual field of about -20 to about -5 dB comprises selecting the individual having the moderate baseline loss of sensitivity in at least one point in the visual field of about -20 to about -5 dB.

[0016] In some embodiments, the individual is identified as having a historical visual field rate of loss of -1 dB / year or less. In some embodiments, the individual is individual is identified as having a historical visual field rate of loss of about -3 to about -1 dB / year.

[0017] In some embodiments, the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof. In some embodiments, the variant sequence of the peptide comprises an amino acid substitution. In some embodiments, the variant sequence comprises one amino acid substitution.

[0018] In some embodiments, the peptide further comprises a modification. In some embodiments, the modification comprises a modified amino acid. In some embodiments, the peptide comprises an amidated C-terminus.

[0019] In some embodiments, the peptide has the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the peptide has the structure of Formula III or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the method comprises administering the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is an acetate salt. In some embodiments, the pharmaceutically acceptable salt is a polyacetate salt. In some embodiments, the pharmaceutically acceptable salt is a triacetate salt. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0021] In some embodiments, the method comprises administering a first dose and a second dose of the peptide or the pharmaceutically acceptable salt of the peptide. In some embodiments, the second dose is administered about 10 weeks or greater after administering the first dose. In some embodiments, the second dose is administered about 12 weeks after the first dose.

[0022] In some embodiments, the method comprises administering a composition comprising the peptide.

[0023] In some embodiments, the composition (e.g., each composition or the composition of the first and / or second dose) further comprises a surfactant. In some embodiments, the surfactant is a polysorbate, a polyethoxylated castor oil derivative, a polyethoxylated fatty acid, a polyethoxylated alcohol, a polyoxyethylenepolyoxypropylene block copolymer, or an oxyethylated tertiary octylphenol formaldehyde polymer. In some embodiments, the surfactant forms about 0.01 % to about 20% weight / weight of the composition. In some embodiments, the surfactant forms about 0.05% to about 10% weight / weight of the composition.

[0024] In some embodiments, the composition (e.g., each composition or the composition of the first and / or second dose) further comprises a tonicity adjusting agent, a buffering agent, or a combination thereof. In some embodiments, the composition is buffered at a pH of 2.5 to 7.5.

[0025] In some embodiments, the composition (e.g., each composition or the composition of the first and / or second dose) comprises about 25 micrograms (pg or ug) to about 250 pg of the peptide.

[0026] In some embodiments, the peptide or the pharmaceutically acceptable salt thereof has a half-life in the vitreous humor of more than about 30 days (e.g., at least 30 days). In some embodiments, the method comprises using the vitreous humor as a depot to provide the peptide or the pharmaceutically acceptable salt thereof to retinal tissue in the eye. In some embodiments, the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor more than about 30 days after administration.

[0027] In some embodiments, the glaucoma comprises elevated intraocular pressure.

[0028] In some embodiments, the visual field is a Humphrey’s visual field. In some embodiments, visual field is measured by a Humphrey visual field analyzer. In some embodiments, the visual field is measured using a clustering analysis to generate measures of local (e.g., specific region within the eye) visual field measurements.

[0029] In some embodiments, treating comprises increasing a visual field functional outcome of the eye of the individual. In some embodiments, the visual field functional outcome comprises a sub-global measure of local (e.g., specific region within the eye) visual field measurements. In some embodiments, measuring the visual field functional outcomes comprises generating local visual field measurements within the eye.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0031] FIG. 1 provides data showing a low association between a subject’s historical rate of Humphrey Visual Field (HVF) loss per year and the subject’s baseline sensitivity to the intensity of a visual light stimulus;

[0032] FIG. 2A provides data showing subjects’ historical rates of HVF loss per year against the subjects’ annual change in HVF, demonstrating that subjects having the most improvement in annual change in HVF had a historical rate of HVF loss between -3 and -1 dB / yr, and that patients that received 50 ug and patients that received 100 ug doses of a Fas inhibitor, ONL1204, both improved;

[0033] FIG. 2B provides data from subjects whose historical rates of HVF were between -3 and -1 dB / yr showing the subjects’ historical rates of HVF loss per year against the subjects’ annual change in HVF;

[0034] FIG. 3A provides an example grey-scale graph of the retinal sensitivity of a subject with black indicating low retinal sensitivity and white indicating high sensitivity, FIG. 3B provides a schematic of retinal zones within which retinal sensitivity readings are averaged over retinal points to provide a cluster measurement, and FIG. 3C provides the annual change and baseline sensitivity of point values for the retinal clusters shown in FIG. 3A;

[0035] FIG. 4A shows the historical rate of HVF loss per year against the rate of HVF change per year after treatment in visual field clusters, and FIG. 4B shows the historical rate of HVF loss per year against the baseline sensitivity in visual field clusters, together these data show that treatment with a Fas inhibitor, ONL1204, can improve the HVF rate of change across points in all visual field clusters;

[0036] FIG. 5A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment at points in the visual field for subjects that received 100ug of a Fas inhibitor, ONL1204, and had a historical rate of HVF loss between -3 and -1 dB / year, and FIG. 5B shows that there is a low association between the same variables for subjects that received 100ug of a Fas inhibitor, ONL1204, inhibitor and had a historical rate of HVF loss outside of the range of -3 and -1 dB / year;

[0037] FIG. 6A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment at points in the visual field for subjects that received 50ug of a Fas inhibitor, ONL1204, and had a historical rate of HVF loss between -3 and -1 dB / year, and FIG. 6B shows that there is a low association between the same variables for subjects that received 50ug of a Fas inhibitor, ONL1204, inhibitor and had a historical rate of HVF loss outside of the range of -3 and -1 dB / year;

[0038] FIG. 7A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment at points in the visual field for subjects that received sham treatment and had a historical rate of HVF loss between -3 and -1 dB / year, and FIG. 7B provides the association of the same variables for subjects that received sham treatment and had a historical rate of HVF loss outsideof the range of -3 and -1 dB / year, both sham groups having low association between baseline sensitivity and rate of HVF change;

[0039] FIG. 8A shows the association of subjects’ baseline sensitivity and the rate of HVF change per year after treatment in visual field clusters for subjects that had a historical rate of HVF loss between -3 and -1 dB / yr and, in comparison, FIG. 8B shows the low association of subjects’ baseline sensitivity and the rate of HVF change per year after treatment in visual field clusters for subjects that had a historical rate of HVF loss outside the range of -3 and -1 dB / yr;

[0040] FIG. 9A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment in visual field clusters for subjects that received 100ug of a Fas inhibitor, ONL1204, and had a historical rate of HVF loss between -3 and -1 dB / year, and FIG. 9B shows that there is a low association between the same variables for subjects that received 100ug of a Fas inhibitor, ONL1204, inhibitor and had a historical rate of HVF loss outside of the range of -3 and -1 dB / year; and

[0041] FIG. 10A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment in visual field clusters for subjects that received 50ug of a Fas inhibitor, ONL1204, and had a historical rate of HVF loss between -3 and -1 dB / year, and FIG. 10B shows that there is a low association between the same variables for subjects that received 50ug of a Fas inhibitor, ONL1204, inhibitor and had a historical rate of HVF loss outside of the range of -3 and -1 dB / year.

[0042] FIG. 11 illustrates an exemplary treatment plan for testing the safety and efficacy of the Fas inhibitor, ONL1204.

[0043] FIG. 12A and FIG. 12B illustrate the increased mean change from baseline (CFB) of thickness in the retinal nerve fiber layer (RNFL) for eyes treated with ONL1204 as compared to a control sham injection and in the fellow, untreated eye of subjects in all treatment groups.

[0044] FIG. 13A and FIG. 13B illustrates the increased mean CFB of thickness in the ganglion cell complex in the superior outer quadrant over time in eyes treated with ONL1204 as compared to the control sham injection and in the fellow, untreated eye of subject in all treatment groups.

[0045] FIG. 14A, FIG. 14B, FIG. 14C, FIG. 14D, and FIG. 14E illustrate the average rate change in HVF across all points or the average point total deviation(TD) over time for all patients or patients having specific moderate baseline loss of sensitivity in at least one point in the visual field and / or historical HVF rate of loss for subjects treated with ONL1204 or with a control sham injection.DETAILED DESCRIPTION

[0046] Described and exemplified herein is the identification of patients respond to glaucoma treatment by having improved visual function (e.g., an improvement in visual field). Accordingly, in certain embodiments, provided are methods for selecting and / or identifying patients that have an increased likelihood of responding to glaucoma treatment by exhibiting an increase in visual function (e.g., as opposed to ceasing and / or reducing a loss in visual function). In such embodiments, the treatment includes Fas inhibitors, such a Fas inhibitor having a structure represented by Formula I described herein.

[0047] Provided herein are Fas inhibitors useful for modulating (e.g., inhibiting, preventing, and / or reducing, etc.) Fas-mediated signaling. In certain instances, the Fas inhibitors useful in treating, inhibiting, preventing, and / or reducing Fas-mediated inflammation. In certain instances, inhibiting, preventing, and / or reducing Fas- mediated inflammation allows for the treatment and / or prevention of RNFL thinning.

[0048] In some embodiments, the Fas inhibitors described herein encompass Met- derived peptides and / or fragments thereof. In some embodiments, the Met protein, also called c-Met or hepatocyte growth factor receptor (HGF receptor), is encoded by the Met gene (NCBI Gene ID 4233, Location: NC_000007.14 (116672196..116798386), UniProtKB - P0858). The Met protein is comprised of two major subunits: the a and [3 subunits, and Met and fragments of Met, including the extracellular domain of Met and its a subunit, have been shown to bind to Fas and prevent cells from undergoing apoptosis. In some embodiments, the Fas inhibitor comprises a Fas-inhibiting peptide.

[0049] Functionality of Fas-inhibitor and / or Fas-inhibiting peptides can be determined by an in vitro assay. For example, in some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide competes for binding to a Fas receptor (FasR) with Fas ligand (FasL). In some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide inhibits, reduces, or prevents caspase 8 activation in cells treated with FasL (e.g., as measured by commercially available luminescent tetrapeptide cleavage assay kit(Promega, Madison, Wl)). In some embodiments, the Fas inhibitor and / or Fas- inhibiting peptide inhibits, reduces, or prevents cell death of cells treated with FasL. By way of further example, in some embodiments, the Fas inhibitor and / or Fas- inhibiting peptide competes for binding to a Fas receptor (FasR) with a Fas-activating antibody (e.g., Fas-agonistic Jo2 monoclonal antibody (BD Biosciences, San Jose, CA)). In some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide inhibits, reduces, or prevents caspase 8 activation in cells treated with a Fas-activating antibody (e.g., as measured by commercially available luminescent tetrapeptide cleavage assay kit (Promega, Madison, Wl)). In some embodiments, the Fas inhibitor and / or Fas-inhibiting peptide inhibits, reduces, or prevents cell death of cells treated with a Fas-activating antibody. In some embodiments, the Fas inhibitor is a peptide, a polypeptide (e.g., FasR or FasL) , an antibody that binds FasR, a inhibitory oligonucleotide (e.g., siRNA, RNAi, antisense oligos), or antibody that binds FasL.

