WO2020023898A1

WO2020023898A1 - Use of neurokinin-1 antagonists to treat chronic pruritus

Info

Publication number: WO2020023898A1
Application number: PCT/US2019/043710
Authority: WO
Inventors: Steven BASTA; Paul Kwon
Original assignee: Menlo Therapeutics Inc.
Priority date: 2018-07-27
Filing date: 2019-07-26
Publication date: 2020-01-30
Also published as: EP3829572A1

Abstract

The disclosure relates to the use of neurokinin-1 (NK-1) antagonists, such as serlopitant, in treating chronic pruritus with a duration of at least about 6 months or 1 year. In some embodiments, the chronic pruritus is characterized by sensitization or hypersensitization of central neuron or/and peripheral neurons. In further embodiments, the chrome pruritus is characterized by spontaneously occurring itch, alloknesis or hyperknesis, or any combination or all thereof. The chronic pruritus can be associated with any medical conditions or can have an unknown cause (idiopathic). One or more additional antipruritic agents can optionally be used in combination with an NK-1 antagonist to treat chronic pruritus.

Description

Use of Neurokinin-! Antagonists to Treat Chronic Pruritus

Cross Reference to Related Applications

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application Number 62/821,126, filed on March 20, 2019, U.S. Provisional Patent Application Number 62/779,285, filed on December 13, 2018, and U.S Provisional Patent Application Number 62/711, 123, filed on July 27, 2018, the entire disclosure of each of which is incorporated herein by reference in its entirety .

[0002] The present disclosure relates to the use of a neurokinin- 1 (NK-1) antagonist such as serlopitant, and optionally one or more additional antipruritic agents, in treating chronic pruritus having a duration of at least about six months or one year.

Background of the Disclosure

[0003] Pruritus (itch) is an unpleasant sensation that provokes a desire to scratch. Pruritus can have its origin directly in tire skin or can develop m the central nervous system (CN S) via hematogenic or neurogenic mediators. Chronic pruritus (pruritus lasting > six weeks) is a common symptom of skin disorders as well as a wide range of systemic, neurological and psychiatric disorders in the absence of a skin condition, and can be induced by many different types of medications. The prevalence of chronic pruritus in the general adult population is about 14-17% and increases with age, with abou t 60% of the elderly (over 65 years of age) suffering from moderate to severe chronic pruritus. Chronic pruritus can be intense, intractable and debilitating, can increase the severity of the underlying disease, and can greatly dimmish tire quality of life, with many patients suffering from insomnia, anxiety and depression. Stress and anxiety can be induced by the constant pruritus, and stress and anxiety increase the intensity and frequency of the itch, leading to a vicious cycle that affects patient behavior (e.g., scratching) and worsens disease prognosis and quality of life. Persistent rubbing or scratching can form secondary skin lesions such as excoriations, erosions, eschars, hyperpigmentation or patches of discoloration, impetiginisations and scars. Pruritus can induce an itch/scratch cycle and self stimulation of the pruritic mechanism and scratching, which can exacerbate existing skm lesions and create new skin lesions. Chronic scratching worsens symptoms and often produces open skin lesions, which are susceptible to secondary infections, scarring and potential disfigurement. Once the itch/scratch cycle becomes established, it can be very difficult to stop, thereby perpetuating pruritus.

Summary of the Disclosure

[0004] The present disclosure provides for the use of an antagonist (or inhibitor) of neurokinin- 1 (NK-l) in treating chronic pruritus having a duration of at least about 6 months or 1 year. In certain embodiments, the chronic pruritus has a duration of at least about 3 years or 5 years. In some embodiments, the chrome pruritus is characterized by sensitization or hypersensitization of the CNS or/and the peripheral nervous system (PNS). In further embodiments, the chronic pruritus is characterized by spontaneous itch, alloknesis or hyperknesis, or any combination or all thereof. In certain embodiments, the NK-l antagonist is seriopitant or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In some embodiments, the chronic pruritus is refractory or resistant to other antipruritic therapies without an NK-l antagonist.

[0005] lire chrome pruritus can be associated with any medical conditions or can have an unknown cause (idiopathic). In some embodiments, the chronic pruritus is, or is associated with, xerosis or xeroderma (dry skin), dermatitis or eczema (e.g., atopic dermatitis), psoriasis (e.g., plaque psoriasis), prurigo (e.g., prurigo nodularis), urticaria (e.g., chronic idiopathic urticaria), a connective tissue disorder (e.g., dermatomyositis), post-burn pruritus, a kidney disorder (e.g., chronic kidney disease, chronic kidney failure or end-stage renal disease), dialysis (e.g., hemodialysis), uremic pruritus, a hepato-biliary disorder (e.g., cholestasis, primary biliary cholangitis, hepatitis, chronic liver disease or cirrhosis), cholestatic pruritus, a benign or malignant neoplasm (e.g., a solid tumor, a carcinoma or a hematological neoplasm [e.g., Hodgkin’s lymphoma, non-Hodgkin’s lymphoma or polycythemia vera]), drug-induced pruritus, neuropathic itch (e.g., brachioradial pruritus or notalgia paresthetica), neurogenic itch, pruritus m the elderly, or chronic idiopathic pruritus.

[0006] In some embodiments, the therapeutically effective amount (e.g., per day or per dose) of the NK-l antagonist for treating chronic pruritus is about 0.25 or 1 to 200 mg, 0.5 or 1 to 150 mg, 0.5 or 1 to 100 mg, 0.5 or 1 to 50 mg, 0.5 or 1 to 10 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40- 50 mg, 50-100 mg, 100-150 mg or 150-200 mg. In further embodiments, the therapeutically effective amount of the NK-l antagonist is administered one or more times a day, once every two days, once every three days, twice a week or once a week (e.g., once or twice daily). In some embodiments, the NK-l antagonist is seriopitant, and the therapeutically effective amount of serlopitant is about 0.25 or 1 to 5 mg or 5-10 mg, or about 0.5 mg, 1 mg, 5 mg or 10 mg, once or twice daily. In certain embodiments, the therapeutically effective amount of serlopitant is about 5 mg once daily. In certain embodiments, treatment of chronic pruritus with the NK-1 antagonist lasts for at least about 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year,

2 years, 3 years, 4 years, 5 years or longer (e.g., at least about 6 weeks, 3 months, 6 months or 1 year). The NK-1 antagonist can also be taken in an irregular manner or pro re naia (as needed), as described elsewhere herein.

[0007] One or more additional antipruritic agents can optionally be used in combination with an NK-1 antagonist (e.g., serlopitant) to treat chronic pruritus.

[0008] A better understanding of features and advantages of the present disclosure will be obtained by reference to the following detailed description, which sets forth illustrative embodiments of the disclosure, and the accompanying drawings.

[0009] FIG, 1 illustrates a Franz diffusion cell for studying skin penneation of a drug in vitro.

[0010] FIG. 2 shows the cumulative release of serlopitant from topical formulations B and C into the receptor chamber of a Franz diffusion cell at various time points in an in vitro study of skin permeation.

[001 1] FIG, 3 shows the amount of serlopitant (called“VPD737”) retained in the skin at the end of the Franz diffusion cell study. Each bar represents ug of serlopitant/g of skin in 250 um skin layers. For each of topical formulations B and C, the bars from left to right represent the amount of serlopitant retained in skin layers from the stratum comeum to the dermis.

Detailed Description of the Disclosure

[0012] While various embodiments of the present disclosure are described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications and changes to, and variations and substitutions of, the embodiments described herein will be apparent to those skilled in the art without departing from the disclosure. It is understood that various alternatives to the embodiments described herein can be employed in practicing the disclosure. It is also understood that every embodiment of the disclosure can optionally be combined with any one or more of the other embodiments described herein which are consistent with that embodiment. [0013] Where elements are presented in list format (e.g., in a Markush group), it is understood that each possible subgroup of tire elements is also disclosed, and any one or more elements can be removed from the list or group.

[0014] It is also understood that, unless clearly indicated to the contrary, in any method described or claimed herein that includes more than one act, the order of the acts of the method is not necessarily limited to the order in which the acts of the method are recited, but the disclosure encompasses embodiments in which the order is so limited.

[0015] It is further understood that, in general, where an embodiment in the description or the claims is referred to as comprising one or more features, the disclosure also encompasses embodiments that consist of, or consist essentially of, such feature(s).

[0016] It is also understood that any embodiment of the disclosure, e.g., any embodiment found within the prior art, can be explicitly excluded from the claims, regardless of whether or not the specific exclusion is recited in the specification.

[0017] It is further understood that the present disclosure encompasses analogs, derivatives, prodrugs, metabolites, salts, solvates, hydrates, clathrates, polymorphs and stereoisomers of all of the compounds/substances disclosed herein, as appropriate. The specific recitation of“analogs”, “derivatives”,“prodrugs”,“metabolites”,“salts”,“solvates”,“hydrates”,“clathrates”, “polymorphs” or“stereoisomers” with respect to a compound/substance or a group of compounds/substances in certain instances of the disclosure shall not be interpreted as an intended omission of any of these forms in other instances of tire disclosure where the compound/substance or the group of compounds/substances is mentioned without recitation of any of these forms, unless stated otherwise or the context clearly indicates otherwise.

[0018] Headings are included herein for reference and to aid in locating certain sections. Headings are not intended to limit the scope of the embodiments and concepts described in the sections under those headings, and those embodiments and concepts may have applicability in other sections throughout the entire disclosure.

[0019] All patent literature and all non-patent literature cited herein are incorporated herein by reference in their entirety to the same extent as if each patent literature or non-patent literature were specifically and individually indicated to be incorporated herein by reference in its entirety. Definitions

[0020] Unless defined otherwise or clearly indicated otherwise by their use herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0021] As used in the specification and the appended claims, the indefinite articles“a” and “an"’ and the definite article‘the” can include plural referents as well as singular referents unless specifically stated otherwise or the context clearly dictates otherwise.

[0022] The abbreviation“aka” denotes“also known as”.

[0023] The term“about” or“approximately” means an acceptable error for a particular value as determined by one of ordinaiy skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the tenn“about” or“approximately” means within one standard deviation. In some embodiments, when no particular margin of error (e.g., a standard deviation to a mean value given in a chart or table of data) is recited, the term“about” or “approximately” means that range which would encompass the recited value and the range which would be included by rounding up or down to the recited value as well, taking into account significant figures. In certain embodiments, the term“about” or“approximately” means within ± 20%, 15%, 10% or 5% of the specified value. Whenever the term“about” or“approximately” precedes the first numerical value in a series of two or more numerical values or in a series of two or more ranges of numerical values, the term“about” or“approximately” applies to each one of the numerical values in that series of numerical values or in that series of ranges of numerical values.

[0024] Whenever the term“at least” or“greater than” precedes the first numerical value in a series of two or more numerical values, the term“at least” or“greater than” applies to each one of the numerical values in that series of numerical values.

[0025] Whenever the term“no more than” or“less than” precedes the first numerical value in a series of two or more numerical values, the temi“no more than” or“less than” applies to each one of the numerical values in that series of numerical values.

[0026] The term“antagonists” includes neutral antagonists and inverse agonists.

[0027] The term“pharmaceutically acceptable” refers to a substance (e.g., an active ingredient or an excipient) that is suitable for use in contact with the tissues and organs of a subject without excessive irritation, allergic response, immunogenicity and toxicity, is commensurate with a reasonable benefit/risk ratio, and is effective for its intended use. A “pharmaceutically acceptable” carrier or excipient of a pharmaceutical composition is also compatible with the other ingredients of the composition.

[0028] The term“therapeutically effective amount” refers to an amount of a substance drat, when administered to a subject, is sufficient to prevent, reduce the risk of de veloping, delay tire onset of, slow the progression of, or cause regression of the medical condition being treated, or to alleviate to some extent the medical condition or one or more symptoms or complications of that condition. The term“therapeutically effective amount” also refers to an amount of a substance that is sufficient to elicit the biological or medical response of a cell, tissue, organ, system, animal or human which is sought by a researcher, veterinarian, medical doctor or clinician.

[0029] The terms“treat”,“treating” and“treatment” include alleviating, ameliorating or abrogating a medical condition or one or more symptoms or complications associated with the condition, and alleviating, ameliorating or eradicating one or more causes of the condition. Reference to“treatment” of a medical condition includes preventing (precluding), reducing the risk of developing, delaying the onset of, slowing the progression of, and causing regression of the condition or one or more symptoms or complications associated with the condition .

[0030] The term“medical conditions” (or“conditions” for short) includes disorders and diseases. The terms“disorders” and“diseases” are used interchangeably herein.

[0031] The term“subject” refers to an animal, including a mammal, such as a primate (e.g., a human, a chimpanzee or a monkey), a rodent (e.g., a rat, a mouse, a gerbil, a hamster or a guinea pig,), a lagomorph (e.g., a rabbit), a swme (e.g., a pig), an equine (e.g , a horse), a canine (e.g., a dog) or a feline (e.g., a cat). The terms“subject” and“patient” are used interchangeably herein in reference, e.g., to a mammalian subject, such as a human subject.

The Role of Substance P and Neurokinin-1 in Pruritus

[0032] An important pruritus pathway is mediated by the neuropeptide substance P.

Substance P is the most potent tachykinin and binds most strongly to neurokinin- 1 (NK-1, also called tachykinin receptor 1 or substance P receptor) among the three tachykinin receptors NK-1, NK-2 and NK-3. NK-1 is expressed in the PNS, including on keratinocytes and immune cells (e.g, mast cells) in the skin, and the CNS, including the dorsal root ganglia (DRG) of spinal nerves, the spinal dorsal horn and the brain. Substance P activates NK-1 in the PNS and the CNS, and the substance P/NK-1 interaction is an important mediator of die induction and maintenance of pruritus. Substance P and NK-1 receptors are overexpressed in pruritic human skin, and the skin of patients with chronic pruritus has a significantly greater density of substance P sensory nerve fibers compared to normal skin. Furthermore, injection of substance P into human skin causes symptoms of neurogenic inflammation such as erythema, edema and intense itch. Moreover, NK-1 receptors in the dorsal root ganglia of rats mediate scratching behavior.

[0033] The pruritogenic effect of substance P is intertwined with its pro-inflammatory effects. Activated pruriceptive neurons, including unmyelinated C nerve fibers, release neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P into the surrounding tissues. Substance P binding to NK-1 on keratinocytes and fibroblasts in the skin stimulates the secretion of inflammatory factors such as histamine, serotonin, interferon-g, interleukin-ΐb (IL-Ib), IL-6, IL-8 and nerve growth factor (NGF). Moreover, substance P binding to NK-1 or MrgprX2 on mast cells in the skin leads to degranulation and secretion of inflammatory factors such as histamine, serotonin, leukotriene B4, prostaglandins D2 and E2, IL- 2, IL-6, IL-8, IL-31 , tumor necrosis factor-alpha (TNF-a), NGF, vascular endothelial growth factor (VEGF) and proteases (e.g., tryptase). The pro-inflammatory factors released from keratinocytes, fibroblasts and mast cells take part in the pathogenesis of pruritus, including by stimulating vasodilation and neurogenic inflammation, whose symptoms include erythema, edema and burning itch. Substance P binding to NK-1 on blood vessels also leads to vasodilation and neurogenic inflammation. Certain pruritogens including histamine, neuropeptides (e.g., substance P, gastrin-releasing peptide [GRP], neurotensin, somatostatin and vasoactive intestinal peptide [VIP]), interleukins (e.g., IL-31, whose receptor is expressed on cutaneous C nerve fibers, keratinocytes and DRG neurons), and proteases (e.g., tryptase) provoke itch directly by binding to pruriceptors or indirectly by inducing release of histamine or other pruritogens. For example, histamine induces itch by stimulating the histamine Hi and Hi receptors on the endings of mechano-insensitive C nerve fibers in the skin (histamine also activates the histamine Hr receptor on inflammatory cells including mast cells and T-lymphocytes [e.g., Th2 cells], thereby intensifying the pruritic signal), proteases (e.g., tryptase) activate the pruriceptor protease- activated receptor 2 (PAR2) on the endings of mechano-sensitive C nerve fibers in the skin, and substance P and GRP induce itch by promoting release of various pruritogens such as histamine and proteases (e.g., tryptase) from, e.g., mast cells in the skin. Binding of pruritogens to their respective receptors on unmyelinated C fibers or thinly myelinated Ad fibers in the skin activates the neurons and results in the opening ofTRPVl or TRPA1 ion channels, which leads to neuronal depolarization, action potential (AP) firing and transmission of itch signals to the CNS [0034] Primary afferents within the skin transmit sensory information from their nerve endings to their ceil bodies in the DRG and trigeminal ganglia. The afferent nerve libers within the skin are mostly slow-conducting, small-diameter unmyelinated C fibers (conduction from 0.5 m/sec to 2 m/sec); medi um-diameter, thinly myelinated Ad fibers; and some fast-conducting, larger-diameter, myelinated Ab fibers (conduction from 4 m/sec to 70 m/sec). The A fibers transmit tactile sensitivity, temperature and noxious sensations and have a role in the perception of itch. About 80% of the C fibers are poiymodal as they can respond to thermal, mechanical and chemical stimuli. The remaining 20% of die C fibers are not responsive to mechanical stimuli, and only about 5% of these C fibers are specific for itch. Free C-fiber nerve endings are located in the derm is and epidermis, and the thin axons of C fibers extend from the epidermis to the nerve cell body. Interactions of the axons with pruriiogens epithelial cells and immune cells can trigger an itch sensation. Itch is detected mainly by C fibers and A5 fibers. Under inflammatory' or/and chronic itch conditions, itch receptors (pruriceptors) are sensitized and become receptive to mechanical stimuli, and the non-itch, mechanoreceptor Ab fibers within the skin also become sensitized and can transmit the itch signal (alloknesis). This leads to an increase in stimuli reception and broadcasting. When the Ad fibers or C fibers become sensitized, they have a lower itch-evoking threshold or/and provide a stronger itch signal (hypefknesis), and stimuli are no longer needed to continue the itch cycle (spontaneous itch).

