Vascular endothelial growth factor (VEGF) inhibitors for use in the treatment of wet macular degeneration
Patent Information
- Authority / Receiving Office
- MX · MX
- Patent Type
- Patents
- Current Assignee / Owner
- REGENERON PHARMACEUTICALS INC
- Filing Date
- 2018-06-01
- Publication Date
- 2026-06-12
Abstract
Description
Vascular endothelial growth factor (VEGF) inhibitors for use in the treatment of macular degeneration HUMID BACKGROUND OF THE INVENTION Macular degeneration is a serious medical condition in which intraretinal fluid accumulates and can damage the retina, resulting in central vision loss. Macular degeneration can be age-related. Dry (non-exudative) and wet (neovascular or exudative) forms of macular degeneration have been recognized. In neovascular macular degeneration, vision loss can result from the abnormal growth of blood vessels (conoidal neovascularization). The proliferation of abnormal blood vessels in the retina is stimulated by vascular endothelial growth factor (VEGF). These new vessels are fragile and can lead to leakage of blood and protein beneath the macula. Bleeding, leakage, and scarring of these blood vessels over time can cause irreversible damage to the photoreceptors and rapid vision loss. The injection of EYLEA® (aflibercept) and Lucentis© (ranibizumab) are biological drugs that have been approved in zzpfrnn / eznz / B / YiAi Ref. 288094 The United States and Europe use them to treat wet macular degeneration. Aflibercept and ranibizumab are VEGF inhibitors. BRIEF DESCRIPTION OF THE INVENTION This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency. The method comprises statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered aflibercept or ranibizumab with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency. The method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an intravitreal anti-VEGF agent with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration, wherein one or more genetic variants are associated with the presence of cystoid (fluid) interretinal edema, compared to the absence of cystoid (fluid) interretinal edema after one year of treatment. This paper describes methods for associating a genetic variant with intraretinal fluid. The method comprises statistically associating (a) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration with (b) intraretinal fluid in the same population of subjects with age-related neovascular macular degeneration, wherein the genetic variant or variants are associated with a lower level of intraretinal fluid in subjects with age-related neovascular macular degeneration who are treated with an anti-VEGF intravitreal agent and who have one or two copies of the allelic genetic variant, compared to the level of intraretinal fluid in subjects with age-related neovascular macular degeneration treated with an anti-VEGF intravitreal agent who do not have one copy of the allelic genetic variant. BRIEF DESCRIPTION OF THE FIGURES The accompanying figures, which are incorporated into and form part of this description, illustrate various modalities of the method and compositions described and together with the description serve to explain the principles of the method and compositions described. Figure 1 shows an overview of a statistical study zzpfrnn / eznz / B / YiAi used to identify genetic variants associated with anti-VEGF drug response as measured by visual acuity, anatomical outcomes, and treatment frequency in the VISTA 1 study. Figure 2 shows baseline characteristics and clinical demographic statistics from a PGx Substudy including gender, age, race, visual acuity, and lesion type that reflected the distributions observed in the full VISTA 1 analysis set. Figure 3 shows quality control measures applied to the SNP-on-chip to generate a final sample set for the VISTA 1 study at 154 sites in the United States and Canada (Randomized Caucasian ~96%) Figure 4 shows quality control measures applied to on-chip SNPs to generate a final sample set for the VISTA 1 study. Figure 5 shows an anatomical response, namely the X chromosome SNP(rs2056688), which showed the greatest association with the anatomical outcome, demonstrating an odds ratio (OR) of 0.2578 and a point association (p-value 7.27 x 10-7) with the presence of intraretinal fluid at week 52. Figure 6 shows that the SNP rs2056688 was located in a non-coding region, with the nearest relevant functional gene mapping (X-linked Protein Kinase (X-PRK)) ~400kb ahead of the putative variant. zzpfrnn / eznz / B / YiAi Figure 7 shows that additional nearby SNPs showed a dose effect. Figure 8 shows the SNPs identified in the Example 1 study. DETAILED DESCRIPTION OF THE INVENTION The method and compositions described can be more easily understood by reference to the following detailed description of particular modalities and the Example included in these and the Figures and their preceding and following description. It should be understood that the methods and compositions described are not limited to specific synthetic methods, analytical techniques, or reagents unless otherwise specified, and as such, may vary. It should also be understood that the terminology used herein is intended to describe only particular modalities and is not meant to be exhaustive. It is understood that the methods and compositions described are not limited to the specific methodology, protocols, and reagents described, as these may vary. It is also understood that the terminology used herein is solely for the purpose of describing particular modalities and is not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless expressly stated otherwise, no method or aspect set forth herein is intended to be interpreted as requiring its steps to be carried out in any specific order. Therefore, where a claim for a method does not specifically state in the claims or descriptions that the steps must be limited to a specific order, no order is