RU2812890C2 - Improved treatment of atopic dermatitis with tradipitant - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: group of inventions relates to a method of administering tradipitant, and is intended for the treatment of a patient suffering from itching or atopic dermatitis. A method of administering tradipitant in an amount effective to treat a patient suffering from pruritus or atopic dermatitis includes selecting the patient for treatment based on determining that the patient's genotype includes a genotype associated with high IgE levels or a positive response to treatment with tradipitant, wherein the genotype associated with high IgE levels was selected from the group consisting of rs4575660 TT, rs276555 CC, rs74416548 ATAT, rs276556 GG, rs276560 CC, rs276561 TT, rs276562 GG, rs276563 CC, rs276564 GG, rs276571 GG, rs140796 TATTGTATTG, rs276573 TT, rs276574 GG, rs4895474 TT, rs4895475 GG, rs9483989 TT, rs9373178 CC, rs4896234 CC, rs2327798 GG, rs62420823 GG, rs17252967 CC, rs9494657 AA, rs94 02871 GG, rs9402872 CC, rs9399201 GG, rs4896235 AA, rs719640 AA, rs9373179 AA, rs9385784 TT, rs2146275 AA, rs6941440 TT, rs4896237 TT, rs6929580 GG, rs4896239 TT, rs4895479 CC, rs4895480 TT, rs4280975 GG, rs6911523 AA, rs6912319 GG, rs2280090 non-GG and rs57930837 non-AA; and the genotype associated with a positive response to tradipitant treatment is selected from the group consisting of rs 16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs73258486 GG/GA, rs6480 251 CC/CT, rs6480252 TT/ TC, rs10822978 TT/TA, rs10997525 GG/GA, rs10997527 CC/CA, rs7074325 CC/CT, rs57930837 CC/CA, rs11453660 CACA/CAC, rs2199792 AA/AG, rs4963245 non-CC, rs129 90449 non-TT, rs727162 non- CC, rs58161637 non-GG, rs62622847 non-CC, rs3213755 non-AA, rs41521946 non-TT, rs28362678 non-AA, rs35624343 non-AA, rs28362677 non-TT, rs11207832 non-CC, rs1954436 non-CC, rs11207834 non-CC, rs370530530 non-CTCT, rs11207838 non-TT, rs150980554 non-AA, rs7551886 non-CC, rs6664979 non-CC, rs12043665 non-AA, rs12030784 non-TT, rs79037385 non-GG, rs74568 317 non-CC, rs3790575 non- CC and rs77939406 non-GG. A method of administering an amount of tradipitant effective to treat a patient suffering from pruritus or atopic dermatitis involves selecting the patient for such treatment based on determining that the patient's IgE level is greater than or equal to 50 kU/L.

EFFECT: use of a group of inventions makes it possible to improve the method of treating itching or atopic dermatitis in an individual in need of such treatment, due to the possibility of selecting a patient for treatment based on determining that the patient's genotype includes a genotype associated with a high level of IgE or with a positive response to treatment with tradipitant.

11 cl, 13 dwg, 12 tbl, 6 ex

Description

Cross references to related applications

This application claims benefit from US Provisional Patent Application No. 62/558,303, filed September 13, 2017, and US Provisional Patent Application No. 62/572,456, filed October 14, 2017.

Background of the present invention

Atopic dermatitis (AD) is a common, chronic and relapsing, inflammatory skin disorder caused by a hypersensitive skin reaction and is characterized by an intense and persistent symptom of scabies or itching that may be localized or even generalized and cannot be relieved by scratching. Other clinical signs include erythema, excoriation, edema, lichenification, oozing, and abnormal dryness. Scratching due to itching can contribute to the development of areas of raw, sensitive, puffy skin and make the skin more susceptible to infection. Atopic dermatitis is also known as diffuse dermatitis or eczema, and is often seen in children.

Immunoglobulin E (IgE)-mediated allergy plays a central role in the pathophysiology of atopic dermatitis and other clinical phenotypes such as asthma and food allergy. Atopy and plasma IgE concentrations are genetically complex traits (i.e., the heritability of which depends on a number of genes), and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active research.

Other genes are also included in the atopic dermatitis phenotype. The CTNNA3 gene encodes structural cadherin, which plays an important role in cell-cell adhesion. CTNNA3 also plays an important role in allergies and asthma. Reduced levels of CTNNA3 were detected in biopsy samples from the bronchi of asthmatics and were inversely correlated with the number of eosinophils. Genome-wide association studies (GWAS) have found that CTNNA3 variants are associated with response to glucorticoid therapy in children with asthma.

INADL is a gene that encodes a protein with multiple PDZ domains that are localized to the tight junctions and the apical membrane of epithelial cells. In patients with atopic dermatitis, tight junction defects have been identified; in particular, the tight junctions are located directly under the stratum corneum of the epidermis and regulate the selective permeability of the transcellular pathway.

Chronic itch, including itch caused by atopic dermatitis, is a serious and unmet medical need. The itch sensation is thought to be induced, at least in part, by the endogenous neuropeptide substance P (SP) upon binding to NK-1R receptors expressed on a variety of skin cells.

NK-1R is expressed in various tissues of the body, with the main activity detected in neuronal tissue. SP and NK-1R interactions in neuronal tissue locally regulate neurogenic inflammation and the pain pathway through the central nervous system. SP and NK-1R activity also occurs in other tissues, including endothelial cells and immune cells. Activation of NK-1R by the natural ligand SP is involved in a variety of physiological processes, including pain perception, behavioral stressors, cravings, and nausea and vomiting. Impaired overexpression of SP, either in neural tissue or peripheral tissues, can lead to pathological conditions such as chemical dependence, anxiety, nausea/vomiting, and pruritus. An NK-1R antagonist may have the ability to reduce such NK-1R overstimulation and, as a result, eliminate the pathophysiology of symptoms underlying these conditions.

Tradipitant is an effective and selective neurokinin-1 receptor antagonist, originally known as VLY-686, and has the chemical names 2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)- 1H-1,2,3-triazol-4-yl]-3-pyridinyl](2-chlorophenyl)methanone and {2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H- [1,2,3]triazol-4-yl]pyridin-3-yl}-(2-chlorophenyl)methanol with the following chemical structure:

Tradipitant is described in patent US7320994 and contains six main structural units: a 3,5-bis-trifluoromethylphenyl residue, two pyridine rings, a triazole ring, a chlorophenyl ring, and a methanone ring. Crystalline forms IV and V of traditionpitant are described in US7381826. The method for the synthesis of tradipitant is described in patents US8772496, US9708291 and US10035787.

Brief Description of the Present Invention

Various aspects of the present invention described herein relate to improved methods of treating pruritus or atopic dermatitis in an individual in need of such treatment by administering tradipitant in amounts effective for such treatment. One such improvement offers the ability to select a patient for treatment based on determining that the patient's genotype includes a genotype that is associated with high IgE levels or a positive response to tradipitant treatment. In particular, in a method of administering tradipitant in an amount effective to treat a patient suffering from pruritus or atopic dermatitis, one object of the present invention is an improvement comprising selecting a patient for treatment based on determining that the patient's genotype includes a genotype that is associated with high IgE level or with a positive response to treatment with tradipitant.

In this regard, the genotype associated with high IgE levels can be selected from the group consisting of: rs4575660 TT, rs276555 CC, rs74416548 ATAT, rs276556 GG, rs276560 CC, rs276561 TT, rs276562 GG, rs276563 CC, rs276563 CC , rs276564 GG, rs276564 GG, rs276571 GG, rs140796 TATTGTATTG, rs276573 TT, rs276574 GG, rs4895474 TT, rs4895475 GG, rs9483989 TT, rs9373178 CC, rs4896234 CC, rs2327798 GG, rs6 2420823 GG, rs 17252967 CC, rs9494657 AA, rs9402871 GG, rs9402872 CC, rs9399201 GG , rs4896235 AA, rs719640 AA, rs9373179 AA, rs9385784 TT, rs2146275 AA, rs6941440 TT, rs4896237 TT, rs6929580 GG, rs4896239 TT, rs4895479 CC, rs48 95480 TT, rs4280975 GG, rs6911523 AA, rs6912319 GG, rs2280090 non-GG and rs57930837 non -AA.