[0050] In some embodiments, the Fas inhibitors described herein comprises a Met-derived compound comprising the amino acid acids HHIYLGAVNYIY (His-His- lle-Tyr-Leu-Gly-Ala-Val-Asn-Tyr-lle-Tyr) (e.g., SEQ ID NOs: 1 -8). In some embodiments, the peptide comprises the amino acid sequence HHIYLGAVNYIY or a variant sequence thereof.

[0051] As used herein, a peptide includes and / or refers to any of various natural or synthetic compounds containing two or more amino acids joined by a peptide bond that link the carboxyl group of one amino acid to the amino group of another. As also used herein, amino acid refers to and / or includes naturally occurring amino acids, unnatural amino acids, amino acid analogues and amino acid mimetics that function in a manner similar to a naturally occurring amino acids. Amino acids are generally referred to herein by either their name, the commonly known three letter symbols, or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0052] In some embodiments, the Fas inhibitor peptides (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) comprises one or more naturally occurring amino acids. In some embodiments, the Fas inhibitor peptides (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) consists of naturally occurring amino acids. As used herein, naturally occurring amino acids include and / or refer to amino acids which are generally found in nature and are not manipulated by man. In some embodiments, naturally occurring includes and / orfurther refers to the 20 conventional amino acids: alanine (A or Ala), cysteine (C or Cys), aspartic acid (D or Asp), glutamic acid (E or Glu), phenylalanine (F or Phe), glycine (G or Gly), histidine (H or His), isoleucine (I or lie), lysine (K or Lys), leucine (L or Leu), methionine (M or Met), asparagine (N or Asn), proline (P or Pro), glutamine (Q or Gin), arginine (R or Arg), serine (S or Ser), threonine (T or Thr), valine (V or Vai), tryptophan (W or Trp), and tyrosine (Y or Tyr).

[0053] In some embodiments, the Fas inhibitor comprises a variant sequence of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY). In some embodiments, amino acid substitutions can be made in the sequence of any of the polypeptides described herein, without necessarily decreasing or ablating its activity. Accordingly, in some embodiments, the variant sequence comprises one or more amino acid substitutions. In some embodiments, the variant sequence comprises one amino acid substitution. In some embodiments, the variant sequence comprises two amino acid substitutions. In some embodiments, the variant sequence comprises three amino acid substitutions. In some embodiments, substitutions include conservative substitutions (e.g., substitutions with amino acids of comparable chemical characteristics). In some embodiments, a non-polar amino acid can be substituted and replaced with another non-polar amino acid, wherein non-polar amino acids include alanine, leucine, isoleucine, valine, glycine, proline, phenylalanine, tryptophan, and methionine. In some embodiments, a neutrally charged polar amino acids can be substituted and replaced with another neutrally charged polar amino acid, wherein neutrally charged polar amino acids include serine, threonine, cysteine, tyrosine, asparagine, and glutamine. In some embodiments, a positively charged amino acid can be substituted and replaced with another positively charged amino acid, wherein positively charged amino acids include arginine, lysine, and histidine. In some embodiments, a negatively charged amino acid can be substituted and replaced with another negatively charged amino acid, wherein negatively charged amino acids include aspartic acid and glutamic acid. Examples of amino acid substitutions also include substituting an L-amino acid for its corresponding D-amino acid, substituting cysteine for homocysteine or other non-natural amino acids.

[0054] In some embodiments, the Fas inhibitor peptides (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) comprises one or more nonnatural amino acids. In some embodiments, the Fas inhibitor peptides (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) consists of non-natural aminoacids. As used herein, non-natural amino acids and / or unnatural amino acids include and / or refer to amino acid structures that cannot be generated biosynthetically in any organism using unmodified or modified genes from any organism. In some embodiments, non-natural amino acids and / or unnatural amino acids further include and / or refer to an amino acid residue that are not present in the naturally occurring (wild-type) Met protein sequence. For example, these include, but are not limited to, modified amino acids and / or amino acid analogues that are not one of the 20 naturally occurring amino acids (e.g., non-natural side chain variant sequence amino acids), D-amino acids, homo amino acids, beta-homo amino acids, N-methyl amino acids, alpha-methyl amino acids, or. By way of further example, non-natural amino acids also include 4-Benzoylphenylalanine (Bpa), Aminobenzoic Acid (Abz), Aminobutyric Acid (Abu), Aminohexanoic Acid (Ahx), Aminoisobutyric Acid (Aib), Citrulline (Cit), Diaminobutyric Acid (Dab), Diaminopropanoic Acid (Dap), Diaminopropionic Acid (Dap), Gamma-Carboxyglutamic Acid (Gia), Homoalanine (Hala), Homoarginine (Harg), Homoasparagine (Hasn), Homoaspartic Acid (Hasp), Homocysteine (Heys), Homoglutamic Acid (Hglu), Homoglutamine (Hgln), Homoisoleucine (Hile), Homoleucine (Hleu), Homomethionine (Hmet), Homophenylalanine (Hphe), Homoserine (Hser), Homotyrosine (Htyr), Homovaline (Hval), Hydroxyproline (Hyp), Isonipecotic Acid (Inp), N aphthylalanine (Nal), Nipecotic Acid (Nip), Norleucine (Nle), Norvaline (Nva), Octahydroindole-2-carboxylic Acid (Oic), Penicillamine (Pen), Phenylglycine (Phg), Pyroglutamic Acid (Pyr), Sarcosine (Sar), tButylglycine (Tie), and Tetrahydro-isoquinoline-3-carboxylic Acid (Tic). Such non-natural amino acid residues can be introduced by substitution of naturally occurring amino acids, and / or by insertion of non-natural amino acids into the naturally occurring (wild-type) Met protein sequence. A non-natural amino acid residue also can be incorporated such that a desired functionality is imparted to the apelin molecule, for example, the ability to link a functional moiety (e.g., PEG).

[0055] In some embodiments, a variant sequence comprises one or more amino acid deletions. In some embodiments, the variant sequence comprises one amino acid deletion. In some embodiments, the variant sequence comprises two amino acid deletions. In some embodiments, the variant sequence comprises three amino acid deletions. In some embodiments, the variant sequence comprises four amino acid deletions. In some embodiments, the variant sequence comprises one or more additional amino acids. In some embodiments, the additional amino acids areadditional amino acids from the Met sequence. In some embodiments, the variant sequence comprises a substitution and a deletion. In some embodiments, the variant sequence comprises a substitution and one or more additional amino acids. In some embodiments, the substitution comprises a natural amino acid or a non-natural amino acid. In some embodiments, the variant sequence is a retro inverse amino acid sequence. In some embodiments, a variant sequence comprises one or more additional amino acid residues (e.g., one, two, or three additions) to the N or C terminus. In some embodiments, a variant sequence comprises one or more deletions (e.g., one, two, or three deletions) to amino acid residues at the N or C terminus.

[0056] Functionality of variant sequences of the peptide (e.g., a variant sequence of the amino acid sequence HHIYLGAVNYIY) can be determined by an in vitro assay. For example, in some embodiments, the variant sequence competes for binding to a Fas receptor (FasR) with Fas ligand (FasL). In some embodiments, the variant sequence inhibits, reduces, or prevents caspase 8 activation in cells treated with FasL (e.g., as measured by commercially available luminescent tetrapeptide cleavage assay kit (Promega, Madison, Wl)). In some embodiments, the variant sequence inhibits, reduces, or prevents cell death of cells treated with FasL. By way of further example, in some embodiments, the variant sequence competes for binding to a Fas receptor (FasR) with a Fas-activating antibody (e.g., Fas-agonistic Jo2 monoclonal antibody (BD Biosciences, San Jose, CA)). In some embodiments, the variant sequence inhibits, reduces, or prevents caspase 8 activation in cells treated with a Fas-activating antibody (e.g., as measured by commercially available luminescent tetrapeptide cleavage assay kit (Promega, Madison, Wl)). In some embodiments, the variant sequence inhibits, reduces, or prevents cell death of cells treated with a Fas-activating antibody. Accordingly, in some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY), wherein the variant sequence competes for binding to a Fas receptor (FasR) with Fas ligand (FasL). In some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY), wherein the variant sequence inhibits, reduces, or prevents caspase 8 activation in cells treated with FasL. In some embodiments, the Fasinhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY), wherein the variant sequence inhibits, reduces, or prevents cell death of cells treated with FasL. In some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY), wherein the variant sequence competes for binding to a Fas receptor (FasR) with a Fas-activating antibody. In some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide comprising the amino acid sequence HHIYLGAVNYIY, wherein the variant sequence inhibits, reduces, or prevents caspase 8 activation in cells treated with a Fas- activating antibody. In some embodiments, the Fas inhibitor comprises a variant sequence (e.g., any one of the variant sequences described herein) of the peptide comprising the amino acid sequence HHIYLGAVNYIY, wherein the variant sequence inhibits, reduces, or prevents cell death of cells treated with a Fas-activating antibody.

[0057] The peptide or a variant sequence thereof can further comprise one or more modifications. In some embodiments, the peptide (e.g., a comprising the amino acid sequence HHIYLGAVNYIY or a variant sequence thereof) comprises a modification. In some embodiments, the peptide is a modified peptide. As used herein, a modification or a modified peptide includes and / or refers to a modification of one or more amino acids in the peptide. In some embodiments, modifications species of stereoisomers. All stereoisomers of the above compounds are contemplated, either in admixture or in pure or substantially pure form. The compounds can have asymmetric centers at any of the atoms. Consequently, the peptide compounds or components thereof can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The present invention contemplates the use of any racemates ( i.e. , mixtures containing equal amounts of each enantiomer), enantiomerically enriched mixtures (i.e., mixtures enriched for one enantiomer), pure enantiomers or diastereomers, or any mixtures thereof. The chiral centers can be designated as R or S or R, S or d, D, 1 , L or d, 1 , D, or L. Compounds comprising amino acid residues include residues of D-amino acids, L-amino acids, or racemic derivatives of amino acids. Compounds comprising sugar residues include residues of D-sugars, L-sugars, or racemic derivatives of sugars. Non-limiting examples of modifications are phosphorylation,glycosylation, ubiquitination, nitrosylation, methylation, acetylation, amidation, or lipidation. Modification can be introduced at the C-terminus of the peptide, the N- terminus of the peptide, or at any place in-between. Thus, a modification or a modified peptide includes and / or refers to modifications of the free amino- and / or carboxyl- terminal (N-terminus and C-terminus, respectively). In some embodiments, N- terminal modifications include but are not limited to acetylation, formylation, pyroglutamylation, carbamide addition, lipidation, sulfonamidation, and alkylamination. In some embodiments, C-terminal modifications include but are not limited to amidation, esterification, and incorporation of an aldehyde group. In some embodiments, the modification comprises amidation. In some embodiments, the amidation is at the c-terminus. In some embodiments, the modification comprises a retro inverse peptide (e.g., YIYNVAGLYIHH). In some embodiments, the modification altering the chirality of one or more amino acid residues of the peptide (e.g., L amino acid to D amino acid).

