WO2020132513A1 - Improved treatment of atopic dermatitis with tradipitant - Google Patents

Abstract

The disclosure relates generally to improvements in the treatment of pruritus, atopic dermatitis (AD), and associated symptoms with tradipitant, and more particularly, to such treatment based on a determination that an individual possesses one or more loss of function (EOF) genetic variants in the individual's epidermal differentiation complex (EDC), or more particularly, the filaggrin (FLG) gene.

Description

IMPROVED TREATMENT OF ATOPIC DERMATITIS WITH TRADIPITANT

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of the following earlier-filed US Provisional Applications: US Serial No. 62/783,723, filed December 21, 2018; US Serial No. 62/811,117, filed February 27, 2019; and US Serial No. 62/912,811, filed October 9, 2019.

BACKGROUND OF THE INVENTION The invention relates generally to improvements in the treatment of pruritus, atopic dermatitis (AD), and associated symptoms with tradipitant, and more particularly, to such treatment based on the presence of a loss of function (LOF) variant in one or more of the individual’s epidermal differentiation complex (EDC) genes, which may particularly be the filaggrin (FLG) gene. Atopic dermatitis is a common, chronic, and relapsing inflammatory skin disorder caused by a hypersensitivity reaction in the skin, and characterized by the symptom of intense and persistent pruritus or itch, which may be localized or even generalized, and may not be relieved by scratching. Other clinical features include erythema, excoriation, edema, lichenification, oozing, and xerosis. Scratching due to the itching may contribute to raw, sensitive, swollen skin, and render skin susceptible to infection. AD is also known as atopic eczema or eczema, and frequently presents during childhood.

The epidermal differentiation complex (EDC) includes over fifty genes encoding proteins involved in the development of keratinocytes, the primary cell type in the epidermis. The proteins encoded are closely related in terms of function, and belong to three gene families: the comified envelope (CE) precursor family, the SI 00 protein family, and the SI 00 fused type protein (SFTP). Of these approximately fifty genes, filaggrin (FLG), located on chromosome 1 q21 and a member of the SFTP family, is the most studied in the context of skin barrier dysfunction. Variants in the filaggrin protein are regarded as risk factors for AD.

Chronic pruritus, including that caused by AD, represents a serious and unmet medical need. Current treatments for AD include topical moisturizers and anti- inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP- specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants.

The itch sensation is believed to be induced at least in part through the action of the endogenous neuropeptide substance P (SP), through the binding at NK-IRs expressed on multiple skin cells. The NK-1R is expressed throughout different tissues of the body, with major activity found in neuronal tissue. SP and NK-1R interactions in neuronal tissue regulate neurogenic inflammation locally and the pain perception pathway through the central nervous system. Other tissues, including endothelial cells and immune cells, have also exhibited SP and NK-1R activity. The activation of NK-1R by the natural ligand SP is involved in numerous physiological processes, including the perception of pain, behavioral stressors, cravings, and the processes of nausea and vomiting. An inappropriate over-expression of SP either in nervous tissue or peripherally could result in pathological conditions such as substance dependence, anxiety, nausea/vomiting, and pruritus. An NK-1R antagonist may possess the ability to reduce this over-stimulation of the NK-1R, and as a result address the underlying pathophysiology of the symptoms in these conditions.

Tradipitant is a highly potent, selective, centrally penetrating, and orally active neurokinin- 1 (NK-1) receptor antagonist, depicted below as the compound of Formula (I):

Tradipitant is disclosed in US Patent 7,320,994, and contains six main structural components: the 3,5-bis-trifluoromethylphenyl moiety, two pyridine rings, the triazol ring, the chlorophenyl ring, and the methanone. Tradipitant is known by the chemical names, 2-[l-[[3, 5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-lH- 1,2,3- triazol-4-yl]-3-pyridinyl](2-chlorophenyl)-methanone, and {2-[l-(3,5- bistrifluoromethylbenzyl)-5-pyridin-4-yl-lH-[l,2,3]triazol-4-yl]-pyridin-3-yl}-(2- chlorophenyl)-methanone, and has also been known as LY686017 and as VLY-686. U.S. Patent 7,320,994 describes methods for using compounds, such as tradipitant, for treating a condition associated with an excess of tachykinins, most particularly where the condition associated with an excess of tachykinins is depression and anxiety.

