RU2793237C2 - Improved treatment of atopic dermatitis with tradipitant - Google Patents

Abstract

FIELD: medicine; therapy; dermatology.

SUBSTANCE: invention relates to the field of medicine, namely to therapy and dermatology; it is intended for the treatment of a patient suffering from itch or atopic dermatitis. A method for the treatment of a patient suffering from itch or atopic dermatitis includes determination, whether a biomarker, which is associated with an effect of treatment with tradipitant, is present in a biological sample of the patient. If the biomarker associated with the effect of treatment with tradipitant is present, then the patient is administered with tradipitant or its pharmaceutically acceptable salt at a dose, which is a regular dose, which would be selected without the determination stage.

EFFECT: use of the invention provides safe and effective treatment in a mode of motor therapy of chronic itch in patients suffering from atopic dermatitis.

14 cl, 13 dwg, 12 tbl, 6 ex

Description

Cross-references to related applications

This application claims priority over U.S. Provisional Application No. 62/558,303, filed September 13, 2017, and U.S. Provisional Patent Application No. 62/572,456, filed October 14, 2017.

BACKGROUND OF THE INVENTION

Atopic dermatitis (AD) is a common chronic and relapsing inflammatory skin disorder caused by a hypersensitive skin reaction and is characterized by intense and persistent scabies or itching that may be localized or even generalized and cannot be alleviated by scratching. Other clinical signs include erythema, excoriation, edema, lichenification, oozing, and dryness. Scratching due to itching can contribute to patches of scaly, sensitive, swollen skin and lead to increased skin susceptibility 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 phenotype of atopic dermatitis. The CTNNA3 gene encodes a structural cadherin that plays an important role in intercellular adhesion. CTNNA3 also plays an important role in allergies and asthma. Decreased levels of CTNNA3 have been found in asthmatic bronchial biopsies and are inversely correlated with eosinophil counts. Genome-wide association studies (GWAS) have shown that CTNNA3 variants are associated with response to glucocorticoid therapy in children with asthma.

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

Chronic pruritus, including pruritus associated with atopic dermatitis, is a serious and unmet medical need. It is believed that the sensation of itching is induced, at least in part, by the action of endogenous neuropeptide substance P (SP) when bound 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 found in neuronal tissue. SP and NK-1R interactions in neuronal tissue locally regulate neurogenic inflammation and the pain perception pathway through the central nervous system. SP and NK-1R activity also appears 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 processes. Impaired overexpression of SP in either 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, reverse the pathophysiology of the symptoms underlying these conditions.

Tradipitant is a potent 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 US Pat. No. 7,320,994 and contains six main structural moieties: a 3,5-bis-trifluoromethylphenyl residue, two pyridine rings, a triazole ring, a chlorophenyl ring, and methanone. Crystalline forms of Tradpitant IV and V are described in US Patent 7,381,826.

Brief description of the essence of the present invention

The various aspects of the present invention described herein relate to improved methods for the treatment of pruritus or atopic dermatitis in an individual in need of such treatment by administering Tradipant in effective amounts for such treatment. In one such improvement, it is possible to select a patient for treatment based on a determination 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 traditionalpitant in an amount effective to treat a patient suffering from pruritus or atopic dermatitis, one object of the present invention is an improvement involving the selection of 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 a high level of IgE can be selected from the group consisting of: rs4575660 TT, rs276555 CC, rs74416548 ATAT, rs276556 GG, rs276560 CC, rs276561 TT, rs276562 GG, rs276563 TT, rs276562 GG, rs276563 4G6 CC, rs276563 GG, rs276571 GG, rs140796 TATTGTATTG, rs276573 TT, rs276574 GG, rs4895474 ТТ, rs4895475 GG, rs9483989 TT, rs9373178 CC, rs4896234 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, rs4895479 CC, rs4895480 TT, rs4280975 GG, rs6911523 AA, rs6912319 GG, rs2280090 non-GG и rs57930837 non- AA.

In addition, the genotype associated with a positive response to traditionalpitant treatment can be selected from the group consisting of: rs16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs73258486 GG/GA025, rs128 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 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, rs19544836 non 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, rs7456833 non-CC and rs77939406 non-GG.

Another object of the present invention relates to a method of administering traditionalpitant in an amount effective for the treatment of a patient suffering from pruritus or atopic dermatitis, which includes an improvement, including the selection of a patient for such treatment, based on determining that the IgE level is greater than or equal to 50 kU/l . Alternatively, such improvement is applied if the patient's IgE level is 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 practiced when administered orally to such a patient at a dose of 100-400 mg/day or 100-300 mg/day or 100-200 mg/day. In particular, the daily dose may include oral administration of tradipant at a dose of 85 mg twice a day to the patient (bid).

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

if the patient's genotype is associated with a high IgE level or a positive response to traditionalpitant treatment, then administering traditionalpitant to the patient at a dosage effective to treat pruritus or atopic dermatitis in the patient, which would be selected without identifying the patient's genotype, and

if the patient's genotype is not associated with a high IgE level or a positive response to traditionalpitant treatment, then oral administration of traditionalpitant to the patient at a higher dosage compared to the dosage that would otherwise be selected for the patient without identification of the patient's genotype.

The above method can be put into practice by identifying the patient's genotype by 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, rs27276 rs276564, 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, rs6912319, rs2280090 and rs57930837.