[0058] Accordingly, in an embodiment, provided herein are peptides comprising the sequence (a)-HHIYLGAVNYIY-(b) (SEQ ID NO: 1 ) or (a)-YIYNVAGLYIHH-(b) (SEQ ID NO: 2), or a variant sequence thereof, wherein:(a) is -H, -OH, -NH2, G1(CH2)n-, R1CONH-, or R2O-;(b) is -H, -CH2OH, -CH2OR2, -CHO, -CO2R2, -CONH2, -CONHR2, - CON(R3)2, -CONH(CH2)yNR(3)2, -(CH2)n-G1, -COCH2-G1, -CONHCH2-G1, - (CH2)nNH2, -(CH2)nNHR2, -(CH2)nN(R3)2, NH-Glu-His-OH, NH-Glu-His-NH2, -Ala-His-NH2, -Gly-His-NH2, -NH-Glu-His-OH, -NH-Glu-His-NH2, -Ala-His- NH2, -Gly-His-NH2, -NH-[D]Glu-[D]-His-OH, -NH-[D]Glu-[D]-His-NH2, - [D]Ala-[D]-His-NH2, -Gly[D]-His-NH2, or -CONH(CH2)n-G2; G1, at each occurrence, is independently -H, -C(=O)NH2, -C(=O)NHR2, -C(=O)N(R3)2, C(=O)OR2, or -C(=O)R1; G2at each occurrence is a heterocyclic ring of 4-7 members comprising at least one tertiary amine functionality NR2within the ring, or a carbocyclic ring of 3-7 members substituted with -N(R3)2;R1, at each occurrence, is independently H, Ci-ealkyl, - (CH2)x(OCH2CH2)mOR5, C1-6 -alkoxy or L;R2, at each occurrence, is independently C 1 -ealkyl, C2-ealkyl substituted with OR5or NR52, -(CH2)x(OCH2CH2)mOR5or L;L, at each occurrence, is a multivalent polyethylene glycol derivative with 2-4 termini, each of which can be independently capped with H, R5;R3, at each occurrence, is independently C 1 -ealkyl, C2-ealkyl substituted with OR5or N(R5)2, -(CH2)x(OCH2CH2)mOR5; or two R3s, taken together with the N atom to which they are attached, can form a monocyclic ring of 4-8 members or a fused, bridged or spiro bicyclic ring of 6-10 members, which can include up to two groups within the ring chosen independently from -O-, -(C=O)-, NR6, S, SO, or SO2;R4, at each occurrence, is independently Ci-ealkyl, Ci-eacyl, or -OPO3(R5)2; R5, at each occurrence, is independently H or Ci -ealkyl;R6, at each occurrence, is H, Ci-ealkyl, C2-6hydroxyalkyl, Ci-ealkoxy-, Ci- ealkyl, or Ci-eacyl; m = 1 -100; n = 0-3; x = 0-6; and y = 2-4, wherein at most one of R1and R2is L.

[0059] In certain instances, provided herein are peptides comprising the structure of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.Formula II wherein:A is H-, -OH, -NH2, G1(CH2)n-, R1CONH-, or R2O-;B is -H, CH2OH, CH2OR2, -CHO, -CO2R2, -CONH2, -CONHR2, -CON(R3)2, - CONH(CH2)yN(R3)2, -(CH2)n-G1, -COCH2-G1, -CONHCH2-G1, -(CH2)nNH2, - (CH2)nNHR2, -(CH2)nN(R3)2 NH-Glu-His-OH, NH-Glu-His-NH2, -Ala-His- NH2, -Gly-His-NH2, NH-Glu-His-OH, NH-Glu-His-NH2, -Ala-His-NH2, -Gly- His-NH2, NH-[D]Glu-[D]-His-OH, NH-[D]Glu-[D]-His-NH2, -[D]Ala-[D]-His- NH2, -Gly[D]-His-NH2, or CONH(CH2)n-G2;E, at each occurrence, is independently -H, -OH, -OR4, SH, -SR4, or halogen;G1, at each occurrence, is independently -H, -C(=O)NH2, -C(=O)NHR2, - C(=O)N(R3)2, C(=O)OR2, or -C(=O)R1;G2at each occurrence is a heteroalicyclic ring of 4-7 members comprising at least one tertiary amine functionality NR2within the ring, or a carbocyclic ring of 3-7 members substituted with N(R3)2;Q, at each occurrence, is independently, 1 -propyl, 2-propyl, 2-methyl-prop- 2-yl, C3-6-cycloalkyl, C4-6-cycloalkenyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothienyl-2-yl, tetrahydrothienyl-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran- 4- yltetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4- yl or 1 -CH(OR5)CH3;R1, at each occurrence, is independently H, Ci-ealkyl, - (CH2)x(OCH2CH2)mOR5, Ci-6alkoxy or L;R2, at each occurrence, is independently Ci -ealkyl, C2-6alkyl substituted with OR5or N(R5)2, -(CH2)x(OCH2CH2)mOR5or L;L, at each occurrence, is a multivalent polyethylene glycol derivative with 2-4 termini, each of which can be independently capped with H, R5or another molecule of the peptide of Formula I or II;R3, at each occurrence, is independently Ci -6-alkyl, C2-6-alkyl substituted with OR5or N(R5)2, -(CH2)x(OCH2CH2)mOR5; or two R3s, taken together with the N atom to which they are attached, can form a monocyclic ring of 4-8 members or a fused, bridged or spiro bicyclic ring of 6-10 members, which can include up to two groups within the ring chosen independently from -O-, -(C=O)-, NR6, S, SO, or SO2;R4, at each occurrence, is independently Ci-ealkyl, Ci-eacyl, or -OPO3(R5)2; R5, at each occurrence, is independently H or Ci-ealkyl;R6, at each occurrence, is H, Ci-ealkyl, C2-ehydroxyalkyl, Ci-ealkoxy-, Ci- ealkyl, or Ci-eacyl; m = 1 -100; n = 0-3; x = 0-6; and y = 2-4, wherein at most one of R1and R2is L.

[0060] In some embodiments, provided is a peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof:Formula III

[0061] In some embodiments, provided is a peptide having the structure ofFormula IV or a pharmaceutically acceptable salt thereof:Formula IV

[0062] In some embodiments, provided is a peptide having the structure ofFormula V or a pharmaceutically acceptable salt thereof:Formula V

[0063] In some embodiments, provided is a peptide having the structure ofFormula VI or a pharmaceutically acceptable salt thereof:Formula VI

[0064] In some embodiments, provided is a peptide having the structure of Formula VII or a pharmaceutically acceptable salt thereof:Formula VII

[0065] In some embodiments, provided is a peptide having the structure ofFormula VIII or a pharmaceutically acceptable salt thereof:Formula VIII

[0066] In some embodiments, provided is a peptide having the structure ofFormula IX or a pharmaceutically acceptable salt thereof:Formula IX

[0067] Further provided herein are salts of the peptide for inhibiting Fas-mediated inflammation in the eye and for use in the methods described here. As used herein, salt is generally synonymous with pharmaceutically acceptable salts, and / or includes or refers to pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are salts with organic or inorganic acids such as (but not limited to) include acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, citric acid, fumaric acid, hydrochloric acid, hydrobromic acid, lactic acid, maleic acid, malonic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, nicotinic acid, phosphoric acid, succinic acid, sulfuric acid, or tartaric acid, prepared using methods well known in the art. In some embodiments, the salt is a hydrochloride salt.

[0068] In addition, these salts can be prepared form addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N -ethylpiperidine, piperidine, and polyamine resins.

[0069] Salts and pharmaceutically acceptable salts are described in in J. Pharmaceutical Sciences, 66: 1 -19 (1977), the contents of which are incorporated by reference herein.

[0070] In some embodiments, the salt is an acetate salt. In some embodiments, the acetate salt is a poly-acetate salt. In some embodiments, the poly-acetate salt is a tri-acetate salt.

[0071] In an embodiment, further provided are pharmaceutical compositions (also referred to as compositions) comprising the Fas inhibiting peptides. In some embodiments, the pharmaceutical compositions described herein comprise the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein comprise the peptide comprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, the pharmaceutical compositions described herein comprise the peptide having the structure of any one of Formulas l-IX or a pharmaceutically acceptable salt thereof. In someembodiments, the pharmaceutical compositions described herein comprise the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein comprise the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof.

[0072] The pharmaceutical composition can comprise one or more excipients. As used herein, an excipient includes and / or refers to any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and / or administration to a patient. A pharmaceutical composition can comprise a single pharmaceutical formulation (e.g., extended release, immediate release, delayed release, nanoparticulate, etc.) or multiple formulations (e.g., immediate release and delayed release, nanoparticulate and nonnanoparticulate, etc.). An excipient further includes and / or refers to an agent that can be added to a formulation to provide a desired consistency (e.g., altering the bulk properties), to improve stability, and / or to adjust osmolality. Examples of commonly used excipients include, but are not limited to, sugars, polyols, amino acids, surfactants, and polymers. In some embodiments, a non-ionic excipient or a non-ionizable excipient, as used herein, includes and / or refers to an agent having no net charge.

[0073] In some embodiments, the non-ionic excipient has no net charge under certain formulation conditions, such as pH. Examples of non-ionic excipients include, but are not limited to, sugars (e.g., sucrose), sugar alcohols (e.g., mannitol), and non- ionic surfactants (e.g., polysorbate 80).

[0074] In some embodiments, the compositions comprise excipients that are suitable for ocular application. Suitable excipients and include, but are not limited to, tonicity agents, preservatives, chelating agents, buffering agents, surfactants, cosolvents and antioxidants. Suitable tonicity-adjusting agents include mannitol, sodium chloride, glycerin, sorbitol, and the like. Suitable preservatives include p- hydroxybenzoic acid ester, benzalkonium chloride, benzododecinium bromide, polyquaternium- 1 , and the like. Suitable chelating agents include sodium edetate and the like. Suitable buffering agents include phosphates, borates, citrates, acetates, tromethamine, and the like. Suitable surfactants include ionic and nonionic surfactants. In some embodiments, the one or more excipients comprises nonionic surfactants, such as polysorbates, polyethoxylated castor oil derivatives,polyethoxylated fatty acids, polyethoxylated alcohols, polyoxyethylenepolyoxypropylene block copolymers (Poloxamer), and oxyethylated tertiary octylphenol formaldehyde polymer (Tyloxapol). Other suitable surfactants can also be included. Suitable antioxidants include sulfites, thiosulfate, ascorbates, BHA, BHT, tocopherols, and the like.