US Patent 7,320,994 further describes the use of compounds such as tradipitant in other such diseases, i.e., because these compounds inhibit the physiological effects associated with an excess of tachykinins. The patent describes the usefulness of such compounds in the treatment of numerous other disorders related to tachykinin receptor activation including psychosis, schizophrenia, and other psychotic disorders; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AIDS-associated dementia, and Down syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders, such as peripheral neuropathy, diabetic and chemotherapy-induced neuropathy, and post-herpetic and other neuralgias; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; disorders of the musculoskeletal system, such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatites; addiction disorders such as alcoholism; stress-related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse

immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis;

gastrointestinal disorders or diseases associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; disorders of bladder function such as bladder detrusor hyper-reflexia and incontinence;

atherosclerosis; fibrosin and collagen diseases such as scleroderma and eosinophilic fascioliasis; irritative symptoms of benign prostatic hypertrophy; disorders associated with blood pressure, such as hypertension; or disorders of blood flow caused by vasodilation and vasospastic diseases, such as angina, migraine, and Reynaud's disease; emesis, including chemotherapy-induced nausea and emesis; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions. Finally, the patent describes such compounds are effective in amounts expected to vary from about 0.001 mg/kg/day to about 100 mg/kg/day.

Tradipitant is known to be therapeutically administered through a variety of routes of administration by which it is bioavailable. US Patent 7,320,994 discloses administration of tradipitant by oral and parenteral routes, e.g., orally, by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, occularly, topically, sublingually, and buccally, with oral administration being generally preferred for treatment. Additionally, use of tradipitant in the treatment of pruritus and atopic dermatitis is disclosed in international patent application publication WO 2016/141341.

Treating patients with medicines typically requires a physician to determine the likelihood that a patient will respond to treatment and the extent of the therapeutic benefit that the prescribed medicine is likely to provide. Several factors can be relevant to the prescribing decision, including the patient’s medical history and the severity of the patient’s symptoms. For some medicines, a specific diagnostic test can provide a predicate for identifying patients that can expect to benefit from a particular medicine. Such companion diagnostic tests may be serve to exclude patients from treatment with a medicine where the test indicates little or no prospect of a significant therapeutic response. In this regard, the US Food and Drug administration guidance states that companion diagnostics can identify patients who are most likely to benefit from a particular therapeutic product,

https://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostic s/ucm407297.htm.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, an improvement is provided for a method consisting of administering to a patient suffering from pruritus or atopic dermatitis, an amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis. The improvement comprises selecting said patient for treatment based upon a determination that the patient’ s gene sequence includes a loss of function (LOF) variant in one of more genes in the epidermal differentiation complex (EDC). In a second aspect of the present invention, a method is provided for treating a patient for atopic dermatitis or pruritus. Such method includes determining whether the patient’s gene sequence includes a loss of function (LOF) variant in one or more genes in the epidermal differentiation complex (EDC) and, if the patient’s gene sequence includes a LOF variant in one or more genes in the EDC, administering tradipitant to the patient in an amount effective to ameliorate or eliminate one or more symptoms of the disease. If the patient’s gene sequence does not include a LOF variant in one or more genes in the EDC, the method includes treating said patient with a medicine other than tradipitant that is indicated for use in the treatment of atopic dermatitis or pruritus.

In a third aspect of the present invention, improvement are provided for methods consisting of administering to a patient suffering from pruritus or atopic dermatitis, an amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis. The improvements comprise selecting said patient for treatment based upon a determination that the patient’ s gene sequence includes a loss of function (LOF) variant in the filaggrin (FLG) gene. The improvements may further comprise selecting said patient for treatment based upon a determination that the patient’s gene sequence includes one, two, or more than two loss of function (LOF) variants in the filaggrin (FLG) gene. In certain embodiments, the FLG LOF variants may be R501X (rs61816761) or 2282del4 (rs558269137).