[0035] The central branches of itch-sensitive primary sensory' neurons, mainly C fibers and Ao fibers, terminate in superficial laminas of the spinal or medullary_' dorsal horn to activate second-order sensory' neurons Pruriceptive primary' afferents convey the itch signal by releasing specific neuro transmitters onto postsynaptic neurons in the superficial dorsal horn of the spinal cord and the trigeminal subnucleus caudalis (Vc), where the itch signal as well as descending synaptic inputs from the brain are processed by local excitatory and inhibitory neurons. The itch information is then transmitted via ascending axons to the contralateral ventrobasal thalamus (spinothalamic tract) and the lateral parahraehial (PB) nucleus bilaterally (spinoparabrachial tract). The ventral posterior nucleus in the thalamus relays somatosensory information such as itch, and the PB nucleus is connected to the amygdala, the hypothalamus and the insular cortex. Most pruriceptive neurons in the superficial dorsal horn of the spinal cord and the Vc are interneurons, while a minority of them are projection neurons that innervate the thalamus or the PB nucleus. Without intending to be bound by theory, itch-signal transmission is believed to involve the release of brain natriuretic peptide (BNP) from the central terminals of pruriceptive C and Ad fibers, which activates atrial natriuretic peptide receptor (NprA)-expressing intemeurons, which in turn release gastrin-releasing peptide (GRP), which activates GRPR-expressing interneurons, which in turn release substance P, which activates NK1 -expressing projection neurons that transmit itch information to the brain. Alternatively, GRP, or both GRP and BNP, may be released from the central terminals of pruriceptive primary afferents. Tire brain perceives itch and activates the motor system to initiate scratching, which relieves itch. Scratching stimulates inhibitory spinal mtemeurons (e.g., those expressing the transcription factor BhlhB5) to release the k-opioid receptor-activating dynorphins and the inhibitory neurotransmitters g~ aminobutyric acid (GABA) and glycine, all of which inhibit itch-signaling neurons. However, rebound of AP firing by itch-signaling central neurons occurs after scratching ceases.

[0036] Scratching provoked by itch damages the skin, consequently maintaining and reinforcing the inflammatory' processes that promote nerve fiber activation and induce further pruritus. During inflammation, keratinocytes, fibroblasts, and certain immune cells (mast cells, macrophages, eosinophils and neutrophils) release pruntogens such as histamine, tryptase, neurotrophins, ieiikotrienes, interleukins and TNF-a. Scratching results in local proliferation of skin nerves, mast cell degranulation and increase in the levels of neuropeptides including substance P (e.g., skin scratching leads to upregulation of NK-l on epidermal keratinocytes and release of substance P from sensory' C fibers), which leads to increased secretion of cytokines and other pro-inflammatory mediators and stimulation of keratinocytes, fibroblasts and mast cells, thereby creating an itch/scratch cycle.

[0037] Without intending to be bound by theory', chronic itch is believed to result from or/and to contribute to increased sensitivity of peripheral or/and central i tch-signaling neurons that hence have a lower itch-evoking threshold or/and provide a stronger itch signal to the CNS, leading to spontaneously occurring itch, alloknesis and hyperknesis. Inflammatory mediators such as bradykinin, prostaglandins, interleukins and neurotrophins (e.g., NGF) sensitize peripheral itch sensory neurons, which is mediated in part by, e.g., TRPA1 , TRPV1, Navi .7, MrgprA3, PAR2 and toll-like receptors (e.g., TLR3). Peripheral sensitization increases the excitability and activity' of primary itch-sensing neurons through hyperinnervation or/and lowering of the threshold of receptors on peripheral nerves to stimuli such that sensitized peripheral nerves react to stimuli that normally induce no, or a much weaker, itch response.

Ele vated le vels of neurotrophins such as NGF also promote sprouting and elongation of itch- sensitive nerve fibers into the epidermis and their survival. Peripheral sensitization triggers central sensitization, which is mediated by increased excitatory synaptic transmission and reduced inhibitory synaptic transmission. Peripheral and central sensitization causes glial activation (e.g., astrogliosis in the spinal dorsal horn) and neuroinflammation in the CMS, which result in the production of cytokines (e.g., TNF-a, IL-Ib and IL-6), chemokines (e.g., (C-C motif) ligand 2 (CCL2) and (C-X-C motif) ligand 1 (CXCL1 )} and neurotrophins (e.g., brain- derived neurotrophic factor [BDNF]) that maintain central sensitization, leading to chronic itch.

In central sensitization, ongoing activation of, e.g., unmyelinated C fibers m patients with chronic pruritus lowers the threshold of second-order neurons in the spinal cord such that sensitized second-order neurons become activated by itch signals that normally are not sufficiently intense, or continuously activates the second-order neurons such that they provide an ongoing or/and stronger itch signal to the brain. In addition to peripheral and central sensitization, impaired inhibition of itch signaling in the spinal or/and medullary' dorsal hom can perpetuate pruritus.

[0038] As mentioned above, substance P is a key neuropeptide transmitter that is released from activated excitatory- spinal intemeurons and activates NKl-expressing spinal dorsal hom neurons. Most spinal dorsal hom neurons with ascending axonal projections to the thalamus and the PB nucleus express NK-l, and such NKl-expressing projection neurons transmit itch information to the brain. NKl-expressing spinal dorsal hom neurons are major contributors to chronic itch (ongoing itch), spontaneous itch, alloknesis (itch induced by a normally non-itchy stimulus, such as light touch), and hyperknesis (enhanced itch induced by a normally itchy stimulus). Therefore, NKl-expressing spinal dorsal hom neurons play an important role in chronic itch and the development and maintenance of itch sensiti zation regardless of the pruritogenic stimuli, and inhibition of such neurons using an NK-l antagonist can curtail chronic itch and itch sensitization regardless of the pruritogenic stimuli.

[0039] Peripheral and central mechanisms of itch and the role of substance P and NK-l in itch are discussed in, e.g., T. Akiyama el a!., Pain , 156: 1240-1246 (2015); E. Carstens and T. Akiyama, Curr. Prohl Dermatol ., 50: 11-17 (2016): J. S. Lee et al, BMB Rep., 49:474-487 (2016); and T. Lots and S. Stander, J Dtsch. Dermatol Ges., 12:557-559 (2014).

Treatment of Chronic Pruritus Using Neurokinin- 1 Antagonists

[0040] The present disclosure provides for the use of a neurokinin- 1 (NK-l) antagonist in treating chronic pruritus having a duration of at least about 6 months. In some embodiments, the chronic pruritus has a duration of at least about 1 year, 2 years, 3 years, 4 years or 5 years. In further embodiments, the chronic pruritus has a duration of at least about 6 years, 7 years,

8 years, 9 years or 10 years. [0041] In some embodiments, the chronic pruritus is characterized by sensitization or hypersensitization of the CNS. In certain embodiments, the chronic pruritus is characterized by sensitization or hypersensitization of dorsal root gangl ion neurons, spinal dorsal horn neurons or spinal trigeminal nucleus (e.g., medullary dorsal bom) neurons or any combination or all thereof. In further embodiments, the chronic pruritus is characterized by sensitization or

hypersensitization of the PNS. In certain embodiments, the chronic pruritus is characterized by sensitization or hypersensitization of unmyelinated C fibers, thinly myelinated Ad fibers or myelinated Ab fibers or any combination or all thereof.

[0042] In some embodiments, the chronic pruritus is characterized by spontaneously occurring itch, alloknesis or hyperknesis, or any combination or all thereof. In further embodiments, the NK-1 antagonist inhibits spontaneously occurring itch, alloknesis or hyperknesis, or any combination or all thereof. In certain embodiments, the NK-1 antagonist reduces the frequency or/and the intensity of spontaneously occurring itch, alloknesis or hyperknesis, or any combination or all thereof by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% (e.g., by at least about 30% or 50%), as measured by a visual analog scale (VAS) score or a numerical rating scale (NRS) score, for example. In some embodiments, the NK-1 antagonist statistically significantly reduces the frequency or/and the intensity of spontaneously occurring itch, alloknesis or hyperknesis, or any combination or all thereof In certain embodiments, the NK-1 antagonist reduces the frequency or/and the intensity of spontaneously occurring itch, alloknesis or hyperknesis, or any combination or all thereof, at least about 20%, 30%, 40%, 50%, 100%, 150% or 200% (e.g., at least about 30% or 50%) more than placebo, as measured by, e.g., a VAS or NRS score and as a percentage of the effect of placebo.

[0043] Non-limiting examples of NK-1 antagonists include aprepitant (L-754030 or MK- (0)869), fosaprepitant (L-758298), befetupitant, burapitant (SSR-2406G0), casopitant (GW- 679769), dapitant (RPR- 100893), ezlopitant (CJ-l 1974), figopitant (BIIF-1149), lanepitant (LY- 303870), maropitant (CJ-l 1972), netupitant, fosnetupitant, nolpitantium (SR-l 40333), orvepitant (GW-823296), rolapitant (SCH-619734), SCH-720881 (active metabolite of rolapitant), serlopitant (MK-(0)594 or VPD-737), tradipitant (VLY-686 or LY-686017), vestipitant (GW- 597599), vofopitant (GR-205171), hydroxyphenyl propamidobenzoic acid,

maltooligosaccharides (e.g., maltotetraose and maltopentaose), spantides (e.g., spantide I and P), AV-608, AV-818, AZD-2624, CGP-49823, CJ-17493, CP-96345, CP-99994, CP-122721, DNK- 333 (NK1/NK2), FK-224 (NK1/NK2), FK-888, GR-82334, GR-203040, GR-205171, GSK- 424887, HSP-117, KRP-103, L-703606, L-733060, L-736281, L-759274, L-760735, LY-686017, M516102, MDL-105212 (NK1/NK2), MK-0303 (L-001182885), MK-8478 (L-001983867), NKP-608, PD-154075, R-116031, R-l 16301, RP-67580, S-41744, SCH-206272 (NK-l /NK- 2/NK-3), SCH-388714, SCH-900978, SLV-317, T-2328, TA-5538, TAK-637, TKA-731 , WIN- 51708, ZD-4974, ZD-6021 (NK1/NK2), and analogs, derivatives, prodmgs, metabolites, salts and stereoisomers thereof.

[0044] In some embodiments, the NK-1 antagonist is a selective NK-1 antagonist. In certain embodiments, the NK-1 antagonist is serlopitant (described below) or a pharmaceutically acceptable salt, solvate, hydrate, c!athrate, polymorph, prodrug, metabolite or stereoisomer thereof. In other embodiments, the NK-1 antagonist is not aprepitant or fosaprepitant.

[0045] The therapeutically effective amount and the frequency of administration of, and the length of treatment with, the NK-1 antagonist to treat chronic pruritus may depend on various factors, including the nature and the severity of the pruritus or the underlying medical condition, the potency of the NK-1 antagonist, the route of administration, the age, the body weight, the general health, the gender and the diet of the subject, and the response of the subject to the treatment, and can be determined by the treating physician. In some embodiments, the therapeutically effective amount of the NK-1 antagonist for treating chronic pruritus is about 0.25 or 1 to 200 mg, 0.5 or 1 to 150 mg, 0.5 or 1 to 100 mg, 0.5 or 1 to 50 mg, 0.5 or 1 to 10 mg, 10- 20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-100 mg, 100-150 mg or 150-200 mg (e.g., per day or per dose), or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In certain embodiments, the therapeutically effective dose (e.g., per day or per dose) of the NK-1 antagonist for treating chrome pruritus is about 0.25 or 1 to 5 mg (e.g., about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg), about 5-10 mg (e.g., about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg), about 10-20 mg (e.g., about 10 mg, 15 mg or 20 mg), about 20-30 mg (e.g., about 20 mg, 25 mg or 30 mg), about 30-40 mg (e.g., about 30 mg, 35 mg or 40 mg), about 40-50 mg (e.g., about 40 mg, 45 mg or 50 mg), about 50-100 mg (e.g., about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg), about 100-150 mg (e.g., about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg or 150 mg), or about 150-200 mg (e.g., about 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg). In some embodiments, the NK-1 antagonist is administered at 0.25 mg, 1 mg, or 5 mg once a day. In some embodiments, the therapeutically effective dose of the NK-1 antagonist is administered 1, 2, 3 or more times a day, once every two days, once every three days, twice a week or once a week, or as deemed appropriate by the treating physician. In certain embodiments, the therapeutically effecti ve dose of the NK-l antagonist is administered once or twice daily.

[0046] In some embodiments, tire NK-l antagonist is serlopitant, and the therapeutically effective dose of serlopitant is about 0.25 or I to 5 mg or 5-10 mg, or about 0.5 mg, 1 mg, 5 mg or 10 mg, once or twice daily. In certain embodiments, the therapeutically effective dose of serlopitant is about 5 mg once daily. In some embodiments, about 0.25 mg, about 1 mg, about 5 mg or about 10 mg of serlopitant is administered once or twice daily.

[0047] For treatment of chronic pruritus, in some embodiments a therapeutically effective amount of the NK-l antagonist (e.g., serlopitant) is administered over a period of at least about 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years,

5 years or longer (e.g., at least about 6 weeks, 3 months, 6 months or 1 year).

[0048] The NK-l antagonist (e.g., serlopitant) can also be taken in an irregular manner. For example, the NK-I antagonist can be administered 1, 2, 3, 4, 5 or more times in a period of 1 week, 2 weeks, 3 weeks or 1 month in an irregular manner. Furthermore, the NK-l antagonist (e.g., serlopitant) can be taken pro re nata (as needed). For instance, tire NK-l antagonist can be administered 1, 2, 3, 4, 5 or more times, whether m a regular or irregular manner, until pruritus improves. Once relief from itch is achieved, dosing of the NK-l antagonist can optionally be discontinued. If pruritus returns, administration of the NK-l antagonist, whether in a regular or irregular manner, can be resumed. The appropriate dosage of, frequency of dosing of and length of treatment with the NK-l antagonist can be determined by the treating physician.

[0049] The NK-l antagonist (e.g., serlopitant) can be administered via any suitable route. Potential routes of administration of the NK-l antagonist include without limitation oral, parenteral (including intramuscular, subcutaneous, imtradermal, intravascular, intravenous, intraarterial, intraperitoneal, intramedullary', intrathecal and topical), intracavitary', and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], pulmonary [e.g., by oral or nasal inhalation], ocular [e.g., by eye drop], buccal, sublingual, rectal [e.g., by suppository] and vaginal [e.g., by suppository]). In certain embodiments, the NK-l antagonist is administered orally (e.g., as a capsule or tablet, optionally with an enteric coating). In other embodiments, the NK-l antagonist is administered parenteraily (e.g., intravenously, subcutaneously or intramuscularly). In further embodiments, the NK-l antagonist is administered topically (e.g., transdennally, transmucosally, pulmonarily, buccally or sublingually).

[0050] For treatment of chronic pruritus, in some embodiments the NK-l antagonist is serlopitant, and serlopitant is administered orally (e.g., as a tablet) in a dose of about 0.25, 0.5, 1, 5 or 10 mg once daily for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks,

2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years or longer. The disclosure specifically discloses each of the 44 possible combinations of dose and treatment length. In certain embodiments, about 5 mg of serlopitant is administered orally (e.g., as a tablet) once daily for at least about 6 weeks, 3 months, 6 months or 1 year.

[0051] In some embodiments where a more rapid establishment of a therapeutic level of the NK-l antagonist (e.g., serlopitant) is desired, the NK-l antagonist is administered under a dosing schedule in which a loading dose is administered, followed by (i) one or more additional loading doses and then a plurality of therapeutically effective maintenance doses, or (ii) a plurality of therapeutically effective maintenance doses without an additional loading dose, as deemed appropriate by the treating physician . To establish a therapeutic level of a drug more quickly, a loading dose of the drug is typically larger (e.g., about 1.5, 2, 3, 4 or 5 times larger) than a subsequent maintenance dose. In certain embodiments, the loading dose is about three times larger than the maintenance dose. The therapeutically effective maintenance dose of the NK-l antagonist can be any therapeutically effective dose described herein, and can he administered in any suitable frequency and for any suitable length of time as described herein. In some embodiments, a loading dose of the NK-l antagonist (e.g., serlopitant) is administered, followed by administration of a maintenance dose of the NK-l antagonist after an appropriate time (e.g., after about 12 hr or 24 hr) and thereafter for the duration of therapy - e.g , a loading dose of the NK-l antagonist is administered on day 1 and a maintenance dose is administered on day 2 and thereafter for the duration of therapy.

[0052] In some embodiments, the loading dose of the NK-l antagonist is about 0 25 to 100 mg, 0.25 to 75 mg, 0.25 to 50 mg, 0.25 to 25 mg, 0.25 to 5 mg, 0.5 to 200 mg, 0.5 to 150 mg, 0.5 to 100 mg, 0.5 to 50 mg, 0.5 to 10 mg, 10 to 20 mg, 20 to 30 mg, 30 to 40 mg, 40 to 50 mg, 50 to 100 mg, 100 to 150 mg or 150 to 200 mg, or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In certain embodiments, the loading dose of the NK-l antagonist is about 0.25 to 2.5 mg (e.g., about 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg or 2.5 mg), about 0.5 to 5 mg (e.g., about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg), about 5 to 10 mg (e.g., about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg), about 10 to 20 mg (e.g., about 10 mg, 15 mg or 20 mg), about 20 to 30 mg (e.g., about 20 mg, 25 mg or 30 mg), about 30 to 40 mg (e.g., about 30 mg, 35 mg or 40 mg), about 40 to 50 mg (e.g., about 40 mg, 45 mg or 50 mg), about 50 to 100 mg (e.g , about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg), about 100 to 150 mg (e.g., about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg or 150 mg), or about 150 to 200 mg (e.g., about 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg). In some embodiments, the loading dose of the NK-1 antagonist is at least about 0 5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg,

80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg,

190 mg, or 200 mg. In some embodiments, the loading dose of the NK-1 antagonist is less than about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg.