[0075] In some embodiments, the composition comprises a non-ionic surfactant. In some embodiments, the composition comprises a polysorbate, a polyethoxylated castor oil derivative, a polyethoxylated fatty acid, a polyethoxylated alcohol, a polyoxyethylene-polyoxypropylene block copolymer (Poloxamer), or an oxyethylated tertiary octylphenol formaldehyde polymer (Tyloxapol). In some embodiments, the composition comprises a polysorbate. In some embodiments, the composition comprises a polyethoxylated castor oil derivative. In some embodiments, the composition comprises a polyethoxylated fatty acid. In some embodiments, the composition comprises a polyethoxylated alcohol. In some embodiments, the composition comprises a polyoxyethylene-polyoxypropylene block copolymer (Poloxamer). In some embodiments, the composition comprises an oxyethylated tertiary octylphenol formaldehyde polymer (Tyloxapol).

[0076] In some embodiments, the surfactant makes up 0.01 % - 20% weight per weight (w / w) of the composition. In some embodiments, the non-ionic surfactant is about 0.01 % w / w of the composition to about 20% w / w of the composition. In some embodiments, the non-ionic surfactant is at least about 0.01 % w / w of the composition. In some embodiments, the non-ionic surfactant is at most about 20% w / w of the composition. In some embodiments, the non-ionic surfactant is about 0.05% w / w of the composition to about 0.1 % w / w of the composition, about 0.05% w / w of the composition to about 0.1 % w / w of the composition, about 0.05% w / w of the composition to about 0.5% w / w of the composition, about 0.05% w / w of the composition to about 1 % w / w of the composition, about 0.05% w / w of the composition to about 2% w / w of the composition, about 0.05% w / w of the composition to about 5% w / w of the composition, about 0.05% w / w of the composition to about 10% w / w of the composition, about 0.05% w / w of the composition to about 20% w / w of the composition, about 0.1 % w / w of the composition to about 0.5% w / w of the composition, about 0.1 % w / w of the composition to about 1 % w / w of the composition, about 0.1 % w / w of the composition to about 2% w / w of the composition, about 0.1 % w / w of the composition to about 5% w / w of the composition, about 0.1 % w / w of thecomposition to about 10% w / w of the composition, about 0.1 % w / w of the composition to about 20% w / w of the composition, about 0.5% w / w of the composition to about 1 % w / w of the composition, about 0.5% w / w of the composition to about 2% w / w of the composition, about 0.5% w / w of the composition to about 5% w / w of the composition, about 0.5% w / w of the composition to about 10% w / w of the composition, about 0.5% w / w of the composition to about 20% w / w of the composition, about 1 % w / w of the composition to about 2% w / w of the composition, about 1 % w / w of the composition to about 5% w / w of the composition, about 1 % w / w of the composition to about 10% w / w of the composition, about 1 % w / w of the composition to about 20% w / w of the composition, about 2% w / w of the composition to about 5% w / w of the composition, about 2% w / w of the composition to about 10% w / w of the composition, about 2% w / w of the composition to about 20% w / w of the composition, about 5% w / w of the composition to about 10% w / w of the composition, about 5% w / w of the composition to about 20% w / w of the composition, or about 10% w / w of the composition to about 20% w / w of the composition. In some embodiments, the non-ionic surfactant is about 0.05% w / w of the composition, about 0.1 % w / w of the composition, about 0.5% w / w of the composition, about 1 % w / w of the composition, about 2% w / w of the composition, about 5% w / w of the composition, about 10% w / w of the composition, or about 20% w / w of the composition.

[0077] In some embodiments, the non-ionic surfactant is about 0.05% w / w of the composition to about 2% w / w of the composition. In some embodiments, the nonionic surfactant is at least about 0.05% w / w of the composition. In some embodiments, the non-ionic surfactant is at most about 2% w / w of the composition. In some embodiments, the non-ionic surfactant is about 0.05% w / w of the composition to about 0.1 % w / w of the composition, about 0.05% w / w of the composition to about 0.1 % w / w of the composition, about 0.05% w / w of the composition to about 0.2% w / w of the composition, about 0.05% w / w of the composition to about 0.3% w / w of the composition, about 0.05% w / w of the composition to about 0.4% w / w of the composition, about 0.05% w / w of the composition to about 0.5% w / w of the composition, about 0.05% w / w of the composition to about 0.6% w / w of the composition, about 0.05% w / w of the composition to about 1 % w / w of the composition, about 0.05% w / w of the composition to about 1 .5% w / w of the composition, about 0.05% w / w of the composition to about 2% w / w of the composition, about 0.1 % w / w of the composition to about 0.1 % w / w ofthe composition, about 0.1 % w / w of the composition to about 0.2% w / w of the composition, about 0.1 % w / w of the composition to about 0.3% w / w of the composition, about 0.1 % w / w of the composition to about 0.4% w / w of the composition, about 0.1 % w / w of the composition to about 0.5% w / w of the composition, about 0.1 % w / w of the composition to about 0.6% w / w of the composition, about 0.1 % w / w of the composition to about 1 % w / w of the composition, about 0.1 % w / w of the composition to about 1 .5% w / w of the composition, about 0.1 % w / w of the composition to about 2% w / w of the composition, about 0.1 % w / w of the composition to about 0.2% w / w of the composition, about 0.1 % w / w of the composition to aboutcomposition, about 0.1 % w / w of the composition to about 0.4% w / w of the composition, about 0.1 % w / w of the composition to about 0.5% w / w of the composition, about 0.1 % w / w of the composition to about 0.6% w / w of the composition, about 0.1 % w / w of the composition to about 1 % w / w of the composition, about 0.1 % w / w of the composition to about 1.5% w / w of the composition, about 0.1 % w / w of the composition to about 2% w / w of the composition, about 0.2% w / w of the composition to about 0.3% w / w of the composition, about 0.2% w / w of the composition to about 0.4% w / w of the composition, about 0.2% w / w of the composition to about 0.5% w / w of the composition, about 0.2% w / w of the composition to about 0.6% w / w of the composition, about 0.2% w / w of the composition to about 1 % w / w of the composition, about 0.2% w / w of the composition to about 1 .5% w / w of the composition, about 0.2% w / w of the composition to about 2% w / w of the composition, about 0.3% w / w of the composition to about 0.4% w / w of the composition, about 0.3% w / w of the composition to about 0.5% w / w of the composition, about 0.3% w / w of the composition to aboutcomposition, about 0.3% w / w of the composition to about 1 % w / w of the composition, about 0.3% w / w of the composition to about 1.5% w / w of the composition, about 0.3% w / w of the composition to about 2% w / w of the composition, about 0.4% w / w of the composition to about 0.5% w / w of the composition, about 0.4% w / w of the composition to about 0.6% w / w of the composition, about 0.4% w / w of the composition to about 1 % w / w of the composition, about 0.4% w / w of the composition to about 1 .5% w / w of the composition, about 0.4% w / w of the composition to about 2% w / w of the composition, about 0.5% w / w of the composition to about 0.6% w / w of the composition, about 0.5% w / w of the composition to about 1 % w / w of the composition, about 0.5% w / w of the compositionto about 1.5% w / w of the composition, about 0.5% w / w of the composition to about 2% w / w of the composition, about 0.6% w / w of the composition to about 1 % w / w of the composition, about 0.6% w / w of the composition to about 1.5% w / w of the composition, about 0.6% w / w of the composition to about 2% w / w of the composition, about 1 % w / w of the composition to about 1.5% w / w of the composition, about 1 % w / w of the composition to about 2% w / w of the composition, or about 1 .5% w / w of the composition to about 2% w / w of the composition. In some embodiments, the nonionic surfactant is about 0.05% w / w of the composition, about 0.1 % w / w of the composition, about 0.1 % w / w of the composition, about 0.2% w / w of the composition, about 0.3% w / w of the composition, about 0.4% w / w of the composition, about 0.5% w / w of the composition, about 0.6% w / w of the composition, about 1 % w / w of the composition, about 1 .5% w / w of the composition, or about 2% w / w of the composition

[0078] In some embodiments, the non-ionic surfactant comprises Polysorbate 20, Poloxamer 407, Tyloxapol, or cremophor. In some embodiments, the non-ionic surfactant is Polysorbate 20. In some embodiments, the non-ionic surfactant is Poloxamer 407. In some embodiments, the non-ionic surfactant is Tyloxapol. In some embodiments, the non-ionic surfactant is cremophor. The non-ionic surfactants described herein can be present within any one of the ranges (e.g., percent w / w) described herein, a specific value that falls within the described ranges.

[0079] In some embodiments, the composition further comprises cosolvents (e.g., between 0.5 and 50% w / w), such as N,N- Dimethylacetamide, ethanol, PEG-400, propylene glycol, dimethylsulfoxide (DMSO); oils, or cyclodextrins can be added to a pharmaceutical preparation. In some embodiments, the composition further comprises a tonicity-adjusting agent. In some embodiments, the composition is an isotonic solution. In some embodiments, the tonicity-adjusting agent is mannitol, sorbitol, glucose or trehalose, or an inorganic salt such as sodium chloride. In some embodiments, the composition comprises mannitol. In some embodiments, the composition comprises sorbitol. In some embodiments, the composition comprises glucose or trehalose. In some embodiments, the composition comprises an inorganic salt. In some embodiments, the tonicity-adjusting agent is present at an amount suitable to bring the tonicity of the composition into the 250-400 mOsm / L range. In some embodiments, the non-ionic surfactant is about 1 % w / w of the composition to about 10% w / w of the composition. In some embodiments, the non-ionic surfactant is at least about 1 % w / w of the composition. In some embodiments, the non-ionicsurfactant is at most about 10% w / w of the composition. In some embodiments, the non-ionic surfactant is about 1 % w / w of the composition to about 2% w / w of the composition, about 1 % w / w of the composition to about 3% w / w of the composition, about 1 % w / w of the composition to about 4% w / w of the composition, about 1 % w / w of the composition to about 5% w / w of the composition, about 1 % w / w of the composition to about 10% w / w of the composition, about 2% w / w of the composition to about 3% w / w of the composition, about 2% w / w of the composition to about 4% w / w of the composition, about 2% w / w of the composition to about 5% w / w of the composition, about 2% w / w of the composition to about 10% w / w of the composition, about 3% w / w of the composition to about 4% w / w of the composition, about 3% w / w of the composition to about 5% w / w of the composition, about 3% w / w of the composition to about 10% w / w of the composition, about 4% w / w of the composition to about 5% w / w of the composition, about 4% w / w of the composition to about 10% w / w of the composition, or about 5% w / w of the composition to about 10% w / w of the composition. In some embodiments, the non-ionic surfactant is about 1 % w / w of the composition, about 2% w / w of the composition, about 3% w / w of the composition, about 4% w / w of the composition, about 5% w / w of the composition, or about 10% w / w of the composition.