In addition, the genotype associated with a positive response to tradipitant treatment can be selected from the group consisting of: rs 16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs73258486 GG/GA, rs648 0251 CC/CT, rs6480252 TT/TC, rs 10822978 TT/TA, rs10997525 GG/GA, rs10997527 CC/CA, rs7074325 CC/CT, rs57930837 CC/CA, rs11453660 CACA/CAC, rs2199792 AA/AG, rs496324 5 non-CC, rs12990449 non-TT , rs727162 non-CC, rs58161637 non-GG, rs62622847 non-CC, rs3213755 non-AA, rs41521946 non-TT, rs28362678 non-AA, rs35624343 non-AA, rs28362677 non-TT, rs11207832 non-CC , rs1954436 non-CC , rs11207834 non-CC, rs370530530 non-CTCT, rs11207838 non-TT, rs150980554 non-AA, rs7551886 non-CC, rs6664979 non-CC, rs 12043665 non-AA, rs 12030784 non-TT, rs79037 385 non-GG, rs74568317 non -CC, rs3790575 non-CC and rs77939406 non-GG.

Another aspect of the present invention relates to a method of administering tradipitant in an amount effective to treat a patient suffering from pruritus or atopic dermatitis, which includes an improvement including selection of the patient for such treatment based on the determination that the IgE level is greater than or equal to 50 kU/L . In another embodiment, such an improvement is used if the patient has an IgE level greater than or equal to 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L, or 300 kU/L. In any case, such improved methods as described above can be used in practice when tradipitant is administered orally to such a patient at a dose of 100-400 mg/day or 100-300 mg/day or 100-200 mg/day. Specifically, the daily dosage may include administering 85 mg of tradipitant orally to the patient twice daily (bid).

The present invention also provides an improved method of treating a patient suffering from pruritus or atopic dermatitis with tradipitant, comprising first selecting a dosage effective to treat the patient based on determining that the patient's genotype for one or more SNPs (single nucleotide polymorphisms) includes genotype that is associated with IgE levels or with a positive response to tradipitant treatment, and then:

if the patient's genotype is associated with high IgE levels or a positive response to tradipitant treatment, then administering tradipitant orally to the patient at a dosage effective to treat the patient's pruritus or atopic dermatitis that would be chosen without identifying the patient's genotype, and

If the patient's genotype is not associated with high IgE levels or a positive response to tradipitant treatment, then administer oral tradipitant to the patient at a higher dosage than the dosage that would otherwise be chosen for the patient without identifying the patient's genotype.

The above method can be put into practice by identifying the patient's genotype from a SNP that is associated with high IgE levels, and this SNP is selected from the group consisting of: rs4575660, rs276555, rs74416548, rs276556, rs276560, rs276561, rs276562, rs276563, rs276 563, rs276564, rs276564, rs276571, rs140796, rs276573, rs276574, rs4895474, rs4895475, rs9483989, rs9373178, rs4896234, rs2327798, rs62420823, rs172529 67, rs9494657, rs9402871, rs9402872, rs9399201, rs4896235, rs719640, rs9373179, rs9385784, rs2146275, rs6941440, rs4896237, rs6929580, rs4896239, rs4895479, rs4895480, rs4280975, rs6911523, rs6912319, rs2280090 and rs57930837.

For example, this method can be used in practice if the genotype associated with high IgE levels is selected from the group consisting of: rs4575660 TT, rs276555 CC, rs74416548 ATAT, rs276556 GG, rs276560 CC, rs276561 TT, rs276562 GG, rs276563 CC, rs2 76563 CC, rs276564 GG, rs276564 GG, rs276571 GG, rs140796 TATTGTATTG, rs276573 TT, rs276574 GG, rs4895474 TT, rs4895475 GG, rs9483989 TT, rs9373178 CC, rs489 6234 CC, rs2327798 GG, rs62420823 GG, rs17252967 CC, rs9494657 AA, rs9402871 GG, rs9402872 CC, rs9399201 GG, rs4896235 AA, rs719640 AA, rs9373179 AA, rs9385784 TT, rs2146275 AA, rs6941440 TT, rs4896237 TT, rs6929580 GG, rs4896 239 TT, rs4895479 CC, rs4895480 TT, rs4280975 GG, rs6911523 AA, rs6912319 GG, rs2280090 non -GG and rs57930837 non-AA.

In another embodiment, this method can be put into practice by identifying the patient's genotype for a SNP that is associated with a positive response to treatment with tradipitant, and the SNP is selected from the group consisting of: rs16847120, rs249122, rs6862796, rs249137, rs249138, rs144713688, rs73258486, rs6480251, rs6480252, rs10822978, rs10997525, rs10997527, rs7074325, rs57930837, rs11453660, rs2199792, rs4963245, rs12990449, rs727162 , rs58161637, rs62622847, rs3213755, rs41521946, rs28362678, rs35624343, rs28362677, rs1l207832, rs1954436, rs1l207834, rs370530530, rs1l 207838, rs150980554, rs7551886, rs6664979, rs12043665, rs12030784, rs79037385, rs74568317, rs3790575 and rs77939406.

In yet another embodiment, the above method can be practiced if the genotype associated with a positive response to treatment with tradipitant is selected from the group consisting of: rs 16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs73258486 GG/GA, rs6480251 CC/CT, rs6480252 TT/TC, rs10822978 TT/TA, rs10997525 GG/GA, rs10997527 CC/CA, rs7074325 CC/CT, rs57930837 CC/CA, rs11453660 CA CA/CAC, rs2199792 AA/AG, rs4963245 non-CC, rs12990449 non-TT, rs727162 non-CC, rs58161637 non-GG, rs62622847 non-CC, rs3213755 non-AA, rs41521946 non-TT, rs28362678 non-AA, rs35624343 non-AA, rs 28362677 non-TT, rs11207832 non-CC, rs1954436 non-CC, rs11207834 non-CC, rs370530530 non-CTCT, rs11207838 non-TT, rs150980554 non-AA, rs7551886 non-CC, rs6664979 non-CC, rs 12043665 non -AA, rs 12030784 non- TT, rs79037385 non-GG, rs74568317 non-CC, rs3790575 non-CC and rs77939406 non-GG.

Another aspect of the present invention relates to a method of treating a patient suffering from pruritus or atopic dermatitis by administering tradipitant in an amount effective for such treatment, which includes selecting an effective dosage to treat the patient based on identifying the patient's baseline IgE level, and

if the patient's baseline IgE level is greater than approximately 100 kU/L, then administering orally to the patient tradipitant at a dosage effective to treat the patient's pruritus or atopic dermatitis that would be chosen without identifying the patient's baseline IgE level, and

If the patient's baseline IgE level does not exceed approximately 100 kU/L, then administer oral tradipitant to the patient at a higher dosage than the dosage that would otherwise be selected without identifying the patient's baseline IgE level.

In addition, the above method may further include identifying the patient's baseline IgE level by examining a biological sample from the patient to determine the amount of IgE in the biological sample. In addition, the above methods lead to the determination of different dosages based on genotype, including administration to a patient receiving a higher dosage when administered orally tradipitant in an amount of greater than 170 mg/day to 340 mg/day, in particular greater than 170 mg/day to 255 mg/day. More preferably, the amount may be greater than 170 mg/day, for example about 25% greater than 170 mg/day. As an example of dosage selection, a patient with an identified baseline IgE level greater than about 100 kU/L receives a dose of 170 mg/day, for example 85 mg twice daily (bid).