For example, this method can be practiced if the genotype associated with high IgE is selected from the group consisting of: rs4575660 TT, rs276555 CC, rs74416548 ATAT, rs276556 GG, rs276560 CC, rs276561 TT, rs276562 GG, rs276563 CC, rs276 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, 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, rs4895479 CC, rs4895480 TT, rs4280975 GG, rs6911523 AA, rs6912319 GG, rs2280090 non -GG and rs57930837 non-AA.

Alternatively, this method may be practiced by identifying the patient's genotype by an SNP that is associated with a positive response to tradipitant treatment, and the SNP is selected from the group consisting of: rs6480251, rs6480252, rs10822978, rs10997525, rs10997527, rs7074325, rs57930837, rs11453660, rs2199792, rs4963245, rs12990449, rs727162, rs58161637, rs62622847, rs3213755, rs41521946, rs28362678, rs35624343, rs28362677, rs11207832, rs1954436, rs11207834, rs370530530, rs11207838, 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 traditionalpitant is selected from the group consisting of: rs16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs7325848 GG/GA, rs6480251 CC/CT, rs6480252 TT/TC, rs10822978 TT/TA, rs10997525 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-AA 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-GG, rs74568317 non-CC, rs3790575 non-CC and rs77939406 non-GG.

Another object of the present invention relates to a method of treating a patient suffering from pruritus or atopic dermatitis by administering an amount of traditionalpitant effective for such treatment, which includes selecting a dosage effective for treating the patient based on the identification of the initial level of IgE in the patient, and

if the patient's baseline IgE level is greater than about 100 kU/L, then administering traditionalpitant to the patient at a dosage effective to treat the patient's pruritus or atopic dermatitis, which would be selected without identifying the patient's baseline IgE level, and

if the patient's baseline IgE level is less than about 100 kU/l, then administering traditionalpitant to the patient at a higher dosage than would otherwise be chosen without identifying the patient's baseline IgE level.

In addition, the above method may further include identifying the initial level of IgE in the patient when examining a biological sample from the patient to determine the amount of IgE in this biological sample. In addition, the above methods lead to the determination of various dosages based on genotype, including administration to a patient receiving a higher dosage when administered in an amount of more than 170 mg/day to 340 mg/day of Tradpitant, in particular from more 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, eg 85 mg twice daily (bid).

In another aspect of the present invention, there is provided a method for selecting a dosage of tradipitant effective for the treatment of a patient suffering from atopic dermatitis, comprising:

(1) идентификацию генотипа пациента по одному или более SNP, выбранного из группы, состоящей из: rs4575660, rs276555, rs74416548, rs276556, rs276560, rs276561, rs276562, rs276563, rs276563, rs276564, rs276564, 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, rs6912319 . And

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

(A) The patient's genotype comprises one or more high IgE variants selected from the group consisting of: rs4575660 TT, rs276555 CC, rs74416548 ATAT, rs276556 GG, rs276560 CC, rs276561 TT, rs276562 GG, rs276566 CC6 5 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, 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, rs4895479 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 traditionalpitant treatment selected from the group consisting of: rs16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs73258486 GG/GA25 rs1CC/048 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, rs492 non-CC 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-CC4 CC, rs11207834 non-CC, rs370530530 non-CTCT, rs11207838 non-TT, rs150980554 non-AA, rs7551886 non-CC, rs6664979 non-CC, rs12043665 non-AA, rs 12030784 non-TT, rs79037-G5,5 -CC, rs3790575 non-CC and rs77939406 non-GG; or

(3) choosing a dosage greater than about 170 mg/day if the patient's genotype does not include a high IgE variant 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 is identified, which comprises 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. Also, the present invention relates to a method for determining the possibility of response in a patient to the treatment of atopic dermatitis with tradipitant, which includes:

(1) идентификацию генотипа пациента по одному или более SNP, выбранного из группы, состоящей из: rs4575660, rs276555, rs74416548, rs276556, rs276560, rs276561, rs276562, rs276563, rs276563, rs276564, rs276564, 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, rs6912319 , rs2280090, rs57930837, rs4963245, rs12990449, rs727162, rs58161637, rs62622847, rs3213755, rs41521946; And

(2) determining the possibility of a patient developing a response to said 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, rs9373178 CC, rs4896234 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, 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: rs16847120 GG, rs249122 AA, rs6862796 CC, rs249137 TT, rs249138 TT, rs144713688 GAGAA, rs73258486 GG/GA, rs652CC0251 TT/TC rs10822978 TT/TA rs10997525 GG/GA rs10997527 CC/CA rs7074325 CC/CT rs57930837 CC/CA rs11453660 CACA/CAC rs2199792 AA/AG 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, rs19544836 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, rs7456833 non-CC and rs77939406 non-GG.

The present invention also relates to a method for identifying a patient whose IgE level is identified as likely to respond to atopic dermatitis treatment with Tradipitant, which includes determining the likelihood of a patient 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 of the present invention, there is provided an improved method for treating pruritus or atopic dermatitis in an individual in need of such treatment, comprising administering traditional tradipitant orally.

In a second aspect of the present invention, there is provided a method which comprises the treatment of pruritus and/or atopic dermatitis in an individual in need of such treatment, comprising administering a traditional plant to that individual. According to this method, a patient may 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 kU/l or 300 kU/l.

In the first or second aspect, the dosage of traditionalpitant may be, for example, 100-400 mg/day, 100-300 mg/day, 100-200 mg/day, or about 170 mg/day, which can be administered at 85 mg twice a day. (bid).