[0080] In some embodiments, the composition comprises a buffering agent. In some embodiments, the buffering agent is an acidifying agent. In some embodiments, the acidifying agent is an acetate buffer at pH 4.5. In some embodiments, the concentration acetate buffer pH 4.5 is about 10 millimolar (mM). Generally, the pH can be controlled by an appropriate buffer suitable for injection into the eye, for example the pH of the composition can be in the 2.5-7.5 range or 3.5-4.5 range.

[0081] As described herein, the composition can comprise one or more excipients. Accordingly, in some embodiments, the composition comprises a non-ionic surfactant, a tonicity-adjusting agent, and a buffering agent, in combination with the peptide. Any of the described excipients can be combined within the amounts and / or ranges described.

[0082] In an embodiment, the compositions described herein comprise an amount of the peptide suitable to inhibit Fas-mediated inflammation and / or treat, inhibit and / or reduce loss in RNFL thickness or the symptoms thereof in an eye. As used herein, a dose or dosage includes and / or refers to the amount of therapeutic agent, such as the peptides described, in a composition (e.g., a composition foradministering to an eye). A dose can refer to either (i) the peptide (parent compound) or the pharmaceutically acceptable salt thereof. In some embodiments, the amount of the peptide in the composition (i.e., pharmaceutical composition) that is suitable for the methods described herein (e.g., treating RNFL thinning) ranges from 5 micrograms (ug or pg) to 10,000 ug. The dosing forms comprising the compositions described herein are generally administered to the vitreous humor of an eye and can be further formulated for injection into the eye (e.g., intravitreal injection). In some embodiments, the amount of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) or a pharmaceutically acceptable salt thereof that is suitable for the methods described herein ranges from 5 ug to 10,000 ug. In some embodiments, the amount of the peptide comprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide that is suitable for the methods described herein ranges from 5 ug to 10,000 ug. In some embodiments, the amount of the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof that is suitable for the methods described herein ranges from 5 ug to 10,000 ug. In some embodiments, the amount of the peptide having the structure of Formula III or a pharmaceutically acceptable salt thereof that is suitable for the methods described herein ranges from 5 ug to 10,000 ug.

[0083] In some embodiments, a dose comprises about 5-1 ,000 ug of the peptide (e.g., Formula III) or the variant sequence thereof. In some embodiments, a dose comprises about 25-500 ug of the peptide or the variant sequence thereof. In some embodiments, a dose comprises about 25-250 ug of the peptide or the variant sequence thereof. In some embodiments, a dose comprises about 50-250 ug of the peptide or the variant sequence thereof. In certain embodiments, a dose com prises about 50 ug of the peptide or the variant sequence thereof. In certain embodiments, a dose comprises about 100 ug of the peptide or the variant sequence thereof. In certain embodiments, a dose comprises about 200 ug of the peptide or the variant sequence thereof. In certain embodiments, a dose comprises about 300 ug of the peptide or the variant sequence thereof. In some embodiments, the peptide is present at a concentration 0.1 milligrams per milliliter (mg / mL) to 10 mg / mL. In some embodiments, the peptide is present at a concentration 0.1 milligrams per milliliter (mg / mL) to 5.0 mg / mL.

[0084] In some embodiments, a dose comprises about 5 ug of a pharmaceutically acceptable salt of the peptide to about 300 ug of a pharmaceutically acceptable salt of the peptide. In some embodiments, a dose comprises at least about 5 ug of a pharmaceutically acceptable salt of the peptide. In some embodiments, a dose comprises at most about 300 ug of a pharmaceutically acceptable salt of the peptide.

[0085] The concentration of the peptide within the composition can be adjusted in a manner suitable for ocular administration. In some embodiments, the concentration of the peptide within the composition ranges from about 0.1 milligrams per milliliter (mg / mL) to about 5 mg / mL. In some embodiments, the concentration of the peptide within the composition ranges from about 0.1 milligrams per milliliter (mg / mL) to about 10 mg / mL. In some embodiments, the concentration of the peptide within the composition ranges from about 0.1 milligrams per milliliter (mg / mL) to about 100 mg / mL. In some embodiments, the concentration of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) or a pharmaceutically acceptable salt thereof ranges from about 0.1 mg / mL to about 5mg / mL. In some embodiments, the concentration of the peptide comprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide ranges from about 0.1 milligrams per milliliter (mg / mL) to about 5mg / mL. In some embodiments, the concentration of the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof ranges from about 0.1 mg / mL to about 5mg / mL. In some embodiments, the concentration of the peptide having the structure of Formula III, or a pharmaceutically acceptable salt thereof ranges from about 0.1 mg / mL to about 5mg / mL.

[0086] In some embodiments, the compositions described herein are administered to an eye of an individual in need thereof. Administration to an eye (i.e., “ocular application” or “ocular administration”) includes subconjunctival, intravitreal, retrobulbar, intracameral administration subretinal, or suprachoroidal. In some embodiments, ocular administration comprises subconjunctival, intravitreal, retrobulbar, or intracameral administration. In some embodiments, ocular administration comprises intravitreal administration. In some embodiments, ocular administration comprises subconjunctival administration. In some embodiments, ocular administration comprises retrobulbar administration. In some embodiments, ocular administration comprises intracameral administration.

[0087] In some embodiments, the dosing forms comprising the compositions described herein are generally administered to the vitreous humor of an eye. In some embodiments, the half-life of the peptide (e.g., a peptide comprising the amino acid sequence HHIYLGAVNYIY) or a pharmaceutically acceptable salt thereof in the vitreous humor is greater than about 30 days to greater than about 275 days. In some embodiments, the peptide comprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide has a half-life in the vitreous humor that is greater than about 30 days to greater than about 275 days. In some embodiments, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof has a half-life in the vitreous humor that is greater than is greater than about 30 days to greater than about 275 days. In some embodiments, the peptide having the structure of Formula III, or a pharmaceutically acceptable salt thereof has a half-life in the vitreous humor that is greater than is greater than about 30 days to greater than about 275 days. In some embodiments, the peptide comprising the amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide has a half-life in the vitreous humor that is greater than about 14 days to greater than about 275 days. In some embodiments, the peptide having the structure of Formula I or a pharmaceutically acceptable salt thereof has a half-life in the vitreous humor that is greater than is greater than about 14 days to greater than about 275 days. In some embodiments, the peptide having the structure of Formula III, or a pharmaceutically acceptable salt thereof has a half-life in the vitreous humor that is greater than is greater than about 14 days to greater than about 275 days.

[0088] In some embodiments, the half-life of the peptide is greater than about 14 days in the eye. In some embodiments, the half-life of the peptide is greater than about 30 days in the eye. In some embodiments, the half-life of the peptide is greater than about 60 days in the eye. In some embodiments, the half-life of the peptide is greater than about 90 days in the eye. In some embodiments, the half-life of the peptide is greater than about 120 days in the eye. In some embodiments, the halflife of the peptide is greater than about 150 days in the eye. In some embodiments, the half-life of the peptide is greater than about 180 days in the eye. In some embodiments, the half-life of the peptide is greater than about 210 days in the eye. In some embodiments, the half-life of the peptide is greater than about 240 days inthe eye. In some embodiments, the half-life of the peptide is greater than about 270 days in the eye.

[0089] In some embodiments, the half-life of the peptide is greater than about 14 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 30 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 60 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 90 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 120 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 150 days in the vitreous humor. In some embodiments, the halflife of the peptide is greater than about 180 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 210 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 240 days in the vitreous humor. In some embodiments, the half-life of the peptide is greater than about 270 days in the vitreous humor.

[0090] Determining the amount of the peptide in the vitreous humor generally requires collecting all of the vitreous fluid or a substantial portion thereof from an eye or sacrificing the eye in order to sample the vitreous humor. In some embodiments, collecting all of the vitreous fluid or a substantial portion thereof in a human eye, or sacrificing an eye is not feasible for maintaining the health of an eye in a human. Accordingly, in some embodiments, the half-life of the peptide in a human eye is determined by measuring and / or extrapolating from a half-life of the peptide in the eye of a mammal. In some embodiments, the mammal is a rabbit. In some embodiments, the mammal is a pig (e.g., minipig). In some embodiments, the mammal is a monkey. Various methods of detecting the presence of a drug are also suitable for detecting the peptide. For example, methods suitable for detecting the peptide include performing mass spectrometry (e.g., liquid chromatography-mass spectrometry (LC-MS) or high-performance LC-MS (HPLC-MS)) on a sample from the vitreous humor.

[0091] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual, the method comprising a glaucoma therapy (e.g., as described herein.)

[0092] In some embodiments, a method provided herein of treating glaucoma comprises administering a glaucoma therapy to an individual having a historical visualfield rate of loss of about -0.5 dB / year or less (e.g., -0.5 to -3 dB / year). In some embodiments, the individual has a historical visual field rate of loss of about -1 dB / year or less (e.g., -1 to -3 dB / year). In some embodiments, the individual has a historical visual field rate of loss of about -1 to about -3 dB / year.

[0093] In some embodiments, a method provided herein of treating glaucoma comprises administering a glaucoma therapy to an individual having a moderate baseline loss of sensitivity in at least one point in a visual field of the eye. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is -3 dB or less (e.g., -3 to -25 dB). In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is -5 dB or less (e.g., -5 to -25 dB). In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -3 dB to about -25 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -5 to about -20 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -10 to about -15 dB.

[0094] In some embodiments, a method provided herein of treating glaucoma comprises administering a glaucoma therapy to an individual having a historical field rate of loss of about -0.5 dB / year or less (e.g., as described above) and having a moderate baseline loss of sensitivity in at least one point in a visual field of the eye (e.g., as described above).

[0095] In some embodiments, a method provided herein of treating glaucoma comprise administering a glaucoma therapy to an individual having an increased likelihood of responding to the glaucoma therapy with an increased visual field functional outcome after treatment with the glaucoma therapy. In some embodiments, such increased likelihood is identified using a method described herein. In some embodiments, such increased likelihood is identified by determining and identifying a historical field rate of loss in the individual, identifying a moderate baseline loss of sensitivity in at least one point in a visual field of an eye of the individual, or a combination thereof.

[0096] In some embodiments, such increased likelihood is identified by determining a historical field rate of loss. In some embodiments, such increased likelihood is identified by identifying a historical field rate of loss of -0.5 dB / year or less (e.g., -0.5 to -3 dB / year). In some embodiments, such increased likelihood is identified by identifying a historical field rate of loss of -1 dB / year or less (e.g., -1 to -3 dB / year). In some embodiments, suchincreased likelihood is identified by identifying a historical field rate of loss of about -1 to about -3 dB / year.