[0053] In some embodiments, the therapeutically effective maintenance dose of the NK-1 antagonist is about 0.25 to 100 mg, 0.25 to 75 mg, 0.25 to 50 mg, 0.25 to 25 mg, 0.25 to 5 mg,

0.5 to 200 mg, 0.5 to 150 mg, 0.5 to 100 mg, 0.5 to 50 mg, 0.5 to 10 mg, 10 to 20 mg, 20 to 30 mg, 30 to 40 mg, 40 to 50 mg, 50 to 100 mg, 100 to 150 mg or 150 to 200 mg, or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In certain embodiments, the therapeutically effective maintenance dose of the NK-1 antagonist is about 0.25 to 2.5 mg (e.g., about 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg or 2.5 mg), about 0.5 to 5 mg (e.g., about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg), about 5 to 10 mg (e.g., about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg), about 10 to 20 mg (e.g., about 10 mg, 15 mg or 20 mg), about 20 to 30 mg (e.g., about 20 mg, 25 mg or 30 mg), about 30 to 40 mg (e.g., about 30 mg, 35 mg or 40 mg), about 40 to 50 mg (e.g., about 40 mg, 45 mg or 50 mg), about 50 to 100 mg (e.g., about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg), about 100 to 150 mg (e.g., about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg or 150 mg), or about 150 to 200 mg (e.g., about 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg). In some embodiments, the therapeutically effective maintenance dose of the NK-1 antagonist is at least about 0.25 mg, 0.5 mg, I mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 1 10 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg,

190 mg, or 200 mg. In some embodiments, the therapeutically effective maintenance dose of the NK-1 antagonist is less than about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg. In some embodiments, the therapeutically effecti ve maintenance dose of the NK-l antagonist is administered once or twice a day, once every two days, once every three days, twice a week or once a week. In some embodiments, the therapeutically effective maintenance dose of the NK-l antagonist is administered over a period of at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years. It is understood that each treatment length may be combined with each loading dose, maintenance dose, and/or administration frequency the same as if each and even_' combination were specifically and individually listed.

[0054] In some embodiments, the NK-l antagonist is serlopitant, and serlopitant is administered in a loading dose of about 0.5-3 mg, 3-15 mg or 15-30 mg once or twice on day 1, followed by a maintenance dose of about 0.25-1 mg (e.g., about 0.25, 0.5 or 1 mg), 1-5 mg (e.g., about 1, 3 or 5 mg) or about 5-10 mg (e.g., about 5, 7.5 or 10 mg) once or twice daily for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months,

5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years or longer, where the loading dose is three times larger than the maintenance dose and serlopitant is administered orally (e.g., as a tablet or capsule). In certain embodiments, serlopitant is administered in a loading dose of about 15 mg orally (e.g., as a tablet) on day 1, followed by a maintenance dose of about 5 mg orally (e.g., as a tablet) once daily, optionally at bedtime, for at least about 6 weeks, 3 months,

6 months, 1 year or longer.

[0055] In other embodiments, a first loading dose of the NK-l antagonist (e.g., serlopitant) is administered on day 1, a second loading dose is administered on day 2, and a maintenance dose is administered on day 3 and thereafter for the duration of therapy. In certain embodiment, the first loading dose is about three times larger than the maintenance dose, and the second loading dose is about two times larger than the maintenance dose.

[0056] The NK-l antagonist (e.g , serlopitant) can be administered at any time convenient to the patient. NK-l antagonists may cause drowsiness. To avoid or minimize drowsiness during the day, tire NK-l antagonist can be administered shortly before the patient goes to bed.

Moreover, use of the NK-l antagonist at night can aid with sleep and decrease nocturnal itch and scratching. Accordingly, in certain embodiments the NK-l antagonist (e.g., serlopitant) is administered at bedtime (e.g., once daily at bedtime). The NK-l antagonist (e.g., serlopitant) can also be administered at any appropriate time during the day or awake hours (e.g , in the morning). [0057] In some embodiments, the NK-1 antagonist (e.g., serlopitant) is administered without food. In some embodiments, the NK-1 antagonist (e.g., serlopitant) is administered at least about 1 or 2 hours before or after a meal at any time of the day. In certain embodiments, the NK-1 antagonist is administered at least about 2 hours after an evening meal, or at least about 2 hours before or after a meal in the morning. The NK-1 antagonist (e.g., serlopitant) can also be taken substantially concurrently with food, such as within about I hour, 30 minutes or 15 minutes before or after a meal, or with a meal, at any time of the day.

[0058] Idle chrome pruritus can be any type of pruritus and can be associated with any medical condition, or can have an unknown cause (idiopathic). The pruritus-associated medical condition typically is chronic. Non-limiting examples of types of chronic pruritus and chronic pruritus-associated medical conditions include xerosis/xeroderma (dry skin), dermatitis/eczema (e.g., xerotic/asteatotic eczema, atopic dermatitis, contact dermatitis, exfoliative dermatitis

[erythroderma], seborrheic dermatitis, stasis dermatitis, neurodermatitis [lichen simplex chronicus] and dermatitis herpetiformis [Duhring^'s disease]), lichen planus, lichen sclerosus, psoriasis (e.g., plaque psoriasis and erythrodermic psoriasis), prurigo (e.g., prurigo nodularis, prurigo simplex and actinic prurigo), urticaria (e.g., chronic idiopathic urticaria), hidradenitis suppurativa, acantholytic disorders {e.g., Grover’s disease and pemphigus (e.g., pemphigus vulgaris and familial benign chronic pemphigus [Hailey-Hailey disease])}, connective tissue disorders (e.g., dermatomyositis, epidermolysis bullosa [e.g., EB simplex], lupus erythematosus [e.g., systemic LE and discoid LE], pemphigoid [e.g., bullous pemphigoid], scleroderma and Sjogren’s syndrome), mastocytosis (cutaneous and systemic), bums (e.g., thermal bums, third- degree burns and major bums), wounds (e.g., venous ulcers), scars (e.g., keloids and

hypertrophic scars), endocrine disorders (e.g., hyperthyroidism [e.g., Graves’ disease], hypothyroidism and hyperpaxathyroidism), metabolic disorders (e.g., diabetes meliitus [including types 1 and 2]), hyperuricemia, iron deficiency, iron overload (due to, e.g., hemochromatosis or hyperierritinemia), malabsorption disorders (e.g., iron-deficiency anemia, celiac disease and inflammatory bowel disease [e.g., Crohn’s disease]), kidney disorders (e.g., diabetic

nephropathy, glomerulonephritis, chronic kidney disease [CKD], chronic kidney failure [CKF], end-stage renal disease [ESRDJ, pruritus associated with dialysis [e.g., hemodialysis, peritoneal dialysis, hemofiltration and hemodiafiltration], uremia and uremic pruritus [which may or may not be caused by uremia]), hepato-biliary disorders (e.g., Alagille syndrome, cholestatic pruritus, cholestasis, primary' biliary_' cholangitis [PBC, aka primary_'· biliary_' cirrhosis], primary_' sclerosing cholangitis, choledocholithiasis, cholangiocarcinoma, hepatitis [e.g., chronic hepatitis B and C and autoimmune hepatitis], alcoholic liver disease, chronic liver disease j CLD j, cirrhosis and chronic liver failure [other than complete liver failure]), cardiovascular disorders (e.g., heart failure [e.g., congestive heart failure] and venous insufficiency), benign and malignant neoplasms {e.g., solid tumors (e.g., those of the breast, cervix, lung, thymus [e.g., thymoma], stomach [e.g., gastric carcinoid], colon, pancreas [e.g., insulinoma], prostate, testicle and rectum), metastatic solid tumors, carcinomas (e.g., those of the breast, lung, stomach, colon, liver, bile duct, pancreas and prostate), adenocarcinomas (e.g., lung adenocarcinoma), sarcomas (e.g., soft-tissue sarcomas), melanoma, neurofibromatosis and hematological neoplasms (including

myelodyspiastic syndrome, myeloproliferative neoplasms such as polycythemia vera, chronic myelogenous leukemia, chronic neutrophilic leukemia and systemic mastocytosis, and lymphoproiiferative neoplasms such as lymphomas [including Hodgkin’s lymphoma and non- Hodgkin’s lymphoma such as cutaneous T-cell lymphoma {CTCL, such as mycosis fungoides, erythrodermic MF and Sezary syndrome ] and cutaneous B-cell lymphoma], chronic lymphocytic leukemia, multiple myeloma, plasmacytoma and lymphocyte-variant hypereosinophila)}, paraneoplastic pruritus (e.g., itch due to paraneoplastic syndromes [e.g., carcinoid syndrome] and paraneoplastic skin disorders [e.g., erythroderma, Grover’s disease, malignant acanthosis nigricans, generalized granuloma annulare, Bazex syndrome and dermatomyositis]), infections (e.g. fungal infections [e.g., candidiasis such as vulvovaginal candidiasis] and viral infections [e.g., HIV/AIDS and hepatitis A, B, C and E]), drug-induced pruritus {e.g., itch due to chloroquine, hydroxethyl starch, androgens, estrogens, angiotensin-converting enzyme (ACE) inhibitors, analgesics (e.g., acetaminophen and opioids), antiarrhythmic drags (e.g., amiodarone and quinidine), anticoagulants, antibiotics (e.g., carbapenems, sulfonamides, erythromycin, flueloxacillin, isoniazid, neomycin, nitrofurantoin, penicillin, trimethoprim/sulfameihoxazole and vancomycin), antifungals (e.g., fluconazole, griseofulvm, itraconazole and ketoconazole), antidiabetics (e.g., antihyperglycemics), calcium channel blockers, chemotherapeutics (e.g , tamoxifen, epidermal growth factor receptor [EGFR] inhibitors such as eriotinib and cetuximab, and anti-CTLA-4 antibodies such as ipilimumab), diuretics (e.g., thiazides such as

hydrochlorothiazide), NSAIDs (e.g., aspirin, diclofenac and sulindac), statins (e.g., simvastatin), and xanthine oxidase inhibitors (e.g., ailopurinoi)}, neuropathic itch (e.g., itch due to peripheral neuropathy, small fiber neuropathy [due to, e.g., diabetes, Fabry disease, HIV infection, shingles, lupus, rheumatoid arthritis and cutaneous sarcoidosis], diabetic neuropathy, postherpetic itch, vnlvodynia, Guiliain-Barre syndrome polyneuropathy, nerve, nerve root and ganglion injuries and lesions, radiculopathy, brachioradial pruritus, notalgia paresthetica, trigeminal trophic syndrome, aneurysms, ischemic stroke, cerebral infarction, myelopathy, multiple sclerosis, neuromyelitis optica, cavernous hemangiomas [cavernomas] of the spinal cord, syringomyelia, tumors and abscesses in and near the spinal cord and the brain, neurofibromatosis type 1 and neurosarcoidosis), neurogenic itch, psychogenic itch (e g., itch due to stress, anxiety disorders, depression, obsessive-compulsive disorders, substance abuse and delusional

parasitosis/infestation), pruritus in the elderly (e.g., elderly patients with xerosis, diabetes, chronic renal insufficiency or chronic venous insufficiency), and chronic idiopathic pruritus.

[0059] In some embodiments, the chronic pruritus is associated with a dermatological condition. In certain embodiments, the chronic pruritus is associated with xerosis or xeroderma (dry^ skhr). In other embodiments, the chronic pruritus is associated with prurigo, such as prurigo nodularis. In further embodiments, the chronic pruritus is associated with an inflammatory skin disorder. In certain embodiments, the chronic pruritus is associated with dermatitis or eczema, such as atopic dermatitis. In other embodiments, the chronic pruritus is associated with psoriasis, such as plaque psoriasis (aka psoriasis vulgaris). In some embodiments, the plaque psoriasis is present in any anatomic location of the subject and covering at most 30%, at most 25%, at most 20%, at most 15%, at most 10% or at most 5% of body surface area in total. In some embodiments, the duration of plaque psoriasis (e.g., prior to beginning treatment) is at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years. In some embodiments, the subject was diagnosed with plaque psoriasis at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years prior to beginning treatment. In yet other embodiments, the chronic pruritus is associated with urticaria, such as chrome idiopathic urticaria. In additional embodiments, the chronic pruritus is associated with damage to the skin, such as post-bum pruritus. The tenn“post-bum pruritus” means pruritus following bum injury', which encompasses pruritus associated with or resulting from healing/repair of the burn injury or wound, including scar formation. In further embodiments, the chronic pruritus is associated with a connective tissue disorder, such as dermatomyositis.

[0060] In other embodiments, the chronic pruritus is associated with a kidney disorder, such as CKD, CKF or ESRD. In certain embodiments, the chronic pruritus is uremic pruritus or is associated with dialysis (e.g., hemodialysis).

[0061] In further embodiments, the chronic pruritus is associated with a hepato-biliary disorder, such as hepatitis (e.g., chrome hepatitis B or C), CLD or cirrhosis. In certain embodiments, the chronic pruritus is cholestatic pruritus or is associated with a cholestatic disorder (e.g., cholestasis or PBC).

[0062] In additional embodiments, the chronic pruritus is associated with a benign or malignant neoplasm, such as a solid tumor, a carcinoma or a hematological neoplasm. In certain embodiments, the chronic pruritus is associated with Hodgkin s lymphoma, non-Hodgkin’s lymphoma (e.g., C^'TCL such as mycosis fungoides or Sezaiy syndrome), or polycythemia vera

[0063] In some embodiments, the chronic pruritus is neuropathic itch, such as brachioradial pruritus or notalgia paresthetica. Nerve damage or injury can cause spontanous firing without stimuli, resulting in spontaneously occurring itch. Neuropathic itch is often associated with central sensitization, alloknesis and hyperknesis. In other embodiments, the chronic pruritus is neurogenic itch, which is not caused by any central or peripheral nerve damage.

[0064] In further embodiments, the chronic pruritus is pruritus in the elderly (over 65 years of age). In still further embodiments, the chronic pruritus is induced by a medication. Radiation therapy can also result in pruritus. In other embodiments, the chronic pruritus is chronic idiopathic pruritus. In additional embodiments, the chronic pruritus is refractory or resistant to other antipruritic therapies without an NK-l antagonist.

[0065] In some embodiments, one or any combination, or all, of the following apply:

i) the subject is about 40 years of age or older;

ii) the chronic pruritus is associated wi th a condition or disorder of mild to moderate severity; or/and

hi) the chronic pruritus is not characterized by or associated with:

a) stinging or/and burning;

b) inflammation; or/and

c) neuropathy.

[0066] In certain embodiments, the chronic pruritus is associated with dermatitis/eczema (e.g., atopic dermatitis), psoriasis (e.g., plaque psoriasis) or prurigo (e.g., prurigo nodularis), or is chronic idiopathic pruritus. In some embodiments, the dermatitis or eczema (e.g., atopic dermatitis) has mild to moderate severity, such as an Investigator’s Global Assessment (IGA) score of 2 (mild) to 3 (moderate) on a 0 to 5 scale. In such an IGA scale, 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe, and 5 = very' severe. In certain embodiments, the psoriasis (e.g., plaque psoriasis) has mild io moderate severity, such as an IGA score of 2 (mild) to 3 (moderate) on a 0 to 5 scale, a Psoriasis Area and Severity Index (PASI) score of about 10 or less, or/and affected body surface area (BSA) of about 10% or less. In some embodiments, the duration of plaque psoriasis (e.g., prior to beginning treatment) is at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years. In some embodiments, the subject was diagnosed with plaque psoriasis at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years prior to beginning treatment.

[0067] An NK-l antagonist (e.g., serlopitant) can be used to treat chronic pruritus of any degree of severity (e.g., mild, moderate or severe) or chronic pruritus associated with a medical condition of any degree of severity (e.g., rnild, moderate or severe). The degree of severity of pruritus may not correlate with the degree of seventy of the underlying medical condition. In addition to its antipruritic effect (e.g., blocking NK1 -expressing spinal projection neurons from transmitting itch signals to the brain), an NK-l antagonist (e.g., serlopitant) can have other beneficial properties that aid in alleviating pruritus or the pruritus-associated medical condition, such as anti-inflammatory, anti-proliferative and anti-metastatic properties.

[0068] In some embodiments, one or more additional antipruritic agents are used in combination with an NK-l antagonist (e.g., serlopitant) to treat chronic pruritus, as described below.

[0069] The disclosure provides an NK-l antagonist (e.g., serlopitant), or a composition comprising an NK-l antagonist (e.g., serlopitant), for use in the treatment of chronic pruritus having a duration of at least about six months or one year, optionally in combination with an additional antipruritic agent. The disclosure further provides for tire use of an NK-l antagonist (e.g., serlopitant) in the preparation of a medicament for the treatment of chronic pruritus having a duration of at least about six months or one year, optionally in combination with an additional antipruritic agent.

Neurokinin- 1 Antagonists

[0070] As described above, the disclosure provides for the use of an NK-l antagonist in the treatment of chronic pruritus having a duration of at least about six months or one year.

