IMPROVED TREATMENT OF ATOPIC DERMATITIS WITH TRADIPITANT

Abstract

The disclosure relates generally to improvements in the treatment of pruritus, atopic dermatitis (AD), and associated symptoms with tradipitant. More particularly, it relates to a method for increasing the likelihood of achieving optimal therapeutic response in the treatment of an AD patient, where the AD patient is one for whom a potential therapy of choice may include the administration of an amount of an NK-1 antagonist, e.g. tradipitant effective to treat the patient's AD.

Claims

1. A method for increasing the probability of achieving an optimal therapeutic response in the treatment of an atopic dermatitis patient for whom administering an amount of tradipitant effective to treat atopic dermatitis might be the therapy of choice, comprising: examining said patient in a manner sufficient to assess one or both of said patient's Investigator's Global Assessment (IGA) and body surface area (BSA) scores; and if said patient's IGA score is 2 or less or if said patient's BSA score is 10% or less or if said patient's IGA and BSA scores are respectively 2 or less and 10% or less, prescribing tradipitant for use by said patient in an amount effective to treat said patient's atopic dermatitis, whereupon said amount of tradipitant is administered to said patient; and if said patient is not prescribed tradipitant based upon said IGA or BSA scores, evaluating whether (1) an alternative medicinal therapy other than tradipitant or (2) the use of tradipitant is the more appropriate medical intervention for treating said patient.

2. The method of claim 1, further comprising: if said patient is not prescribed tradipitant based upon said IGA or BSA scores, administering an alternative medicinal therapy other than tradipitant to the patient.

3. The method of claim 1, further comprising: if said patient is not prescribed tradipitant based upon said IGA or BSA scores, determining that tradipitant is the appropriate medical intervention for treating said patient, and administering tradipitant to the patient.

4. The method according to claim 1, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 100-400 mg/day.

5. The method according to claim 4, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 170 mg/day.

6. The method according to claim 5, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 85 mg bid.

7. A method for increasing the probability of achieving an optimal therapeutic response in the treatment of an atopic dermatitis patient for whom administering an amount of an NK-1 antagonist effective to treat atopic dermatitis might be the therapy of choice, comprising: examining said patient in a manner sufficient to assess one or both of said patient's Investigator's Global Assessment (IGA) and body surface area (BSA) scores; and if said patient's IGA score is 2 or less or if said patient's BSA score is 10% or less or if said patient's IGA and BSA scores are respectively 2 or less and 10% or less, prescribing the NK-1 antagonist for use by said patient in an amount effective to treat said patient's atopic dermatitis, whereupon said amount of the NK-1 antagonist is administered to said patient; and if said patient is not prescribed the NK-1 antagonist based upon said IGA or BSA scores, evaluating whether (1) an alternative medicinal therapy other than the NK-1 antagonist or (2) the use of the NK-1 antagonist is the more appropriate medical intervention for treating said patient.

8. The method of claim 7, further comprising: if said patient is not prescribed the NK-1 antagonist based upon said IGA or BSA scores, administering an alternative medicinal therapy other than the NK-1 antagonist to the patient.

9. The method of claim 7, further comprising: if said patient is not prescribed the NK-1 antagonist based upon said IGA or BSA scores, determining that the NK-1 antagonist is the appropriate medical intervention for treating said patient, and administering the NK-1 antagonist to the patient.

10. The method of claim 7, wherein the NK-1 antagonist is selected from the group consisting of: aprepitant, casopitant, ezlopitant, fosaprepitant, netupitant, rolapitant, serlopitant, tradipitant, vestipitant, and vofopitant.

11. The method of claim 10, wherein the NK-1 antagonist is tradipitant.

12. The method according to claim 11, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 100-400 mg/day.

13. The method according to claim 12, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 170 mg/day.

14. The method according to claim 13, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 85 mg bid.

15. The method according to claim 4, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 150-400 mg/day.

16. The method according to claim 15, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 150-300 mg/day.

17. The method according to claim 12, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 150-400 mg/day.

18. The method according to claim 17, wherein the amount of tradipitant effective to treat said patient's pruritus or atopic dermatitis is 150-300 mg/day.

19. A method comprising: selecting for treatment an individual suffering from atopic dermatitis, wherein the individual is selected for treatment based upon: examining the individual in a manner sufficient to assess one or both of the individual's Investigator's Global Assessment (IGA) and body surface area (BSA) scores; and determining that the individual has an IGA score of 2 or less, or the individual has a BSA score of 10% or less, or the individual has both of an IGA score of 2 or less and a BSA score of 10% or less; and administering an NK-1 antagonist to the selected individual in an amount effective to treat the atopic dermatitis, wherein the NK-1 antagonist is selected from the group consisting of: aprepitant, casopitant, ezlopitant, fosaprepitant, netupitant, rolapitant, serlopitant, tradipitant, vestipitant, and vofopitant.