In a third aspect of the present invention, there is provided a method for treating a patient with Tradipant, wherein 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 the level of IgE or with the effect of treatment with traditionalpitant, and if the patient's genotype is associated with a high level of IgE or with a positive response to traditionalpitant treatment, then introducing traditionalpitant into the patient in the first dosage , and if the patient's genotype is not associated with high IgE levels or a positive response to traditionalpitant treatment, then oral administration of traditionalpitant to the patient at a second dosage that exceeds the first dosage, or oral administration of an active pharmaceutical ingredient other than traditionalpitant.

In a fourth aspect of the present invention, there is provided a method for treating a patient with Tradipant, wherein the patient suffers from pruritus and/or atopic dermatitis. The method includes the following steps: identification of the initial level of IgE in the patient, and if the initial level of IgE in the patient exceeds or equals the 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 the introduction of the traditional in the first dosage to the patient, and if the initial level of IgE in the patient does not exceed the limit value, then the introduction of the traditional in the patient in the second dosage, which exceeds the first dosage, or the introduction of the active pharmaceutical ingredient different from traditional. In various embodiments, the implementation of the present invention, the first dosage may be approximately 170 mg/day, which can be administered at 85 mg twice a day, and the second dosage may be, for example, approximately >170-340 mg/day or >170-255 mg/day. day.

In a fifth aspect of the present invention, there is provided a method for selecting a dosage of tradipitant for the treatment of a patient suffering from atopic dermatitis, which comprises identifying the patient's genotype from one or more SNPs that are associated with high IgE levels or a positive response to tradipitant treatment, where the dosage is about 170 mg/day if the patient's genotype includes one or more high IgE variants and the dosage is greater than about 170 mg/day if the patient's genotype does not include a high IgE variant or a positive response to tradipitant treatment.

In a sixth aspect of the present invention, there is provided a method for selecting a dosage of tradipitant for the treatment of a patient suffering from atopic dermatitis, which comprises identifying a 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 threshold 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 has a baseline IgE level is less than the limit.

In a seventh aspect of the present invention, a method is provided for predicting the likelihood of a patient's response to treatment for atopic dermatitis and/or pruritus with tradipitant, comprising identifying a patient's genotype from one or more SNPs associated with high IgE levels or with a positive response to treatment with tradipitant, where the patient response to the indicated treatment may occur if the patient's genotype includes one or more high IgE variants and the patient is unlikely to respond to the indicated treatment if the patient's genotype does not include the high IgE or positive response variant for traditional treatment.

In an eighth aspect of the present invention, a method is provided for predicting the likelihood of a patient's response to atopic dermatitis and/or pruritus treatment with traditionalpitant, comprising identifying a baseline IgE level in a patient where the patient may experience a response to said traditionalpitant treatment if the patient's baseline IgE level is a cutoff. level or greater, such as 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's likelihood of responding to said treatment is unlikely if the patient's baseline IgE level is below cut-off.

Brief description of the figures

On FIG. 1 is a scatterplot of visual analog scale (VAS) versus concentration-mass of the traditional (Spearman's rank correlation p=0.0204) as described in Example 1.

On FIG. 2 is a scatterplot of serum levels of Tradipant, i.e. showing the change in concentration-mass versus time of physician visit, as described in Example 1.

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

On FIG. 4 shows the change in pruritus scores over time from baseline in the trials as described in Example 3.

On FIG. 5 shows the time course of disease scores during the trials described in Example 3.

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

On FIG. 7 shows the association of SNP rs276571 with baseline SCORAD as described in Example 5.

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

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

On FIG. 10 shows the proportion of responders and non-responders to tradipitant treatment of atopic dermatitis among carriers of the CTNNA3 rs57930837 minor allele as described in Example 6.

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

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

On FIG. 13 shows the association of INADL rs11207834 variants with changes in scores on the severe pruritus test as described in Example 6.

Detailed description of the present invention

In various embodiments, 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 a patient is developing response to treatment of atopic dermatitis and/or pruritus with Tradipitant.

The method of using traditionalpitant for the treatment of atopic dermatitis and/or pruritus in a patient may include, first of all, the identification of the patient's genotype by one or more SNPs that are associated with one or both parameters - with the level of IgE or with the effect of treatment with traditionalpitant. As described in the Examples section below, baseline immunoglobulin E (IgE) levels are associated with the effect of tradipitant treatment. For this reason, IgE genetic modifiers 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 related to the effect of tradipitant treatment, regardless of the level of IgE. Examples of such SNPs are presented here, for example in Tables 8, 10, 11 and 12.

The identification step may include a number of different identification methods. In one aspect of the present invention, genotype identification may include performing genotyping of a biological sample taken from a patient in need of treatment. The biological sample may include, for example, blood, serum, saliva, urine, and the like, as is known in the art. In another aspect of the present invention, genotype identification may include examining a patient's medical history, study report, or other document containing the results of previous analysis or genetic testing. In other aspects of the present invention, identification may include a directive or request that another person be tested, or a directive or request to review a patient's medical history, result report, or other document containing the result of a previously performed test or genetic test.

In the event that the patient's genotype in one of these SNPs is associated with one or both of a high level of immunoglobulin E (IgE) or a significant effect of treatment with tradipitant, then the method further comprises 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 85-170 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 in one of the indicated SNPs is not associated with one or both of the parameters - with a high level of IgE or with a significant effect of traditional treatment in any of the indicated SNPs, then the method includes an alternative treatment. Such alternative treatment may include, for example, oral administration of a second 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 be greater than 170 mg/day to 255 mg/day, or 170 mg/day to 340 mg/day. A dose above 170 mg/day could mean, for example, 25% more. Such increased dosages may be accompanied by increased monitoring of the patient. In other embodiments of the present invention, the alternative treatment may include oral administration of an active pharmaceutical ingredient other than traditional.