In another aspect, the present invention provides a method for selecting a dosage of tradipitant effective for treating a patient suffering from atopic dermatitis, comprising:

(1) identification of the patient's genotype by one or more SNPs selected from the group consisting of: rs4575660, rs276555, rs74416548, rs276556, rs276560, rs276561, rs276562, rs276563, rs276563, rs276564, rs27 6564, rs276571, rs140796, rs276573, rs276574, rs4895474 , rs4895475, rs9483989, rs9373178, rs4896234, rs2327798, rs62420823, rs17252967, rs9494657, rs9402871, rs9402872, rs9399201, rs4896235, rs719640, rs9373179, rs9385784, rs2146275, rs6941440, rs4896237, rs6929580, rs4896239, rs4895479, rs4895480, rs4280975, rs6911523, rs6912 319 , rs2280090, rs57930837, rs4963245, rs12990449, rs727162, rs58161637, rs62622847, rs3213755, rs41521946, rs28362678, rs35624343, rs2836 2677 and rs1l207834; And

(2) select a dosage of approximately 170 mg/day if:

(A) the patient's genotype includes one or more variants associated with high IgE levels selected from the group consisting of: rs4575660 TT, rs276555 CC, rs74416548 ATAT, rs276556 GG, rs276560 CC, rs276561 TT, rs276562 GG, rs276563 CC, rs2 76563 CC , rs276564 GG, rs276564 GG, rs276571 GG, rs140796 TATTGTATTG, rs276573 TT, rs276574 GG, rs4895474 TT, rs4895475 GG, rs9483989 TT, rs9373178 CC, rs489 6234 CC, rs2327798 GG, rs62420823 GG, rs17252967 CC, rs9494657 AA, rs9402871 GG, rs9402872 CC, rs9399201 GG, rs4896235 AA, rs719640 AA, rs9373179 AA, rs9385784 TT, rs2146275 AA, rs6941440 TT, rs4896237 TT, rs6929580 GG, rs4896239 TT, rs4 895479 CC, rs4895480 TT, rs4280975 GG, rs6911523 AA, rs6912319 GG, rs2280090 non- GG and rs57930837 non-AA; or

(B) one or more variants associated with a positive response to tradipitant treatment, selected from the group consisting of: rs16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs73258486 GG/GA, rs64 80251 CC/ CT, rs6480252 TT/TC, rs10822978 TT/TA, rs10997525 GG/GA, rs 10997527 CC/CA, rs7074325 CC/CT, rs57930837 CC/CA, rs11453660 CACA/CAC, rs2199792 AA/AG, rs496 3245 non-CC, rs12990449 non -TT, rs727162 non-CC, rs58161637 non-GG, rs62622847 non-CC, rs3213755 non-AA, rs41521946 non-TT, rs28362678 non-AA, rs35624343 non-AA, rs28362677 non-TT, rs 11207832 non -CC,rs 1954436 non-CC, rs 11207834 non-CC, rs370530530 non-CTCT, rs1l207838 non-TT, rs150980554 non-AA, rs7551886 non-CC, rs6664979 non-CC, rs 12043665 non-AA, rs 12030784 non-TT, rs79037385 non -GG, rs74568317 non-CC, rs3790575 non-CC and rs77939406 non-GG; or

(3) choosing a dosage greater than approximately 170 mg/day unless the patient's genotype includes a variant associated with high IgE or a positive response to tradipitant treatment.

The present invention also includes a method for determining a dosage of tradipitant effective for treating a patient suffering from atopic dermatitis in whom a baseline IgE level has been identified, which includes selecting a dosage of about 170 mg/day if the patient's baseline IgE level is greater than about 100 kU/L, or dosages greater than 170 mg/day if the patient's baseline IgE level does not exceed approximately 100 kU/L. The present invention also relates to a method for determining the possibility of a patient’s response to treatment of atopic dermatitis with tradipitant, which includes:

(1) identification of the patient's genotype by one or more SNPs selected from the group consisting of: rs4575660, rs276555, rs74416548, rs276556, rs276560, rs276561, rs276562, rs276563, rs276563, rs276564, rs27 6564, rs276571, rs140796, rs276573, rs276574, rs4895474 , rs4895475, rs9483989, rs9373178, rs4896234, rs2327798, rs62420823, rs17252967, rs9494657, rs9402871, rs9402872, rs9399201, rs4896235, rs719640, rs9373179, rs9385784, rs2146275, rs6941440, rs4896237, rs6929580, rs4896239, rs4895479, rs4895480, rs4280975, rs6911523, rs6912 319 , rs2280090, rs57930837, rs4963245, rs12990449, rs727162, rs58161637, rs62622847, rs3213755, rs41521946, rs28362678, rs35624343, rs2836 2677 and rs1l207834; And

(2) determining the possibility of a patient developing a response to the specified treatment if the patient’s genotype includes one or more variants selected from: rs4575660 TT, rs276555 CC, rs74416548 ATAT, rs276556 GG, rs276560 CC, rs276561 TT, rs276562 GG, rs276563 CC, rs276563 CC, rs276564 GG, rs276564 GG, rs276571 GG, rs140796 TATTGTATTG, rs276573 TT, rs276574 GG, rs4895474 TT, rs4895475 GG, rs9483989 TT, rs937317 8 CC, rs4896234 CC, rs2327798 GG, rs62420823 GG, rs 17252967 CC, rs9494657 AA, rs9402871 GG, rs9402872 CC, rs9399201 GG, rs4896235 AA, rs719640 AA, rs9373179 AA, rs9385784 TT, rs2146275 AA, rs6941440 TT, rs4896237 TT, rs6929580 GG, rs4 896239 TT, rs4895479 CC, rs4895480 TT, rs4280975 GG, rs6911523 AA, rs6912319 GG, rs2280090 non-GG and rs57930837 non-AA; or

one or more variants associated with a positive response to tradipitant treatment, selected from the group consisting of: rs 16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs73258486 GG/GA, rs6480 251 CC/CT, rs6480252 TT/TC, rs 10822978 TT/TA, rs10997525 GG/GA, rs10997527 CC/CA, rs7074325 CC/CT, rs57930837 CC/CA, rs11453660 CACA/CAC, rs2199792 AA/AG, rs496324 5 non-CC, rs12990449 non-TT , rs727162 non-CC, rs58161637 non-GG, rs62622847 non-CC, rs3213755 non-AA, rs41521946 non-TT, rs28362678 non-AA, rs35624343 non-AA, rs28362677 non-TT, rs11207832 non-CC , rs1954436 non-CC , rs11207834 non-CC, rs370530530 non-CTCT, rs11207838 non-TT, rs150980554 non-AA, rs7551886 non-CC, rs6664979 non-CC, rs 12043665 non-AA, rs 12030784 non-TT, rs79037 385 non-GG, rs74568317 non -CC, rs3790575 non-CC and rs77939406 non-GG.

The present invention also provides a method for identifying a patient whose IgE level is identified as likely to respond to tradipitant treatment for atopic dermatitis, which includes determining the patient's likelihood of responding to tradipitant treatment if the patient's baseline IgE level exceeds 100 kU/L.

Based on the foregoing, the present invention is characterized by a number of objects, which can be described as follows.

In a first aspect, the present invention provides an improved method of treating pruritus or atopic dermatitis in an individual in need of such treatment, comprising orally administering tradipitant.

In a second aspect, the present invention provides a method that includes treating pruritus and/or atopic dermatitis in an individual in need of such treatment, comprising administering orally tradipitant to the individual. According to this method, a patient can be selected for treatment based on the patient's IgE level being greater than or equal to a cut-off value, which may be, for example, 50 kU/L, 75 kU/L, 100 kU/L, 150 kU/L, 200 kE/l or 300 kE/l.

In the first or second aspect, the dose of tradipitant may be, for example, 100-400 mg/day, 100-300 mg/day, 100-200 mg/day, or approximately 170 mg/day, which may be administered at 85 mg twice daily (bid).

In a third aspect, the present invention provides a method of treating a patient with tradipitant where the patient suffers from pruritus and/or atopic dermatitis. The method includes the following steps: identification of the patient's genotype by one or more SNPs associated with IgE levels or with the effect of treatment with tradipitant, and if the patient's genotype is associated with a high level of IgE or with a positive response to treatment with tradipitant, then administering tradipitant orally to the patient in the first dosage and if the patient's genotype is not associated with high IgE levels or with a positive response to treatment with tradipitant, then administering to the patient a second dosage of tradipitant that is higher than the first dosage, or orally administering an active pharmaceutical ingredient other than tradipitant.