In a fourth aspect of the present invention, methods are provided for treating a patient for atopic dermatitis or pruritus. Such method includes determining whether the patient’s gene sequence includes a loss of function (LOF) variant in the filaggrin (FLG) gene, and may more particularly include determining whether the patient’ s gene sequence includes zero, one, two, or more than two loss of function (LOF) variants in the filaggrin (FLG) gene. If the patient’s gene sequence includes a FLG LOF variant, and particularly if the patient’s gene sequence includes one, two, or more than two FLG LOF variants, the method includes administering tradipitant to the patient in an amount effective to ameliorate or eliminate one or more symptoms of the disease. In certain embodiments, the FLG LOF variants present may be R501X (rs61816761) or 2282del4 (rs558269137). If the patient’s gene sequence does not include a FLG LOF variant, the method includes treating said patient with a medicine other than tradipitant that is indicated for use in the treatment of atopic dermatitis or pruritus.

These and other aspects, advantages and salient features of the invention will become apparent from the following detailed description, which, when taken in conjunction with the annexed figure(s) disclose embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates in bar chart form an association between number of FLG LOF mutations carried by an individual and age of onset of atopic dermatitis.

The drawing is intended to depict only typical aspects of the disclosure, and therefore should not be considered as limiting the scope of the disclosure.

DETAILED DESCRIPTION

In various embodiments of the invention, the methods described herein include improved methods for treating pruritus and/or atopic dermatitis using tradipitant, and methods of identifying patients who are most likely to respond favorably to tradipitant when used in methods of treatment of atopic dermatitis and/or pruritus.

In one embodiment of the present invention, an improvement is provided for a method consisting of administering to a patient suffering from pruritus or atopic dermatitis, an amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis. In such a method, the improvement comprises selecting the patient for treatment with tradipitant based upon a determination that said patient’s gene sequence includes a loss of function (LOF) variant in one or more genes in the epidermal differentiation complex (EDC). The gene in which the LOF variant is present may be the filaggrin (FLG) gene, e.g., in some embodiments, selecting the patient for treatment with tradipitant may be based upon a determination of said patient’s FLG loss of function (LOF) mutation status.

In various embodiments, the LOF variant may be a rare LOF variant, and may particularly be a rare FLG LOF variant, e.g., R501X (rs61816761) or 2282del4 (rs558269137). In other embodiments, the LOF variant is a FLG2 LOF variant, a HRNR LOF variant, a LCE4A LOF variant, a LCE5A LOF variant, a TCHH LOF variant, a TCHHL1 LOF variant, or a LOF variant in another gene in the EDC.

In other embodiments, a patient may be selected on the basis of a

determination that the patient’s gene sequence includes one or two or more than two LOF variants (mutations) in the FLG gene. These variants may include one or both of R501X (rs61816761) and 2282del4 (rs558269137), although other FLG LOF variants will be known to one skilled in the art. These FLG LOF variants are associated with age of onset of atopic dermatitis (AD), with earlier age of AD onset observed in the FLG LOF carrier group. The inclusion of two or more FLG LOF variants associates with age of AD onset of two years of age.

Prior to selecting the patient for treatment in accordance with the

aforementioned improvement, the patient may be identified as carrying one of the foregoing genetic variants. The patient may be identified as carrying one of the specified genetic variants by performing a genotyping assay on a biological sample collected from the patient to be treated. The biological sample may include, e.g., blood, serum, saliva, urine, et al. as is known in the art. In another aspect, the identifying may include reviewing a patient’s medical history, result report, or other document containing the result of a previously-performed assay or genetic test. In still further aspects, the identifying may include causing or requesting an assay to be performed by another individual, or causing or requesting the review of the patient’ s medical history, result report, or other document containing the result of a previously- performed assay or genetic test.

Regardless of which LOF variant(s) in an EDC or FLG gene the patient is determined to carry, the amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis may be, e.g., 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 as, e.g., 50 to 200 mg bid, 50 to 150 mg bid, 50 to 100 mg bid, or about 85 mg bid. In other embodiments, the amount may be for example, from greater than about 170 mg/day to 255 mg/day, or from greater than about 170 mg/day to 340 mg/day.