Another method of using traditionalpitant for the treatment of atopic dermatitis and/or pruritus in a patient involves, first of all, the identification of the initial level of IgE. The IgE level of a patient can be identified, for example, by taking 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.

In both pruritus severity and disease severity, there is consistently a stronger treatment effect among patients with high IgE levels compared with low IgE levels, regardless of the specific threshold used to delineate high and low IgE levels. For example, this relationship is observed regardless of whether the high IgE group is defined as being above a cut-off 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 with low IgE as lower than a cut-off value, such as 75 kU/l, 100 kU/l, 150 kU/l, 200 kU/l or 300 kU/l. Any of these high or low IgE definitions may be used in the practice of the present invention.

If the patient has a high IgE level, for example, the IgE level is greater than or equal to the limit value, which is 50 kU/l, 75 kU/l, 100 kU/l, 150 kU/l, 200 kU/l, or 300 kU/l, then it can be expected that the patient will experience a significant effect of treatment with tradipitant. Such a patient can be administered orally Tradipant in the first dosage. However, if the patient's baseline IgE level is below a selected cutoff, 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 traditionally at a second dosage that is greater than the first dosage, or may be administered orally with an active pharmaceutical ingredient other than traditionally administered. The first dosage and the second dosage may exceed the previously described dosages.

It also describes how to select a dosage for the treatment of a patient suffering from atopic dermatitis and/or itching, using tradipitant. Such a method may include identifying the patient's genotype from one or more SNPs described as being associated with one or both of the IgE levels or the effect of tradipitant treatment, or alternatively, identifying the IgE level of the patient. Methods for identifying the specified genotype or IgE level may include the methods described previously. Based on the identification or determination of the genotype or IgE level in an individual, the dosage for a particular patient can be selected. For example, if the patient's genotype includes one or more variants associated with high IgE or with a positive response to treatment with traditionalpitant, or if the patient's IgE level is identified as being above a cut-off value, such as 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 a dosage may be, for example, 85 mg twice daily (bid). If a patient's IgE level is identified below a cut-off, 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 dose greater than approximately 170 mg/day. Such a 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, more than about 170 mg/day to 255 mg/day, or more than about 170 mg/day to 340 mg/day.

Also further described are methods for predicting the likelihood of a patient's response to atopic dermatitis treatment with tradipitant. Such methods may include identifying a patient's genotype from one or more of the SNPs described herein as being associated with one or both of the IgE level or the effect of tradipitant treatment, or alternatively, identifying the patient's IgE level. Methods for identifying the specified genotype or IgE level may include the methods described previously. Based on the identification or determination of an individual's genotype or IgE level, it can be predicted whether a patient will have a favorable response to treatment of atopic dermatitis and/or pruritus with Tradipant. For example, if the patient's genotype includes one or more variants associated with high IgE or with a positive response to traditionalpitant treatment, or if the patient's IgE level is identified as exceeding a cut-off value, such as 50 kU/L, 75 kU/L, 100 kU/L, 150 kU/l, 200 kU/l, or 300 kU/l, then the patient may experience a response 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 traditionalpitant treatment, or if the patient's IgE level is identified below a 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 considered unlikely or less likely to respond to tradipitant treatment, or the patient is unlikely or less likely to develop a significant response to tradipitant treatment. Such information is useful to patients and healthcare professionals as it is essential for the routine identification of patients who would particularly benefit from Tradipitant treatment, as well as for reducing erroneous trials and attempts to determine successful therapy, especially in the case of individuals for whom it is unlikely 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 traditional administration, such as 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.

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

As used herein, the term "effective amount" of traditional tradipitant means an amount effective in the treatment of the disorders described herein.

With regard to dosage, "qd" means administration once a day, and "bid" usually means administration once in the morning and once in the evening, generally at intervals of at least about 8 hours or more than about 16 hours, for example, at intervals of 10-14 hours or at intervals of 12 hours (Q12H).

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

One skilled in the art will appreciate that further preferred embodiments of the present invention may be selected by combining the preferred embodiments indicated above or by referring to the examples provided herein.

Example 1

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

A Phase II proof-of-concept clinical study was conducted to investigate the safety and efficacy of Tradipant in the treatment of chronic pruritus with motor therapy 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 a very significant and clinically significant improvement from baseline with tradipitant treatment (40.5 mm improvement from baseline, p<0.0001) as measured by the visual analog scale (VAS) in a 100 mm scoring device pruritus, a very high placebo effect (36.5 mm improvement from baseline, p<0.0001), on change from baseline resulted in no statistically significant difference from placebo. However, a subsequent pharmacokinetic (PK) analysis among 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 at the time of pruritus assessment.

The predefined endpoint in the Phase II Proof-of-Concept trial was the change in pruritus from baseline on the Visual Analogue Scale (VAS). Due to the high placebo effect, no significant difference from placebo was observed for this pre-set endpoint. However, the results of subsequent analyzes surprisingly found that there is a relationship between response and exposure. There has been a significant and clinically significant response to some of the pruritus-related outcomes assessed in individuals with higher plasma levels of tradipitant. Based on the data reviewed during the study, the lower plasma levels of tradipitant may be below the threshold of efficacy sufficient to reduce the sensation of itching in patients.