In a fourth aspect, the present invention provides a method of treating a patient with tradipitant where the patient suffers from pruritus and/or atopic dermatitis. The method includes the following steps: identifying the patient's baseline IgE level, and if the patient's baseline IgE level is greater than or equal to a limit value, which may be, for example, 50 kU/L, 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L or 300 kU/L, then administering tradipitant orally to the patient in the first dosage, and if the patient’s initial IgE level does not exceed the limit value, then administering tradipitant orally to the patient in a second dosage that exceeds the first dosage, or administering the active pharmaceutical ingredient , different from tradipitant. In various embodiments of the present invention, the first dosage may be approximately 170 mg/day, which may be administered at 85 mg twice daily, and the second dosage may be, for example, approximately >170-340 mg/day or >170-255 mg/day. day.

A fifth aspect of the present invention provides a method for selecting a dosage of tradipitant for the treatment of a patient suffering from atopic dermatitis, which includes identifying the patient's genotype for one or more SNPs that are associated with high IgE levels or with a positive response to treatment with tradipitant, where the dosage is approximately 170 mg/day if the patient's genotype includes one or more variants associated with high IgE, and the dosage exceeds approximately 170 mg/day, unless the patient's genotype includes a variant associated with high IgE or a positive response to tradipitant treatment.

A sixth aspect of the present invention provides a method for selecting a dosage of tradipitant for treating a patient suffering from atopic dermatitis, which includes identifying the patient's baseline IgE level, wherein the dosage is approximately 170 mg/day if the patient's baseline IgE level is greater than or equal to a cutoff level such such as 50 kU/L, 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L, or 300 kU/L, and the dosage is greater than about 170 mg/day if the patient's baseline IgE level is less than the maximum level.

A seventh aspect of the present invention provides a method for predicting the likelihood of a patient's response to treatment for atopic dermatitis and/or pruritus with tradipitant, comprising identifying the patient's genotype for one or more SNPs associated with high IgE levels or with a positive response to treatment with tradipitant, wherein the patient has may respond to a specified treatment if the patient's genotype includes one or more variants associated with high IgE, and the patient is unlikely to respond to a specified treatment unless the patient's genotype includes a variant associated with high IgE or a positive response for treatment with tradipitant.

An eighth aspect of the present invention provides a method for predicting the likelihood of a patient's response to treatment for atopic dermatitis and/or pruritus with tradipitant, including identifying a patient's baseline IgE level, wherein the patient may respond to said tradipitant treatment if the patient's baseline IgE level is equal to the cutoff value. level or greater than, for example, equal to or greater than 50 kU/L, 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L, or 300 kU/L, and the patient is likely to respond to said treatment. unlikely if the patient's baseline IgE level is below the cutoff level.

Brief description of the figures

In FIG. Figure 1 shows a scatter diagram of changes in visual analogue scale (VAS) indicators depending on the concentration-mass of tradipitant (Spearman's rank correlation p = 0.0204), as described in Example 1.

In FIG. Figure 2 is a scatter plot of tradipitant serum levels, that is, it shows the change in concentration-weight depending on the time of visit to the doctor, as described in Example 1.

In FIG. 3 shows the test setup as described in Example 3.

In FIG. Figure 4 shows the change in itching scores over time compared to baseline results during testing as described in Example 3

In FIG. Figure 5 shows the dependence of disease indicators on time during the tests described in Example 3.

In FIG. Figure 6 shows the association of SNP rs276571 with IgE levels, as described in Example 5.

In FIG. Figure 7 shows the association of SNP rs276571 with the original SCORAD value, as described in Example 5.

In FIG. Figure 8 shows the association of SNP rs4575660 with log-transformed IgE levels data as described in Example 5.

In FIG. Figure 9 shows the association of SNP rs2280090 with IgE levels, as described in Example 5.

In FIG. 10 shows the proportion of patients with and without response to treatment of atopic dermatitis with tradipitant among carriers of the minor allele of CTNNA3 rs57930837, as described in Example 6.

In FIG. 11 shows the number of patients (n) with and without response to treatment of atopic dermatitis with tradipitant, stratified by CTNNA3 rs57930837 genotypes, as described in Example 6.

In FIG. 12 shows the association of CTNNA3 rs57930837 variants with IgE levels, as described in FIG. 6.

In FIG. 13 shows the association of INADL rs11207834 variants with changes in the Severe Pruritus Test scores as described in Example 6.

Detailed Description of the Present Invention

In various embodiments of the present invention, the improved methods described herein include methods for treating pruritus and/or atopic dermatitis using tradipitant, methods for selecting a dosage of tradipitant to treat a patient suffering from atopic dermatitis and/or pruritus, and methods for determining whether the patient may develop response to treatment of atopic dermatitis and/or pruritus with tradipitant.

A method of using tradipitant to treat atopic dermatitis and/or pruritus in a patient may involve first identifying the patient's genotype for one or more SNPs that are associated with one or both of IgE levels or the effect of tradipitant treatment. As described in the Examples section below, baseline immunoglobulin E (IgE) levels are associated with the effect of tradipitant treatment. For this reason, genetic modifiers of IgE can also be considered as markers of the effect of tradipitant treatment. In addition, the present invention has identified a number of genetic markers that are directly associated with the effect of tradipitant treatment, regardless of IgE levels. Examples of such SNPs are presented here, for example in Tables 8, 10, 11 and 12.

The identification stage may include a number of different identification methods. In one aspect of the present invention, genotype identification may include genotyping a biological sample taken from a patient in need of treatment. The biological sample may include, for example, blood, serum, saliva, urine, etc., as is known in the art. In another aspect of the present invention, genotype identification may include examination of a patient's medical history, study report, or other document containing the results of prior testing or genetic testing. In other aspects of the present invention, identification may include directing or requesting that another person perform a test, or directing or requesting to review a patient's medical history, results report, or other document containing the result of a previously performed test or genetic test.

If the patient's genotype at one of these SNPs is associated with one or both of high levels of immunoglobulin E (IgE) or a significant effect of tradipitant treatment, then the method further includes administering a first dose of tradipitant orally to the patient. The first dose may be, for example, 100 to 400 mg/day, 100 to 300 mg/day, 100 to 200 mg/day, or about 85 to 170 mg/day, which may be administered, for example, as a dose of 50 up to 200 mg twice daily, 50 to 150 mg twice daily, 50 to 100 mg twice daily, or approximately 85 mg twice daily (bid).

In the event that the patient's genotype at one of the specified SNPs is not associated with one or both of the parameters - with a high level of IgE or with a significant effect of treatment with tradipitant at any of the specified SNPs, then the method includes an alternative treatment. Such alternative treatment may include, for example, administering a second oral dose of tradipitant that is greater than the first dose. For example, the second dose may be 150%, 200%, 250%, or 300% of the first dose, or may exceed a dose of 170 mg/day to 255 mg/day, or 170 mg/day to 340 mg/day. A dose higher than 170 mg/day may mean, for example, 25% more. Such increased dosages may be accompanied by increased patient monitoring. In other embodiments of the present invention, the alternative treatment may include the oral administration of an active pharmaceutical ingredient other than tradipitant.

Another method of using tradipitant to treat atopic dermatitis and/or pruritus in a patient involves first identifying a baseline IgE level. The IgE level of a patient can be identified, for example, by collecting a biological sample from the patient and determining the amount of IgE present in the biological sample. The biological sample may be a blood sample, a serum sample, or a similar sample known in the art.

For both pruritus severity and disease severity, a greater treatment effect was consistently observed among patients with high IgE levels compared with low IgE levels, regardless of the specific cutoff used to define the boundary between high and low IgE levels. For example, this relationship occurs regardless of whether the high IgE group is defined as being greater than a cutoff value, such as 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L, or 300 kU/L, and whether the group is defined low IgE as a value lower than the limit value, for example 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L or 300 kU/L. In practice of the present invention, any of these definitions of high or low IgE levels may be used.