In other embodiments of the present invention, methods are provided for determining whether a patient has an enhanced likelihood of responding to treatment of atopic dermatitis or pruritus with tradipitant as disclosed herein. Such methods may include determining whether the patient’s gene sequence includes a loss of function (LOF) variant in a gene in the epidermal differentiation complex (EDC), or particularly in filaggrin (FLG). In particular, such methods may include determining whether the patient’s gene sequence includes one, two, or more than two LOF variants (mutations) in the FLG gene, and/or identifying patients whose gene sequences include one, two, or more than two FLG LOF variants. These variants may include one or both of R501X (rs61816761) and 2282del4 (rs558269137), although other FLG LOF variants will be known to one skilled in the art.

The methods of determining the presence or absence of an LOF variant in a gene in the EDC or particularly in FLG may include e.g., performing a genotyping assay on a biological sample collected from the patient to be treated. The biological sample may include, e.g., blood, serum, saliva, urine, et al. as is known in the art. In another aspect, the determining may include reviewing a patient’ s medical history, result report, or other document containing the result of a previously-performed assay or genetic test. In still further aspects, the identifying may include causing or requesting an assay to be performed by another individual, or causing or requesting the review of the patient’s medical history, result report, or other document containing the result of a previously-performed assay or genetic test. As discussed above, the LOF variant may be in any of a number of genes in the EDC, including filaggrin (FLG), FLG2, HRNR, LCE4A, LCE5A, TCHH, TCHHL1, or another member of the EDC. More particularly, the variant may be the FLG LOF variant defined by R501X (rs61816761) or 2282del4 (rs558269137).

Based on the presence or absence of an EDC or FLG gene LOF variant(s) in the patient’s gene sequence, it can be determined whether the patient is more likely to respond favorably to treatment of atopic dermatitis and/or pruritus with tradipitant than a patient lacking the LOF variants. For example, if the patient’s genotype includes one or more LOF variants in genes in the EDC or particularly in FLG, e.g., R501X (rs61816761) or 2282del4 (rs558269137), then the patient will be more likely to respond to tradipitant treatment, for example in an amount of 170 mg/day or more particularly 85 mg bid, than a patient with no such LOF variant. However, if the patient’s genotype does not include any LOF variants in genes of the EDC or particularly in FLG as disclosed herein, then the patient will be less likely to benefit from tradipitant treatment or less likely to demonstrate a significant response to the tradipitant treatment. Additionally, if the patient’s genotype includes one or more FLG LOF variants, then the patient’s age of onset of atopic dermatitis is likely to be 10 years of age or younger. If the patient’s genotype includes two FLG LOF variants, the patient’s age of onset of atopic dermatitis is likely to be 2 years of age or younger.

In an additional embodiment of the present invention, a method is provided for treating a patient for atopic dermatitis or pruritus. Such method comprises determining whether the patient’s gene sequence includes a loss of function (LOF) variant in one or more genes in the epidermal differentiation complex (EDC), particularly in FLG. The loss of function variant in the EDC may particularly be a filaggrin (FLG) LOF variant, which may be defined by R501X (rs61816761) or 2282del4 (rs558269137), or may be a LOF variant in FLG2, HRNR, LCE4A,

LCE5A, TCHH, TCHHL1, or another gene in the EDC.

If the patient’s gene sequence includes a LOF variant in one or more genes in the EDC such as, e.g., FLG, and more particularly if the patient’s gene sequence includes one, two, or more than two FLG LOF variants such as, e.g., R501X

(rs61816761), 2282del4 (rs558269137), or another variant as known in the art, the method includes administering tradipitant to said patient in an amount effective to ameliorate or eliminate one or more symptoms of the disease. Such symptoms may include intense and persistent pruritus or itch, which may be localized or generalized, erythema, excoriation, edema, lichenification, oozing, xerosis, raw, sensitive, swollen skin, and susceptibility of the skin to infection. The amelioration or elimination of such symptoms may be measured or measurable using any one or more known measures of pruritus or atopic dermatitis disease severity, for example, a 100mm unit Visual Analog Scale (VAS) for itch, Verbal Rating Scale (VRS), Dermatology Life Quality Index (DLQI), Clinical Global Impression of Change (CGI-C), Patient Benefit Index (PBI), objective and subjective SCORing Atopic Dermatitis Index (SCORAD), SKINDEX-16, Eczema Area and Severity Index (EASI) and Patient Global Impression of Change (PGIC) scale with respect to both itch and AD, and other measures of symptom severity and atopic dermatitis disease severity as known in the art.