Examples of NK-l antagonists include without limitation aprepitant (L-754030 or MK -(0)869), fosaprepitant (L-758298), hefetupitant, burapitant (SSR-240600), casopitant (GW-679769), dapitant (RPR- 100893), ezlopitant (CJ-11974), figopitant (BIIF-1149), lanepitant (LY-303870), maropitant (CJ-11972), netupitant, fosnetnpitant, nolpitantium (SR- 140333), orvepitant (GW- 823296), rolapitant (SCH-619734), SCH-720881 (active metabolite of rolapitant), serlopitant (MK-(0)594 or VPD-737), tradipitant (VJLY-686 or LY-686017). vestipitant (GW-597599), vofopitant (GR-205171), hydroxyphenyl propamidobenzoic acid, maltooligosaccharides (e.g., maltotetraose and maltopentaose), spantides (e.g., spantide I and II), AV-608, AV-818, AZD- 2624, CGP-49823, CJ-17493, CP-96345, CP-99994, CP-122721, DNK-333 (NK1/NK2), FK-224 (NK1/NK2), FK-888, GR-82334, GR-203040, GR-205171, GSK-424887, HSP-117, KR P- 103. L-703606, L-733060, L-736281, L-759274, L-760735, LY-686017, M516102, MDL-105212 (NK1/NK2), MK-0303 (L-001182885), MK-8478 (L-001983867), NKP-608, PD-154075, R- 116031, R- 1 16301 . RP-67580, S-41744, SCH-206272 (NK-1/NK-2/NK-3), SCH-388714, SCH- 900978, SLV-317, T-2328, TA-5538, TAK-637, TKA-731, WIN-51708, ZD-4974, ZD-6021 (NK1/NK2), and analogs, derivatives, prodrugs, metabolites, salts and stereoisomers thereof. In some embodiments, the NK- 1 antagonist is aprepitant, fosaprepitant, rolapitant, orvepitant, serlopitant, or tradipitant, or a pharmaceutically acceptable salt, solvate, hydrate, ciathrate, polymorph, prodrug, metabolite or stereoisomer thereof.

[0071] In some embodiments, the NK-1 antagonist is a selective NK-1 antagonist. In certain embodiments, the NK-1 antagonist is serlopitant or a pharmaceutically acceptable salt, solvate, hydrate, ciathrate, polymorph, prodrug, metabolite or stereoisomer thereof.

[0072] In other embodiments, the NK-1 antagonist is aprepitant or fosaprepitant, or a pharmaceutically acceptable salt, solvate, hydrate, ciathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In additional embodiments, the NK-1 antagonist is befetupitant or a pharmaceutically acceptable salt, solvate, hydrate, ciathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In certain embodiments, the NK-1 antagonist is burapitant or a pharmaceutically acceptable salt, solvate, hydrate, ciathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In further embodiments, the NK-I antagonist is casopitant or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In still further embodiments, the NK-1 antagonist is dapitant or a pharmaceutically acceptable salt, solvate, hydrate, ciathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In yet further embodiments, the NK-I antagonist is ezlopitant or a pharmaceutically acceptable salt, solvate, hydrate, ciathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In certain embodiments, the NK-1 antagonist is figopitant or a pharmaceutically acceptable salt, solvate, hydrate, ciathrate, polymorph, prodrag, metabolite or stereoisomer thereof. In other embodiments, the NK-1 antagonist is lanepitant or a

pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In still other embodiments, the NK-1 antagonist is maropitant or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrag, metabolite or stereoisomer thereof.

[0073] In additional embodiments, the NK-1 antagonist is netupitant or fosnetupitant, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In further embodiments, the NK-1 antagonist is nolpitantium or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrag, metabolite or stereoisomer thereof In still further embodiments, the NK-1 antagonist is orvepitant or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrag, metabolite or stereoisomer thereof. In yet further embodiments, the NK-1 antagonist is rolapitant or SCH- 720881 (active metabolite of rolapitant), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrag, metabolite or stereoisomer thereof. In other embodiments, the NK-1 antagonist is tradipitant or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof. In still other embodiments, the NK-1 antagonist is vestipitant or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrag, metabolite or stereoisomer thereof. In yet other embodiments, the NK-1 antagonist is vofopitant or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof.

[0074] In some embodiments, the NK-1 antagonist is not aprepitant or fosaprepitant.

[0075] Serlopitant is a potent and highly selecti ve antagonist of neurokinin- 1 (also called substance P receptor). By binding to and not activating NK-1, serlopitant can block actions of substance P, including transmission of itch signals to the brain, elicitation of inflammation, stimulation of growth of cancer cells, and promotion of metastasis of cancer cells.

[0076] Serlopitant has the structure shown below. The IUPAC name for serlopitant is 3- [(3aR,4R,5S,7aS)-5-|(lR)-l-|3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)- l,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-l-one. The US AN name for serlopitant is 3-[(3aR,4R,5S,7aS)-5-[(lR)-l-[3,5-bis(tiifluoromethyl)phenyl]ethoxy]-4-(4- fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-l -one. The disclosure also

encompasses all stereoisomers of serlopitant, including both enantiomers and all diastereomers of serlopitant in substantially pure form and mixtures of both enantiomers (including a racemic mixture) and mixtures of two or more diastereomers of serlopitant in any ratio. The disclosure further encompasses all isotopically enriched forms of serlopitant, including without limitation those enriched in the content of ²H (deuterium), ¹³C, ^!5N, ^!70, ^lsO or ¹⁹F, or any combination thereof, at one or more, or all, locations of the corresponding atom(s). Moreover, the disclosure encompasses any and all salt forms of serlopitant. Various methods of synthesizing serlopitant are known in the art. See, e.g., Jiang et al., J Med. Chern., 52:3039-3046 (2009); US Pat.

7,544,815 by Kuethe et al.; and US Pat. 7,217,731 by Bunda et al.

[0077] Whether as a free base or a salt, serlopitant can exist unsolvated or unhydrated, or solvated or hydrated. Solvated forms of serlopitant can be formed with a pharmaceutically acceptable solvent, such as water or ethanol. In certain embodiments, serlopitant, whether as a free base or a salt, is used substantially unhydrated.

[0078] The disclosure also encompasses polymorphs (crystalline forms) of serlopitant. Examples of polymorphs of serlopitant include wi thout limitation anhydrous crystalline Forms I and 11 of free base serlopitant as disclosed in US Pub. 2009/0270477 by Kuethe et al. Form I is characteri zed by diffraction peaks obtained from X-ray powder diffraction pattern corresponding to d-spacings of 10.4, 9.9, 9.2, 5.5, 5.0, 4.1, 3.9, 3.6 and 3.5 angstroms. Form II is characterized by diffraction peaks obtained from X-ray powder diffraction pattern corresponding to d-spacings of 7.7, 5.3, 4.9, 4.8, 4.6, 4.2, 3.9, 3.8 and 2.8 angstroms. Form I is thermodynamically more stable below 70 °C and is non-hygroscopic under all tested relative humidity conditions. In certain embodiments, serlopitant is used in the fonn of polymorph Form I.

Stereoisomers

[0079] The present disclosure encompasses all possible stereoisomers, including both enantiomers and all possible diastereomers in substantially pure form and mixtures of both enantiorners in any ratio (including a racemic mixture of enantiomers) and mixtures of two or more diastereomers in any ratio, of die compounds described herein, including without limitation neurokinin- 1 antagonists, and not only the specific stereoisomers as indicated by drawn structure or nomenclature. Some embodiments of the disclosure relate to the specific stereoisomers indicated by drawn structure or nomenclature. If the phrase“or stereoisomers thereof’ or the like with respect to a compound is recited in certain instances of the disclosure, such recitation shall not be interpreted as an intended omission of any of the other possible stereoisomers of the compound in other instances of the disclosure where the compound is mentioned without recitation of the phrase“or stereoisomers thereof’ or the like, unless stated otherwise or the context clearly indicates otherwise.

Sait Forms of Drug Substances

[0080] Drag substances (e.g., NK-1 antagonists such as serlopitant) may exist in a non-salt form (e.g , a free base or a free acid, or having no basic or acidic atom or functional group) or as salts if they can form salts. Drug substances that can form salts can be used in the non-salt form or in the form of pharmaceutically acceptable salts if a drag has, e.g., a basic nitrogen atom, the drug can form an addition salt with an acid (e.g., a mineral acid [such as HC1, HBr, HI, nitric acid, phosphoric acid or sulfuric acid] or an organic acid [such as a carboxylic acid or a sulfonic acid]). Suitable acids for use in the preparation of pharmaceutically acceptable salts include without limitation acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonie acid, (t-)-(lS)-eamphor- IQ-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2- hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid,

glucoheptonic acid, D-giuconic acid, D-glucuronic acid, L-glutamic acid, alpha-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (±)-DL- lactic acid, (+)-L-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphihalene-2-sulfonic acid, naphthalene- 1,5- disulfonic acid, 1 -hydroxy -2 -naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, propionic acid, L- pyroglutamic acid, pyruvic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (±)-DL-tartaric acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecyienic acid, and valeric acid.

[0081] If a drug has an acidic group (e.g., a carboxyl group), the drug can form an addition salt with a base. Pharmaceutically acceptable base addition salts can be formed with, e.g., metals (e.g., alkali metals or alkaline earth metals) or amines (e.g., organic amines). Non-limiting examples of metals useful as cations include alkali metals (e.g., lithium, sodium, potassium and cesium), alkaline earth metals (e.g., magnesium and calcium), aluminum and zinc. Metal cations can be provided by way of, e.g., inorganic bases, such as hydroxides, carbonates and hydrogen carbonates. Non-limiting examples of organic amines useful for forming base addition salts include chloroprocaine, choline, cyclohexylanhne, dibenzylamine, N,N'- dibenzylethyienediamine, dicyclohexylamine, diethanolamine, ethylenediamine, N- ethylpiperidme, histidine, isopropylamine, N-methylglucamine, procaine, pyrazine, tnethyianune and trimethylamine. Pharmaceutically acceptable salts are discussed in detail in Handbook of Pharmaceutical Salts, Properties, Selection and Use, P. Stahl and C. Wermuth, Eds., Wi!ey-VCH (2011).

Pharmaceutical Compositions

[0082] To treat chronic pruritus, an NK-I antagonist (e.g., serlopitant) can be administered alone or in the form of a pharmaceutical composition. In some embodiments, a pharmaceutical composition comprises an NK-i antagonist (e.g , serlopitant) or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof, and one or more pharmaceutically acceptable carriers or excipients. The composition can optionally contain an additional therapeutic agent described herein. In general, a pharmaceutical composition contains a therapeutically effective amount of a therapeutic agent (e.g., an NK-1 antagonist) or an appropriate fraction thereof and one or more pharmaceutically acceptable carriers or excipients, and is formulated for administration to a subject for therapeutic use. For purposes of the content of a pharmaceutical composition, the terms '‘therapeutic agent”,“active ingredient”,“active agent” and“drug” encompass prodrugs.

[0083] A pharmaceutical composition contains a therapeutic agent (e.g., an NK-1 antagonist) in substantially pure form . In some embodiments, the purity of the therapeutic agent is at least about 95%, 96%, 97%, 98% or 99%. In certain embodiments, the purity of the therapeutic agent is at least about 98% or 99%. In addition, a pharmaceutical composition is substantially free of contaminants or impurities. In some embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 5%, 4%, 3%, 2% or 1% relative to the combined weight of the intended active and inacti ve ingredients. In certain embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 2% or 1% relative to the combined weight of the intended active and inactive ingredients. Pharmaceutical compositions generally are prepared according to current good manufacturing practice (GMP), as recommended or required by, e.g., the Federal Food, Drag, and Cosmetic Act §50l(a)(2)(B) and the International Conference on Harmonisation Q7 Guideline.

[0084] Pharmaceutical eompositions/formulations can be prepared in sterile form. For example, pharmaceutical compositions/formulations for parenteral administration by injection or infusion generally are sterile. Sterile pharmaceutical compositions/formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards known to those of skill in the art, such as those disclosed in or required by the United States Pharmacopeia Chapters 797, 1072 and 121 1, and 21 Code of Federal Regulations 21 1.

[0085] Pharmaceutically acceptable carriers and excipients include pharmaceutically acceptable vehicles, substances and materials. Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, solubilizers, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials. Hie use of such excipients in pharmaceutical formulations is known in the art. For example, conventional vehicles and carriers include without limitation oils (e.g., vegetable oils such as olive oil and sesame oil), aqueous solvents {e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer’s solution)}, and organic solvents (e.g., dimethyl sulfoxide | DMSOl and alcohols [e.g., ethanol, glycerol and propylene glycol]). Except insofar as any conventional earner or excipient is incompatible with the active ingredient, the disclosure encompasses the use of conventional carriers and excipients in formulations containing a therapeutic agent (e.g., an NK-1 antagonist). See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Preformulation and Formulation, Gibson, Ed., CRC Press (Boca Raton, Florida) (2004).

[0086] Proper formulation can depend on various factors, such as the route of administration chosen. Potential routes of administration of pharmaceutical compositions comprising a therapeutic agent (e.g., an NK-! antagonist) include without limitation oral, parenteral (including intramuscular, subcutaneous, intraderma!, intravascular, intravenous, intraarterial, intraperitoneal, intramedullary , intrathecal and topical), intracavitary, and topical (including dermal/

epicutaneous, transdennal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], pulmonary' [e.g., by oral or nasal inhalation], ocular [e.g., by eye drop], buccal, sublingual, rectal [e.g., by suppository;] and vaginal [e.g., by suppository]).

[0087] As an example, formulations of an NK-1 antagonist (e.g., serlopitant) suitable for oral administration can be presented as, e.g., boluses; tablets, capsules, pills, cachets or lozenges; as powders or granules; as semisolids, electuaries, pastes or gels; as solutions or suspensions in an aqueous liquid or/and a non-aqueous liquid; or as oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0088] Tablets can contain an NK-1 antagonist (e.g., serlopitant) in admixture with, e.g., a filler or inert diluent (e.g., calcium carbonate, calcium phosphate, lactose, mannitol or microcrystalline cellulose), a binding agent (e.g., a starch, gelatin, acacia, alginic acid or a salt thereof, or microcrystalline cellulose), a lubricating agent (e.g., stearic acid, magnesium stearate, talc or silicon dioxide), and a disintegrating agent (e.g., crospovidone, croscarmellose sodium or colloidal silica), and optionally a surfactant (e.g., sodium lauryl sulfate). The tablets can be uncoated or can be coated with, e.g., an enteric coating that protects the active ingredient from the acidic environment of the stomach, or with a material that delays disintegration and absorption of the active ingredient in the gastrointestinal tract and thereby provides a sustained action over a longer time period In certain embodiments, a tablet comprises an NK- 1 antagonist (e.g., serlopitant), mannitol, microcrystalline cellulose, magnesium stearate, silicon dioxide, croscarmellose sodium and sodium lauryl sulfate, and optionally lactose monohydrate, and the tablet is optionally film-coated (e.g., with Qpadry®)

[0089] Push-fit capsules or two-piece hard gelatin capsules can contain an NK-1 antagonist (eg;., serlopitant) in admixture with, e.g., a tiller or inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin or lactose), a binder (e.g., a starch), a glidant or lubricant (e.g., talc or magnesium stearate), and a disintegrant (e.g., crospovidone), and optionally a stabilizer or/and a preservative. For soft capsules or single-piece gelatin capsules, an NK-1 antagonist (e.g., serlopitant) can be dissolved or suspended in a suitable liquid (e.g., liquid polyethylene glycol or an oil medium, such as a faty oil, peanut oil, olive oil or liquid paraffin), and the liquid-filled capsules can contain one or more other liquid excipients or/and semi-solid excipients, such as a stabilizer or/and an amphiphilic agent (e.g., a fatty acid ester of glycerol, propylene glycol or sorbitol).

[0090] Compositions for oral administration can also be formulated as solutions or suspensions in an aqueous liquid or/and a non-aqueous liquid, or as oil-in-water liquid emulsions or water-in-oil liquid emulsions. Dispersible powder or granules of an NK-1 antagonist (e.g., serlopitant) can be mixed with any suitable combination of an aqueous liquid, an organic solvent or/and an oil and any suitable excipients (e.g., any combination of a dispersing agent, a wetting agent, a suspending agent, an emulsifying agent or/and a preservative) to form a solution, suspension or emulsion.

[0091] In some embodiments, an NK-1 antagonist (e.g., serlopitant) is contained in an amphiphilic vehicle of a liquid or semi-solid formulation for oral administration which provides improved solubility, stability and bioavailability of the NK-1 antagonist, as described in US Pub. 2010/0209496 by Dokou et al. The amphiphilic vehicle contains a solution, suspension, emulsion (e.g., oil-in-water emulsion) or semi-solid mixture of the NK-1 antagonist (e.g., serlopitant) admixed with liquid or/and semi-solid excipients which fills an encapsulated dosage form (e.g., a hard gelatin capsule or a soft gelatin capsule containing a plasticizer [e.g., glycerol or/and sorbitol]). In some embodiments, the amphiphilic vehicle comprises an amphiphilic agent selected from fatty acid esters of glycerol (glycerin), propylene glycol and sorbitol. In certain embodiments, the amphiphilic agent is selected from mono- and di-glycerides of Cs-Cn saturated fatty acids. In further embodiments, the amphiphilic agent is selected from CAPMUL® MCM, CAPMUL® MCM 8, CAPMUL® MCM 10, IMWITOR® 308, IMWITOR® 624, 1MWITOR® 742, IMWITOR® 988, CAPRYOL™ PGMC, CAPRYOL™ 90, LAUROGLY COL™ 90, CAPTEX® 200, CRILL™ 1, CRILL™ 4, PECEOL® and MAISINE™ 35-1. In some embodiments, the amphiphilic vehicle further comprises propylene glycol, a propylene glycol- sparing agent (e.g., ethanol or/and glycerol), or an antioxidant (e.g., butylated hydroxyaniso!e, butylated hydroxytoluene, propyl gallate or/and sodium sulfite), or any combination or all thereof. In additional embodiments, the amphiphilic vehicle contains on a weight basis about 0.1-5% of the NK-1 antagonist (e.g., serlopitant), about 50-90% of the amphiphilic agent, about 5-40% of propylene glycol, about 5-20% of the propylene glycol-sparing agent, and about 0.01- 0.5% of the antioxidant

[0092] An NK-1 antagonist (e.g., serlopitant) can also be formulated for parenteral administration by injection or infusion to circumvent gastrointestinal (Gl) absorption and first- pass metabolism. A representative parenteral route is intravenous. Additional advantages of intravenous administration include direct administration of a therapeutic agent into systemic circulation to achieve a rapid systemic effect, and the ability to administer the agent continuously or/and in a large volume if desired. Formulations for injection or infusion can be in the form of, e.g., solutions, suspensions or emulsions in oily or aqueous vehicles, and can contain excipients such as suspending agents, dispersing agents or/and stabilizing agents. For example, aqueous or non-aqueous (e.g., oily) sterile injection solutions can contain an NK-1 antagonist (e.g., serlopitant) along with excipients such as an antioxidant, a buffer, a bacteriostat and solutes that render the formulation isotonic with the blood of the subject. Aqueous or non-aqueous sterile suspensions can contain an NK-1 antagonist (e.g., serlopitant) along with excipients such as a suspending agent and a thickening agent, and optionally a stabilizer and an agent that increases the solubility_' of the NK-1 antagonist to allow for the preparation of a m ore concentrated solution or suspension. As another example, a sterile aqueous solution for injection or infusion (e.g., subcutaneously or intravenously) can contain an NK-1 antagonist (e.g., serlopitant), NaCl, a buffering agent (eg., sodium citrate), a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or/and an acid (e.g., HC1) to adjust pH.