If the patient is determined to have a high IgE level, for example, the IgE level is greater than or equal to the cutoff value, which is 50 kU/L, 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L, or 300 kU/L, then the patient can be expected to experience a significant response to tradipitant treatment. In such a patient, tradipitant can be administered orally in the first dosage. However, if the patient's baseline IgE level is below the selected cutoff value, such as less than 50 kU/L, less than 75 kU/L, less than 100 kU/L, less than 150 kU/L, less than 200 kU/L, or less than 300 kU/L, then the patient may be administered orally tradipitant at a second dosage that is greater than the first dosage, or an active pharmaceutical ingredient other than tradipitant may be administered orally. The first dosage and the second dosage may be higher than previously described dosages.

Methods for selecting dosage for treating a patient suffering from atopic dermatitis and/or pruritus with tradipitant are also described herein. Such a method may include identifying the patient's genotype for one or more SNPs described to be associated with one or both of IgE levels or the effect of tradipitant treatment, or alternatively identifying the patient's IgE level. Methods for identifying said genotype or IgE level may include methods described previously. Based on the identification or determination of the genotype or IgE level of an individual, dosage can be selected for a particular patient. For example, if the patient's genotype includes one or more variants associated with high IgE or with a positive response to tradipitant treatment, or if the patient's IgE level is identified as exceeding a cutoff value, e.g., 50 kU/L, 75 kU/L, 100 kU/L , 150 kU/L, 200 kU/L, or 300 kU/L, then the patient can choose a dosage of approximately 170 mg/day. More preferably, such dosage may be, for example, 85 mg twice daily (bid). If the patient's IgE level is identified below the cutoff value, such as below 50 kU/L, 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L, or 300 kU/L, then the patient may be given a dosage greater than approximately 170 mg/day. Such dosage may be, for example, 150%, 200%, 250% or 300% of the first dosage of approximately 170 mg/day. Thus, the dosage may be, for example, greater than about 170 mg/day to 255 mg/day, or greater than about 170 mg/day to 340 mg/day.

Methods for predicting the possibility of a patient's response to treatment of atopic dermatitis with tradipitant are also further described. Such methods may include identifying a patient's genotype for one or more SNPs described herein as being associated with one or both of IgE levels or the effect of tradipitant treatment, or alternatively identifying the patient's IgE level. Methods for identifying said genotype or IgE level may include methods described previously. Based on the identification or determination of an individual's genotype or IgE level, it can be predicted whether the patient will have a favorable response to treatment of atopic dermatitis and/or pruritus with tradipitant. For example, if the patient's genotype includes one or more variants associated with high IgE or with a positive response to tradipitant treatment, or if the patient's IgE level is identified as exceeding a cutoff value, for example, 50 kU/L, 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L, or 300 kU/L, the patient may respond to treatment with tradipitant. However, if the patient's genotype does not include any of the variants associated with high IgE or with a positive response to tradipitant treatment, or if the patient's IgE level is identified below the cutoff value, for example below 50 kU/L, 75 kU/L, 100 kU/L, 150 kU/L, 200 kU/L, or 300 kU/L, the patient may be considered unlikely or less likely to respond to treatment with tradipitant, or the patient may be considered unlikely or less likely to develop a significant response to treatment with tradipitant. Such information is useful for patients and health care professionals because it is important for routine identification of patients who will particularly benefit from treatment with tradipitant, as well as for reducing misguided trials and attempts to determine successful therapy, especially in individuals who are unlikely to benefit from treatment with tradipitant. development of a response to treatment with tradipitant at a dose of 170 mg/day. Such individuals may benefit from treatment with, for example, a different pharmacologically active ingredient or a higher dose of tradipitant.

As used herein, the terms “patient” and “individual” mean a mammal that suffers from one or more disorders that are ameliorated by administration of tradipitant, for example, atopic dermatitis, pruritus, and pruritus associated with atopic dermatitis. Examples of mammals within this term are guinea pigs, dogs, cats, rats, mice, horses, cattle and humans. It should be understood that the most preferred patient is a human being.

It should also be noted that one skilled in the art can treat the disorder or provide prophylaxis to a patient suffering from the disorder with an effective amount of tradipitant. Thus, the terms “treatment” or “therapy” are intended to include all processes that can slow, interrupt, arrest, control, or arrest the progression of the diseases or disorders described herein, and these terms are intended to include preventive measures against such disorders , but do not necessarily indicate complete elimination of all symptoms of the disorder.

As used herein, the term “effective amount” of tradipitant means an amount effective in treating the disorders described herein.

With respect to dosage, "qd" means administration once daily, and "bid" generally means administration once in the morning and once in the evening, generally at least about 8 hours apart or more than about 16 hours apart, e.g. 10-14 hours or at 12 hour intervals (Q12H).

The terms used here are “first”, “second”, etc. do not denote any order, quantity or importance, but rather are used to distinguish one element from another, and the term herein in the singular does not denote a limitation of quantity, but rather the presence of at least one of the enumerated elements. The term "approximately" as used herein in connection with a quantity includes the indicated value and has a meaning determined by the context (eg, includes the degree of error associated with the measurement of a particular quantity). The plural reference in parentheses is intended to denote both the singular and the plural of the term, thereby including one or more such terms (eg, metal(s) means one or more metals). The intervals described herein are inclusive and independently combinable intervals (e.g., the intervals “up to about 25 mg, or particularly from about 5 mg to about 20 mg” include the end points and all intermediate values of the intervals “from about 5 mg to about 25 mg”, etc.).

It will be apparent to one skilled in the art that additional preferred embodiments of the present invention can be selected by combining the preferred embodiments above or by reference to the examples presented herein.

Example 1

Tradipitant monotherapy for the treatment of chronic pruritus in patients suffering from atopic dermatitis

A phase II proof-of-concept clinical trial was conducted to investigate the safety and efficacy of tradipitant in the monotherapy treatment of chronic pruritus in patients suffering from atopic dermatitis (Study ID VP-VLY-686-2101, "Proof of Concept of VLY-686 in Subjects With Treatment-Resistant Pruritus Associated With Atopic Dermatitis").

Despite the highly significant and clinically significant improvement from baseline with tradipitant (40.5 mm improvement from baseline, p < 0.0001), measured by visual analogue scale (VAS) in a 100 mm assessment device pruritus, a very large placebo effect (36.5 mm improvement from baseline, p < 0.0001) on change from baseline resulted in no statistically significant difference from placebo. However, subsequent pharmacokinetics (PK) analysis of the population of all patients included in the study revealed significant and clinically significant responses across multiple endpoints assessed in individuals with higher levels of tradipitant exposure during the pruritus assessment.

The prespecified endpoint of the phase II proof of concept clinical trial was change from baseline in pruritus on a visual analogue scale (VAS). Due to the high placebo effect, no significant difference from placebo was observed for this prespecified endpoint. However, subsequent analyzes unexpectedly revealed that there was a response-exposure relationship. There was a significant and clinically significant response observed in several pruritus-related outcomes assessed in individuals with higher plasma levels of tradipitant. Based on the data examined in the study, lower plasma levels of tradipitant may be below the threshold of effectiveness sufficient to reduce the sensation of itching in patients.

Methods

During the trial, patients who experienced pruritus VAS greater than 70 mm on one of the two days before trial entry were randomized to receive either 100 mg oral tradipitant (n=34) or placebo (n=35) once daily. In the evening. In the tradipitant arm trials, patients took oral tradipitant capsules containing standard excipients at a dose of 100 mg in the evening. Clinical tests were performed 3 or 4 weeks after daily dosing or at both 3 and 4 weeks, with each test performed in the morning of the day after the last dosing or at noon on the day after the last dosing. Tradipitant was administered in an immediate-release form comprising tradipitant and pharmaceutically acceptable excipients in a capsule. The particle size of tradipitant was approximately D ₁₀ : <5 µm, D ₅₀ : <10 µm and D ₉₀ : <25 µm, where D ₁₀ means that 10% of the particles have the stated average particle size, D ₅₀ means that 50% of the particles have the indicated average particle size and D ₉₀ means that 90% of the particles have the indicated average particle size.