Methods

In the trial, patients who experienced VAS pruritus greater than 70 mm on one of the two days prior to trial entry were randomized to receive either 100 mg of traditional tradipitant (n=34) or placebo (n=35) orally once daily In the evening. During the trials in the Traditional Pit group, patients took traditional capsules orally with standard excipients in an amount of 100 mg in the evening. Clinical analyzes were performed 3 or 4 weeks after daily dosing, or both 3 weeks and 4 weeks, with each analysis performed on the morning of the day after the last dosing or at noon on the day after the last dosing. Tradipant was administered in an immediate release form comprising traditional and pharmaceutically acceptable excipients in a capsule. The traditional particle size 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 specified average particle size, D ₅₀ means that 50% of the particles have the specified average particle size and D ₉₀ means that 90% of the particles have the specified average particle size.

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

results

As shown in FIG. 1, PK-PD (Pharmacokinetic-Pharmacodynamic Data) data in the tradipitant groups indicated a significant correlation between blood levels of tradipitant and changes in VAS compared to baseline (p<0.05). Individuals with higher circulating levels of traditionalpitant have a higher response value at the time of efficacy evaluation. A separate PK analysis at the time of pruritus assessment, shown in FIG. 2 indicates that half of the patients in the trial visited the lab for assessment of morning itching (AM group, ~12 h 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 h post-dose).

Mean plasma concentrations of traditionalpitant in the AM and PM groups studied ranged from about 125 ng/mL to about 225 ng/mL. Patients examined in the afternoon (PM) (mean = approximately 20 hours after last administration) generally had lower plasma concentrations of tradipant than those examined in the morning (AM) (mean = approximately 15 h after the last injection). The mean plasma concentration in the RM group is approximately 125 ng/ml and the mean plasma concentration in the AM group is approximately 225 ng/ml, the difference being largely related to the length of time after administration. More importantly, the results indicate a correlation between plasma concentration and efficacy when patients have plasma concentrations >100 ng/mL (e.g., 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) is generally more effective than in patients with lower plasma concentrations.

Post-analysis in the AM group showed a significant and clinically significant effect of traditionalpitant compared to placebo, as shown in Table 1. Higher concentrations of traditionalpitant are associated with higher efficacy in treating chronic pruritus during trials. A similar analysis in the RM group showed no significant difference between traditional and placebo.

These data are consistent with the hypothesis that traditional NK-1R antagonist may lead to symptomatic relief in patients suffering from pruritus (subjective assessment by VAS, VRS, SCORAD). The trials also collected data on endpoints that corresponded to the underlying disease (SKINDEX apparatus, SCORAD objective score, EASI eczema severity and area index and DLQI). These results do not show any significant differences from placebo that would be expected from a drug targeting the symptom of pruritus in a short-term 4-week study. It is important to note that since patients mainly complain of persistent pruritus associated with atopic dermatitis, the effects that were also observed on the CGI-C scale and on the PBI scales indicate a marked overall clinically significant effect both from the point of view of the clinician and from the point of view of patient. Conclusion

These data support the conclusion that patients suffering from pruritus, e.g., pruritus associated with atopic dermatitis, can be treated by oral administration of Tradipitant, e.g. Form IV or Form V (or a pharmaceutically acceptable salt thereof) in an amount and frequency of administration, required to achieve plasma concentrations of at least about 100 ng/mL, e.g., 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 more. Such plasma concentration levels can be achieved, for example, by oral administration of traditional tradipitant in the form of immediate release solid dosage forms once a day at a higher dose or immediate release forms with improved bioavailability or controlled release forms or by oral administration of tradipitant several times. per day, for example, two or more times a day, at a lower dose in the form of immediate release or controlled release forms. While test data indicate that effective plasma concentrations can be reached in about 12-18 hours, e.g., about 15 hours, after treatment with traditional 100 mg/day 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, it should be noted that although these trials did not show an overall effect of a predetermined dose of Tradipitant, mainly due to a significant placebo effect, the trials show a relationship between PK and response, as well as significant beneficial effects. effects in the group of patients who were examined at times of higher concentrations of tradipitant. In these trials, traditional 100 mg once daily was well tolerated and had a low adverse event profile that was similar to placebo.

The treatment of the patient may continue until the patient's pruritic symptoms are improved or eliminated, for example improved such that the patient is able to function more or less normally during the waking hours and sleep more or less normally during the 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 efficacy of various dosing regimens.

Example 2

Plasma levels of traditionalpitant

During the trial, healthy participants were given 85 mg of traditional tradipitant orally on trial day 3, and then 85 mg of tradipitant every 12 hours (Q12H) on trial days 4-16. Plasma concentration levels of traditionalpitant were measured on day 3, day 7 and day 11.

In these trials, it was found that administration of 85 mg of traditionalpitant once a day (on day 3) resulted in a mean plasma concentration over 0-12 hours, which is approximately 50% of the plasma concentration observed in the RM group in Example 1. On days 7 and 11, the average plasma concentration within 0-12 hours after the administration of traditional 85 mg twice a day (bid, in particular, Q12H) is about 150% of the plasma concentration observed in the RM group in Example 1 The mean plasma concentration over 0-12 hours at each measurement point was determined by dividing the AUC value (in units (h) × (ng/mL)) over 0-12 hours by 12 hours.

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

Example 3

Tradipitant treatment of chronic pruritus associated with atopic dermatitis

A multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial, ("Tradipitant for Treatment-Resistant Atopic Dermatitis-Associated Pruritus", clintrials.gov trial ID NCT02651714) was conducted to determine the efficacy of traditionalpitant versus placebo in reducing chronic itching as measured by the VAS scale.