[0093] For topical administration, an NK-1 antagonist (e.g., serlopitant) can be formulated as, e.g., a buccal or sublingual tablet or pill. Advantages of a buccal or sublingual tablet or pill include avoidance of first-pass metabolism and circumvention of GI absorption. A buccal or sublingual tablet or pill can also be designed to provide faster release of the NK-1 antagonist for more rapid uptake of it into systemic circulation. In addition to a therapeutically effective amount of the NK-l antagonist (e.g , serlopitant), the buccal or sublingual tablet or pill can contain suitable excipients, including without limitation any combination of fillers and diluents (eg., mannitol and sorbitol), binding agents (e.g., sodium carbonate), weting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and crosearmel!ose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor), sweetening agents (e.g., sucraiose), and coloring agents (e.g., yellow iron oxide).

[0094] For topical administration, an NK-1 antagonist (e.g., ser!opitant) can also be formulated for intranasal administration. The nasal mucosa provides a big surface area, a porous endothelium, a highly vascular subepithelial layer and a high absorption rate, and hence allows for high bioavailability. Moreover, intranasal administration avoids first-pass metabolism and can introduce a significant concentration of the NK-1 antagonist to the CNS, allowing the NK-1 antagonist to block, e.g., itch transmission from the spinal and medullary dorsal horns to the brain. An intranasal solution or suspension formulation can comprise an NK-1 antagonist (e.g., serlopitant) along with excipients such as a solubility enhancer (e.g , propylene glycol), a humectant (e.g., mannitol or sorbitol), a buffer and water, and optionally a preservative (e.g., benzalkonium chloride), a mucoadhesive agent (e.g., hydroxyethylcellulose) or/and a penetration enhancer. In certain embodiments, a nasal spray formulation comprises an NK-1 antagonist (e.g., serlopitant), microciystaliine cellulose, sodium carboxymethy!cellulose, dextrose and water, and optionally an acid (e.g., HC1) to adjust pH. An intranasal solution or suspension formulation can be administered to the nasal cavity by any suitable means, including but not limited to a dropper, a pipette, or spray using, e.g., a metering atomizing spray pump.

[0095] An additional mode of topical administration of an NK-1 antagonist (eg., serlopitant) is pulmonary, including by oral inhalation and nasal inhalation. The lungs serve as a portal to the systemic circulation. Advantages of pulmonary drug delivery include, for example: 1) avoidance of first pass hepatic metabolism; 2) fast drug action; 3) large surface area of the alveolar region for absorption, high permeability of the lungs (thin air-blood barrier), and profuse vasculature of the airways; 4) reduced extracellular enzyme levels compared to the GI tract due to the large alveolar surface area; and 5) smaller doses to achieve equivalent therapeutic effect compared to other oral routes, and hence reduced systemic side effects. Oral inhalation can also enable more rapid action of an NK-1 antagonist in the CNS, such as inhibition of central itch transmission.

An advan tage of oral inhalation over nasal inhalation includes deeper penetration/deposition of the drug into the lungs. Oral or nasal inhalation can be achieved by means of, e.g., a metered- dose inhaler (MDi), a dry powder inhaler (DPI) or a nebulizer, as is known in the art. In certain embodiments, a sterile aqueous solution for oral inhalation contains an NK-1 antagonist (e.g., serlopitant), sodium chloride, a buffering agent (eg., sodium citrate), optionally a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or/and an acid (e.g., HC1) to adjust pH. [0096] Other suitable topical compositions and dosage forms include without limitation ointments, creams, gels, lotions, pastes and the like, as described in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005). Ointments are semi-solid preparations that are typically based on petrolatum or a petroleum derivative. Creams are viscous liquids or semi-solid emulsions, either oil-in-water or water-m-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the“internal” phase, generally comprises petrolatum and a fatty alcohol (e.g., cetyl or stearyl alcohol). The aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and usually contains a humectant. The emulsifier in a cream formulation is generally a non-ionic, anionic, cationic or amphoteric surfactant. Gels are semi-solid, suspension-type systems. Single-phase gels contain organic macromolecules (polymers) distributed substantially uniformly throughout the carrier liquid, which is typically aqueous but can also contain an alcohol (e.g., ethanol or isopropanol) and optionally an oil. Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semi-liquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of finely divided solids and typically contain suspending agents to produce better dispersion as well as compounds useful for localizing and holding the active agent in contact with the skin. Pastes are semi-solid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from single-phase aqueous gels.

[0097] Various excipients can be included in a topical composition. For example, solvents, including a suitable amount of an alcohol, can be used to solubilize the active agent. Other optional excipients include without limitation gelling agents, thickening agents, emulsifiers, surfactants, stabilizers, buffers, antioxidants, preservatives, cooling agents (e.g. menthol), opacifiers, fragrances and colorants. For an active agent having a low rate of permeation through the skin or mucosal tissue, a topical composition can contain a permeation enhancer to increase the permeation of the active agent through the skin or mucosal tissue A topical composition can also contain an irritation-mitigating excipient that reduces any irritation to the skin or mucosa caused by the active agent, the permeation enhancer or any other component of the composition.

[0098] Other topical, namely transdennal and transmucosal, compositions are described below. [0099] In some embodiments, an NK-1 antagonist (e.g., serlopitant) is delivered from a sustained-release composition. As used herein, the term“sustained-release composition” encompasses sustained-release, prolonged-release, extended-release, slow-release and controlled- release compositions, systems and devices. Use of a sustained-release composition can have benefits, such as an improved profile of the amount of the drug delivered to the target site(s) over a time period, including delivery of a therapeutically effective amount of the drag over a prolonged time period. In certain embodiments, a sustained-release composition delivers an NK-

1 antagonist over a period of at least about 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month,

2 months, 3 months or longer. In some embodiments, a sustained-release composition is a drug- encapsulation system, such as, e.g., nanoparticles, microparticles or a capsule made of, e.g., a biodegradable polymer or/and a hydrogel. In certain embodiments, a sustained-release composition comprises a hydrogel. Non-limiting examples of polymers of which a hydrogel can be composed include polyvinyl alcohol, acrylate polymers (e.g., sodium polyacrylate), and other homopolymers and copolymers having a relatively large number of hydrophilic groups (e.g., hydroxyl or/and carboxyiate groups). In other embodiments, a sustained-release drug- encapsulation system comprises a membrane-enclosed reservoir, wherein the reservoir contains a drag and the membrane is permeable to the drag. Such a drag-delivery system can be in the form of, e.g., a transdermal patch.

|01qq] In certain embodiments, a sustained-release composition is an oral dosage form, such as a tablet or capsule. For example, a drag can be embedded in an insoluble porous matrix such that the dissolving drug must make its way out of the matrix before it can be absorbed through the GI tract. Alternatively, a drug can be embedded in a matrix that swells io form a gel through which the drag exits. Sustained release can also be achieved by way of a single-layer or multi layer osmotic controlled-release oral delivery system (OROS). An QRQS is a tablet with a semi- permeable outer membrane and one or more small laser-drilled holes in it. As the tablet passes through the body, water is absorbed through the semi-permeable membrane via osmosis, and the resulting osmotic pressure pushes the drag out through the hole(s) in the tablet and into the GI tract where it can be absorbed.

[0101] In further embodiments, a sustained-release composition is formulated as polymeric nanoparticles or microparticles, which can be delivered, e.g., by injection or inhalation or as an implant (e.g., a depot). In some embodiments, the polymeric implant or polymeric nanoparticles or microparticles are composed of a biodegradable polymer. In certain embodiments, the biodegradable polymer comprises lactic acid or/and glycolic acid fe.g., an L-lactic acid-based copolymer, such as poly(L-lactide-co-glycolide) or poly(L-lactic acid-co-D,L-2-hydroxyoctanoic acid)] . For instance, biodegradable polymeric microspheres composed of polyiactie acid or/and polyglycolic acid can serve as sustained-release pulmonary drug-delivery' systems. The biodegradable polymer of the polymeric implant or polymeric nanoparticles or microparticles can be selected so that the polymer substantially completely degrades around the time the period of treatment is expected to end, and so that the byproducts of the polymer’s degradation, like the polymer, are biocompatible.

[0102] For a delayed or sustained release of an NK-l antagonist (e.g., seriopitant), a composition can also be formulated as a depot that can be implanted in or injected into a subject, e.g., intramuscularly or subcutaneously. A depot formulation can be designed to deliver an NK-l antagonist over a longer period of time, e.g., over a period of at least about 1 week, 2 weeks,

3 weeks, 1 month, 6 weeks, 2 months, 3 months or longer. For example, an NK-l antagonist (e.g., seriopitant) can be formulated with a polymeric material (e.g , polyethylene glycol [PEG], polylactic acid j TLA] or polyglycolic acid [PGA], or a copolymer thereof [e.g., PLGA]), a hydrophobic material (e.g., as an emulsion in an oil) or/and an ion-exchange resin, or as a sparingly soluble derivative (e.g , a sparingly soluble salt). As an illustrative example, an NK-l antagonist (e.g., seriopitant) can be incorporated or embedded in sustained-release microparticles composed of PLGA and formulated as a monthly depot.

[0103] An NK-l antagonist (e.g , seriopitant) can also be contained or dispersed in a matrix material. The matrix material can comprise a polymer (e.g., ethylene-vinyl acetate) and controls release of the drag by controlling dissolution or/and diffusion of the drag from, e.g., a reservoir, and can enhance the stability of the drug while contained in the reservoir. Such a release system can be designed as a sustained-release system, can be configured as, e.g., a transdermal or transmucosai patch, and can contain an excipient that can accelerate the drag’s release, such as a water-sweiiabie material (e.g., a hydrogel) that aids in expelling the drag out of the reservoir.

US Pat. Nos. 4,144,317 and 5,797,898 describe examples of such a release system.

[0104] Tire release system can provide a temporally modulated release profile (e.g., pulsatile release) when time variation in plasma levels is desired, or a more continuous or consistent release profile when a constant plasma level is desired. Pulsatile release can be achieved from an individual reservoir or from a plurality of reservoirs. For example, where each reservoir provides a single pulse, multiple pulses (“pulsatile” release) are achieved by temporally staggering the single pulse release from each of multiple reservoirs. Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of a release system and other materials into a single reservoir. Continuous release can be achieved by incorporating a release system that degrades, dissolves, or allows diffusion of a compound through it over an extended time period. In addition, continuous release can be approximated by releasing several pulses of a compound m rapid succession (“digital” release). An active release sy stem can be used alone or in conjunction with a passive release system, as described in US Pat. 5,797,898

[0105] In addition, pharmaceutical compositions comprising an NK-1 antagonist (e.g., serlopitant) can be formulated as, e.g., liposomes, micelles (e.g., those composed of

biodegradable natural or/and synthetic polymers, such as lactosomes), nanoparticles, microparticles or microspheres, whether or not designed for sustained release. For example, liposomes can be used as a sustained-release pulmonary drug-delivery system that delivers a drug to the alveolar surface for treatment of a systemic disorder.

[0106] The pharmaceutical compositions can be manufactured in any suitable manner known in the art, e.g., by means of conventional mixing, dissolving, suspending, granulating, dragee making, levigating, emulsifying, encapsulating, entrapping or compressing processes.

[0107] A pharmaceutical composition can be presented in unit dosage form as a single dose wherein all active and inactive ingredients are combined in a suitable system, and components do not need to be mixed to form the composition to be administered. Tire unit dosage form can contain an effective dose, or an appropriate fraction thereof, of a drug (e.g., an NK-1 antagonist). Representative examples of a unit dosage form include a tablet, capsule or pill for oral administration, and a single-use pen comprising a pre-filled syringe, a needle and a needle cover for parenteral (e.g., intravenous or subcutaneous) injection of the drug.

[0108] Alternatively, a pharmaceutical composition can he presented as a kit in which the therapeutic agent, excipients and carriers (e.g., solvents) are provided in two or more separate containers (e.g., ampules, vials, tubes, bottles or syringes) and need to be combined to form the composition to be administered. The kit can contain instructions for storing, preparing and administering the composition (eg., a solution to be injected intravenously or subcutaneously).

[0109] A kit can contain all active and inactive ingredients in unit dosage form or the active ingredient and inactive ingredients in two or more separate containers, and can contain instructions for administering or using the pharmaceutical composition to treat chronic pruritus. [0110] In some embodiments, a kit contains an NK-1 antagonist (e.g., serlopitant) or a pharmaceutical composition comprising the same, and instructions for administering or using the NK-1 antagonist or the pharmaceutical composition comprising the same to treat chronic pruritus.

Topical Compositions Comprising a Therapeutic Agent such as an NK-1 Antagonist

[0111] Topical compositions for application to the skin or mucosa can be useful for treatment of conditions of the upper skin or mucosal layers and for transdermal or transmucosal administration of a drug to the local tissue underlying the skin or mucosa and, if desired, into the blood for systemic distribution. Advantages of topical administration can include circumvention of GI absorption and first-pass metabolism, deliver}' of a drug with a short half-life and low' oral bioavailability, more controlled and sustained release of the drug, more uniform plasma dosing or deliver}' profile of the drug, less frequent dosing of the drug, less side effects, minimal or no invasiveness, ease of self-administration, and increased patient compliance

[0112] In general and in addition to tire disclosure on topical compositions described elsewhere herein, compositions suitable for topical administration include without limitation liquid or semi-liquid preparations such as sprays, gels, liniments and lotions, oil-in-water or water-in-oil emulsions such as creams, foams, ointments and pastes, and solutions or suspensions such as drops (e.g., eye drops, nose drops and ear drops). In some embodiments, a topical composition comprises a drug dissolved, dispersed or suspended in a carrier. The carrier can be in the form of, e.g., a solution, a suspension, an emulsion, an ointment or a gel base, and can contain, e.g., petrolatum, lanolin, a wax (e.g., bee wax), mineral oil, a long-chain alcohol, polyethylene glycol or polypropylene glycol, or a diluent (e.g., water or/and an alcohol [e.g., ethanol or propylene glycol]), or any combination thereof. A solvent such as an alcohol can be used to solubilize the drug. A topical composition can contain any of a variety of excipients, such as a gelling agent, an emulsifier, a thickening agent, a buffer, a stabilizer, an antioxidant, a preservative, a chemical permeation enhancer (CPE) or an irritation-mitigating agent, or any combination thereof. A topical composition can include, or a topical formulation can be administered by means of, e.g., a transdermal or transmucosal delivery device, such as a transdermal patch, a microneedle patch or an iontophoresis device. A topical composition can deliver a drug transdermally or transmucosally via a concentration gradient (with or without the use of a CPE) or an active mechanism (e.g., iontophoresis or microneedles). [0113] To enhance the penetration of a small-molecule (or polypeptide) drug into and across the skin or mucosa, a chemical penetration/permeation enhancer (CPE) can be mixed with the drug for topical administration. Non-limiting examples of CPEs include hydrocarbons (e.g., alkanes and alkenes [e.g., squalene]); terpenes and terpenoids (e.g , D-limonene, carvone, eucalyptol, menthol, menthone and nerolidol); essential/volatile oils (e.g., anise oil, caraway oil, cardamom oil, chenopodmm oil, eucalyptus od and lemon oil); ethers and fatty ethers (e.g., 2-n- nonyl-l,3-dioxolane); phenols (e.g., eugenol); alcohols and fatty alcohols (e.g., methanol, ethanol, isopropyl alcohol, pentanol, laury! alcohol, oleyl alcohol, benzyl alcohol, diethylene glycol mono-ethyl ether, propylene glycol, dipropylene glycol, polyethylene glycol and glycerol); benzoic acids (e.g , salicylic acid and acetylsalicylic acid); faty acids (e.g., valeric acid, 1 auric acid, oleic acid and linoleic add); esters, fatty alcohol esters and fatty acid esters (e.g., ethyl acetate, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl oleate, ethyl oleate, propylene glycol mono-oleate, glycerol mono-oleate, triacetin and pentadecalactone); hydroxyl-containing esters, fatty alcohol esters and faty acid esters (e.g., lauryl lactate, glyceryl/glycerol monolaurate, glycerol monoleate [mono-olein], sorbitan oleate and octyl salicylate); amines (e.g., diethanolamine and triethanolamine); amides, fatty amine amides and fatty acid amides (e.g., urea, dimethylformamide, dimethylacetamide, diethylacetamide, diethyltoluamide, N-lauroyl sarcosine, 1 -dodecylazacycloheptane-2-one [!aurocapram or Azone ^: j. Azone-related compounds, and pyrrolidone compounds [e.g., 2-pyrrolidone and N- methyl-2-pyrrolidone]); ionic and non-ionic surfactants (e.g., cetyltnmethylammonium bromide, sodium laurate, sodium laureth sulfate [sodium lauryl ether sulfate], sodium eholate, sodium lauroyl sarcosinate, N-lauroyl sarcosine, sorbitan monolaurate, Brij^® surfactants, Pluronic^® surfactants, Tween^® surfactants, saponins, alkyl glycosides, and fatty ether and fatty ester saccharides); phospholipids (e.g., lecithin); organic sulfoxides (e.g., dimethyl sulfoxide and decylmethyl sulfoxide); and ginsenosides US 2007/0269379 provides an extensive list of CPEs.