20. The method of claim 19, wherein the NK-1 antagonist is tradipitant, and the amount effective to treat the atopic dermatitis is about 170 mg/day.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 illustrates change in Worst Itch-Numerical Rating Scale (WI-NRS) by week in the EPIONE study described in the Example herein.

[0017] FIGS. 2A-2D illustrate baseline attributes of the study population in the EPIONE study described in the Example herein. In particular, FIG. 2A shows distinct endotypes and clinical presentation of AD as defined by IGA 1 and 2 (mild) and IGA 3 and 4 (moderate and severe). FIG. 2B shows distribution of clinical variables across endotypes as defined by IGA 1 and 2 (mild) and IGA 3 and 4 (moderate and severe). FIG. 2C shows significant differences in Eosinophil counts across endotypes as defined by IGA 1 and 2 (mild) and IGA 3 and 4 (moderate and severe). FIG. 2D shows lollipop plots displaying the location and frequency of the identified variants in Filaggrin (FLG) A significant enrichment of rare LOF variants is observed in FLG in IGA 3 and 4 AD patients (moderate and severe) as compared to IGA 1 and 2 AD patients (mild).

[0018] FIGS. 3A-3D illustrate the role of substance Pin the mediation of itch. Pruritus-related mechanisms comprise interleukins as well as neuropeptides that are relevant to neurogenic inflammation such as substance P and the pruritogen-keratinocyte communication. In the mild AD population (FIG. 3C), relatively fewer itch mediation factors including cytokines, serotonin, histamine, and eosinophils are present, leaving substance P as the predominant factor in itch. In contrast, in the more severe AD population (FIG. 3D), there are increasingly multiple factors other than Substance P involved in the cause of itch.

[0019] The drawings are intended to depict only typical aspects of the disclosure, and therefore should not be considered as limiting the scope of the disclosure.

DETAILED DESCRIPTION

[0020] In various embodiments of the invention, the methods described herein include methods for increasing the probability of achieving an optimal therapeutic response in the treatment of a patient suffering from atopic dermatitis (AD), and particularly, where the patient is one for whom administration of an effective amount of an NK-1 antagonist may be a therapy of choice to treat the AD. NK-1 antagonists are known in the art to include, e.g., aprepitant, casopitant, ezlopitant, fosaprepitant, netupitant, rolapitant, serlopitant, tradipitant, vestipitant, and vofopitant. In certain embodiments and examples described herein, the NK-1 antagonist may particularly be tradipitant. However, it is recognized that one skilled in the art may affect the patient's pruritus and/or AD by treating the patient in the manner described with an NK-1 antagonist other than tradipitant.

[0021] In one such method for increasing the probability of achieving optimal therapeutic response in the treatment of an AD patient, a provider first identifies a patient with reported pruritus associated with one or more skin lesions. “Provider” as used herein may refer to a healthcare provider, e.g., a physician, other healthcare practitioner, or licensed prescriber of medications. The provider may examine or evaluate the clinical presentation of the patient to confirm the diagnosis of AD and pruritus associated therewith, and to determine the severity of the pruritus and of the underlying AD.

[0022] In particular, the provider may identify the type of AD based on the appearance and extent of the skin lesions, and may characterize the physical appearance of the lesions using any of a number of diagnostic tools and criteria. Examples of such diagnostic tools and criteria include, for example, Investigator's Global Assessment (IGA), a 100 mm 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 provider may further assess and determine the patient's body surface area (BSA) affected by AD, which is provided as a percentage. These factors may be used to determine whether the patient suffers from mild, moderate, or severe AD.

[0023] In particular, IGA, BSA, or IGA and BSA may be used to determine severity of AD disease. Patients having an IGA score of 1 or 2, a BSA of less than or equal to (<) 10%, or both of an IGA or 1 or 2 and a BSA of <10% may be identified as having mild AD. Patients having an IGA score of 3 or 4, a BSA of greater than 10%, or both of an IGA score of 3 or 4 and a BSA of greater than 10%, may be determined to have moderate to severe AD.

[0024] In other embodiments, other assessments may also be used, either alone or in combination with one another or with IGA, BSA, or a combination of any of the foregoing, to determine and/or confirm the severity of AD. In particular, the provider may evaluate biochemical and genetic markers to determine whether the patient suffers, or has the propensity to suffer, from mild AD. For example, in one embodiment the provider may perform, or requisition to be performed, a diagnostic test to assess the patient's eosinophil blood count. This may be done by performance of, e.g., a complete blood count (CBC), white blood cell differential, or absolute eosinophil count. Any of the foregoing may be performed on a biological sample, e.g., blood sample, collected from the patient to be treated. An eosinophil count that is within normal reference limits may be associated with mild AD (FIG. 2C).