Methods

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

BMI - body mass index

Patients were randomized to receive either 85 mg traditional or placebo (1:1) twice daily (bid). A design for a multicenter, randomized, double-blind, placebo-controlled clinical trial is shown in FIG. 3. Subjects with chronic pruritus associated with atopic dermatitis were treated with 85 mg of tradipitant or BID placebo for 8 weeks. The moderate severity of pruritus and the highest severity of pruritus were assessed by VAS parameters, and VRS parameters were assessed every two weeks. In addition, treatment was assessed twice a week using objective and subjective assessment of the atopic dermatitis index (SCORAD) (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 trials also used the Global Clinical Change Assessment (CGI-C), the Patient Global Assessment (PGIC) for both pruritus and atopic dermatitis, the Patient Benefit Index (PBI), and SKINDEX-16. Twice daily, patients completed questionnaires to report severe and moderate pruritus on the Numerical Rating Scale (NRS).

Objective SCORAD evaluation includes parameters including extent, intensity, abrasions, erythema, oozing or scab, presence of edema or papules, lichenification, and skin dryness. The subjective assessment of SCORAD includes the patient's assessment of pruritus and insomnia.

results

As indicated, 168 trial patients were randomized to BID traditional (n=84) and placebo (n=84). Among the 84 patients randomized to the tradipitant group, 56 completed the trials and 28 completed the trials early. Among 84 patients randomized to placebo, 59 completed the trial and 25 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 trials in the AM group described in Example 1, there are statistically significant differences between the traditional and placebo groups in terms of severe pruritus ((p=0.019), PB1 (p=0.038), CGIC (p=0.007) and objective score on the scale SCORAD scale (p=0.005) The effects of treatment on both pruritus and disease severity are seen as early as week 2 (Figures 4-5). 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 with an improvement in SCORAD score of 50% or more. , or an improvement of 75% or more on the EASI scale, is statistically significantly higher in patients treated with tradipitant compared with placebo.

conclusions

The results described above indicate that tradipitant reduces the intensity of severe pruritus in patients, as well as the severity of atopic dermatitis. Tradipant is characterized by a significant and clinically significant improvement with a number of measures to reduce the intensity of itching. First of all, significant improvements are observed when measuring the parameters of severe pruritus on the VAS scale (p=0.019). Tradipitant also has a significant effect as assessed by patients responding to treatment for severe pruritus with an improvement of greater than or equal to 40 points from baseline on the VAS severe pruritus (p=0.037) or greater than or equal to 30 points (p=0.049). When assessing the predefined primary endpoint of mean pruritus on the VAS scale, tradipitant shows an improvement over placebo, but this improvement is not significant due to the high placebo effect and the lack of sensitivity of this measurement.

According to the observed improvements on the Severe Itching Score associated with scratching, Tradipitant also has disease-modifying properties, i.e. a significant improvement on the SCORAD Global Parameter Scale (p=0.008) and the Objective SCORAD Scale (p=0.005). In particular, Tradipant is characterized by significant improvements in several clinical indicators of the severity of atopic dermatitis, including excoriation, erythema, oozing and dryness.

These clinically relevant effects are also associated with significant improvements in the Overall Clinical Score of Change (CGI-C) (p=0.007), the Patient's Global Clinical Assessment of Pruritus (PGI-C) (p=0.024), and the PGI-C atopic dermatitis (p=0.007). Similarly, Tradipant also has benefits directly reported by patients as assessed by the Patient Benefit Index (PB1) (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 four body regions: head and neck, trunk, upper extremities, and lower extremities) and disease severity (evaluation of redness, thickness , scratching and lichenification)) demonstrate the effectiveness of tradipitant in improving the severity of the underlying disease of atopic dermatitis in addition to the 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 treatment of atopic dermatitis and pruritus. For study purposes, trial participants with IgE levels greater than or equal to 100 kU/L were considered high IgE patients, while 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 in Table 5 below.

The mean and range of the overall SCORAD values shown in Table 5 indicate that the study population undergoes varying levels of disease severity, from mild to severe. Table 5 also shows the similarity of disease severity between high IgE and low IgE groups. Table 6 (below) presents the results of trials of tradipitant in 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 the 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 breakdown by IgE level of the data shown in Table 4 above.

Tables 6-7 show the results compared to baseline. As shown in Table 6, in patients with high baseline IgE, there is a significant effect of tradipitant (p<0.05) on most of the parameters studied, including, for example, severe pruritus and sleep. It was unexpectedly found that when comparing individuals with low levels of IgE (table 7), individuals with high levels of IgE (table 6) also observed significant treatment effects in terms of severity of atopic dermatitis. 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 to 11% of patients treated with placebo (p = 0.0008 ).

For the purposes of this study, individuals with an IgE level greater than or equal to 100 kU/l were considered as patients with high levels of IgE, and patients with an IgE level of less than 100 kU/l were considered as patients with low levels of IgE. Additional studies were also conducted in which individuals with high IgE levels were considered as patients with IgE levels greater than or equal to 50 kU/l to greater than or equal to 300 kU/l. Both in terms of pruritus and disease severity, a significantly higher treatment effect was observed in the high IgE group compared to the low IgE group, regardless of whether the high IgE group is defined by the following values, e.g. IgE≥ 50 kU/L, ≥100 kU/L, or ≥300 kU/L, and whether the low IgE group is defined by the following values, such as IgE <50 kU/L, <100 kU/L, or <300 kU/L. As the cut-off value for the high IgE group, for the most detailed study (Tables 6-7), a value greater than or equal to 100 kU/L was chosen as the value that is considered by the control laboratory as the upper limit of the normal range for adults. Based on these results and an extrapolation of the normal range in children, a group with high IgE levels in the pediatric population can also be defined 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 impact on both pruritus and disease severity compared to patients with low IgE levels. Although the 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, more than 75 kU/l, more than 100 kU/l, more 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 levels of IgE. 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 traditional.