[0097] In some embodiments, such increased likelihood is identified by determining a baseline loss of sensitivity in at least one point in the visual field. In some embodiments, such increased likelihood is identified by identifying a moderate baseline loss of sensitivity in at least one point in the visual field. In some embodiments, such increased likelihood is identified by identifying a moderate baseline loss of sensitivity in at least one point in the visual field of -3 dB or less (e.g., -3 to -25 dB). In some embodiments, such increased likelihood is identified by identifying a moderate baseline loss of sensitivity in at least one point in the visual field of -5 dB or less (e.g., -5 to -25 dB). In some embodiments, such increased likelihood is identified by identifying a moderate baseline loss of sensitivity in at least one point in the visual field of about -3 to about -25 dB. In some embodiments, such increased likelihood is identified by identifying a moderate baseline loss of sensitivity in at least one point in the visual field of about -5 to about -20 dB. In some embodiments, such increased likelihood is identified by identifying a moderate baseline loss of sensitivity in at least one point in the visual field of about -10 to about -15 dB.

[0098] In some embodiments, individuals having the historical field rate of loss described above are selected for treatment with the glaucoma therapy. In some embodiments, individuals having the moderate baseline loss of sensitivity in at least one point in the visual field as described above are selected for treatment with the glaucoma therapy. In some embodiments, individuals having the historical field rate of loss and moderate baseline loss of sensitivity in at least one point in the visual field as described above are selected for treatment with the glaucoma therapy.

[0099] In some embodiments, provided herein are methods of identifying an individual having an increased likelihood of responding with an increased visual field functional outcome after treatment with a glaucoma therapy, the methods comprising: (a) determining a historical visual field rate of loss for an eye of the individual having glaucoma; and (b) identifying the historical visual field rate of loss as being at most -0.5 dB / year. In some embodiments, the historical visual field rate of loss is at most -1 dB / year. In some embodiments, the historical visual field rate of loss is between about - 3 and about -1 dB / year.

[0100] In certain embodiments, the method further comprises: (c) administering the glaucoma therapy to the individual having the historical visual field rate of loss as beingat most -0.5 dB / year. In some embodiments, the historical visual field rate of loss is at most -1 dB / year. In some embodiments, the historical visual field rate of loss is between about -3 and about -1 dB / year.

[0101] In some embodiments, the individual also has a moderate baseline loss of sensitivity in at least one individual point within the visual field. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is at most -3 dB. In some embodiments, the baseline loss of sensitivity in at least one point in the visual field is at most -5 dB. In some embodiments, the moderate baseline loss of sensitivity in the at least one individual point within the visual field is about -3 dB to about -25 dB. In some embodiments, the moderate baseline loss of sensitivity in the at least one individual point within the visual field is about -5 dB to about -20 dB. In some embodiments, the moderate baseline loss of sensitivity in the at least one individual point within the visual field is about -10 dB to about -15 dB.

[0102] In some embodiments, provided herein are methods of identifying an individual having an increased likelihood of responding with an increased visual field functional outcome after treatment with a glaucoma therapy, the methods comprising: (a) determining a baseline loss of sensitivity in at least one point within the visual field for an eye of the individual having glaucoma; and (b) identifying the moderate baseline loss of sensitivity in at least one point in the visual field as being at most -3 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is at most -5 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -25 to about -3 db. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about - 20 to about -5 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -15 to about -10 dB.

[0103] In certain embodiments, the method further comprises: (c) administering the glaucoma therapy to the individual having the moderate baseline loss of sensitivity in at least one point in the visual field of at most -3 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is at most -5 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -25 to about -3 db. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -20 to about -5 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -15 to about -10 dB.

[0104] In some embodiments, the individual may also be identified as having a historical visual field rate of loss. In some embodiments, the individual may be identified as having a historical visual field rate of loss of at most -0.5 dB / year. In some embodiments, the individual may be identified as having a historical visual field rate of loss of at most -1 dB / year. In some embodiments, the individual may be identified as having a historical visual field rate of loss of about -3 and about -1 dB / year.

[0105] In certain embodiments, the glaucoma therapy comprises a Fas inhibitor. In certain embodiments, the Fas inhibitor is a peptide comprising an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, administration of the peptide to an individual with glaucoma having a historical visual field rate of loss of -0.5 dB / year or less is sufficient to treat glaucoma and increase a functional visual field outcome as compared to sham injection (see FIGS. 14C-14E). In some embodiments, administration of the peptide to an individual with glaucoma having a historical visual field rate of loss of -0.5 dB / year or less and having a moderate baseline loss of sensitivity in at least one point in the visual field is sufficient to treat the glaucoma and increase a visual field functional outcome as compared to sham injection (see FIGS. 14B and 14D-14E).

[0106] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual, the methods comprising: (a) identifying the individual as having a historical visual field rate of loss as being at most -0.5 dB / year (e.g., at most about -1 dB / year or between about -3 and about -1 dB / year); and (b) administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, the historical visual field rate of loss is at most-1 dB / year. In some embodiments, the historical visual field rate of loss is between about -3 and about -1 dB / year. In some embodiments, administration of the peptide to an individual with glaucoma having a historical visual field rate of loss of -0.5 dB / year or less is sufficient to treat the glaucoma and increase a functional visual field outcome as compared to sham injection (see FIGS. 14C-14E).

[0107] In some embodiments, the individual may also have a moderate baseline loss of sensitivity in at least one individual point within the visual field. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is at most -3 dB. In some embodiments, the moderate baseline loss of sensitivity in at least onepoint in the visual field is at most -5 dB. In some embodiments, the moderate baseline loss of sensitivity in the at least one individual point within the visual field is about -3 dB to about -25 dB. In some embodiments, the moderate baseline loss of sensitivity in the at least one individual point within the visual field is about -5 dB to about -20 dB. In some embodiments, the moderate baseline loss of sensitivity in the at least one individual point within the visual field is about -10 dB to about -15 dB. In some embodiments, administration of the peptide to an individual having a moderate baseline loss of sensitivity in at least one point in the visual field with or without having a historical visual field rate of loss of -0.5 dB / year or less is sufficient to treat the glaucoma and increase a visual field functional outcome (see FIGS. 14B and 14D-14E).

[0108] In some embodiments, provided herein are methods of treating glaucoma in an eye of an individual, the methods comprising: (a) identifying the individual as having a moderate baseline loss of sensitivity in at least one point in the visual field of at least -3 dB (e.g., at least about -5 dB, or about -20 to about -5 dB); and (b) administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is at most -5 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about - 3 dB to about -25 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about -5 dB to about -20 dB. In some embodiments, the moderate baseline loss of sensitivity in at least one point in the visual field is about - 10 dB to about -15 dB.

[0109] In some embodiments, the individual may also be identified as having a historical visual field rate of loss. In some embodiments, the individual may be identified as having a historical visual field rate of loss of at most -0.5 dB / year. In some embodiments, the individual may be identified as having a historical visual field rate of loss of at most -1 dB / year. In some embodiments, the individual may be identified as having a historical visual field rate of loss of about -3 and about -1 dB / year.

[0110] In certain embodiments, the method further comprises administering a first dose and a second dose of the peptide or the pharmaceutically acceptable salt of the peptide, and wherein the second composition is administered about 10 weeks or greater after administering the first dose. In certain embodiments, the second dose is administered about 12 weeks after the first dose. In some embodiments, the firstdose and the second dose of the peptide are the same composition comprising the peptide. In some embodiments, the first dose and the second dose of the peptide are different compositions comprising the peptide.

[0111] In certain embodiments, the peptide or the pharmaceutically acceptable salt thereof has a half-life in the vitreous humor of more than about 30 days (e.g., at least 30 days). In certain embodiments, the method comprises using the vitreous humor as a depot to provide the peptide or the pharmaceutically acceptable salt thereof to retinal tissue in the eye, wherein the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor more than about 30 days after administration.

[0112] In certain embodiments, the glaucoma comprises elevated intraocular pressure.

[0113] In certain embodiments, the variant sequence comprises an amino acid substitution. In certain embodiments, the variant sequence comprises one amino acid substitution.

[0114] In certain embodiments, the peptide further comprises a modification. In certain embodiments, the modification comprises a modified amino acid. In certain embodiments, the peptide comprises an amidated C-terminus. In certain embodiments, the peptide has the structure of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the peptide has the structure of Formula III or a pharmaceutically acceptable salt thereof.

[0115] In certain embodiments, the method comprises administering the pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutically acceptable salt is an acetate salt. In certain embodiments, the pharmaceutically acceptable salt is a polyacetate salt. In certain embodiments, the polyacetate salt is a triacetate salt. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0116] In certain embodiments, the method comprises administering a composition comprising the peptide. In certain embodiments, the composition (e.g., each composition or the first / second composition) further comprises one or more excipients. In certain embodiments, the composition (e.g., each composition or the first / second composition) further comprises a surfactant. In certain embodiments, the surfactant is a non-ionic surfactant. In certain embodiments, the surfactant is a polysorbate, a polyethoxylated castor oil derivative, a polyethoxylated fatty acid, apolyethoxylated alcohol, a polyoxyethylene-polyoxypropylene block copolymer, or an oxyethylated tertiary octylphenol formaldehyde polymer. In certain embodiments, the surfactant forms about 0.01 % to about 20% weight / weight of the composition. In certain embodiments, the surfactant forms about 0.05% to about 10% weight / weight of the composition. In certain embodiments, the composition (e.g., each composition or the first / second composition) further comprises a tonicity adjusting agent, a buffering agent, or a combination thereof. In certain embodiments, the composition is buffered at a pH of 2.5 to 7.5. In certain embodiments, the composition comprises about 25 micrograms (ug or pg) to about 250 ug of the peptide.

[0117] In certain embodiments, the visual field functional outcome comprises a sub-global measure of local (e.g., region specific within the eye) visual field measurements. In certain embodiments, measuring the visual field functional outcomes comprises generating local visual field measurements within the eye. In certain embodiments, the visual field is measured using a clustering analysis to generate measures of local (e.g., region specific within the eye) visual field measurements.

[0118] In certain embodiments, treating comprises increasing a visual field functional outcome of the eye of the individual (see FIGs. 14A-14E). In certain embodiments, (a) comprises selecting the individual having the historical visual field rate of loss as being between about -3 and about -1 dB / year for treatment with the peptide (see FIGS. 14C, 14D, and 14E). In certain embodiments, the visual field functional outcome is Humphrey’s visual field. In certain embodiments, the visual field is measured by a Humphrey visual field analyzer.

[0119] In certain embodiments, treating comprises increasing the mean change from baseline of thickness in the retinal nerve fiber layer (RNFL) (see FIGS. 12A and 12B). In certain embodiments, treating comprises increasing the mean change from baseline of thickness in the ganglion cell complex. In certain embodiments, the treating comprises increasing the mean change from baseline of thickness in the superior outer quadrant of the ganglion cell complex (see FIGS. 13A and 13B).

[0120] As used herein, inhibition or inhibiting or reducing includes and / or refers to the reduction or suppression of a given condition, symptom, disorder, or disease, and / or a decrease in the baseline activity of a biological activity or process.

[0121] As used herein, individual is synonymous with patient and / or subject and includes and / or refers to a human and can be a human that has been diagnosed asneeding to treat a disease or condition as disclosed herein. However, examples are not limited to humans and include, chimpanzees, marmosets, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, and the like. The individual is typically a human and can be a human that has been diagnosed as needing to treat a disease or condition as disclosed herein.