[0114] In some embodiments, the CPE includes a surfactant. In certain embodiments, the CPE includes two or more surfactants, such as a non-ionic surfactant (e.g., sorbitan monolaurate or N-lauroyl sarcosine) and an ionic surfactant (e.g., an anionic surfactant such as sodium lauroyl sarcosinate). In further embodiments, the CPE includes a surfactant (e.g., an anionic surfactant such as sodmm laureth sulfate) and an aromatic compound (e.g., 1-phenylpiperazine). Such combinations of CPEs can greatly enhance penetration of a drug into and through the skin or mucosa with a low potential for skin or mucosal irritation. In additional embodiments, the CPE includes an organic sulfoxide and a compound selected from fatty acids, fatty acid esters and Azone-related compounds.

[0115] For transmucosal administration, in certain embodiments the CPE is or includes an alkyl glycoside (e.g., a 1-0 or S-C&-C20 alkyl glycoside such as the corresponding glucoside, galactoside, mannoside, lactoside, maltoside [e.g., dodecyi, tridecyl or tetradecyi maltoside], melibioside or sucroside [e.g., dodecyi sucrose]), or a fatty ether or faty ester saccharide (e.g., a Cs-Cro alkyl ether or ester saccharide such as the corresponding glucoside, galactoside, mannoside, lactoside, maltoside, melibioside, sucroside [e.g., sucrose monododecanoate] or trehaloside).

[0116] To enhance the penetration of a polypeptide (e.g., a peptide or a protein) into and across the skin or mucosa, alternative to or in addition to a chemical penetration enhancer, a transdermal peptide enhancer (TPE) can be mixed with the polypeptide for topical

administration. TPEs include cell-penetrating peptides (CPPs) and transdermal-enhanced peptides (TEPs, also called skin-penetrating peptides [SPPs j). CPPs may be more polar or charged (e.g., positively' charged) than TEPs/SPPs. Non-limiting examples of CPPs for transdermal or transmucosal administration include polyarginine homopolymers (e.g., those comprising 6 to 15 arginine residues, such as Re, R?, Rg and Rg), arginine-rich CPPs {e.g., TAT- related CPPs such as TAT(49-57), the IMT-P8 peptide and low molecular weight protamine (LMWP)}, other polycationic CPPs (e.g., the peptide for ocular delivery [POD], which is also capable of penetrating through non-ocular tissues such as the skin), and amphipathic CPPs (e.g., magainin 2, penetratin, Pep-1, transportan, the WLR [name] peptide [aka W3], and the YARA [name ] peptide j aka PTD4] ). Examples of TEPs/SPPs for transdermal or transmucosal administration include without limitation the dermis-localizing peptide (DLP), the linear peptide- 12 (LP-12), tlie skin-penetrating and cell-entering (SPACE) peptide, the T2 peptide, the TD-1 peptide, the TD-34 peptide, and the TDN (name) peptide. A CPP or/and an SPP can be used, or a TPE can be a CPP directly or indirectly linked to an SPP, such as TD-1 linked to polyarginine (e.g., octa-arginine). The po!ypeptide/TPE complex can diffuse passively through the skin or mucosa down a concentration gradient, even if the complex is charged (has no net charge or has a net charge). If the complex is charged (e.g., the polypeptide is negatively charged and the TPE [e.g., a CPP] is positively charged), translocation of the complex through the skin or mucosa can be facilitated by, e.g., iontophoresis. Tire TPE may also enhance the aqueous solubility or/and the stability of the polypeptide. The polypeptide solution can be prepared with a solvent that also functions as a CPE, such as ethanol in an aqueous ethanol solution. F. Milletti, Drug Discov. Today, 17:850-860 (2012) is a review of CPPs. R. Ruan et al, Ther. Dehv., 7:89-100 (2016) discuss CPPs and SPPs for transdermal deliver)_' of macromolecules.

[0117] In some embodiments, a polypeptide is transdermally or transmucosally administered with a CPP (e.g., a polyarginine such as nona-arginine) or a TEP/SPP (e.g., the SPACE peptide) and without a CPE (other than an alcohol that may be used to prepare the polypeptide solution, such as ethanol). In other embodiments, a polypeptide is transdermally or transmucosally administered with a CPP (e.g., a polyarginine such as nona-arginine) or a TEP/SPP (e.g., the SPACE peptide), and with a CPE (e.g., a fatty acid such as oleic acid).

[0118] Transdermal or transmucosal delivery of a polypeptide (or small-molecule) drug can also be enhanced by using a tight junction modulator (TJM) alternative to or in addition to a TPE or/and a CPE. TJMs reversibly open tight junctions between cells and thereby facilitate intercellular/paracellular transport of drugs across epithelial barriers. A TPE or a CPE may also disrupt tight junctions. Examples of TJMs that can be mixed with a drug for transdermal or transmucosal deliver)_' of the drag include without limitation chitosans, cloudin-4, the ATI 002 peptide, and the zonula occludens toxin (ZOT).

[0119] In some embodiments, a therapeutic agent is administered via a transdermal patch. In certain embodiments, a transdermal patch is a reservoir-type patch comprising an impermeable backing layer/film, a liquid- or gel-based drag reservoir, a semi-permeable membrane that controls drag release, and a skin-contacting adhesive layer. The semi-permeable membrane can be composed of, e.g., a suitable polymeric material such as cellulose nitrate or acetate, polyisobutene, polypropylene, polyvinyl acetate or a polycarbonate. In other embodiments, a transdermal patch is a drag -in-adhesive patch comprising an impermeable backing layer/film and a skin-contacting adhesive layer incorporating a drug in a polymeric or viscous adhesive. The adhesive of the drag-loaded, skin-contacting adhesive layer can be, e.g., a pressure-sensitive adhesive (PSA), such as a PSA composed of an acrylic polymer (e.g., polyacry!ate), a polyalkylene (e.g., poly isobutylene) or a silicone-based polymer (e.g., silicone-2675 or silicone- 2920). A transdermal patch can optionally contain a CPE, a CPP or a TEP/SPP, or any combination thereof, to enhance transdermal delivery_' of the drag. Transdermal drag-delivery_' systems, including patches, can be designed to provide controlled and prolonged release of a drug over a period of about 1 week, 2 weeks, 3 weeks, 1 month or longer. [0120] Transdermal penetration of a polypeptide (or small -molecule) drug, whether or not delivered via a patch, can be further enhanced by use of a physical enhancement technique, such as iontophoresis, cavitational or non-cavitational ultrasound, electroporation, thermal ablation, radio frequency, microdermabrasion, microneedles or jet injection.

[0121] Representative kinds of topical compositions are described below for purposes of illustration.

[0122] In some embodiments, a topical composition comprises a therapeutic agent (e.g., an NK-1 antagonist) and a permeation enhancer. The composition can optionally contain an additional therapeutic agent. In certain embodiments, the composition contains the therapeutic agent(s) in free base form.

[0123] The permeation enhancer increases the permeability of the skin or mucosa to the therapeutic agent(s). In certain embodiments, the permeation enhancer is N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate, isopropyl myri state, oleic acid, glyceryl oleate or sodium lauryl sulfoacetate, or any combination thereof. In certain embodiments, the composition contains on a weight/ volume (w/v) basis the permeation enhancer m an amount of about 1-20%, 1-15%, 1-10% or 1-5%. To enhance further the ability of the therapeutic agent(s) to penetrate the skin or mucosa, the composition can also contain a surfactant, an azone-like compound, an alcohol, a fatty acid or ester, or an aliphatic thiol.

[0124] The composition can further contain one or more additional excipients. Suitable excipients include without limitation solubilizers (e.g., Ci-Cs alcohols), moisturizers or humectants (e.g., glycerol [glycerin], propylene glycol, amino acids and derivatives thereof, polyamino acids and derivatives thereof, and pyrrolidone carboxylic acids and salts and derivatives thereof), surfactants (e.g., sodium laureth sulfate and sorbitan monolaurate), emulsifiers (e.g., cetyl alcohol and stearyl alcohol), thickeners (e.g., methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, poly vinyl alcohol and acrylic polymers), and formulation bases or carriers (e.g., polyethylene glycol as an ointment base). As a non-limiting example, the base or carrier of the composition can contain ethanol, propylene glycol and polyethylene glycol (e.g., PEG 300), and optionally an aqueous liquid (e.g., isotonic phosphate-buffered saline). [0125] The topical composition can have any suitable dosage form, such as a solution (e.g., eye drop, nose drop or ear drop), a suspension, an emulsion, a cream, a lotion, a gel, an ointment, a paste, a jelly, a foam, a shampoo, or a spray. In some embodiments, the composition is applied to the skin or mucosa covering a surface area of about 10-800 cm², 10-400 cm² or 10-200 cm². The composition can deliver the therapeutic agent(s) to the skin or mucosa or the underlying tissue. The composition can also be formulated for transdermal administration of the therapeutic agent(s) to the systemic circulation, e.g., as a transdermal patch or a microneedle patch.

II. Topical Compositions Comprising a Permeation Enhancer and a Volatile Liquid

[0126] In further embodiments, a topical composition comprises a therapeutic agent (e.g., an NK-1 antagonist), a permeation enhancer and a volatile liquid. The composition can optionally contain an additional therapeutic agent. In certain embodiments, the composition contains the therapeutic agent(s) in free base form.

[0127] The permeation enhancer increases the permeability of the skin or mucosa to the therapeutic agent(s). In some embodiments, the permeation enhancer is selected from Cs-Cis alkyl aminobenzoates (e.g., Cs-Cis alkyl p-aminobenzoates), Cs-Cis alkyl

dimethylaminobenzoates (e.g., Cs-Cis alkyl p-dimethylaminobenzoates), Cs-Cis alkyl cinnamates, Cs-Cis alkyl methoxyemnamates (e.g., Cs-Cis alkyl p-methoxycinnamates), and Cs- Cis alkyl salicylates. In certain embodiments, the permeation enhancer is octyl salicylate, octyl p-dmiethyiaminobenzoate or octyl p-methoxycinnamate, or any combination or all thereof.

[0128] Hie volatile liquid can be any volatile, skin- or mucosa-tolerant solvent. In certain embodiments, the volatile liquid is a C2-C5 alcohol or an aqueous solution thereof, such as ethanol or isopropanol or an aqueous solution thereof. An aerosol propellant (e.g., dimethyl ether) can be considered as a volatile liquid. In some embodiments, the volatile liquid functions as a carrier or vehicle of the composition.

[0129] The composition can optionally contain a thickening agent. Non-limiting examples of thickening agents include cellulosic thickening agents (e.g., ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylceiluiose), povidone, polyacrylic acids/polyacrylates (e.g., Carbopol® polymers), Sepigel® (polyacrylamide/isoparaffm/laureth-7), and the Gantrez® series of polymethyl vinyl ether/maleic anhydride copolymers (e.g., butyl ester of PMV/MA copolymer Gantrez® A-425). [0130] In some embodiments, the composition contains on a weight basis about 0.5-10%, 0.5-5% or 1-5% of a therapeutic agent (e.g., an NK-1 antagonist), about 1-20%, 1-15% or 1-10% of the permeation enhancer, and about 40-98%, 45-95%, 50-90% or 60-80% of the volatile liquid. In further embodiments, the composition optionally contains on a weight basis about 1- 40%, 1-30%, 1-20% or 5-20% water or/and about 0.1-15%, 0.5-10% or 1-5% of a thickening agent.

[0131] For purposes of illustration, in certain embodiments a topical spray composition contains about 0.5-5% w/v of a therapeutic agent (e.g., an NK-1 antagonist), about 2-10% w/v of octyl salicylate or octyl p-methyoxycinnamate, and about 95% aqueous ethanol as the carrier. In further embodiments, a topic gel composition comprises about 0.5-5% w/v of a therapeutic agent (e.g., an NK-1 antagonist), about 1-10% w/v of octyl salicylate or octyl p-methyoxycinnamate, about 0.5-5% w/v of a Carbopol® polyacrylic acid, and about 70% aqueous ethanol as the carrier, and optionally about 1-10% w/v of a basic solution (e.g., 0.1 N NaOH). In additional embodiments, a topical lotion composition contains about 0.5-5% w/v of a therapeutic agent (e.g., an NK-1 antagonist), about 1-10% w/v of octyl salicylate or octyl p-methyoxycinnamate, about 1-5% w/v of ethyl cellulose or hydroxypropyl cellulose, and about 90% aqueous ethanol as the earner.

[0132] The composition can further comprise other excipients, such as a compounding agent (e.g., paraffin oil, silicone oil, a vegetable oil, or a fatty ester such as isopropyl myristate), a diluent, a co-solvent (e.g., acetone or a glycol ether such as diethylene glycol monoethyl ether), an emulsifier, a surfactant (e.g., an ethoxylated fatty alcohol, glycerol mono stearate or a phosphate ester), a stabiliser, an antioxidant or a preservative (e.g., a hydroxybenzoate ester), or any combination thereof. For example, a co-solvent or/and a surfactant can be used to maintain the therapeutic agent(s) in solution or suspension at the desired concentration.

[0133] The topical composition can have any suitable dosage form, such as a cream, a lotion, a gel, an ointment, a mousse, a spray or aerosol, or any transdermal device (e.g., a patch) that administers a drug by absorption through the skin or mucosa. In some embodiments, the topical composition is applied to the skin or mucosa covering a surface area of about 10-800 cm², 10- 400 cm² or 10-200 cm². III. Topical Compositions Comprising a Permeation Enhancer and Another

[0134] In additional embodiments, a topical composition comprises a therapeutic agent (e.g., an NK-1 antagonist), a permeation enhancer, and at least one of a lipophilic solvent, a formulation base and a thickener. In some embodiments, the composition contains a lipophilic solvent and a formulation base, or the same substance can function as both a lipophilic solvent and a formulation base. In further embodiments, the composition contains a lipophilic solvent, a formulation base and a thickener. The composition can optionally comprise an additional therapeutic agent. In certain embodiments, the composition contains the therapeutic agent(s) in free base form.

[0135] The permeation enhancer increases the permeability of the skin or mucosa to the therapeutic agent(s). Non-limiting examples of permeation enhancers include dimethyl sulfoxide (DMSO), decylmethyl sulfoxide, laurocapram, pyrrolidones (e.g., 2-pyiTolidone and N-methyl-2- pyrrolidine), surfactants, alcohols (e.g., oieyl alcohol), polyethylene glycol (e.g., PEG 400), diethylene glycol monoethyl ether, oleic acid, and fatty acid esters (e.g., isopropyl myri state, methyl laurate, glycerol monooleate, and propylene glycol monooieate).

[0136] Non-limiting examples of liphophilic solvents include lipophihc alcohols (e.g., hexylene glycol, octyldodecanol, oieyl alcohol and steary! alcohol), polyethylene glycol (e.g., PEG 100, PEG 300, PEG 400 and PEG 3350), diethylene glycol monoethyl ether, poiysorbates (e.g., Tween:® 20 to 80), Labrasol®, fatty acid esters (e.g., isopropyl myristate and diisopropyl adipate), diethyl sebacate, propylene glycol monocaprylate, propylene glycol laurate, mono- and di -glycerides (e.g., Capmul® MCM), medium-chain triglycerides, eaprylie/eapric triglyceride, glyceryl monocaprylate, glyceryl mono-oleate, glyceryl mono-linoleate, glycerol

oleate/propylene glycol, mineral oil, and vegetable oils.

[0137] A liphophilic solvent may also function as a formulation base or carrier. For example, polyethylene glycol (e.g, from PEG 100 to PEG 3500, such as PEG 300, PEG 400 and PEG 3350) can function as a liphophilic solvent and a formulation base.

[0138] The composition can also contain a hydrophilic solvent, such as a Ci-Cs alcohol (e.g, ethanol, isopropanol, glycerol, propylene glycol and 1,2-pentanediol) or/and water. [0139] The composition can contain a thickener to increase the viscosity or/and the physical stability of the composition. Examples of thickeners include without limitation glycerol, stearyl alcohol, and polymers (e.g., poiydimethylsiioxane [dimethicone] and Carbopol® polymers).

[0140] In some embodiments, the composition further contains an antioxidant. Non-limiting examples of antioxidants include butyiated hydroxyanisole (BHA), butyiated hydroxytoluene (BHT), tocopherols (e.g., Vitamin E and esters thereof), flavinoids, glutathione, ascorbic acid and esters thereof, DMSO, and chelating agents (e.g., EDTA and citric acid).

[0141] In certain embodiments, the topical composition comprises on a w/w basis about 0.5- 10% or 1-5% of a therapeutic agent (e.g., an NK-l antagonist), about 2-30% or 5-20% of a permeation enhancer, about 20-80% or 30-70% of a lipophilic solvent that may also function as a formulation base, about 0.1-10% or 1-7.5 % of a thickener, and about 0.01-2% or 0.05-1% of an antioxidant. As a non-limiting example, a topical composition can contain a therapeutic agent (e.g., an NK-l antagonist), PEG 400 or/and PEG 3350 as lipophilic solvent(s) and fonnulation base(s), diethylene glycol monoethyl ether, oleyi alcohol or/and isopropyl myristate as permeation enhancer(s), stearyl alcohol as a thickener, and BHT as an antioxidant.