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 the corresponding signs and symptoms. atopic dermatitis.

Example 5

IgE genetic modifiers

To identify genetic risk factors that lead to IgE deregulation, a genome-wide association study was performed using whole genome sequencing of 117 atopic dermatitis samples. Using linear regression, the relationship 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 deregulation include a strong signal in the 6q23 region, which contains immune response genes such as the interleukin 20 receptor alpha subunit (IL20RA) and the interleukin 22 receptor alpha subunit (IL22RA2). This family of cytokines may have a pro-inflammatory effect 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 levels of IgE, such that individuals with GG rs276571 genotype have higher levels of IgE than individuals with AG or AA rs276571 genotypes. In addition, as shown in FIG. 7, the identified variant is not only a modifier of the IgE level, but also has a significant effect on the original SCORAD. In particular, the GG rs276571 genotype provides significantly higher baseline SCORAD parameters for the severity of atopic dermatitis compared to the AA or AG rs276571 genotypes. The risk allele also correlates with higher expression of IL20RA. The rs276571 locus was found to be a significant quantitative trait-in-expression locus (eQTL) for IL20RA in the tissue-specific expression genotype (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 have significantly higher IgE levels than individuals with the TG or GG rs4575660 genotypes. At the rs4575660 locus, the minor allele provides a higher level of IgE. As discussed further 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 33 disintegrin and metalloprotease gene (ADAM33) is also associated with IgE deregulation. As shown in FIG. 9, individuals with the heterozygous AG rs2280090 genotype exhibit significantly higher levels of IgE than those with the GG rs2280090 genotype. 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 have a higher magnitude of treatment effect of tradipitant in terms of severity of both pruritus and atopic dermatitis disease than those 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 associated with high IgE levels, a greater magnitude of treatment effect of tradipitant in terms of 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 performed to identify additional genetic markers that are directly correlated with a 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 a measure of the response results. The identified variants are listed below in Table 10.

In addition, a variant in CTNNA3, rs57930837, was found to have a significant difference between atopic dermatitis responders and non-responders to atopic dermatitis treatment. As shown in FIG. 10, the majority of carriers of the minor allele show a response to tradipitant treatment of atopic dermatitis compared to carriers who do not respond to such treatment. On FIG. 11 is an illustration of the number of responders and non-responders to traditionalpitant treatment, divided by rs57930837 genotype. As can be seen, all individuals with the CC rs57930837 genotype show a response to treatment, most individuals with the CA rs57930837 genotype show a response to treatment, and most individuals with the AA rs57930837 genotype do not respond to treatment. It was found that the rs57930837 variant is characterized by increased frequency of the minor allele (MAF) (0.44) compared with control samples (0.04). In addition to the response marker, it was found that there is a significant difference in the level of IgE 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 achieved 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 presented gene groups was performed. Other important loci indicate lipoproteins LRP1B (non-synonymous), MYO10 and NRXN3 enriched in low density lipoprotein receptor activity (GO: 0005041) and bioactive lipid receptor activity (GO: 0045125). The rs57930837 SNP is displayed in an open chromatin region characterized by DNase hypersensitivity and shows the presence of Foxp1 and other regulatory motifs.

Using top-significant SNPs selected by p cut-off, individuals were classified by their status as patients responding to tradipitant treatment, with an AUC value of 0.95 (10-fold cross-validation). Loss of function (LOF) variants and protein-coding variants were examined by VAS scores in a cohort of cases. Significant variants were identified in the NPSR1, KRTAP1-1, CD200R1L, LRP1B, and BTNL2 genes, as shown in Table 11.

In addition, in the treated cohort as described in Example 4, Table 6, the top loci identified by modifying severe pruritus (VAS) are variants located in the INADL gene, as shown in Table 12 below.

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

Although various embodiments of the present invention are described herein, based on the present description, it should be understood that those skilled in the art may use 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 adapt the teachings of the present invention to a particular situation or material without departing from its essential scope. Therefore, it is intended that the invention not be limited to the specific embodiment disclosed, but that the invention will include all embodiments included within the scope of the appended claims.

Claims (31)