[0122] As used herein, treating or treatment of includes and / or refers to ameliorating the disease or disorder or symptoms thereof (e.g., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In certain embodiments, treating or treatment also includes and / or refers to alleviating or ameliorating at least one physical and / or biological parameters including those which may not be discernible by the patient. In certain embodiments, treating or treatment includes and / or refers to modulating a disease, disorder, or biological process either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical and / or biological parameter), or both. In certain embodiments, treating or treatment includes and / or refers to preventing or delaying the onset or development or progression of the disease or disorder. In certain embodiments, treating or treatment includes and / or refers to preventing or delaying or inhibiting the deterioration of (i) a healthy physiological state or (ii) a baseline physiological state (e.g., the progression of a disease or disorder).

[0123] As used herein, “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification includes and / or refers to “one” and also consistent with the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.

[0124] As used herein, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps. As used herein, in any instance or embodiment described herein, “comprising” may be replaced with “consisting essentially of” and / or “consisting of”, used herein, in any instance or embodiment described herein, “comprises” may be replaced with “consists essentially of” and / or “consists of”.

[0125] As used herein, the term “about” in the context of a given value or range includes and / or refers to a value or range that is within 20% of the given value or range.

[0126] As used herein, the term “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each were set out individually herein.

[0127] As used herein, a “sample” includes and / or refers to any fluid or liquid sample which is being analyzed in order to detect and / or quantify an analyte. In some embodiments, a sample is a biological sample. Examples of samples include without limitation a bodily fluid, an extract, a solution containing proteins and / or DNA, a cell extract, a cell lysate, or a tissue lysate. Non-limiting examples of bodily fluids include urine, saliva, blood, serum, plasma, cerebrospinal fluid, tears, semen, sweat, pleural effusion, liquified fecal matter, and lacrimal gland secretion.EXAMPLESExample I - Identification of subjects likely to be high-responders to Fas inhibition treatmentObjective

[0128] The primary objective was to determine if subjects who are likely to respond well to treatment with a Fas inhibitor can be identified based on subjects’ historical rate of visual field loss.Study design

[0129] Patients showing open-angle glaucoma were enrolled in ascending dose groups and received a two intravitreal injections (day 0, day 90) of a peptide having an acetate salt of the structure of Formula III (ONL1204). Visual function metrics were measured at over two screening time points, a baseline, and at about days 90, 177, 180, and 270. Measures for visual function included visual field analysis pre- and post-treatment with ONL1204. Randomization was be stratified by HVF mean deviation (-5.00 dB to >-10.00 dB and <-10.00 dB to -15.00 dB).

[0130] Visual function data including historical rate of Humphrey Visual Field (HVF) loss, baseline sensitivity at start of study, and rate of HVF loss after treatment, were collected and analyzed. FIG. 1 provides data showing a lowassociation between a subject’s historical rate of Humphrey Visual Field (HVF) loss per year and the subject’s baseline sensitivity to the intensity of a visual light stimulus. In some analyses, data from individual points in the visual field were grouped into clusters, indicating an approximation of only an Interior sector and a Superior sector to generate equivalent sectors in the data sets detecting HVF and detecting the thickness of the Retinal Nerve Fiber Layer (RNFL).Outcomes

[0131] Patients receiving multiple doses comprising 50 ug and 100 ug of ONL1204 showed favorable in visual field outcomes (e.g., inhibiting the rate of decline or improving visual function as measured by Humphrey Visual Field (HVF)) analysis that included cluster trend analysis (e.g., measuring changes in local predefined regions / clusters) (see Gardiner et al. Detection of Functional Change Using Cluster Trend Analysis in Glaucoma. Invest Ophthalmol Vis Sci. 2017 May 1).

[0132] Surprisingly, the patients that exhibited an improvement in the HVF analysis had a historical rate of HVF loss between about -3 and about -1 dB / yr. FIG. 2A provides data showing subjects’ historical rates of HVF loss per year against the subjects’ annual change in HVF, demonstrating that subjects having the most improvement in annual change in HVF had a historical rate of HVF loss between -3 and -1 dB / yr, and that patients that received 50 ug and patients that received 100 ug doses of a Fas inhibitor, ONL1204, both improved; FIG. 2B provides data from subjects whose historical rates of HVF were between -3 and -1 dB / yr showing the subjects’ historical rates of HVF loss per year against the subjects’ annual change in HVF. FIG. 3A depicts an example grey-scale graph of the retinal sensitivity of a subject treated with 100 ug of ONL1204 with black indicating low retinal sensitivity and white indicating high sensitivity. FIG. 3B provides a schematic of retinal zones within which retinal sensitivity readings are averaged over retinal points to provide a cluster measurement. FIG. 3C provides the annual change and baseline sensitivity of point values for the retinal clusters for the same patient as in FIG. 3A. FIG. 4A shows the historical rate of HVF loss per year against the rate of HVF change per year after treatment in visual field clusters, and FIG. 4B shows the historical rate of HVF loss per year against the baseline sensitivity in visual field clusters, together these data show that treatment with a Fas inhibitor, ONL1204, can improve the HVF rate of change across points in all visual field clusters.

[0133] FIG. 5A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment at points in the visual field for subjects that received 100ug of a Fas inhibitor, ONL1204, and had a historical rate of HVF loss between -3 and -1 dB / year, and FIG. 5B shows that there is a low association between the same variables for subjects that received 100ug of a Fas inhibitor, ONL1204, inhibitor and had a historical rate of HVF loss outside of the range of -3 and -1 dB / year; FIG. 6A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment at points in the visual field for subjects that received 50ug of a Fas inhibitor, ONL1204, and had a historical rate of HVF loss between -3 and -1 dB / year, and FIG. 6B shows that there is a low association between the same variables for subjects that received 50ug of a Fas inhibitor, ONL1204, inhibitor and had a historical rate of HVF loss outside of the range of -3 and -1 dB / year; FIG. 7A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment at points in the visual field for subjects that received sham treatment and had a historical rate of HVF loss between -3 and -1 dB / year, and FIG. 7B provides the association of the same variables for subjects that received sham treatment and had a historical rate of HVF loss outside of the range of -3 and -1 dB / year, both sham groups having low association between baseline sensitivity and rate of HVF change;

[0134] FIG. 8A shows the association of subjects’ baseline sensitivity and the rate of HVF change per year after treatment in visual field clusters for subjects that had a historical rate of HVF loss between -3 and -1 dB / yr and, in comparison, FIG. 8B shows the low association of subjects’ baseline sensitivity and the rate of HVF change per year after treatment in visual field clusters for subjects that had a historical rate of HVF loss outside the range of -3 and -1 dB / yr. FIG. 9A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment in visual field clusters for subjects that received 100ug of a Fas inhibitor, ONL1204, and had a historical rate of HVF loss between -3 and -1 dB / year, and FIG. 9B shows that there is a low association between the same variables for subjects that received 100ug of a Fas inhibitor, ONL1204, inhibitor and had a historical rate of HVF loss outside of the range of -3 and -1 dB / year. FIG. 10A provides the association between the subjects’ baseline sensitivity and the rate of HVF change per year after treatment in visual field clusters for subjects that received 50ug of a Fas inhibitor, ONL1204, and had a historical rate of HVF loss between -3and -1 dB / year, and FIG. 10B shows that there is a low association between the same variables for subjects that received 50ug of a Fas inhibitor, ONL1204, inhibitor and had a historical rate of HVF loss outside of the range of -3 and -1 dB / year.

[0135] Taken together, the data show that populations of patients that respond with improved HCV can be identified using historical HVF data, where these responders have a historical HVF loss between -3 and -1 dB / year.Example II - Validation of Fas inhibitor treatment safety and efficacy in patient studyBackground

[0136] Based on the initial data presented in Example I, further clinical studies were developed to assess the safety of Formula III (ONL1204) in patients with progressing open angle glaucoma (OAG) despite good pressure control.

[0137] Eligible patients had progressive OAG with evidence of either visual field decline detected via (1 ) Humphrey Visual Field (HVF) mean deviation (MD) decline of -0.5 dB / year or more negative or (2) loss of retinal nerve fiber layer (RNFL) thickness of -1.00 pm / year or more negative as detected through optical coherence tomography (OCT). Patients were randomized (2:2:1 ) into one of three treatment groups: (a) ONL1204 50 pg low dose; (b) ONL1204 100 pg high dose; and (c) sham injection. Patients in the treatment groups were administered intravitreal (IVT) injections of the ONL1204 ophthalmic solution of the proper dosage or of the sham solution at Day 1 and Day 90 (FIG. 11 ). The duration of the study was approximately 9 months. Randomization was stratified by baseline HVF MD (1 ) -5.00 dB to greater than -10.00 dB and (2) less than or equal to -10.00 dB to -15.00 dB.

[0138] The primary objective of the study was safety and tolerability of ONL1204, and secondary objectives were to assess efficacy by visual fields and OCT.Resu / ts

[0139] A total of 25 patients were enrolled in the study with 9 patients in the ONL1204 100 pg high dose group, 10 in the ONL1204 50 pg low dose group, and 6 in the sham injection group.

[0140] For overall safety, the majority of the reported treatment-emergent adverse events (TEAEs) were of mild or moderate severity. Four cases of vitreous opacitieswere reported, with three in the ONL1204 100 pg high dose group and one in the ONL1204 50 pg low dose group, all with mild or moderate severity and with no intraocular pressure (IOP) impact. Serious ophthalmic TEAEs were reported in four subjects in the ONL1204 50 pg low dose group, all of which were assessed to be related to study treatment (see Table 1 ). Overall, ONL1204 had no evidence of dose limiting toxicity.Table 1

[0141] Humphrey 24-2 VFs were used to detect treatment effects on visual function. Change from baseline (CFB) in MD did not show a trend across treatment groups. However, a subgroup analysis of subjects with more severe VF defects at baseline showed a trend for improvement in ONL1204-treated eyes compared to sham-treated eyes, as treatment with ONL1204 at either dosage demonstrated a significant increase in RNFL as compared to sham-treated eyes (FIG. 12A) or fellow eyes (FIG. 12B). Similar effects were seen in the thickness of the GCC in the superior outer quadrant in ONL1204-treated eyes for both dosages as compared to sham- treated eyes (FIG. 13A) or fellow eyes (FIG. 13B). These findings indicated an improvement or stabilization of visual field in many patients.

[0142] Additionally, total deviation (TD) values were averaged at each time point for each point (4 at baseline, 1 at Day 90, 4 at Day 180, and 4 at Day 270). A total of260 points were identified for five of the sham injection patients, 260 points identified for five of the patients receiving 50 pg of ONL1204, and 416 points identified for eight patients receiving 100 pg of ONL1204. Averaged point TD values were used to calculate a slope to assess the change over the 270 days of the study. The slope was annualized to the rate of change in dB / year for each point, and a single slope was provided for each of the 52 points for each subject. The slopes were then averaged cross subjects within a single treatment group to generate the average rate of change in the HVF points (dB / year) for all patients using all HVF points identified (FIG. 14A). Based on the total analysis of all patients with at all determined HVF points, treatment with ONL1204 at either dosage did not indicate a substantial difference in functional outcome following treatment as compared to sham injection.