The amount effective to ameliorate or eliminate one or more of the foregoing symptoms of the disease may be, e.g., 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 as, e.g., 50 to 200 mg bid, 50 to 150 mg bid, 50 to 100 mg bid, or about 85 mg bid. In other embodiments, the amount may be, e.g., from greater than about 170 mg/day to 255 mg/day, or from greater than about 170 mg/day to 340 mg/day. With regard to dosing, qd refers to dosing once per day; and bid dosing typically means dosing once in the morning and once in the evening, generally no less than about 8 hours or more than about 16 hours apart, e.g., 10 to 14 hours apart, or 12 hours apart (Q12H).

If, however, the patient’s gene sequence does not include a LOF variant in one or more genes in the EDC, or particularly FLG, the present method includes treating said patient in an alternative manner. This may include treatment with a medicine other than tradipitant that is indicated for use in the treatment of pruritus or atopic dermatitis, treatment with a higher dose of tradipitant, or other alternate therapy.

The present methods are particularly useful to patients and medical professionals given the value in prospectively identifying patients who may particularly benefit from treatment with tradipitant, and for reducing trial and error attempts to identify a successful therapy, particularly in the case of individuals who are unlikely to respond to tradipitant treatment at a dose of 170 mg/day. Such likely non-responders may benefit from treatment with an alternative medicine or, if tradipitant is nonetheless indicated for use in the patient, higher doses of tradipitant.

The skilled artisan will appreciate that additional embodiments may be selected by combining the embodiments above, or by reference to the examples given herein.

Example 1: LOF variants within the EDC

The frequency and effect of rare loss-of-function (LOF) variants within the EDC are investigated in a population of patients participating in a phase II, multicenter, randomized, double-blind, placebo-controlled clinical study (“Tradipitant in Treatment-resistant Pruritus Associated with Atopic Dermatitis,” clinicaltrials.gov Study ID NCT02651714) which includes 168 patients with chronic pruritus associated with atopic dermatitis, who are treated with tradipitant or placebo. The dataset includes 117 whole genome sequencing (WGS) samples.

Among 117 WGS samples from AD patients, 45 are found to carry significantly more, rare loss-of-function (LOF) mutations in the SFTP family of genes. By comparison, 55 are found to carry similar mutations in a control population of 316 (p-value = 0.000004). This group of EDC LOF (stopgain, frameshift) rare variants (EDC-LR) consists of 20 variants observed in the 45 AD patients resulting in a calculated Odds Ratio of 2.96 and a Relative Risk of 2.38. Among the detected LOF variants, there are 25 cases of FLG LOF mutations as defined by R501X

(rs61816761), 2282del4 (rs558269137), other LOFs in FLG, as well as LOFs in FLG2, HRNR, LCE4A, LCE5A, TCHH, TCHHL1, and other members of the EDC.

The regional accumulation of rare LOF variants (with SKAT-0 analysis) are also examined. The regional accumulation of rare LOF variants represent an effect that would be missed in a single marker genome- wide setting. To formalize, two tests are performed on 1) the FLG region alone, and 2) the entire EDC region (LOF set), comparing AD with controls (WGS). For the entire EDC, a p- value of 4.7e-20 is observed, much lower than for FLG alone (p-value of 4.5e-6). This indicates an even greater effect when analyzed jointly (entire family vs. FLG alone) in the AD context.

The high frequency of EDC variants in the AD cohort further reiterates the relevance of rare LOF variants within the EDC region in terms of diagnosis and treatment.

Conclusions

Whole genome sequencing of AD samples shows enrichment for rare variants in the EDC region in cases compared with controls. These significantly affect risk for AD. The identified LOF variants within the region can serve as biomarkers as well as help delineate the genetic profile in AD patients.