intended to be observed in any respect. This is necessary for all possible unexpressed grounds for interpretation, including logical issues concerning the organization of steps or operational flow, the common meaning derived from grammatical arrangement or punctuation, or the number or type of aspects described. Materials, compositions, and components that can be used for, in conjunction with, or in the preparation of the described methods and compositions are described herein. These and other materials are described herein, and it is understood that when combinations, subsets, interactions, groups, etc., of these materials are described, while a specific reference to each of the various individual and collective combinations and permutations of these compounds may not be explicitly included, each is specifically considered and described herein. For example, if a PRR antagonist is described and proposed, and various possible modifications are indicated, each and every combination and permutation of the PRR antagonist and any possible modifications are specifically considered, unless specifically stated otherwise.Therefore, if a class of molecules A, B, and C is described, as well as a class of molecules D, E, and F, and an example combination of molecules AD is described, then each is considered to have been considered both individually and collectively, even if each is not mentioned individually. Thus, in this example, each of the combinations AE, AF, BD, BE, BF, CD, CE, and CF is specifically considered and should be considered described based on the descriptions of A, B, and C; D, E, and F; and the example combination AD. Likewise, any subset or combination of these is also specifically considered and described. So, for example, the subgroups AE, BF, and CE are specifically considered and should be considered described based on the descriptions of A, B, and C; D, E, and F; and the example combination AD.This concept applies to all aspects of this application, including, but not limited to, the steps in the methods of preparation and use of the described compositions. Therefore, if there are a variety of additional steps that may be carried out, it is understood that each of these additional steps may be carried out using any modality or combination of modalities specific to the methods described, and that each such combination is specifically contemplated and should be considered as described. Definitions As used in the description and in the appended claims, the singular forms a, one, and the include plural referents unless the context clearly indicates otherwise. Thus, for example, a reference to a pharmaceutical carrier includes mixtures of two or more of the carriers and the like. Throughout the description and claims of this description, the word "comply" and variations thereof, such as "comprising" and "includes," mean what is included in a non-exhaustive manner and are not intended to exclude, for example, other additives, components, wholes, or steps. In particular, in methods described as comprising one or more steps or operations, it is specifically understood that each step comprises what is mentioned (unless the step includes a limiting term such as "consisting of"), meaning that each step is not intended to exclude, for example, other additions, components, wholes, or steps not mentioned in the step. Intervals may be expressed herein as "from around a particular value" and / or "to around another particular value." When the interval is expressed, "another modality" includes "from that particular value" and / or "to the other particular value." Similarly, when values are expressed as approximations, by using the antecedent "around," it will be understood that the particular value forms another modality. It will further be understood that the endpoints of each interval are important both in relation to the other endpoint and independently of the other endpoint. It will also be understood that there are several values described herein and that each value is also indicated herein as "around that particular value," in addition to the value itself. For example, if the value 10 is indicated, then "around 10" is also indicated.It is also understood that when a value is described that is less than or equal to, greater than or equal to, and any intervals between values, it is also understood to be described, as understood by someone skilled in the art. For example, if the value 10 is described, then less than or equal to 10, as well as greater than or equal to 10, are also described. It is further understood that throughout the application, information is provided in different formats, and that this information represents endpoints, start points, and intervals for any combination of information points. For example, if a particular information point 10 and a particular information point 15 are described, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered to be described, as well as between 10 and 15. Likewise, it is understood that each unit between any two particular units is also described.For example, if 10 and 15 are described, then 11, 12, 13, and 14 are also described. Optionally or optionally means that the event or circumstance described below may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. The word "or" as used herein means any member of a particular list and also includes any combination of the members of that list. As used herein, the term subject means an individual. In one respect, a subject is a mammal, such as a human being. In another respect, a subject can be a non-human primate. Non-human primates include, for example, titi monkeys, monkeys, chimpanzees, gorillas, orangutans, and gibbons. The term subject also includes domesticated animals such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., ferrets, chinchillas, mice, rabbits, rats, gerbils, guinea pigs, etc.), and bird species (e.g., chickens, turkeys, ducks, pheasants, pigeons, parrots, cockatoos, geese, etc.). Subjects may also include, but are not limited to, fish (e.g., zebrafish, goldfish, tilapia, salmon, and trout), amphibians, and reptiles. As used herein, a subject is the same as a patient, and the terms may be used interchangeably. The term polymorphism refers to the occurrence of one or more genetically determined alternative sequences, or alleles, in a population. A polymorphic site is the locus where sequence divergence occurs. Polymorphic sites have at least one allele. A diallelic polymorphism has two alleles. A triallelic polymorphism has three alleles. Diploid organisms can be homozygous or heterozygous for allelic forms. A polymorphic site can be as small as a base pair. Examples of polymorphic sites include restriction fragment length polymorphisms (RFLPs), variable number of tandem repeats (VNTRs), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats, and single sequence repeats. As used herein, the reference to polymorphism may encompass a set of polymorphisms (i.e., a haplotype). A single nucleotide polymorphism (SNP) can occur at a polymorphic site occupied by a single nucleotide, which is the site of variation between allelic sequences. This site may be preceded and followed by highly conserved sequences such as zzpfrnn / cznz / B / YiAi. An SNP can arise due to the substitution of one nucleotide for another at the polymorphic site. The replacement of one purine for another purine or one pyrimidine for another pyrimidine is called a transition. The replacement of a purine for a pyrimidine, or vice versa, is called a transversion. A synonymous SNP refers to a nucleotide substitution in the coding region that does not change the amino acid sequence of the encoded polypeptide. A non-synonymous SNP refers to a nucleotide substitution in the coding region that changes the amino acid sequence of the encoded polypeptide.An SNP can also arise from the deletion or insertion of a nucleotide or nucleotides with respect to a reference allele. A set of polymorphisms means one or more polymorphisms, for example, at least 1, at least 2, at least 3, at least 4, at least 5, at least 6 or more than 6 polymorphisms. As used herein, a nucleic acid, polynucleotide, or oligonucleotide can be a polymeric form of nucleotides of any length, can be DNA or RNA, and can be single- or double-stranded. Nucleic acids may include promoters or other regulatory sequences. Oligonucleotides can be prepared synthetically. Nucleic acids include segments of DNA, or their complements, that cover or flank any of the zzpfrnn / eznz / B / YiAi polymorphic sites. Segments can be between 5 and 100 contiguous bases and can range from a lower limit of 5, 10, 15, 20, or 25 nucleotides to an upper limit of 10, 15, 20, 25, 30, 50, or 100 nucleotides (where the upper limit is greater than the lower limit). Nucleotide sequences of 5-10, 5-20, 10-20, 12-30, 15-30, 10-50, 20-50, or 20-100 bases are common. The polymorphic site can occur within any position of the segment.A reference to the sequence of one strand of a double-stranded nucleic acid defines the complementary sequence, and unless it is evident from the context, a reference to one strand of a nucleic acid also refers to its complement. The term nucleotide, as described herein, refers to molecules that, when joined together, form the individual structural units of the nucleic acids RNA and DNA. A nucleotide is composed of a nucleobase (nitrogenous base), a 5-carbon sugar (either ribose or 2-deoxyribose), and a phosphate group. Nucleic acids are polymeric macromolecules formed from nucleotide monomers. In DNA, the purine bases are adenine (A) and guanine (G), while the pyridine bases are thymine (T) and cytosine (C). RNA uses uracil (U) instead of thymine (T). As used herein, the term variant genetic variant refers to a nucleotide sequence in which the sequence differs from the most prevalent sequence in a population, for example, by one nucleotide, as in the case of the SNPs described herein. For example, some variations or substitutions in a nucleotide sequence alter a codon so that it codes for a different amino acid, resulting in a variant genetic polypeptide. Other, non-exhaustive examples of variant genetic variants include insertions, deletions, indels, frameshift variants, stop codon variants, synonym variants, non-synonym variants, and copy number variants (e.g., deletions and duplications).The term genetic variant can also refer to a polypeptide in which the sequence differs from the most prevalent sequence in a population at a position that does not change the amino acid sequence of the encoded polypeptide (i.e., a conserved change). Genetic variant polypeptides can be encoded by a risk haplotype, a protective haplotype, or a neutral haplotype. Genetic variant polypeptides can be associated with risk, protection, or be neutral. The terms isolated nucleic acid or purified nucleic acid mean DNA that does not have flanking genes in the naturally occurring genome of the organism from which the DNA of the invention is derived. The term, therefore, includes, for example, recombinant DNA that is incorporated into a vector, such as a plasmid or self-replicating virus, or incorporated into the genomic DNA of a prokaryotic or eukaryotic cell (e.g., a transgene), or that exists as a separate molecule (e.g., as cDNA or a genomic or cDNA fragment produced by PCR or restriction enzyme digestion or in vitro synthesis). It also includes recombinant DNA that is part of a hybrid gene encoding an additional polypeptide sequence.The term isolated nucleic acid also refers to RNA, for example, an mRNA molecule that is encoded by an isolated DNA molecule, or that is chemically synthesized, or that is separated or substantially released from at least some cellular components, for example, other types of RNA molecules or polypeptide molecules. As used herein, treatment or treating refers to the