[0142] The topical composition can have any suitable dosage form, such as a cream, a lotion, a gel, an ointment, a jelly, a paste, or any transdermal device (e.g., a patch) that administers a drag by absorption through the skin or mucosa.

IV. Topical Compositions Comprising a Permeation Enhancer and an Adhesive

[0143] In other embodiments, a topical composition comprises a therapeutic agent (e.g., an NK-l antagonist), a permeation enhancer and an adhesive. The composition can optionally contain an additional therapeutic agent. In certain embodiments, the composition contains the therapeutic agent(s) in free base fonn.

[0144] The permeation enhancer increases the permeability of the skin or mucosa to the therapeutic agent(s). The permeation enhancer can be, e.g., a fatty acid ester having a fatty acyl chain length of

alcohol component (e.g., isopropanol). In certain embodiments, the permeation enhancer is isopropyl myristate or isopropyl palmitate. In some embodiments, the permeation enhancer is in an amount of about 0.1-20%, 0.5-15%, 1-15%, 2-12% or 4-10% by weight of the composition or the skin-contacting layer of a transdermal patch . [0145] The adhesive maintains contact of the topical composition to the skin or rnucosa. Non-limiting examples of adhesives include acrylics/acrylates (e.g., polyacrylates, including polyalkyl acrylates and Duro-Tak® polyacrylates), polyvinyl acetate, ethy!enevinylaeetate copolymers, po!ysiloxanes, polyurethanes, plasticized polyether block amide copolymers, natural and synthetic rubbers, plasticized styrene-butadiene rubber block copolymers (e.g., Duro-Tak® 87-6173), and mixtures thereof.

[0146] The topical composition can comprise one or more additional excipients. The additional excipient(s) can be, e.g., a diluent, an emollient, a plasticizer, or an agent that reduces irritation to the skin or mucosa, or any combination thereof.

[0147] In certain embodiments, the topical composition prior to application to the skin or mucosa is substantially free of water, tetraglycol (glycofurol) or/and a hydrophilic organic solvent (e.g., a C1-C5 alcohol).

[0148] The composition can administer the therapeutic agent(s) transdermally or transmucosally through a body surface or membrane such as intact unbroken skin or mucosal tissue into the systemic circulation.

[0149] In some embodiments, the topical composition is in tire form of a transdermai patch for application to the skin. In certain embodiments, the patch has a skin-contacting layer laminated or otherwise attached to a support layer. The skin-contacting layer can be covered by a removable release liner before use to protect the skin-contacting surface and to keep it clean until it is applied to the skin.

[0150] The support layer of the patch acts as a support for tire skin-contacting layer and as a barrier that prevents loss of the therapeutic agent(s) in the skin-contacting layer to the environment. The material of the support layer is compatible with the therapeutic agent(s), the permeation enhancer and the adhesive, and is minimally permeable to the components of the patch. The support layer can be opaque to protect the components of the patch from degradation via exposure to ultraviolet light. The support layer is also capable of binding to and supporting the adhesive layer, yet is sufficiently pliable to accommodate the movements of the subject using the patch. The material of the support layer can be, e.g., a metal foil, a metalized polyfoil, or a composite foil or film containing a polymer (e.g., a polyester [such as polyester terephthalate ] or aluminized polyester, polyethylene, polypropylene, polytetrafluoroethyiene, a polyethylene methyl methacrylate block copolymer, a polyether block amide copolymer, a polyurethane, polyvinylidene chloride, nylon, a silicone elastomer, rubber-based polyisobutylene, styrene, or a styrene-butadiene or styrene-isoprene copolymer). The release liner can be made of the same material as the support layer, or can be a film coated with an appropriate release surface.

Combination Therapies with an NK-1 Antagonist and Other Antipruritic Agents

[0151] One or more additional antipruritic agents can optionally be used in combination with an NK-1 antagonist (e.g., serlopitant) to treat chronic pruritus. The NK-1 antagonist may synergize or enhance the activity of the one or more additional antipruritic agents.

[0152] Examples of antipruritic agents include without limitation:

antagonists of transient receptor potential cation channels, including but not limited to transient receptor potential ankyrin A1 (TRPA1) antagonists {e.g., camphor, isopentenyl pyrophosphate, ruthenium red, A967079, AP-18, GRC-17536, HC-030031, (47?)- 1,2,3, 4- tetrahydro-4~[3-(3-methoxypropoxy)phenyl]~2-thioxo~3/7~indeno[i,2-ri]pyrimidin-5-one, 2- amino-4-arylthiazole compounds disclosed in WO 2012/085662 Al, bicyclic heterocyclic compounds of Formula (I) disclosed in WO 2017/064068 Al, and specialized pro-resolving mediators (SPMs) (e.g., metabolites of polyunsaturated fatty acids [PUFAs])}, transient receptor potential vanilloid (TRPV) antagonists {e.g., TRPV1 antagonists (e.g., capsazepine, iodo- resmiferatoxin, ratliemum red, AMG-517, GRC-6211, JNJ- 1720321, NGD-8243, SB-705498, Xen-D0501 and SPMs [e.g., PUFA metabolites]), TRPV3 antagonists (e.g., ruthenium red and SPMs [e.g., PUFA metabolites]), and TRPV4 antagonists (e.g., ruthenium red, HC-067047, RN- 1734, RN-9893 and SPMs [e.g., PUFA metabolites such as resolvin Dl])>, and analogs, derivatives and salts thereof;

TRPVl agonists that cause decrease in TRPV I activity (desensitization) upon prolonged or repeated exposure of TRPVl to the stimuli, including but not limited to capsaicinoids (e.g., capsaicin, homocapsaiciu, dihydrocapsaicin, horaodihydrocapsaicin, nordihydrocapsaicin, and nomvamide [pelargonic acid vanillylamide]), camphor, carvacrol, menthol, methyl salicylate resiniferatoxin, linyatoxin, and analogs, derivatives and salts thereof;

antihistamines, including but not limited to antihistamines that inhibit the histamine HI receptor (e.g., acrivastine, antazoline, astemizole, azatadine azelastine, bepotastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorcyclizine, ehiorodiphenhydramine, chlorpheniramine, chlorpromazine, chloropyramine, cidoxepin, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine,

dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxepin, doxylamine, ebastine, embramine, esmirtazapine [(5)-(-t-)-mirtazapineJ, fexofenadine, hydroxyzine, ketotifen, levocabastine, levocetirizine, loratadine, meclozme [meclizine], mepyramme, mirtazapine, mizolastine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, quetiapine, qmfenadine, rupatadine, terfenadine, trimeprazine

[alimemazine], tripelennamine and triprolidine), antihistamines that inhibit the histamine H4 receptor (e.g, clobenpropit, tlnoperamide, A943931, A987306, JNJ-7777120, JNJ-28307474, JNJ-38518168 [toreforant], JNJ-39758979, PF-3893787, UR-63325, VUF-6002 and ZPL-389), and analogs, derivatives and salts thereof;

antagonists of serotonin receptors, including but not limited to 5-HT2 antagonists (e.g., aitanserin, clozapine, cyproheptadine, epHvanserin, glemanserin, ketanserin, (<S)-(+)-mirtazapme [esmirtazapine], olanzapine, pimavanserin, pizotifen [pizotyiinej, quetiapine, risperidone, ntanserin and volinanserin), 5-HT3 antagonists (e.g., alosetron, bemesetron, cilansetron, dolasetron, granisetron, (i?)-(-)-mirtazapine, ondansetron, palonosetron, ricasetron, tropanserin, tropisetron, zatosetron, and substances present in ginger [e.g., galanolactone, gingerols and shogaols]), 5-HT7 antagonists (e.g., amitriptyline, amoxapine, clomipramine, clozapine, imipramine, ketanserin, maprotiline, mianserin, olanzapine, pimozide, ritanserm and

vortioxetime), and analogs, derivatives and salts thereof;

antagonists of muscarinic acetylcholine receptors (e.g., Ml to M5), including but not limited to aclidinium, atropine, benzatropine, biperiden, chlorpheniramine, cyclopentolate, darifenacin, dicyclomine, dimenhydrinate, diphenhydramine, doxepin, doxylamine, flavoxate, glycopyrroiate, hyoscyamine, ipratropium, orphenadrine, oxitropium, oxybutynin, pirenzepine, procychdine, scopolamine (hyoscine), solifenacin, tolterodine, tiotropium, trihexyphenidyl, tropicamide, tricyclic antidepressants, and analogs, derivatives and salts thereof;

antagonists of Mas-related G-protein coupled receptors (Mrgpr), including but not limited to MrgprA3 antagonists, MrgprC l l antagonists, MrgprD antagonists, MrgprXl antagonists (e.g., 2-diphenylmethyl-3-substituted azabicyclo-octanes disclosed in P Kunapuli et a!., Anal.

Biochem ., 351:50-61 (2006)}, MrgprX2 antagonists (e.g., Gln-Trp-Phe, Gln-Trp-Phe-NFL·, Ac- Gln-Trp-Phe-Nth, Gln-D-Trp(formyl)-Phe benzyl ester, Boc-Gln-D-Trp(formyl)-Phe benzyl ester [all of the QWF-based peptides also antagonize NK-1]), and analogs, derivatives and salts thereof;

antagonists of protease -activated receptors (PARs) and inhibitors of activating proteases, including but not limited to PAR! antagonists (e.g , SCH-530, 348), PAR2 antagonists {e.g., AY- 117, ENMD-1068, ENMD-106836, GB-83, GB-88, tetracyclines (e.g., doxycycline, minocycline and tetracycline), FSLLRY -NH . (PAR-3888-Pi), Ac-FSLLRY -NH₂ and anti-PAR2 antibodies (e.g , SAM-11 [SC-13504], P2pal-2l and P2pal-2135)}, PAR4 antagonists (e.g, ethanol, YD-3, statins (e.g , atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin), pepducin P4 pal- 10, pepducin P4 pal- 15, trans-cinnamoyl- APGKF-NFh, trans-cinnamoyl-YPGKF-NEb, and anti-PAR4 antibodies (e.g., C-19 and SC- 1249)}, inhibitors of serine proteases {e.g., benzamidine hydrochloride, 4-iodo-l- benzothiophene-2-carboximidamide hydrochloride (inhibits trypsin and tryptase), inhibitors of kallikrems (e.g., carnosiai, nafamostai, gabexate, ecallantide and Cl -inhibitor), trypsin inhibitors (e.g , BCX-1470, tosyllysine chloromethy! ketone [TLCK] hydrochloride, ai-antitrypsin, aprotinin, ovomucin and soybean trypsin inhibitor), and tryptase inhibitors (e.g , camostat, nafamostai, gabexate, AMG-126737 and APC-366)}, inhibitors of cysteine proteases (e.g., E-64 (non-specific inhibitor), JNJ-10329670, RWJ-445380, cystatin C, leupeptin, stefin A, stefin B, testican-l, fluoromethyl ketone, naphthalene endoperoxide (inhibits cathepsin B, L and S), CA- 074 (inhibits cathepsin B), odanacatib (MK-0822, inhibits cathepsin K), CLIK-148 and CLIK- 195 (both inhibit cathepsin L), and CLIK-60 and E-6438 (both inhibit cathepsin S)}, and analogs, derivatives, fragments and salts thereof:

antagonists of endothelin receptors, including but not limited to selective endothelin A receptor (ETAR) antagonists {e.g , ambrisentao, atrasentan, sitaxexitaxi, zibotentan, BQ-123, 4- amino~

ETAR/ETBR antagonists (e.g., bosentan, macitentan and tezosentan), and analogs, derivatives and salts thereof;

inhibitors of Toll-like receptors (TLRs), including but not limited to TLR3 antagonists {e.g., compound 4a in K. Cheng el al., J. Am. Chem. Soc ., 133:3764-3767 (2011), and anti-TLR3 antibodies and fragments thereof disclosed in US Pat. 8, 153,583 and US Pub. 2017/0058041 }, TLR4 antagonists (e.g., eritoram, amitriptyline, cyelobenzaprine, ketotifen, imipramine, mianserin, (+)-naloxone, (+) -naltrexone, ibudilast, pinocembrin and propentofylline), TLR7/non- TLR9 inhibitors (e.g., ODN 2087, ODN 20958 and ODN 20959), dual TLR7/TLR9 inhibitors (e.g., hydroxychloroquine, quinacrine, AT791, DV056, E6446, GMO-3100, IMO-8400 and ODN 2088), and analogs, derivatives, fragments and salts thereof;

agomsts of cannabinoid receptors (e.g., CB1 and CB2), including but not limited to CB2 agonists (e.g., anandamide [N-arachidonoylethano!amine], 2-arachidonoylglycerol, 2-arachidonyl glyceryl ether, virodliamine [O-arachidonoylethanolamine], palmitoylethanolamide [PEA, N- palmitoyletlianoiamine], tetrahydrocannabinol, b-caryophyllene, minocycline, AM-1221, AM- 1235, AM-1241, AM-2232, GW-405833, GW-833972A, HU-308, JWH-007, JWH-015, JWH- 018, JWH-133, L-759633, L-759656, S-777469 and UR-144), and analogs, derivatives and salts thereof;

fatty acid amide hydrolase (FAAH) inhibitors, including but not limited to ARN2508, BMS-469908, CAY-10402, JNJ-245, JNJ-1661010, JNJ-28833155, JNJ-40413269, JNJ- 421 19779, JNJ-42165279, LY-2183240, MK-3168, MK-4409, MM-433593, OL-92, OL-135, PF-622, PF-750, PF-3845, PF-04457845, PF-04862853, RN-450, SA-47, SA-73, SSR-41 1298, ST-4068, TK-25, URB524, URB597 (KDS-4103), URB694, URB937, VER-156084, V-158866, and analogs, derivatives and salts thereof;

inhibitors of mitogen-activated protein (MAP) kinases, including but not limited to p38

inhibitors of mitogen-activated protein kinase kinases (MEKs), including but not limited to MEK1 inhibitors

inhibitors of calcitonin gene-related peptide (CGRP) or receptor therefor or the production thereof, including but not limited to CGRP receptor antagonists (e.g., oieegepaut ie!cagepant, ubrogepant, eptinezumab [ALD-403], AMG-334, LY -2951742, TEV-48125 and compounds of Formula I disclosed in WO 2007/146349 .42), and analogs, derivatives, fragments and salts thereof;

inhibitors of nerve growth factor (NGF) or receptors therefor (e.g., tropomyosin kinase receptor A [TrkA]) or the production thereof, including but not limited to NGF inhibitors (e.g., !uiraniunab and tanezumab), TrkA inhibitors (e.g., AG879, CT327 and K252a), and analogs, derivatives, fragments and salts thereof;

inhibitors of neurotensin or receptors therefor (e.g., neurotensin receptor 1 [NTSR1], NTSR2 and sortilin 1) or the production thereof, including but not limited to selective NTSRi antagonists (e.g., SR-48,692), selective NTSR2 antagonists (e.g., levocabastine), unselective receptor antagonists (e.g., SR-142,948), and analogs, derivatives and salts thereof;

inhibitors of somatostatin or receptors therefor (e.g., somatostatin receptors [SSTRs] 1 to 5) or the production thereof, including but not limited to selective SSTR2 antagonists (e.g., CYN 154806), selective SSTR5 antagonists (e.g., BIM 23056), unselective SSTR antagonists (e.g., cyclosomatostatin), and analogs, derivatives, fragments and salts thereof;

inhibitors of vasoactive intestinal peptide (VIP) or receptors therefor (e.g., VIPR1 and VIPR2) or the production thereof, including but not limited to VIP receptor antagonists {e.g., PG

derivatives, fragments and salts thereof;

inhibitors of bradykinin or receptors therefor (e g., B2) or the production thereof, including but not limited to bradykinin inhibitors (e.g , aloe, bromelain and polyphenols), bradykinin receptor B2 antagonists (e.g., icaiibant, FR-173657 and D-Arg-JFlyp³, Thrfo D-Phe⁷]- bradykimn), inhibitors ofkallikreins (e.g., ecallantide, camostat, nafamostat, gabexate and Cl- inhibitor), and analogs, derivatives and salts thereof;

inhibitors of platelet-activating factor (PAF) or the receptor therefor (PAFR) or the production thereof, including but not limited to PAFR antagonists (e.g., apafant, israpafant, lexipafanc, modipafant, mpatadine, CV-3988 and SM-12502). and analogs, derivatives and salts thereof; inhibitors of corticotropin-releasing hormone (CRH, aka corticoliberin) or receptors therefor (e.g., CRHR1 and CRHR2) or the production thereof, including but not limited to CRHR1 antagonists (e.g , antalarmin, pexacerfont, CP-154,526 LWH-234, NBI-27914 and R- 121,919), CRHR2 antagonists (e.g., astressin-B), and analogs, derivatives and salts thereof; inhibitors of phospholipase A2 (e.g., secreted and cytosolic PLA2), including but not limited to glucocorticoids, arachidonyl trifluoromethyi ketone, bromoenol lactone, cytidine 5- diphosphoaniines, darapladib, qumacrine, vitamin E, RO-061606, ZPL-521 , lipocortins