1. A method of treating a patient suffering from pruritus or atopic dermatitis, which is characterized by: determining whether or not a biomarker that is associated with the effect of traditionalpitant treatment is present in a biological sample from a patient, where the biomarker associated with the effect of traditionalpitant treatment is: a) the patient's genotype for the SNP that is associated with baseline IgE, selected from the group consisting of: rs4575660, rs276555, rs74416548, rs276556, rs276560, rs276561, rs276562, rs276563, rs276563, rs276564, rs276564, 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, rs6912319, rs2280090 и rs57930837; or b) the patient's genotype no SNP selected from the group consisting of: rs16847120, rs249122, rs6862796, rs249137, rs249138, rs144713688, rs73258486, rs6480251, rs6480252, rs10822978, rs10997525, rs10997527, rs7074325, rs57930837, rs1 1453660, rs2199792, rs4963245, rs12990449, rs727162, rs58161637, rs62622847, rs3213755, rs41521946, rs28362678, rs35624343 , rs28362677, rs11207832, rs1954436, rs11207834, rs370530530, rs11207838, rs150980554, rs7551886, rs6664979, rs12043665, rs12030784, rs79037385, rs74568317, rs3790575 и rs77939406; or c) the patient's baseline IgE level compared to the cut-off IgE level; And if a biomarker associated with the treatment effect of Tradipitant is present, then administering to the patient Tradipitant or a pharmaceutically acceptable salt thereof at a dose that is the usual dose that would be selected without the determination step. 2. The method of claim 1, further comprising: if a biomarker associated with the treatment effect of traditionalpitant is not present, then administering traditionalpitant to the patient at a dose that is higher than the usual dose. 3. The method according to claim 1 or 2, wherein the biomarker in a) is present if the SNP genotype is selected from the group consisting of: rs4575660 ТТ, rs276555 СС, rs74416548 АТАТ, rs276556 GG, rs276560 СС, rs276561 ТТ, rs276562 GG, rs276563 СС, rs276563 СС, rs276564 GG, 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, 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, rs4895480 TT, rs4280975 GG, rs6911523 AA, rs6912319 GG, rs2280090 non-GG and rs57930837 non-AA; And the biomarker in a) is not present if the SNP genotype is selected from the group consisting of: rs276560 non-TT, rs276555 non-CC, rs74416548 non-ATAT, rs276556 non-GG, rs276560 non-CC, rs276561 non-TT, rs276562 non-GG, rs276563 non-CC, rs276563 non-CC, rs276564 non-GG rs276564 non-GG, rs276571 non-GG, rs140796 non-TATTGTATTG, rs276573 non-TT, rs276574 non-GG, rs4895474 non-TT, rs4895475 non-GG, rs9483989 non-TT, rs9373178 non-CC2, rs4896 rs2327798 non-GG, rs62420823 non-GG, rs17252967 non-CC, rs9494657 non-AA, rs9402871 non-GG, rs9402872 non-CC, rs9399201 non-GG, rs4896235 non-AA, rs719640AA, rs93-AA rs9385784 non-TT, rs2146275 non-AA, rs6941440 non-TT, rs4896237 non-TT, rs6929580 non-GG, rs4896239 non-TT, rs4895479 non-CC, rs4895480 non-TT, rs4280975 non-GG, rs691,3 non-AA52 rs6912319 non-GG, rs2280090 GG and rs57930837 AA. 4. The method of claim 1 or 2, wherein the biomarker in b) is present if the SNP genotype is selected from the group consisting of: rs16847120 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, rs12990449 non-TT, rs727162 non-CC, rs58161637 non-GG, rs62622847 non-CC, rs32137555 -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, rs150980558 -CC, rs6664979 non-CC, rs12043665 non-AA, rs12030784 non-TT, rs79037385 non-GG, rs74568317 non-CC, rs3790575 non-CC and rs77939406 non-GG; And where the biomarker in b) is not present if the SNP genotype is selected from the group consisting of: rs16847120 non-GG, rs249122 non-AA, rs6862796 non-CC, rs249137 non-TT, rs249138 non-TT, rs144713688 non-GAGAA, rs73258486 non-GG/GA, rs6480251 non-CC/CT, rs6480252 non-TT/TC , rs10822978 non-TT/TA, rs10997525 non-GG/GA, rs10997527 non-CC/CA, rs7074325 non-CC/CT, rs57930837 non-CC/CA, rs11453660 non-CACA/CAC, rs2199792 non-AA/AG, rs4963245 CC, rs12990449 TT, rs727162 CC, rs58161637 GG, rs62622847 CC, rs3213755 AA, rs41521946 TT, rs28362678 AA, rs35624343 AA, rs28362677 TT, rs11207832 CC, rs1954436 CC, rs11207834 CC, rs370530530 CTCT, rs11207838 TT, rs150980554 AA, rs7551886 CC , rs6664979 CC, rs12043665 AA, rs12030784 TT, rs79037385 GG, rs74568317 CC, rs3790575 CC and rs77939406 GG. 5. The method according to claim 1 or 2, where: the biomarker in c) is present if the patient's baseline IgE level is above the cut-off value, the biomarker in c) is not present if the patient's baseline IgE level is below the cut-off value, and the limit value is greater than or equal to 50 kU/l. 6. The method according to claim 5, wherein the level limit greater than or equal to 50 kU/l is greater than or equal to 75 kU/l. 7. The method according to claim 6, wherein the level limit greater than or equal to 50 kU/l is greater than or equal to 100 kU/l. 8. The method according to claim 7, wherein the level limit greater than or equal to 50 kU/l is greater than or equal to 150 kU/l. 9. The method according to claim 8, wherein the level limit greater than or equal to 50 kU/l is greater than or equal to 200 kU/l. 10. The method according to claim 9, wherein the level limit greater than or equal to 50 kU/l is greater than or equal to 300 kU/l. 11. The method according to any one of paragraphs. 1-10, where the usual dose of tradipitant is 170 mg/day. 12. The method of claim 11, wherein the usual dose of tradipitant is 85 mg twice daily (bid). 13. The method according to any one of paragraphs. 2-10, where the dose, which is greater than the usual dose of tradipitant, is from more than 170 mg/day to 340 mg/day. 14. The method according to claim 13, wherein the dose which is greater than the usual dose of traditional tradipitant is from more than 170 mg/day to 255 mg/day.

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