Example 2: LOF variants in FLG

The prevalence of loss-of-function (LOF) variants in filaggrin (FLG) and treatment response to tradipitant are investigated in a population of patients participating in a phase II, multicenter, randomized, double-blind, placebo-controlled clinical study (“Tradipitant in Treatment-resistant Pruritus Associated with Atopic Dermatitis,” clinicaltrials.gov Study ID NCT02651714) which includes 168 patients with chronic pruritus associated with atopic dermatitis, who are treated with tradipitant or placebo. The dataset includes 117 whole genome sequencing (WGS) samples.

Among 117 WGS samples from AD patients, 23 cases of LOF FLG mutations are observed. Consistent with previous literature, 20% of the AD patient population shows at least one LOF mutation in FLG, which contrasts with about 4% in a control population.

A responder analysis is conducted in these 23 FLG LOF variant cases. A responder is defined as showing at least a 40mm reduction in worst itch, as measured by worst itch visual analogue scale (WI-VAS), and at least a 50% improvement in AD disease severity as measured by the SCORing Atopic Dermatitis (SCORAD) index.

Of the 23 patients having FLG LOF variants, 14 are randomized to placebo, while 9 are randomized to tradipitant treatment. Among 14 cases treated with placebo, no patients (0/14) exhibit response to treatment. In contrast, 3/9 (33%) of tradipitant-treated patients demonstrate response as defined above ( - value = 0.047).

Conclusions

Tradipitant is known, e.g., from international patent application publication WO 2016/141341, to be effective in the treatment of pruritus and atopic dermatitis. Similarly to the previously demonstrated effect of tradipitant in the full AD population, tradipitant is shown to be effective in a responder analysis in carriers of FLG LOF variants. This further underscores the utility of tradipitant in patients with impaired skin barrier.

Example 3: Correlation of age-of-onset of atopic dermatitis with FLG LOF carrier status

An investigation into the frequency and effect of rare FLG loss-of-function (LOF) variants, and the association of these variants with self-reported age-of-onset of atopic dermatitis (AD) is undertaken. In this investigation, samples are obtained from clinical study VP-VLY-686-3101, a randomized, double-blind, placebo-controlled, multi-center study of patients with chronic pruritus associated with AD, who are treated with tradipitant or placebo. The dataset consists of 356 whole genome sequencing (WGS) samples and 414 samples genotyped for the two most prevalent FLG LOF mutations, R501X (rs61816761), and 2282del4 (rs558269137).

FLG LOF status is observed to be significantly associated with age-of-onset of atopic dermatitis (AD). In particular, earlier age of AD onset is observed in the FLG LOF carrier group (p-value 0.0003, Wilcoxon two-sample test as shown in Table 1).

Table 1: Wilcoxon Two-Sample Test

The association between FLG LOF carrier status is observed with respect to the two most prevalent FLG mutations, R501X (rs61816761), and 2282del4 (rs558269137). Interestingly, the observed effect is even stronger when considering all detected FLG LOF variants than with R501X and 2282del4 alone.

As shown in FIG. 1, an individual’s status as having two or more FLG LOF variants is associated with onset of AD at 2 years of age. The odds ratio (OR) of having onset before 10 years of age if the subject is a mutation carrier is 3.27 (p-value 0.0037). Additionally, table 2 provides mean age-of-onset values for individuals carrying 0 or 1 FLG mutations.

Table 2: Mean values of age-of-onset given 0 or 1 FLG mutations

Conclusions

While enrichment of whole genome studies (WGSs) for rare variants in the EDC region compared to controls has previously been shown, age of onset analysis now shows not only the effect of the FLG and likely EDC variants in terms of heightened risk of AD, but also enables prediction of early onset AD. This lends further credence to the penetrance and causative effect of the identified variants. Understanding the genetic background and risk of early onset is suggestive of skin barrier dysfunction etiology of the itch- scratch cycle present in early onset AD. The ability to predict early onset of AD further improves the ability of practitioners to identify individuals for treatment with tradipitant, in whom tradipitant is likely to provide effective treatment of at least one symptom of AD.

* * * The foregoing description of various aspects of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and modifications and variations are possible. Such modifications and variations that may be apparent to a person skilled in the art are intended to be included within the scope of the invention as defined by the accompanying claims.