medical care of a patient with the intent to cure, improve, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment specifically directed at improving a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed at eliminating the cause of the disease, pathological condition, or associated disorder.Furthermore, this term includes palliative treatment, that is, treatment designed to relieve symptoms rather than cure the disease, pathological condition, or disorder; preventive treatment, that is, treatment aimed at minimizing or inhibiting, either completely or partially, the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment used to complement other specific therapy aimed at improving the associated disease, pathological condition, or disorder. In several respects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed; (b) inhibiting the disease, that is, halting its development; or (c) alleviating the disease, that is, causing the disease to regress. The terms administering, administered, and administration refer to any method of providing a pharmaceutical preparation to a subject. Methods known to those skilled in the art include, but are not limited to, oral administration, sublingual administration, transoral administration via mucosa, transdermal administration, inhalation administration, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, intrathecal administration, rectal administration, intraperitoneal administration, and parenteral administration, including injectables such as intravenous administration, intra-arterial administration, intramuscular administration, intradermal administration, and subcutaneous administration.Ophthalmic administration may include topical, subconjunctival, subtenon's, epibulbar, retrobulbar, intraorbital, and infraocular administration, including intravitreal administration. Administration may be continuous or intermittent. In several respects, a preparation may be administered therapeutically; that is, administered to treat an existing disease or condition. In several additional respects, a preparation may be administered prophylactically; that is, administered to prevent a disease or condition. Sequence similarity or sequence identity between sequences (the terms are used interchangeably herein) is calculated as follows. To determine the percentage of identity between two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison (e.g., spaces may be introduced into one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and comparison; non-homologous sequences may be omitted). In some embodiments, the length of an aligned reference sequence for comparison is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, or 100% of the length of the reference sequence.The amino acid residues or nucleotides are then compared at corresponding amino acid or nucleotide positions. When a position in the first sequence is occupied by the same amino acid or nucleotide residue as the corresponding position in the second sequence, then the molecules are identical at that position. The percentage of identity between the two sequences is a function of the number of identical positions that the sequences share, taking into account the number of gaps and the length of each gap, which must be introduced for optimal alignment of the two sequences. Sequence comparison and determination of the percentage of identity between two sequences can be achieved using a mathematical algorithm. In a preferred embodiment, the percentage of identity between two amino acid sequences is determined using the Needleman and Wunsch algorithm (1970, J. Mol. Biol. 48: 444-453), which is incorporated into the GAP program in the GCG software package zzpfrnn / eznz / B / YiAi, using either a Blossum 62 array or a PAM250 array, and a space weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percentage of identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using an NWSgapdna. The CMP matrix and a hole weight of 40, 50, 60, 70 or 80 and a length weight of 1, 2, 3, 4, 5 or 6.A particularly preferred parameter set (and the one that should be used unless otherwise specified) is a Blossum score matrix of 62 with a gap penalty of 12, a gap extension penalty of 4, and a displacement frame gap penalty of 5. The percentage of identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller (1989, Cabios, 4: 11-17), incorporated in the ALIGN program (version 2.0) using a residue weight table PAM 120, a gap length penalty of 12 and a gap penalty of 4. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the described method and compositions pertain. While in the practice or evaluation of the method and compositions herein any similar or equivalent methods and materials may be used, the particularly useful methods, devices, and materials are as described. Publications cited herein and the material to which they are cited are specifically incorporated by reference. Nothing contained herein should be construed as an admission that the present invention is not entitled to prior art under any prior invention. There is no acceptance that any of the references constitute prior art.The discussion of references establishes the claims of their authors, and applicants reserve the right to debate the accuracy and relevance of the cited documents. It is clearly understood that, although reference is made herein to a number of publications, this reference does not constitute acceptance that any of these documents forms part of common knowledge. Skilled practitioners will recognize, or be able to determine through routine experimentation alone, many equivalents of the specific modalities of the method and the compositions described herein. It is intended that such equivalents are covered by the following claims. Methods This paper describes methods for associating a zzpfrnn / cznz / B / YiAi genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an intravitreal anti-VEGF agent with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration, where one or more genetic variants are associated with the presence of cystoid (fluid) interretinal edema, compared to the absence of cystoid (fluid) interretinal edema after one year of treatment. Examples of anti-VEGF agents or intravitreal agents include, but are not limited to, bevacizumab, ranibizumab, ramucirumab, aflibercept, sunitinib, sorafenib, vandetanib, vatalanib, tivozanib, axitinib, imatinib, or pazopanib. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency. The method comprises: comparing the anatomical outcome of subjects with age-related neovascular macular degeneration who have been administered an anti-VEGF intravitreal agent and who have one or two copies of the allelic genetic variant with the anatomical outcome of a population of subjects with age-related neovascular macular degeneration who have been administered an anti-VEGF intravitreal agent and who do not have one copy of the zzpfrnn / eznz / B / YiAi allelic genetic variant; and statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an anti-VEGF antivitreal agent with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with neovascular age-related macular degeneration who have been administered an intravitreal anti-VEGF agent for one year with (ii) an anatomical outcome from the same population of subjects with neovascular age-related macular degeneration, where one or more genetic variants are associated with the presence of cystoid (fluid) interretinal edema in subjects who have one or more copies of the allelic genetic variant, compared to the level of cystoid (fluid) interretinal edema in subjects who do not have one copy of the allelic genetic variant. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency. The method comprises: comparing the anatomical outcome in a population of subjects with age-related neovascular macular degeneration who have been administered an anti-VEGF intravitreal agent and who have one or two copies of the allelic genetic variant with the anatomical outcome of a population of subjects with age-related neovascular macular degeneration who have been administered an anti-VEGF intravitreal agent and who do not have one copy of the allelic genetic variant;and to statistically associate (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered (ii) an anatomical outcome in the same population of subjects with age-related neovascular macular degeneration, wherein the subjects' DNA samples are genotyped prior to the statistical association stage. In some respects, the anatomical outcome is a gain of 15 letters (visual acuity). In some respects, the treatment frequency may reflect a continued need for aggressive treatment with an intravitreal anti-VEGF agent after one year of dosing. The statistical associations described herein may include logistic regression analysis, quality control (QC) of genetic information, including Hardy-Weinberg equilibrium (HWE) testing, identity by state estimates (IBS), and / or gender confirmation. Population structure may be assessed using principal component analysis (PCA). Statistical association may include logistic regression with base values and any potential population structure variables as covariates in the model. In some aspects, the anatomical outcome is the presence of cystoid interretinal edema, a gain in vision / improvement in visual acuity, or a decrease in intraretinal fluid. Other anatomical outcomes that may be used include, but are not limited to, a reduction in central retinal thickness measured by optical coherence tomography (OCT), complete resolution of intraretinal and subretinal fluid, a reduction in the ceroid neovascular area (CNV), a reduction in the total neovascular lesion size measured by fluorescein angiography, and a reduction in subretinal hyperreflective material (SHM) measured by OCT. In some respects, statistical association can be measured as a p-value. For example, different types of p-values can be obtained: p-values from simple t-tests for the original data and transformed data assuming equal variances, and p-values from Chebby's checker. These p-values can be presented on an individual basis as well as considering multiple comparisons. The mix-o-matic method can be applied to provide additional information about these p-values. In some respects, the p-value for association is less than or equal to 1 x 10⁻⁵, 1 x 10⁻⁶, 1 x 10⁻⁷, 1 x 10⁻⁸, etc. In some respects, the p-value for association is less than or equal to 1 x 10⁻⁵, i.e., suggestive statistical significance, and 1 x 10⁻⁸, i.e., statistical significance relative to the experiment. In some respects, the effect size of a statistical association can be measured as an odds ratio. For example, the effect size of a statistical association can be measured as the ratio of the odds of cystoid (fluid) interretinal edema in subjects with neovascular age-related macular degeneration treated with an anti-VEGF intravitreal agent who have one or two copies of an allele, to the odds of the presence of cystoid (fluid) interretinal edema in subjects with neovascular age-related macular degeneration treated with an anti-VEGF intravitreal agent who do not have the copy of the allele. In some respects, the odds ratio is less than or equal to 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9. Having one copy of the allele would have less influence than individuals who have two copies of the allele. In some respects, the statistical association can be measured as the odds ratio of a 15-letter gain (visual acuity) in subjects with age-related neovascular macular degeneration treated with an intravitreal anti-VEGF agent who have one or two copies of an allele, to the odds ratio of a 15-letter gain in subjects with age-related neovascular macular degeneration treated with an intravitreal anti-VEGF agent who do not have one copy of the allele. In some respects, the odds ratio is greater than or equal to 2.4, 2.5, 2.6, 2.7, 2.8, or 2.9. In some respects, the statistical association can be measured as the odds ratio of subjects with age-related macular degeneration who have a greater need for aggressive treatment with an intravitreal anti-VEGF agent and who have one or two copies of an allele, compared to the odds ratio of subjects with age-related macular degeneration who have a lower need for aggressive treatment with an intravitreal anti-VEGF agent and who do not have the copy of the allele. In some respects, the odds ratio is less than or equal to 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, or 3.2. In some respects, these methods can be used to associate a genetic variant with visual acuity, anatomical outcomes, or treatment frequency. In some respects, the genetic variant may be one or more single nucleotide polymorphisms. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an intravitreal anti-VEGF agent zzpfrnn / eznz / B / YiAi with (11) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration, where one or more genetic variants are associated with a reduced level of cystoid (fluid) interretinal edema, after one year of treatment. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an anti-VEGF intravitreal agent with (ii) an anatomical outcome in the same population of subjects with age-related neovascular macular degeneration, where the genetic variant or variants are associated with a reduced level of intraretinal fluid in subjects who have 1 or 2 copies of the allelic genetic variant, compared to the level of intraretinal fluid in subjects with age-related neovascular macular degeneration who have been administered an anti-VEGF intravitreal agent who do not have one copy of the allelic genetic variant. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an intravitreal anti-VEGF agent with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration, where one or more genetic variants are associated with the presence of cystoid (fluid) interretinal edema, compared to the absence of cystoid (fluid) interretinal edema after one year of treatment. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an intravitreal anti-VEGF agent with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration, where the genetic variant or variants are associated with a reduced level of intraretinal fluid compared to the level of intraretinal fluid in subjects with age-related neovascular macular degeneration who are not treated with an intravitreal anti-VEGF agent, where the genetic variant is a single nucleotide polymorphism selected from the group consisting of rs2056688, rs5962084, rs5962087, rs5915722, and zzpfrnn / eznz / B / YiAi rs5962095.In some respects, the genetic variant is a single nucleotide polymorphism that is selected from the group consisting of rs2056688, rs5962084, rs5962087, rs5915722, rs5962095, rs2106124, rsl879796, rsl2148845, rsl2148100, rsl7482885 and rsl7629019. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an intravitreal anti-VEGF agent with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration, where one or more genetic variants are associated with the presence of cystoid (fluid) interretinal edema, compared to the absence of cystoid (fluid) interretinal edema after one year of treatment. This paper describes methods for associating a genetic variant with intraretinal fluid. The method comprises statistically associating (a) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration with (b) intraretinal fluid in the same population of subjects with age-related neovascular macular degeneration, wherein the genetic variant(s) are associated with reduced intraretinal fluid in subjects with age-related neovascular macular degeneration treated with an intravitreal anti-VEGF agent, compared to the level of intraretinal fluid in subjects with age-related neovascular macular degeneration not treated with an intravitreal anti-VEGF agent, wherein the reduced intraretinal fluid is associated with better visual acuity in subjects with age-related neovascular macular degeneration treated with an intravitreal anti-VEGF agent.compared to the level of intraretinal fluid in subjects with age-related neovascular macular degeneration not treated with an intravitreal anti-VEGF agent. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an intravitreal anti-VEGF agent with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration, where one or more genetic variants are associated with the presence of cystoid (fluid) interretinal edema, compared to the absence of cystoid (fluid) interretinal edema after one year of treatment. This paper describes methods for associating a zzpfrnn / eznz / B / YiAi genetic variant with intraretinal fluid. The method comprises statistically associating (a) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration with (b) intraretinal fluid in the same population of subjects with age-related neovascular macular degeneration, wherein the genetic variant(s) are associated with reduced intraretinal fluid in subjects with age-related neovascular macular degeneration treated with an intravitreal anti-VEGF agent, compared to the level of intraretinal fluid in subjects with age-related neovascular macular degeneration not treated with an intravitreal anti-VEGF agent, wherein the p-value of the association is less than or equal to 1 x 10-6. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an intravitreal anti-VEGF agent with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration, where one or more genetic variants are associated with the presence of cystoid (fluid) intraretinal edema, compared to the absence of cystoid (fluid) intraretinal edema after one year of treatment. This paper describes methods for associating a genetic variant with intraretinal fluid. The method comprises statistically associating (a) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration with (b) intraretinal fluid in the same population of subjects with age-related neovascular macular degeneration, wherein the genetic variant(s) are associated with reduced intraretinal fluid in subjects with age-related neovascular macular degeneration treated with an intravitreal anti-VEGF agent, compared to the level of intraretinal fluid in subjects with age-related neovascular macular degeneration not treated with an intravitreal anti-VEGF agent.where the odds ratio of reduced intraretinal fluid in subjects with age-related neovascular macular degeneration treated with an intravitreal anti-VEGF agent relative to reduced intraretinal fluid in subjects with age-related neovascular macular degeneration not treated with an intravitreal anti-VEGF agent is less than or equal to 0.5. This paper describes methods for associating a genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with neovascular age-related macular degeneration who have been administered an intravitreal anti-VEGF agent with (ii) an anatomical outcome from the same population of subjects with neovascular age-related macular degeneration, where one or more genetic variants are associated with the presence of cystoid (fluid) interretinal edema, compared to the absence of cystoid (fluid) interretinal edema after one year of treatment. This paper describes methods for associating a genetic variant with intraretinal fluid. The method comprises statistically associating (a) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration with (b) intraretinal fluid in the same population of subjects with age-related neovascular macular degeneration, wherein the genetic variant or variants are associated with reduced intraretinal fluid in subjects with age-related neovascular macular degeneration who are treated with an anti-VEGF intravitreal agent, compared to the level of intraretinal fluid in subjects with age-related neovascular macular degeneration not treated with an anti-VEGF intravitreal agent, wherein the genetic variant is a single nucleotide polymorphism. This paper describes methods for associating a zzpfrnn / eznz / B / YiAi genetic variant with visual acuity, anatomical outcomes, or treatment frequency, where the method comprises: (a) statistically associating (i) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration who have been administered an intravitreal anti-VEGF agent with (ii) an anatomical outcome from the same population of subjects with age-related neovascular macular degeneration, where one or more genetic variants are associated with the presence of cystoid (fluid) interretinal edema, compared to the absence of cystoid (fluid) interretinal edema after one year of treatment. This paper describes methods for associating a genetic variant with intraretinal fluid. The method comprises statistically associating (a) one or more genetic variants in a population of subjects with age-related neovascular macular degeneration with (b) intraretinal fluid in the same population of subjects with age-related neovascular macular degeneration, wherein the genetic variant(s) are associated with reduced intraretinal fluid in subjects with age-related neovascular macular degeneration treated with an intravitreal anti-VEGF agent, compared to the level of intraretinal fluid in subjects with age-related neovascular macular degeneration not treated with an intravitreal anti-VEGF agent, wherein the genetic variant is a single nucleotide polymorphism, wherein the single nucleotide polymorphism is selected from a group consisting of rs2056688, rs5962084, rs5962087, rs5915722 and rs5962095. Kits This document also describes kits for using the methods described herein. The kits described herein may comprise one or more assays for detecting one or more genetic variants in a sample from a subject. And temples The following examples are provided to give those skilled in the art a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods claimed herein are made and evaluated. They are intended solely to illustrate the invention and are not intended to limit the scope of the inventors' understanding of it. Every effort has been made to ensure the accuracy of the figures (e.g., quantities, temperature, etc.), but it should be noted that errors and deviations may exist. Unless otherwise stated, parts are parts by weight, temperature is expressed in °C or ambient temperature, and pressure is atmospheric pressure or close to it. VISTA 1 and VISTA 2 are Phase III clinical studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in wet AMD) zzpfrnn / cznz / B / YiAi of neovascular age-related macular degeneration (AMD) in which treatment subjects received an intravitreal injection of afilbercept (Heier JS, et al., Am. Acad. Ophthalmol. 119: 2537 (2012)). The purpose of this statistical study was to identify genetic variants associated with antiVEGF drug response as measured by visual acuity, anatomical outcomes, and treatment frequency in the VISTA 1 study. An overview of the VISTA 1 study is presented in Figure 1. The VISTA 1 study evaluated the efficacy and safety of intravitreal aflibercept injection (IAI) compared with ranibizumab for the treatment of neovascular AMD. At week 52, all IAI groups showed similar improvements in all visual acuity endpoints compared with Rq4. The incidence of ocular adverse events was similar across all treatment groups; adverse events occurring in >10% of patients included conjunctival hemorrhage, eye pain, retinal hemorrhage, and reduced visual acuity. A genome-wide association study (GWAS) was conducted in 362 VISTA 1 patients. DNA samples were genotyped using the Illumina Omni Express Exorne Chip. Logistic regression was performed using baseline values to establish the association between genetic variants and efficacy variables. A GWAS analysis of approximately 1 million variants was performed. The association between genetic variants and efficacy variables was determined using logistic regression