[0143] A subgroup analysis averaged the slopes of points with moderate loss of baseline sensitivity, which, in this example, was determined to be between about -5 dB and -20 dB, to generate the average rate of change in HVF points (dB / year) for all patients and at HVF points with a baseline sensitivity within the determined range (FIG. 14B). This subgroup analysis identified 85 points in the sham injection group, 90 points in the ONL1204 50 pg group, and 159 points in the ONL1204 100 pg group. By viewing only changes for the HVF points that displayed a moderate baseline loss of sensitivity at the start of the experiment, the data indicate that treatment with ONL1204 at either dosage is sufficient to increase change in HVF field over time, suggesting that ONL1204 administered to this subgroup can increase a visual field functional outcome.

[0144] Additional subgroup analysis was conducted for subjects with a historical HVF rate of loss worse than -1 dB / year, excluding -0.5 to -1.0 dB / year to remove potential non-progressors, to generate the average rate in HVF points (dB / year) for patients with the determined historical field rate of loss and at all HVF points (FIG. 14C). A total of 208 points in four patients were identified for the sham injection group, 208 points in four patients for the ONL1204 50 pg group, and 260 points in five patients in the ONL1204 100 pg group. By viewing only changes in HVF over time for patients with the determined historical visual field rate of loss at the start of the experiment, treatment with ONL1204 at either dosage appears sufficient to increase change in HVF field over time, suggesting that ONL1204 administered to this subgroup can increase a visual field functional outcome in this subgroup as well.

[0145] A further subgroup analysis identified patients with the historical field rate of loss of at least -1 dB / year and at points with the moderate baseline loss of sensitivity determined above (about -20 to about -5 dB) to generate an average rate of change in HVF points (dB / year) for patients with both the determined historical field rate of loss and moderate baseline loss of sensitivity (FIG. 14D). A total of 67 points in four patients were identified for the sham injection, 89 points in for patients in the ONL1204 50 pg group, and 124 points in five patients in the ONL1204 100 pg group. When the change in HVF over time in points displaying moderate baseline loss of sensitivity in only patients having the determined historical field rate of loss were isolated, the trend for increased HVF over time is more pronounced following ONL1204 treatment with either dosage as compared to the sham injection.

[0146] Finally, the average TD for patients with the determined historical field rate of loss and moderate baseline sensitivity were plotted over the time course of the study (FIG. 14E). These data illustrate that ONL1204 treatment in the identified patients with the historical visual field rate of loss of -1 dB / year and at HVF points with moderate baseline loss of sensitivity generally displayed an increased total deviation as compared to sham injection at each time point.

[0147] In all, it appeared that ONL1204 had more effect in subjects with a historical rate of loss worse than -1 dB / year or at HVF points with a moderate loss of baseline sensitivity prior to treatment. This effect is more pronounced when both markers were present.Conclusions

[0148] ONL1204 ophthalmic solution, at both 50 pg and 100 pg, dosed IVT with two injections, 90 days apart, was shown to be safe and well-tolerated in this study in subjects with progressing OAG. Worsening glaucoma and elevated IOP were observed in three subjects in the 50 pg treatment group, resulting in two subject discontinuations. Analysis of OCT data showed evidence of an increase in RNFL and GCC layer thickness in ONL1204-treated eyes. Pointwise analysis of VF data suggested the possibility of increased sensitivity in areas with moderate loss at baseline. These findings support the further development of ONL1204 as a novel neuroprotective agent for progressive OAG in patients with at least -0.5 dB / year visual field decline.SEQUENCES

Claims

CLAIMS1 . A method of identifying an individual having an increased likelihood of responding with an increased visual field functional outcome after treatment with a glaucoma therapy, the method comprising:(a) determining a historical visual field rate of loss for an eye of the individual having glaucoma; and(b) identifying the historical visual field rate of loss as being -1 dB / year or less.

2. The method of claim 1 , wherein the method further comprises:(c) administering the glaucoma therapy to the individual having the historical visual field rate of loss as being between -1 dB / year or less.

3. The method of claim 1 or 2, wherein the historical visual field rate of loss is about -3 and about -1 dB / year.

4. The method of any one of claims 1 -3, wherein the individual is identified as having a moderate baseline loss of sensitivity in at least one point of a visual field of the eye.

5. The method of claim 4, wherein the moderate baseline loss of sensitivity is about -20 to about -5 dB.

6. A method of identifying an individual having an increased likelihood of responding with an increased visual field functional outcome after treatment with a glaucoma therapy, the method comprising:(a) determining a baseline loss of sensitivity in at least one point in a visual field in an eye of the individual having glaucoma; and(b) identifying the baseline loss of sensitivity as being about -3 dB or less.

7. The method of claim 6, wherein the method further comprises:(c) administering the glaucoma therapy to the individual having the baseline loss of sensitivity as being about -3 dB or less.

8. The method of claim 6 or 7, wherein the baseline loss of sensitivity is about -20 to about -5 dB.

9. The method of any one of claims 6-8, wherein the individual is identified as having a historical visual field rate of loss of -1 dB / year or less.

10. The method of claim 9, wherein the individual is identified as having a historical visual field rate of loss of about -3 to about -1 dB / year.11 . The method of any one of claims 1 -10, wherein the glaucoma therapy comprises a Fas inhibitor.

12. The method of claim 11 , wherein the Fas inhibitor is a peptide comprising an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

13. A method of treating glaucoma in an eye of an individual, the method comprising:(a) identifying the individual as having a historical visual field rate of loss as being between about -3 and about -1 dB / year; and(b) administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

14. The method of claim 13, wherein treating comprises increasing a visual field functional outcome of the eye of the individual.

15. The method of claim 13 or 14, wherein (a) comprises selecting the individual having the historical visual field rate of loss as being between about -3 and about -1 dB / year for treatment with the peptide.

16. The method of any one of claim 13-15, wherein the individual is identified as having a moderate baseline loss of sensitivity in at least point in a visual field of the eye.

17. The method of claim 15, wherein the moderate baseline loss of sensitivity is -3 dB or less.

18. The method of claim 16, wherein the moderate baseline loss of sensitivity is about -20 to about -5 dB.

19. A method of treating glaucoma in an eye of an individual, the method comprising:(a) identifying the individual as having a moderate baseline loss of sensitivity in at least one point in a visual field of the eye of about -20 to about -5 dB; and(b) administering a peptide to the eye, wherein the peptide comprises an amino acid sequence HHIYLGAVNYIY or variant sequence thereof, or a pharmaceutically acceptable salt of the peptide.

20. The method of claim 19, wherein treating comprises increasing a visual field functional outcome of the eye of the individual.

21. The method of claim 19 or 20, wherein (a) comprises selecting the individual having the moderate baseline loss of sensitivity of about -20 to about -5 dB for treatment with the peptide.

22. The method of any one of claims 1 -21 , wherein visual field is Humphrey’s visual field.

23. The method of claim 22, wherein visual field is measured by a Humphrey visual field analyzer.

24. The method of any one of claims 13-23, wherein the method further comprises administering a first dose and a second dose of the peptide or the pharmaceutically acceptable salt of the peptide, and wherein the second dose is administered about 10 weeks or greater after administering the first dose.

25. The method of claim 24, wherein the second dose is administered about 12 weeks after the first dose.

26. The method of any one of claims 13-25, wherein the peptide or the pharmaceutically acceptable salt thereof has a half-life in the vitreous humor of more than about 30 days (e.g., at least 30 days).

27. The method of any one of claims 13-26, wherein the method comprises using the vitreous humor as a depot to provide the peptide or the pharmaceutically acceptable salt thereof to retinal tissue in the eye, wherein the peptide or the pharmaceutically acceptable salt thereof is present in the vitreous humor more than about 30 days after administration.

28. The method of any one of claims 13-27, wherein the glaucoma comprises elevated intraocular pressure.

29. The method of any one of claims 13-28, wherein the variant sequence comprises an amino acid substitution.

30. The method of claim 29, wherein the variant sequence comprises one amino acid substitution.31 . The method of any one of claims 13-30, wherein the peptide further comprises a modification.

32. The method of claim 31 , wherein the modification comprises a modified amino acid.

33. The method of any one of claims 13-32, wherein the peptide comprises an amidated C-terminus.

34. The method of any one of claims 13-33, wherein the peptide has the structure of Formula I or a pharmaceutically acceptable salt thereof.

35. The method of any one of claims 13-34, wherein the peptide has the structure ofFormula III:(Formula III) or a pharmaceutically acceptable salt thereof.

36. The method of any one of claims 13-35, wherein the method comprises administering the pharmaceutically acceptable salt thereof.

37. The method of claim 36, wherein the pharmaceutically acceptable salt is an acetate salt.

38. The method of claim 37, wherein the pharmaceutically acceptable salt is a polyacetate salt.

39. The method of claim 38, wherein the polyacetate salt is a triacetate salt.

40. The method of claim 39, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

41. The method of any one of claims 13-40, wherein the method comprises administering a composition comprising the peptide.

42. The method of claim 41 , wherein the composition (e.g., each composition or the composition of the first and / or second dose) further comprises one or more excipients.

43. The method of any one of claims 41-42, wherein the composition (e.g., each composition or the composition of the first and / or second dose) further comprises a surfactant.

44. The method of claim 43, wherein the surfactant is a non-ionic surfactant.

45. The method of claim 44, wherein the surfactant is a polysorbate, a polyethoxylated castor oil derivative, a polyethoxylated fatty acid, a polyethoxylated alcohol, a polyoxyethylene-polyoxypropylene block copolymer, or an oxyethylated tertiary octylphenol formaldehyde polymer.

46. The method any one of claims 43-45, wherein the surfactant forms about 0.01 % to about 20% weight / weight of the composition.

47. The method of claim 46, wherein the surfactant forms about 0.05% to about 10% weight / weight of the composition.

48. The method of any one of claims 41-47, wherein the composition (e.g., each composition or the composition of the first and / or second dose) further comprises a tonicity adjusting agent, a buffering agent, or a combination thereof.

49. The method of any one of claims 41-48, wherein the composition is buffered at a pH of 2.5 to 7.5.

50. The method of any one of claims 41 -49, wherein the composition comprises about 25 micrograms (ug or pg) to about 250 ug of the peptide.51 . The method of any one of claims 1 -50, wherein the visual field functional outcome comprises a sub-global measure of local (e.g., specific region within the eye) visual field measurements.

52. The method of claim 51 , wherein measuring the visual field functional outcomes comprises generating local visual field measurements within the eye.

53. The method of any one of claims 1-52, wherein the visual field is measured using a clustering analysis to generate measures of local (e.g., specific region within the eye) visual field measurements.

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