Baseline VAS scores were 76.1 and 77.2 in the tradipitant and placebo groups, respectively. Efficacy was assessed using a range of clinical trial instruments. In addition, blood samples were collected concurrently with efficacy assessments for pharmacokinetic (PK) analysis to determine plasma levels of tradipitant.

results

As shown in FIG. 1, PK-PD (pharmacokinetic-pharmacodynamic data) data in the tradipitant groups indicate a significant correlation between tradipitant blood levels and changes in VAS compared to baseline (p<0.05). Individuals with higher circulating levels of tradipitant at the time of efficacy assessment have a higher response rate. A separate PK analysis at the time of pruritus assessment shown in FIG. 2 suggests that half of the patients in the trial had a laboratory assessment for pruritus in the morning (arm AM, ~12 hours post-dose) and that these patients also had higher blood levels of tradipitant than in patients who visited the laboratory in the afternoon (RM group, ~18 hours after dosing).

The mean plasma concentrations of tradipitant in the AM and PM groups studied ranged from approximately 125 ng/mL to approximately 225 ng/mL. Patients assessed in the afternoon (PM) (mean = approximately 20 hours after last dose) generally had lower tradipitant plasma concentrations than patients assessed in the morning (AM) (mean = approximately 15 hours after last dose). h after the last injection). The mean plasma concentration in the PM group was approximately 125 ng/mL, and the mean plasma concentration in the AM group was approximately 225 ng/mL, with the difference largely related to the length of time after administration. More importantly, the results indicate a correlation between plasma concentration and efficacy when in patients with plasma concentrations >100 ng/mL (eg, approximately 125 ng/mL or more, approximately 150 ng/mL or more, approximately 175 ng/mL or more, approximately 200 ng/mL or more, or approximately 225 ng/mL or more) generally results in greater efficacy than in patients with lower plasma concentrations.

Post hoc analysis in the AM group showed a significant and clinically significant effect of tradipitant compared with placebo, as shown in Table 1. Higher concentrations of tradipitant were associated with higher efficacy in the treatment of chronic itch in the trials. A similar analysis in the PM group showed no significant difference between tradipitant and placebo.

These data are consistent with the hypothesis that the NK-1R antagonist tradipitant may lead to symptomatic relief in patients suffering from pruritus (subjective assessment by VAS, VRS, SCORAD). The trials also collected data on disease-specific endpoints (SKINDEX, SCORAD, EASI and DLQI). These results do not show any significant differences from placebo that would be expected from a drug targeting the symptom of itching in a short-term 4-week study. It is important to note that since patients primarily complain of intractable itching associated with atopic dermatitis, the effects that were also observed on the CGI-C and PBI scales indicate a significant overall clinically significant effect from both a physician and physician perspective. patient.

Conclusion

These data support the conclusion that patients suffering from pruritus, such as pruritus associated with atopic dermatitis, can be treated with oral administration of tradipitant, for example, as Form IV or Form V (or a pharmaceutically acceptable salt thereof) in the amount and frequency of administration, required to achieve plasma concentrations of at least about 100 ng/ml, for example, 125 ng/ml or more, 150 ng/ml or more, 175 ng/ml or more, 200 ng/ml or more, or 225 ng/ml or more. Such plasma concentration levels can be achieved, for example, by orally administering tradipitant as immediate-release solid dosage forms once daily at a higher dose or immediate-release forms with improved bioavailability or controlled-release forms, or by orally administering tradipitant on multiple occasions. per day, for example, two or more times per day, at a lower dose in immediate-release or controlled-release forms. While trial data indicate that effective plasma concentrations can be achieved within approximately 12 to 18 hours, e.g., approximately 15 hours, following treatment with tradipitant 100 mg/day in solid form, i.e., immediate-release capsules, it should be understood that effective plasma concentrations can be achieved using different doses and/or different formulations, including, but not limited to, controlled release formulations.

In conclusion, although these trials did not show an overall effect of the predetermined dose of tradipitant, largely due to a significant placebo effect, the trials do provide evidence of a PK-response relationship and significant beneficial effects. effects in a group of patients studied at higher tradipitant concentrations. In these trials, tradipitant 100 mg once daily was well tolerated and had a low adverse event profile that was similar to placebo.

Treatment of the patient may continue until the patient's itching symptoms are improved or eliminated, for example, improved such that the patient is able to function more or less normally during waking hours and sleep more or less normally during sleep hours.

As described above, data suggest that patients suffering from pruritus, such as pruritus associated with atopic dermatitis, can be treated with oral administration of tradipitant. The following trials demonstrate the safety and effectiveness of various dosing schedules.

Example 2

Tradipitant Plasma Concentration Levels

In the trial, healthy participants took 85 mg of tradipitant orally on trial day 3, and then 85 mg of tradipitant every 12 hours (Q12H) on trial days 4–16. Tradipitant plasma concentration levels were measured on day 3, day 7 and day 11.

These trials found that 85 mg of tradipitant administered once daily (on Day 3) resulted in mean plasma concentrations over 0 to 12 hours that were approximately 50% of the plasma concentrations observed in the PM group in Example 1. On days 7 and 11, the mean plasma concentrations during the 0-12 hours following administration of tradipitant 85 mg twice daily (bid, specifically Q12H) are approximately 150% of the plasma concentrations observed in the PM group in Example 1 The mean plasma concentration during 0-12 hours at each measurement time was determined by dividing the AUC value (in units (h) × (ng/ml)) during 0-12 hours by 12 hours.

These results suggest that patients suffering from pruritus, such as pruritus associated with atopic dermatitis, can be treated with oral administration of tradipitant, for example, as Form IV or Form V (or a pharmaceutically acceptable salt thereof) at 85 mg two times daily, for example 85 mg Q12H, to achieve plasma concentrations above 125 ng/ml observed in the PM group in Example 1.

Example 3

Treatment with tradipitant of chronic itching associated with atopic dermatitis

A multicenter, randomized, double-blind, placebo-controlled phase II clinical trial (Tradipitant for Treatment-Refractory Pruritus Associated with Atopic Dermatitis, clintrials.gov Trial ID NCT02651714) was conducted to determine the effectiveness of tradipitant compared with placebo in reducing chronic itching as measured by the VAS scale.

Methods

Trial inclusion criteria include a history of chronic (≥6 weeks) pruritus associated with treatment-resistant atopic dermatitis, mean pruritus VAS score≥70 mm (out of 100 mm), Verbal Rating Scale (VRS) score≥3 on at least one of the last three days before randomization, and SCORAD <80. Study demographics are shown in Table 2 below.

Patients were randomized to receive either 85 mg tradipitant or placebo (1:1) twice daily (bid). The design of the multicenter, randomized, double-blind, placebo-controlled clinical trial is shown in FIG. 3. Individuals with chronic pruritus associated with atopic dermatitis were administered 85 mg of tradipitant or placebo BID for 8 weeks. Average itching severity and highest severity of itching were assessed using VAS parameters, and VRS parameters were assessed every two weeks. In addition, treatment was assessed twice weekly using the Severity Scoring of Atopic Dermatitis: The SCORAD Index, Consensus Report of the European Task Force on Atopic Dermatitis, Dermatology 1993; 186:23- 31) and Eczema Area and Severity Index (EASI) (Hanifin et al., The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis, Experimental Dermatology 10(1): 11-18 (2001)).

The trial also used the Clinical Global Assessment of Change (CGI-C), Patient Global Intervention (PGIC) scale for both pruritus and atopic dermatitis, Patient Benefit Index (PBI) and SKINDEX-16. Twice daily, patients completed questionnaires to report severe and moderate pruritus on a Numeric Rating Scale (NRS).

The objective SCORAD assessment includes parameters including extent, intensity, abrasions, erythema, oozing or scabs, presence of edema or papules, lichenification, and dry skin. The subjective SCORAD assessment includes the patient's assessment of itching and insomnia.

results

As described, 168 trial patients were randomized to BID tradipitant (n=84) or placebo (n=84). Among the 84 patients randomized to tradipitant, 56 patients completed the trial and 28 patients completed the trial early. Among the 84 patients randomized to placebo, 59 patients completed the trial and 25 patients completed the trial early.