Claims

CLAIMS We claim:

1. In a method consisting of administering to a patient suffering from pruritus or atopic dermatitis, an amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis, the improvement comprising: selecting said patient for treatment based upon a determination that the patient’s gene sequence includes a loss of function (LOF) variant in one or more genes in the epidermal differentiation complex (EDC).

2. The improvement according to claim 1, wherein the LOF variant is a filaggrin (FLG) LOF variant.

3. The improvement according to claim 2, wherein the LOF variant in the FLG gene is R501X (rs61816761).

4. The improvement according to claim 2, wherein the LOF variant in the FLG gene is 2282del4 (rs558269137).

5. The improvement according to any one of claims 2-4, further comprising selecting said patient for treatment based upon a determination that the patient’s gene sequence includes two loss of function (LOF) variants in the filaggrin (FLG) gene.

6. The improvement according to claim 1, wherein the LOF variant is a FLG2 LOF variant, a HRNR LOF variant, a LCE4A LOF variant, a LCE5A LOF variant, a TCHH LOF variant, or a TCHHL1 LOF variant.

7. The improvement according to any of claims 1-6, wherein the amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis is 100-400 mg/day.

8. The improvement according to claim 7, wherein the amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis is 100-300 mg/day.

9. The improvement according to claim 8, wherein the amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis is 100-200 mg/day.

10. The improvement according to claim 9, wherein the amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis is 170 mg/day.

11. The improvement according to claim 10, wherein the amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis is 85 mg bid.

12. The improvement according to claim 7, wherein the amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis is about 170-340 mg/day.

13. The improvement according to claim 7, wherein the amount of tradipitant effective to treat said patient’s pruritus or atopic dermatitis is about 170-255 mg/day.

14. A method of treating a patient for atopic dermatitis or pruritus comprising: determining whether the patient’s gene sequence includes a loss of function (LOF) variant in one or more genes in the epidermal differentiation complex (EDC), and if the patient’ s gene sequence includes a LOF variant in one or more genes in the EDC, administering tradipitant to said patient in an amount effective to ameliorate or eliminate one or more symptoms of the pruritus or atopic dermatitis.

15. The method of claim 14, further comprising: if the patient’ s gene sequence does not include a LOF variant in one or more genes in the EDC, treating said patient with a medicine other than tradipitant that is indicated for use in the treatment of pruritis or atopic dermatitis.

16. The method of claim 14 or 15, wherein the LOF variant is a filaggrin (FLG) LOF variant.

17. The method of claim 16, wherein the FLG LOF variant is R501X (rs61816761).

18. The method of claim 16, wherein the FLG LOF variant is 2282del4

(rs558269137).

19. The method of claim 16, wherein the patient’s gene sequence includes two LOF variants in the FLG gene.

20. The method of claim 14 or 15, wherein the LOF variant is a FLG2 LOF variant, a

HRNR LOF variant, a LCE4A LOF variant, a LCE5A LOF variant, a TCHH LOF variant, or a TCHHL1 LOF variant.

21. The method according to any of claims 14-20, wherein the amount effective to ameliorate or eliminate one or more symptoms of the pruritus or atopic dermatitis is 100-400 mg/day.

22. The method according to claim 21, wherein the amount effective to ameliorate or eliminate one or more symptoms of the pruritus or atopic dermatitis is 100-300 mg/day.

23. The method according to claim 22, wherein the amount effective to ameliorate or eliminate one or more symptoms of the pruritus or atopic dermatitis is 100-200 mg/day.

24. The method according to claim 23, wherein the amount effective to ameliorate or eliminate one or more symptoms of the pruritus or atopic dermatitis is 170 mg/day.

25. The method according to claim 24, wherein the amount effective to ameliorate or eliminate one or more symptoms of the pruritus or atopic dermatitis is 85 mg bid.

26. The method according to claim 21, wherein the amount effective to ameliorate or eliminate one or more symptoms of the pruritus or atopic dermatitis is about 170-340 mg/day.

27. The method according to claim 21, wherein the amount effective to ameliorate or eliminate one or more symptoms of the pruritus or atopic dermatitis is about 170-255 mg/day.