with baseline values. All treatment groups were combined. For each SNP, genotypes were encoded according to an additive inheritance pattern. Variants associated with a gain of >15 ETDRS letters at week 52, the presence of cystoid interretinal edema (fluid measured by time-domain optical coherence tomography [TD-OCT]) at week 52, and treatment frequency at week 96 were evaluated.The variants were also associated with treatment burden. Specifically, patients requiring more than 7 injections from Week 52 to Week 96 [Year 2 of the Study] were analyzed. Additionally, the variants were associated with the presence of intraretinal cystoid edema (defined as fluid) at Week 52. Demographic factors and baseline characteristics of VISTA 1 patients were also identified (see Figure 2). Quality control measures were applied to on-chip SNPs to generate a final sample set. (See figures 3 and 4). Anatomical response, namely the X chromosome SNP (rs2056688), showed the strongest association with anatomical outcome, demonstrating an odds ratio (OR) of 0.2578 and a point association (p value 7.27 x 10-7) zzpfrnn / eznz / B / YiAi with the presence of intraretinal fluid at week 52. (See Figure 5). Four nearby SNPs (rs5962084, rs5962087, rs5915722, rs5962095) showed similar ORs (0.3151–0.3461) and point associations (5.48 × 10⁻⁶–8.59 × 10⁻⁶). The SNP rs2056688 was located in a non-coding region, with the nearest relevant functional gene mapping (X-linked protein kinase (X-PRK)) approximately 400 kb upstream of the putative variant. (See Figure 6). Additional SNPs with lesser significance were found in association with the proportion of patients with a gain of >15 ETDRS letters in vision at week 52 and treatment frequency at week 96. Additional nearby SNPs showed a dose effect. Increasing numbers of 0>1->2 variant copies were found to reduce the likelihood of fluid present at Week 52 from ~50% to ~25% to ~10%. (See Figure 7.) Figure 8 summarizes the SNPs identified in the study. Conclusions: A GWAS in patients with neovascular AMD undergoing anti-VEGF treatment in the VISTA 1 trial identified a suggestive association between a genetic variant and the presence of intraretinal fluid at week 52 as measured by TD-OCT. The variant was located on the X chromosome near the gene for PRK-X, a serine / threonine protein kinase involved in angiogenesis. zzpfrnn / eznz / B / YiAi It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention.
Claims
CLAIMS zzRtrnn / cznz / e / YiAi Having described the invention as above, the following claims are claimed as property:
1. A vascular endothelial growth factor (VEGF) inhibitor for use in the treatment of wet macular degeneration, wherein the VEGF inhibitor is adapted to be administered intravitreally to a patient, wherein the patient has previously been treated intravitreally with the VEGF inhibitor for approximately one year, and has one or more genetic variants that are single nucleotide polymorphisms selected from rs2106124, rsl879796, rsl2148845, rsl2148100, rsl7482885, and rsl7629019.
2. The VEGF inhibitor for use according to claim 1, wherein the VEGF inhibitor is adapted to be administered quarterly in a dosage of 2 mg or 0.5 mg.
3. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the VEGF inhibitor is either aflibercept or ranibi zumab.
4. The VEGF inhibitor for use in accordance with any of the preceding claims - 41, wherein one or more genetic variants are determined by establishing the genotype of a DNA sample obtained from the patient.
5. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the patient is heterozygous for one or more genetic variants.
6. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the patient is homozygous for one or more genetic variants.
7. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the patient has the rs2106124 single nucleotide polymorphism.
8. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the patient has the rsl879796 single nucleotide polymorphism.
9. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the patient has the rsl2148845 single nucleotide polymorphism.
10. The VEGF inhibitor for use in accordance with any of the preceding claims zzRtrnn / cznz / e / YiAi - 42, wherein the patient has the rsl2148100 single nucleotide polymorphism.
11. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the patient has the rsl7482885 single nucleotide polymorphism.
12. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the patient has the rsl7629019 single nucleotide polymorphism.
13. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the VEGF inhibitor is ranibizumab.
14. The VEGF inhibitor for use in accordance with any of the preceding claims, wherein the VEGF inhibitor is aflibercept.
15. A method of associating a genetic variant with decreased interstitial fluid in a patient with wet macular degeneration who has previously been treated intravitreally with a VEGF inhibitor for approximately one year, characterized in that it comprises: performing a genotype determination assay on a DNA sample obtained from the patient to determine the presence or absence of a single nucleotide polymorphism selected from rs2106124, rsl879796, zzRtrnn / cznz / e / YiAi - 43 rsl2148845, rsl2148100, rsl7482885, and rsl7629019, wherein, when the patient has the genetic variant, the patient is a candidate for intravitreal administration with a VEGF inhibitor in an amount of approximately 2 mg quarterly.
16. The method according to claim 15, characterized in that the VEGF inhibitor is aflibercept or ranibrzumab.
17. The method according to any of claims 15 or 16, characterized in that the patient is heterozygous for one or more genetic variants.
18. The method according to any of claims 15 to 16, characterized in that the patient is homozygous for one or more genetic variants.
19. The method according to any of claims 15 to 18, characterized in that the determination of the genotype is performed using a chip.