[0025] In another embodiment, the provider may perform a genotyping assay on a biological sample collected from the patient to be treated to identify genetic variants, e.g., in the filaggrin (FLG) gene. FLG is a member of the S100 fused type protein (SFTP family), and is located on chromosome 1 q21. FLG encodes the filaggrin protein, a skin barrier structural protein. The biological sample may include, e.g., blood, serum, saliva, urine, et al. as known in the art. The accumulation of mutations in the patient's FLG gene is associated with non-mild, e.g., moderate to severe AD disease severity in the patient, while the non-accumulation of mutations in the patient's FLG gene is associated with mild AD disease in the patient (FIG. 2D).

[0026] Using the foregoing indicia of severity, e.g., one or more of an IGA score of 1 or 2 or a BSA score of <10%, and associated biomarkers including relatively low eosinophil count, FLG genotype, and other measures, patients can be identified as suffering from mild AD or non-mild (i.e. moderate to severe) AD. As described in the Example herein, patients suffering from mild AD are more likely to experience response to treatment with tradipitant than patients with non-mild AD.

[0027] If the patient is determined to suffer from pruritus associated with mild AD, based on IGA score, BSA score, and/or other indicia described herein, an NK-1 antagonist, e.g., tradipitant may be prescribed for use by the patient, in an amount effective to treat said patient's atopic dermatitis. In various embodiments, the amount of tradipitant effective to treat the patient's pruritus or atopic dermatitis may be, e.g., 100-400 mg/day, 150-400 mg/day, 100-300 mg/day, 150-300 mg/day, 100-200 mg/day, 170-340 mg/day, or 170-255 mg/day. In certain embodiments, the amount may be 170 mg/day, and may be dosed as 85 mg twice daily (bid). The NK-1 antagonist, e.g., tradipitant may subsequently be administered in such an amount to the patient to treat the patient's pruritus and/or underlying AD. The antipruritic effect may be seen immediately after the first full day of tradipitant dosing, along with significant improvement in nighttime sleep.

[0028] If the patient is not prescribed the NK-1 antagonist, e.g. tradipitant, based upon the foregoing indicia including, e.g., IGA score and BSA score, i.e. the patient is not diagnosed as suffering from mild AD, the provider may then evaluate whether (1) an alternative medicinal therapy other than the NK-1 antagonist, e.g. tradipitant, or (2) the use of the NK-1 antagonist, e.g. tradipitant, is the more appropriate medical intervention for treating that particular patient. In the event of case (1), more appropriate treatment options are selected from those known in the art. Examples of such alternatives can be found at https://www.mayoclinic.org/diseases-conditions/atopic-dermatitis-eczema/diagnosis-treatment/drc-20353279 and include topical medicines (e.g., a corticosteroid cream or ointment, a calcineurin inhibitor, or antibiotic cream or ointments) and systemic medicines (e.g., oral corticosteroids, including prednisone or injectable preparations such as dupilumab).

[0029] Depending on the determination, an alternative medical therapy may be administered, or the NK-1 antagonist, e.g. tradipitant may be administered. In the case that tradipitant is administered to the patient, but not on the basis of IGA and/or BSA score, the patient may be monitored more closely for response to treatment, as AD patients demonstrating a response to tradipitant treatment may respond as soon as after the first full day of tradipitant dosing. The provider may monitor the patient at least through this window of time following administration to assess whether satisfactory treatment response is obtained with tradipitant.

[0030] 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: EPIONE Study

[0031] A randomized, placebo-controlled phase III study is conducted in atopic dermatitis (AD) patients with severe pruritus with a range of disease severity presentation from mild (23%) to moderate (64%) and severe (13%) as determined by the Investigator's Global Assessment scale (IGA). In the study, patients (n=341) are randomized 1:1 to receive either tradipitant or placebo for a treatment period of eight (8) weeks. Patients in the tradipitant arm of the study are dosed with 85 mg tradipitant twice daily (bid). Patients are assessed at baseline and post-randomization with a number of symptomatic and disease severity scales at regular intervals.

[0032] At week 8, patients in both the tradipitant and placebo arms of the study demonstrate significant and meaningful improvement in pruritus, as measured by the Worst Itch Numeric Rating Scale (WI-NRS). The tradipitant magnitude of improvement is greater than that of placebo, although the difference between treatment groups is not statistically significant.