The results of these tests are shown in Tables 3-4 as well as in FIG. 4-5. Similar to the results of the AM group described in Example 1, there were statistically significant differences between the tradipitant and placebo groups for severe pruritus ((p=0.019), PBI (p=0.038), CGIC (p=0.007) and objective scale scores. SCORAD scale (p=0.005), with treatment effects of both itching and disease severity appearing as early as week 2 (Figures 4-5).A variety of symptoms of atopic dermatitis were recorded using daily questionnaires, which also showed differences earlier than week 2.

These results also show statistically significant differences in PGI-C scores for both pruritus and atopic dermatitis (p=0.0246 and 0.007, respectively), as well as the proportion of patients who achieved a 50% or greater improvement in SCORAD scores. , or an improvement of 75% or more on the EASI score, was statistically significantly greater in patients receiving tradipitant compared with placebo.

conclusions

The results described above indicate that tradipitant reduces the severity of severe pruritus in patients, as well as the severity of atopic dermatitis. Tradipitant exhibits significant and clinically significant improvement across a range of pruritus reduction measures. First of all, significant improvements were observed when measuring severe pruritus on the VAS scale (p=0.019). Tradipitant also had a significant effect in patients assessing treatment response for severe pruritus with an improvement greater than or equal to 40 points from baseline on the VAS severe pruritus scale (p=0.037) or greater than or equal to 30 points (p=0.049). When assessed by the prespecified primary endpoint of mean pruritus VAS, tradipitant showed improvement compared with placebo, but this improvement was not significant due to the high placebo effect and the lack of sensitivity of this measure.

Consistent with the observed improvements in the severity of itching scores associated with scratching, tradipitant also exhibited disease-modifying properties, with significant improvements in the global SCORAD score (p=0.008) and the objective SCORAD score (p=0.005). In particular, tradipitant has significant improvements in several clinical measures of atopic dermatitis severity, including excoriation, erythema, weeping, and dryness.

These clinically significant effects were also associated with significant improvements in the Clinical Global Assessment of Change (CGI-C) score (p=0.007), the Patient Global Clinical Assessment of Pruritus (PGI-C) score (p=0.024), and the PGI-C score. atopic dermatitis (p=0.007). Likewise, tradipitant was also characterized by direct patient-reported benefits as measured by the Patient Benefit Index (PBI) (p=0.037). These improvements, as well as improvements in the Eczema Severity and Area Index (EASI), a measure of extent (proportion of lesions in each of the four body regions: head and neck, trunk, upper extremities, and lower extremities) and disease severity (score of redness, thickness , scratching, and lichenification)) demonstrate the effectiveness of tradipitant in improving measures of underlying atopic dermatitis disease severity in addition to symptoms of pruritus.

Example 4

Immunoglobulin E

In the trials described above in Example 3, an exploratory study was conducted to evaluate immunoglobulin E (IgE) levels and the effect of tradipitant in treating atopic dermatitis and pruritus. For the purposes of the study, trial participants with IgE levels greater than or equal to 100 kU/L were considered high IgE patients, whereas trial participants with IgE levels less than 100 kU/L were considered low IgE patients. The baseline mean and overall range of SCORAD scores for each study population, high IgE group and low IgE group are shown below in Table 5.

The mean and range of SCORAD total scores reported in Table 5 indicate that the study population experiences varying levels of disease severity, ranging from mild to severe. Table 5 also shows the similarity in disease severity between the high IgE and low IgE groups. Table 6 (below) presents the results of trials of tradipitant for the treatment of pruritus associated with treatment-resistant atopic dermatitis in individuals with high baseline IgE levels (IgE≥100 kU/L), and Table 7 (below) presents results of trials of tradipitant in the treatment of pruritus associated with treatment-resistant atopic dermatitis in individuals with low baseline IgE levels (IgE <100 kU/L). The data shown in Tables 6-7 represent the IgE breakdown of the data shown in Table 4 above.

Tables 6-7 show the results compared to the baseline. As demonstrated in Table 6, patients with high baseline IgE values showed a significant effect of tradipitant (p < 0.05) on most measures tested, including, for example, severe pruritus and sleep. Surprisingly, when comparing individuals with low IgE levels (Table 7), individuals with high IgE levels (Table 6) also showed significant treatment effects on measures of atopic dermatitis disease severity. In the same analysis, at week 8, 47% of patients treated with tradipitant achieved at least a 50% reduction in SCORAD score (SCORAD 50) compared with 11% of patients treated with placebo (p=0.0008 ).

For the purposes of this study, individuals with IgE levels greater than or equal to 100 kU/L were considered to have high IgE levels, and those with IgE levels less than 100 kU/L were considered to have low IgE levels. Additional studies were also conducted in which individuals with high IgE levels were considered to have IgE levels greater than or equal to 50 kU/L to greater than or equal to 300 kU/L. For both pruritus and disease severity, a significantly greater treatment effect was observed in the high IgE group compared with the low IgE group, regardless of whether the high IgE group was defined by values such as IgE≥ 50 kU/L, ≥100 kU/L, or ≥300 kU/L, and whether the low IgE group is defined by the following values, for example, IgE <50 kU/L, <100 kU/L, or <300 kU/L. As the cutoff value for the high IgE group, a value greater than or equal to 100 kU/L was selected for the most detailed study (Tables 6-7) as the value considered by the reference laboratory to be the upper limit of the normal range for adults. Based on these results and extrapolation of the normal range in children, it is also possible to identify a group with high IgE levels in the pediatric population by the effect of tradipitant on pruritus and disease severity in atopic dermatitis.

Based on these data, it can be concluded that patients with high baseline IgE levels have a greater effect on both pruritus and disease severity compared with patients with low IgE levels. Although a value of 100 kU/L was used as a cutoff to distinguish between high and low IgE levels in Tables 6-7, it should be noted that individuals with IgE levels, for example, greater than 75 kU/L, greater than 100 kU/L, greater than 150 kU/L l, more than 200 kU/L, 30-700 kU/L, 50-200 kU/L, 100-200 kU/L or 200-2000 kU/L, can be considered as patients with high IgE levels. Accordingly, individuals with IgE levels, for example, more than 75 kU/L, more than 100 kU/L, more than 150 kU/L, more than 200 kU/L, 30-700 kU/L, 50-200 kU/L, 100-200 kU /l or 200-2000 kU/l, can be selected, for example, for treatment with an NK-1 receptor antagonist such as tradipitant.

In addition, the data obtained indicate that tradipitant has a significant disease modifying effect in relation to atopic dermatitis. This effect can be quantified using indicators such as IGA, EASI, SCORAD, CGIC and PGIC, as well as relevant signs and symptoms atopic dermatitis.

Example 5

Genetic modifiers of IgE

To identify genetic risk factors that lead to IgE dysregulation, a genome-wide association study was performed using whole-genome sequencing of 117 atopic dermatitis samples. Using linear regression, the association between 14322979 single nucleotide polymorphisms (SNPs) and log-transformed IgE levels was directly examined. The most highly significant functional relevance loci include LRP1B, IL20RA and IL22RA2 (see Table 8 below).

LRP1B, IL20RA and IL22RA2 and IgE

SNPs that are associated with IgE dysregulation include a strong signal in the region 6q23, which contains immune response genes such as interleukin 20 receptor alpha subunit (IL20RA) and interleukin 22 receptor alpha subunit (IL22RA2). This family of cytokines may have pro-inflammatory effects and may be involved in skin inflammation. The top loci of this study are characterized by increased cytokine receptor activity and interleukin-20 binding (GO: 0042018, GO: 0042020).

As shown in FIG. 6, SNP rs276571 (Table 8) is a typical SNP associated with high IgE levels, such that individuals with the GG genotype of rs276571 have higher IgE levels than individuals with the AG or AA genotypes of rs276571. Moreover, as shown in FIG. 7, the identified variant is not only a modifier of IgE levels, but also has a significant effect on baseline SCORAD. Specifically, the GG genotype of rs276571 provided significantly higher baseline SCORAD parameters of atopic dermatitis disease severity compared with the AA or AG genotypes of rs276571. The risk allele also correlates with higher IL20RA expression. The rs276571 locus was found to be a significant expression quantitative trait locus (eQTL) for IL20RA in genotype tissue-specific expression (GTEx). Table 9 below shows the population allele frequencies of rs276571.