[0033] A significant interaction is observed between baseline disease severity and treatment (p=0.0004), where disease severity is measured by Investigator's Global Assessment (IGA) on a scale of 1-4. This suggests that study participants with different baseline disease severity experience different treatment outcomes.

[0034] When accounting for baseline disease severity and treatment interaction, a significantly larger improvement in WI-NRS is seen with tradipitant compared to placebo at the pre-specified endpoint of week 8 in the full trial population (p=0.0217). Similar effects are seen throughout the treatment periods at all post-randomization visits comprising weeks 2, 4, 6 and 8 (Table 1).

TABLE-US-00001 TABLE 1 EPIONE Results Summary Endpoints.sup.1 Visit Tradipitant Placebo Diff P-value WI-NRS Week 2 −1.68 −1.44 0.23 0.3092 ITT (n = 341) Week 4 −2.58 −2.20 0.39 0.1664 Tradipitant (n = 171) Week 6 −3.00 −2.89 0.11 0.7105 Placebo (n = 170) Week 8 −3.61 −3.43 0.18 0.5667 WI-NRS Adjusting for IGA Severity Week 2 −2.43 −1.29 1.14 0.0069 ITT (n = 341) Week 4 −3.34 −2.05 1.29 0.0042 Week 6 −3.75 −2.74 1.01 0.0284 Week 8 −4.36 −3.28 1.08 0.0217 WI-NRS Week 2 −2.59 −0.98 1.61 0.0003 IGA 1, 2 (n = 79) Week 4 −3.39 −1.48 1.92 0.0005 Tradipitant (n = 40) Week 6 −4.18 −2.32 1.86 0.0024 Placebo (n = 39) Week 8 −4.74 −3.14 1.60 0.0152 Diary WI−NRS Week 2 −1.54 −0.36 1.18 0.0002 IGA 1, 2 (n = 79) Week 4 −2.78 −1.07 1.71 0.0002 Week 6 −3.48 −1.72 1.76 0.0011 Week 8 −4.23 −2.14 2.09 0.0010 Responder Analysis (%).sup.2 (n = 79) WI-NRS ≥4 Improvement Week 8 72.5 33.3 39.2 0.0007 SCORAD 50% Improvement Week 8 55.0 30.8 24.2 0.0411 IGA 0 or 1 Week 8 60.0 38.5 21.5 0.0729 .sup.1P-values are from MMRM analysis. .sup.2P-values are from Fisher’s exact test.

[0035] A subgroup analysis shows that patients with mild disease severity (23% of study patients, IGA 1, 2) experience the largest improvement over placebo. Specifically, in the mild AD group, tradipitant significantly improves WI-NRS over placebo at every visit (Table 1, FIG. 1). The categorical WI-NRS responder analysis (>4 point improvement) showed that 72.5% of tradipitant patients had a clinically meaningful response as compared to 33.3% of placebo patients.

[0036] These results suggest a large and significant antipruritic effect of tradipitant in mild AD, which is consistent with patient daily diary entries. For mild AD patients, a time course of response also shows that the antipruritic effect is seen immediately after the first full day of tradipitant dosing, suggesting a large and immediate therapeutic effect. Similar improvement is observed for nighttime sleep, which is often disrupted in patients with severe pruritus.

[0037] Additionally, results suggest that mild and non-mild (e.g. severe) AD appear to be distinct endotypes with a different set of causative factors and course. Non-mild, i.e., moderate to severe AD (IGA 3, 4) is associated with significantly higher count of eosinophils in the blood as compared to mild AD (IGA 1, 2), as shown in FIG. 2C. Eosinophils are mediators of the inflammatory response and are responsible for recruiting other immune cells in the lesions. Eosinophils are involved directly or indirectly in the production and secretion of pruritogenic and inflammatory mediators including histamine, serotonin, substance P, NGF, and a number of interleukin cytokines. As such, it is likely that severe pruritus associated with mild and severe AD may have different mediators. (FIGS. 3A-3D).

[0038] Further, whole genome sequence analysis (WGAS) shows that particular genetic markers are associated with mild AD vs. non-mild (i.e. moderate to severe) AD. For example, the accumulation of rare loss of function (LOF) mutations in the patient's filaggrin (FLG) gene is associated with non-mild (e.g. moderate to severe) AD disease severity in the patient, while non-accumulation of mutations in the patient's FLG gene is associated with mild AD disease in the patient (FIG. 2D).

[0039] Tradipitant appears to produce a large and rapid antipruritic effect in mild AD, providing a significant and immediate onset of itch reduction by the first full day of treatment while having a relatively safe profile. This may provide a much-needed therapy for the majority of AD patients that experience mild AD lesion severity but still suffer from significant pruritus.

[0040] 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.