Another SNP of interest, rs4575660 (Table 8), found in the LRP1B gene, is also associated with IgE levels. As shown in FIG. 8, individuals with the TT rs4575660 genotype exhibit significantly higher IgE levels than individuals with the TG or GG rs4575660 genotypes. At the rs4575660 locus, the minor allele provides higher levels of IgE. As further discussed below, LRP1B variants are of particular interest due to their association with VAS and SCORAD scores, as discussed below in Example 6.

ADAM33 and IgE

In addition, the missense variant rs2280090 found in the disintegrin and metalloprotease gene 33 (ADAM33) is also associated with IgE dysregulation. As shown in FIG. 9, individuals with the heterozygous AG genotype of rs2280090 have significantly higher IgE levels than individuals with the GG genotype of rs2280090. Among the study participants, the number of people with the AA rs2280090 genotype was n=0.

conclusions

As described above in Example 4, individuals with high baseline IgE levels exhibited a greater magnitude of treatment effect of tradipitant on the severity of both pruritus and atopic dermatitis than did patients with low IgE levels. Therefore, for patients suffering from atopic dermatitis whose genotypes include one or more of the SNP genotypes listed in Table 8 as being associated with high IgE levels, a greater magnitude of treatment effect of tradipitant on the severity of both pruritus and atopic dermatitis disease can be expected. than in patients whose gene sequences do not include any of the SNPs listed in Table 8 as associated with high IgE.

Example 6

Genetic markers correlated with response to tradipitant treatment

The following study was conducted to identify additional genetic markers that directly correlate with positive response to tradipitant treatment. To identify genetic markers, association analysis was performed using a logistic additive model. The visual analogue scale (VAS) was used as the outcome measure of response. The identified variants are listed below in Table 10.

Additionally, a variant in CTNNA3, rs57930837, was found to be significantly different between atopic dermatitis treatment responders and atopic dermatitis non-responders. As shown in FIG. 10, the majority of carriers of the minor allele respond to tradipitant treatment for atopic dermatitis compared with carriers who do not respond to such treatment. In FIG. Figure 11 provides an illustration of the number of responders and non-responders to tradipitant treatment, divided by rs57930837 genotype. As can be seen, all individuals with the CC genotype rs57930837 respond to treatment, most individuals with the CA genotype rs57930837 respond to treatment, and most individuals with the AA genotype rs57930837 do not respond to treatment. The rs57930837 variant was found to have an increased minor allele frequency (MAF) (0.44) compared to control samples (0.04). In addition to the response marker, it was found that there is a significant difference in IgE levels in individuals with CC/CA genotypes compared to the AA genotype at this locus, as shown in FIG. 12. For this option, the results of this analysis achieve the highest level of significance (rs57930837, P = 2.19×10 ^-7 , 7% compared to 83%).

To assess the biological consequences of the top loci that distinguish responders from non-responders, analysis of the represented gene groups was performed. Other important loci point to the lipoproteins LRP1B (non-synonymous variant), MYO10 and NRXN3, enriched in low-density lipoprotein receptor activity (GO: 0005041) and bioactive lipid receptor activity (GO: 0045125). SNP rs57930837 maps to a region of open chromatin characterized by DNase hypersensitivity and demonstrates the presence of Foxp1 and other regulatory motifs.

Using the top significant SNPs selected by the cutoff p value, individuals were classified into tradipitant responder status, with an AUC value of 0.95 (10-fold cross-validation). Loss-of-function (LOF) and protein-coding variants were examined based on VAS scores in the case cohort. Significant variants were identified in the NPSR1, KRTAP1-1, CD200R1L, LRP1B and BTNL2 genes, as shown in Table 11.

Additionally, in the treated cohort as described in Example 4, Table 6, the top loci identified for the severe pruritus alteration modification (VAS) were variants located in the INADL gene, as shown below in Table 12.

As shown in FIG. 13, the minor allele of rs11207834 is associated with a reduced response to treatment with 85 mg tradipitant twice daily (bid) as measured by change in severe pruritus (VAS). On the contrary, patients suffering from atopic dermatitis whose genotype rs11207834 is the TT genotype show an improvement in the pruritus scale, and such individuals can be expected to show a greater effect after treatment.

Although various embodiments of the present invention are described herein, it should be understood from the present description that those skilled in the art may utilize various combinations of elements, variations, and improvements that are included within the scope of the present invention. In addition, many modifications can be made to suit the teachings of the present invention to a particular situation or material without departing from its essential scope. Accordingly, it is intended that the invention is not limited to the particular embodiment disclosed, but that the invention will include all embodiments included within the scope of the appended claims.

Claims (13)

1. A method of administering tradipitant in an amount effective to treat a patient suffering from pruritus or atopic dermatitis, comprising selecting the patient for treatment based on determining that the patient's genotype includes a genotype associated with high IgE levels or a positive response to treatment with tradipitant , Where the genotype associated with high IgE levels was selected from the group consisting of rs4575660 TT, rs276555 CC, rs74416548 ATAT, rs276556 GG, rs276560 CC, rs276561 TT, rs276562 GG, rs276563 CC, rs276564 GG, rs 276571 GG, rs140796 TATTGTATTG, rs276573 TT, rs276574 GG, rs4895474 TT, rs4895475 GG, rs9483989 TT, rs9373178 CC, rs4896234 CC, rs2327798 GG, rs62420823 GG, rs17252967 CC, rs9494657 AA, rs9402 871 GG, rs9402872 CC, rs9399201 GG, rs4896235 AA, rs719640 AA, rs9373179 AA, rs9385784 TT , rs2146275 AA, rs6941440 TT, rs4896237 TT, rs6929580 GG, rs4896239 TT, rs4895479 CC, rs4895480 TT, rs4280975 GG, rs6911523 AA, rs6912319 GG, rs2 280090 non-GG and rs57930837 non-AA; And the genotype associated with a positive response to tradipitant treatment was selected from the group consisting of rs 16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs73258486 GG/GA, rs6480251 CC/CT, rs6480252 TT/TC , rs10822978 TT/TA, rs10997525 GG/GA, rs10997527 CC/CA, rs7074325 CC/CT, rs57930837 CC/CA, rs11453660 CACA/CAC, rs2199792 AA/AG, rs4963245 non-CC, rs129904 49 non-TT, rs727162 non-CC , rs58161637 non-GG, rs62622847 non-CC, rs3213755 non-AA, rs41521946 non-TT, rs28362678 non-AA, rs35624343 non-AA, rs28362677 non-TT, rs11207832 non-CC, rs1954436 non- CC, rs11207834 non-CC , rs370530530 non-CTCT, rs11207838 non-TT, rs150980554 non-AA, rs7551886 non-CC, rs6664979 non-CC, rs12043665 non-AA, rs12030784 non-TT, rs79037385 non-GG, rs7456831 7 non-CC, rs3790575 non-CC and rs77939406 non-GG. 2. A method of administering tradipitant in an amount effective to treat a patient suffering from pruritus or atopic dermatitis, comprising selecting the patient for such treatment based on determining that the patient's IgE level is greater than or equal to 50 kU/L. 3. The method according to claim 2, where the IgE level is greater than or equal to 75 kU/l. 4. The method according to claim 3, where the IgE level is greater than or equal to 100 kU/l. 5. The method according to claim 4, where the IgE level is greater than or equal to 150 kU/l. 6. The method according to claim 5, where the IgE level is greater than or equal to 200 kU/l. 7. The method according to claim 6, where the IgE level is greater than or equal to 300 kU/l. 8. Method according to any one of paragraphs. 1-7, further comprising administering tradipitant orally to the patient at a dose of 100-400 mg/day. 9. The method according to claim 8, further comprising administering tradipitant orally to the patient at a dose of 100-300 mg/day. 10. The method according to claim 8, further comprising administering tradipitant orally to the patient at a dose of 100-200 mg/day. 11. The method according to claim 10, further comprising administering tradipitant orally to the patient at a dose of 85 mg twice a day (bid).