(annexins, such as annexin Al), annexin mimetic peptides (e.g., annexin At mimetics [e.g , Ac2- 26 and CGEN-855A]), and analogs, derivatives, fragments and salts thereof;

inhibitors of pro-inflammatory prostaglandins (e.g., prostaglandin E2) or receptors therefor (e.g., EP3) or the production thereof, including but not limited to cyclooxygenase (COX) inhibitors {e.g., NSAIDs (inhibit COX-1 or/and COX-2), glucocorticoids (inhibit COX activity and expression), omega-3 fatty acids (e.g., docosahexaenoic acid [DHA], docosapentaenoic acid [DPA], eicosapentaenoic acid [EPA], a-linolenic acid [ALA], and fish oil [which contains, e.g., DHA and EPA]) and esters (e.g., glyceryl and ethyl esters) thereof, curcuminoids (e.g., curcumin), stilbenoids (e.g., resveratrol, which inhibits COX-1 and -2 activity and expression), and vitamin E and analogs thereof (e.g., a-tocopherol and trolox)}, cyclopentenone

prostaglandins (e.g., prostaglandin J2 [PGJ2], A12-PGJ2 and 15-deoxy-A12,14-PGJ2), hydroxyeinnamic acids and esters thereof (e.g., ethyl caffeate, which suppresses COX-2 expression), triterpenoids (e.g , oleanolic acid analogs [infra, such as TP -225], which suppress COX-2 expression), and analogs, derivatives and salts thereof;

inhibitors of ieukotrienes (e.g , LTB4) or receptors therefor or the production thereof, including but not limited to cysteinyl leukotriene receptor 1 (cysLTRl) antagonists (e.g., cinalukast, gemilukast [dual cysLTRl/cysLTR2 antagonist], iralukast, montelukast, pranlukast, tomelukast, verlukast, zafirlukast, CP-195494, CP-199330, ICI-198615, MK-571 and lipoxins [e.g., LXA4 and I5-epi-LXA4]), cysLTR2 antagonists (e.g., HAMI-3379), LTB4 receptor (e.g., BLT1 or/and BLT2) antagonists (e.g., etalocib), 5 -lipoxygenase (5-LOX) inhibitors (e.g., baicalein, cafteic acid, curcumin, hyperform, g-lmoienic acid [GLA], meclofenamic acid, meciofenamate sodium, minocycline, zileuton, MK-886, and omega-3 fatty acids and esters thereof), immunomodulatoiy xanthine derivatives, and analogs, derivatives and salts thereof; mast cell stabilizers, including but not limited to cromoglicic acid (cromolyn), ketotifen, methylxanthines, nedocromil, nicotinamide, olopatadine, omalizumab, pemirolast, quercetin, b₂- adrenoreceptor agonists {including short-acting pi-adrenergic agonists (e.g., bitolterol, fenoterol, isoprenaline [isoproterenol], levosalbutamoi [levalbuterol], orciprenaiine [metaproterenoi], pirbuterol, procaterol, ritodrine, salbutamol [albuterol] and terbutaline), long-acting B.-adrencrgic agonists (e.g , arformoterol, bambuterol, clenbuterol, formoterol and salmeterol), and ultralong- acting Pr-adrenergic agonists (e.g., carmoterol, indacaterol, milveterol, olodaterol and vilanterol)}, zinc sulfate, and analogs, derivatives and salts thereof;

Janus kinase (JAK) inhibitors, including but not limited to JAK1 inhibitors (e.g., itacitinib, GLPG0634 and GSK2586184), JAK2 inhibitors (e.g., lestaurtimb, pacritinib, CYT387, TG101348, SOCSi mimetics \infro\ and SOCS3 mimetics), JAK3 inhibitors (e.g., ASP-015K, R348 and VX-509), dual JAK1/JAK2 inhibitors (e.g., baricitinih and ruxolitinib), dual

JAK1/JAK3 inhibitors (e.g., tofacitinib), triple JAK1/JAK2/JAK3 inhibitors (e.g, odacitmib), and analogs, derivatives and salts thereof:

immunomodulators, including but not limited to imides (e.g , thalidomide, lenalidomide, pomalidomide and apremilast), xanthine derivatives (e.g., lisofylline, pentoxifylline and propentofylline), and analogs, derivatives and salts thereof;

immunosuppressants, including but not limited to IFN-b, TNF-a inhibitors, fiimaric acid esters (e.g., dimethylfumarate and monoethylfumarate), glucocorticoids, antimetabolites (e.g., hydroxyurea [hydroxy carbamide], antifolates [e.g., methotrexate], and purine analogs [e.g., azathioprine, mercaptopurine and thioguanine]), pyrimidine synthesis inhibitors (e.g., leflunomide and teriflunoinide), calcineurin inhibitors (e.g., ciclosporin [cyclosporine A], pimecrolimus and tacrolimus), inosine-5 '-monophosphate dehydrogenase (IMPDH) inhibitors (e.g., mycophenolic acid and derivatives thereof [e.g., mycophenolate sodium and

mycophenolate mofetil]), mechanists c/maminalian target of rapamycin (mTOR) inhibitors (e.g., rapamycin [sirolimus], deforolimus [ridaforolimus], everolimus, temsirolimus, umirolimus

[biolimus A9[, zotarolimus and RTP-801), modulators of sphmgosine-1 -phosphate receptors (e.g., S1PR1) (e.g., fingolimod), serine C -palmitoyltransferase inhibitors (e.g., myriocin), inhibitors of the activation of CD4⁺ and CD8⁺ T cells (e.g., alefacept), and analogs, derivatives and salts thereof;

eorticosteroids/glucocorticoids, including but not limited to hydrocortisone types (e.g., cortisone and derivatives thereof [e.g., cortisone acetate], hydrocortisone and derivatives thereof [e.g., hydrocortisone acetate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, hydrocortisone-17-butyrate and hydrocortisone- i 7-valerate], prednisolone, methy!prednisolone and derivatives thereof [e.g., methylprednisolone aceponate], prednisone, and tixocortol and derivatives thereof [e.g., tixocortol pivalate]), betamethasone types (e.g., betamethasone and derivatives thereof [e.g., betamethasone dipropionate, betamethasone sodium phosphate and betamethasone valerate], dexamethasone and derivatives thereof [e.g., dexamethasone sodium phosphate], and iiuoeortolone and derivatives thereof [e.g., iiuoeortolone caproate and fluocortolone pivalate]), halogenated steroids (e.g., alciometasone and derivatives thereof [e.g., alelometasone dipropionate], beclometasone and derivatives thereof [e.g., beclometasone dipropionate], clobetasol and derivatives thereof [e.g., cl obetasol- 17-propionate], clobetasone and derivatives thereof [e.g., clobetasone-17-butyrate], desoximetasone and derivatives thereof [e.g., desoximetasone acetate], difiorasone and derivatives thereof [e.g., difiorasone diacetate], diflucortolone and derivatives thereof [e.g., dif!ucortolone valerate], f!uprednidene and derivatives thereof [e.g., fluprednidene acetate], fluticasone and derivatives thereof [e.g., fluticasone propionate], halobetasol [ulobetasol ] and derivatives thereof [e.g., halobetasol proprionate], halometasone and derivatives thereof [e.g., halometasone acetate], and mometasone and derivatives thereof [e.g., mometasone furcate]), acetonides and related substances (e.g., amcinonide, budesonide, cidesonide, desonide, fluocinonide, fluocinolone acetonide, flurandrenolide [ flurandrenolone or fludroxy collide], haicinonide, triamcinolone acetonide and triamcinolone alcohol), carbonates (e.g., prednicarbate), and analogs, derivatives and salts thereof;

inhibitors of pro-inflammatory cytokines or receptors therefor, including but not limited to inhibitors of (e.g., antibodies or fragments thereof targeting) tumor necrosis factor-alpha (TNF-a) (e.g., adalimumab, certohzumab pegol, golimumab, infliximab, etanercept, bupropion, curcumm, catechms and ART-621) or the receptor therefor (TNFR1), inhibitors of thymic stromal lymphopoietin (e.g., anti-TSLP antibodies and fragments thereof [e.g., tezepeiumab and M702] and immunoconjugates comprising the extracellular domain of TSLPR) or the receptor therefor (TSLPR, aka cytokine receptor-like factor 2 [CRLF2]), inhibitors of (e.g., antibodies or fragments thereof targeting) pro-inflammatory interferons (e.g., interferon-alpha [IFN-aj) or receptors therefor, inhibitors of (e.g., antibodies or fragments thereof targeting) pro-inflammatory interleukins or receptors therefor {e.g., IL-i (e.g., IL-ia and IC-Ib [e.g., canakinumah and rilonacept]) or IL-1R (e.g., anakinra and isunakinra [EBI-005]), IL-2 or IL-2R (e.g., basiliximab and daclizumab), IL-4 or IL-4R (e.g., dupilumab), IL-5 (e.g., rnepolizumab and reslizumab) or IL-5R, IL-6 (e.g., clazakizumab, elsihmomab, olokizumab, siltuximab and sirakumab) or IL-6R (e.g., sarilumab and tocilizumab), IL-8 or IL-8R, IL-12 (e.g., briakinumab and ustekinumab) or IL-12R, IL-13 or IL-13R, IL-15 or IL-15R, IL-17 (e.g., ixekizumab and secukinumab) or IL-17R (e.g., brodalumab), IL-18 (e.g., GSK1070806) or 1L-18R, IL-20 (e.g., the antibody 7E) or 1L- 20R, IL-22 (e.g., fezakinumab) or IL-22R, IL-23 (e.g., briakinumab, guselkumab, nsankizumab. tildrakizumab [SCH-900222], ustekinumab and BI-655066) or IL-23R, IL-31 (e.g.. anti-11,-31 antibodies disclosed in US Pat. 9,822,177) or IL-31R (e.g., anti-IL-31 receptor A antibodies such as nemolizumab), IL-33 or IL-33R, and 1L-36 or IL-36R}, and analogs, derivatives, fragments and salts thereof;

inhibitors of the production of pro-inflammatory cytokines or receptors therefor, including but not limited to inhibitors of the production of TNF-a {e.g., hydroxychloroquine sulfasalazine, mesalazine (5-aminosalicylic acid), /V-acetyl-L-cysteine, S-adenosyl-L-methionine, L-camitine, melatonin, parthenolide, taurine, flavonoids (e.g., epigallocatechin-3-gallate

[EGCG], naringenin and quercetin), omega-3 fatty acids and esters thereof, glucocorticoids, immunomodulatory imides and xanthine derivatives, PDE4 inhibitors, p38 MAP kinase inhibitors, inhibitors of TLRs such as TLR7 and TLR9, serine protease inhibitors (e.g., gabexate and nafamostat), prostacyclin and analogs thereof (e.g., ataprost, beraprost [e.g., esuberaprost], carbacyclin, isocarbacyclin, ciprostene, eptaloprost, cicaprost, iloprost, taprostene, treprostinil and 5,6,7-trinor-4,8-inter-m-phenylene-9-fluoro-PGI2), SOCS1 mimetics, myxoma virus MO 13 protein, Yersinia YopM protein, apolipoprotein .4-1 (apoA-I) mimetic peptides (e.g., 4F), and apoE mimetic peptides (e.g., AEM-28 and hEp)}, IFN-a (e.g., alefacept and inhibitors of TLRs such as TLR7 and TLR9), IL-1 (e.g., IL-1 a and II,- 1 p) (e.g., hydroxychloroquine, nafamostat. sulfasalazine, mesalazine, prostacyclin and analogs thereof! glucocorticoids, TNF-a inhibitors, inhibitors of TLRs such as TLR7 and TLR9, PARI antagonists, MO 13 protein, YopM protein and apoA-I mimetics [e.g., 4F]), IL-1 [3 (e.g. melatonin, metformin, rotenone, flavonoids [e.g., EGCG and naringenin], annexin A1 mimetics, and caspase-1 inhibitors [e.g., belnacasan, pralnacasan and parthenolide]). IL-2 (e.g., glucocorticoids, calcineurin inhibitors and PDE4 inhibitors), IL-4 (e.g., glucocorticoids and serine protease inhibitors [e.g., gabexate and nafamostat]), IL-5 (e.g., glucocorticoids), 1L-6 (e.g., nafamostat, parthenolide, prostacyclin and analogs thereof, tranilast, L-camitine, taurine, flavonoids [e.g., EGCG, naringenin and quercetin], omega-3 fatty acids and esters thereof, glucocorticoids, immunomodulatory imides, TNF-a inhibitors, inhibitors of TLRs such as TLR7 and TLR9, M013 protein and apoE mimetics [e.g., AEM-28 and hEp]), IL-8 (e.g., alefacept glucocorticoids and PAR2 antagonists [e.g., tetracyclines]), IL-12 (e.g., apilimod, PDE4 inhibitors, inhibitors of TLRs such as TLR7 and TLR9, and YopM protein), IL-15 (e.g., YopM protein), IL-17 (e.g., protein kinase C [PKC] inhibitors such as sotrastaurin), IL-18 (e.g., M013 protein, YopM protein and caspase-1 inhibitors), and IL-23 (e.g., apilimod, alefacept and PDE4 inhibitors), and analogs, derivatives, fragments and salts thereof;

inhibitors of pro-inflammatory transcription factors or tire activation of expression thereof, including but not limited to inhibitors of NF-KB or the activation of expression thereof (e.g., aliskiren, melatonin, minocycline and parthenolide (both inhibit NF-kB nuclear translocation), nafamostat (-)-DHMEQ, IT-603, IT-901, PBS-1086, omega-3 fatty acids and esters thereof, f!avonoids (e.g., EGCG and quercetin), hydroxy cinnamic acids and esters thereof (e.g., ethyl caffeate), lipoxins (e.g., 15-epi-LXA4 and LXB4), stilbenoids (e.g., resveratrol), statins (e.g., rosuvastatin), triterpenoids (e.g., oleanolic acid analogs [infra, such as TP -225]), NGF inhibitors, TNF-a inhibitors, activators of sirtuin 1 (SIRT1, which inhibits NF-kB) (e.g., flavones [e.g., luteolin], phenylethanoids [e.g., tyrosol, which induces SIRT1 expression], stilbenoids [e.g., resveratrol, which increases SIRT1 activity and expression] and lamin A), M013 protein, penetratin, and apoE mimetics (e.g., AEM-28)}, inhibitors of STAT (signal transducer and activator of transcription) proteins or the activation of expression thereof (e.g., JAK1 , JAK2 and JAK3 inhibi tors, suppressor of cytokine signaling (SOCS) mimetic peptides (e.g., SOCSl mimetics [e.g., SOCSI -KIR, NewSOCSI-KIR, PS-5 and Tkipj and SOCS3 mimetics), iiydroxycinnamic acids and esters thereof (e.g., rosmarinic acid), and lipoxins (e.g., 15-epi-LXA4 and LXB4)}, and analogs, derivatives, fragments and salts thereof;

other kinds of anti-inflammatory agents, including but not limited to antagonists of the prostaglandin D2 receptor (DPI) or/and the chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) (e.g., TS-022 and compounds of Formula I disclosed in WO 2008/012511 Al), phosphodiesterase (PDE) inhibitors (e.g., PDE4 inhibitors such as apremilast, cilomiiast, ibudiiast, piclamiiast, roflumilast, atizoram, crisaboroie, diazepam, luteolin, mesembrenone, rolipram, eipamfyliine, theophylline, E6005 and RO 20-1724), IgE inhibitors (e.g., anti-TgE antibodies such as omahzumab), myeloperoxidase inhibitors (e.g., dapsone), inhibitors of the complement system or components thereof (e.g., inhibitors of C3 [the converging protein of all three complement activation pathways], such as CB-2782, compstatin and analogs and derivatives thereof [e.g., AMY-101 , APL-1, APL-2, Cp40 and POT-4], neurotropin, and mycophenolic acid-glucosamine conjugates [downregulate C3]), specialized pro-resolving mediators (SPMs) {e.g., metabolites of polyunsaturated fatty acids (PUFAs) such as lipoxins (including LXA4, 15-epi-LXA4, LXB4 and 15-epi-LXB4), resolvins (including resolvins derived from 5Z,8Z,l lZ,i4Z,17Z-eicosapentaenoic acid [EPA], resolvins derived from 4Z,7Z,lOZ,13Z,16Z,19Z-docosahexaenoic acid [DHA], and resolvins derived from

7Z,lOZ,13Z,16Z,l9Z-docosahexaenoic acid [n-3 DPA]), protectins/neuroprotectins (including DHA-derived protectins/neuroprotectins and n-3 DPA-derived protectins/neuroprotectins), maresms (including DHA-derived mare sins and n-3 DPA-derived maresms), n-3 DPA metabolites, n-6 DPA (4Z,7Z,iOZ,13Z,16Z~docosapentaemoie acid) metabolites, oxo-DHA metabolites, oxo-DPA metabolites, docosahexaenoyl ethanol amide metabolites, cyclopentenone prostaglandins (e.g., A12-PGJ2 and 15-deoxy-A12,14-PGJ2), and cyclopentenone isoprostanes (e g . 5,6-epoxyisoprostane A2 and 5,6-epoxyisoprostane E2)}, triterpenoids {e.g , oleanolic acid analogs such as TP-151 (CDDO), TP-155 (CDDO methyl ester), TP-190, TP-218, TP-222, TP- 223 (CDDO carboxamide), TP-224 (CDDO monomethylamide), TP-225, TP-226 (CDDO dimethylamide), TP-230, TP-235 (CDDO imidazolide), TP-241, CDDO monoethylamide,

CDDO mono(trifluoroethyl)amide, and (+)-TBE-B}, disease-modifying antirheumatic drags (DMARDs, e.g., leflunomide, sulfasalazine and mesalazine), anti-allergic agents (e.g., antihistamines, leukotriene antagonists, mast cell stabilizers, glucocorticoids, epinephrine

[adrenaline] and tranilast), ultraviolet radiation (e.g., ultraviolet A and B), and analogs, derivatives, fragments and salts thereof;

inhibitors of brain natriuretic peptide (BMP, aka natriuretic poly peptide B [XppB]) or the receptor therefor (atrial natriuretic peptide receptor [NprA]) or the production thereof, including but not limited to NprA antagonists (e.g., A71915, A74I 86 and HS-142-1 [a glucose-caproic acid polymer]), and analogs, derivatives and salts thereof;

inhibitors of gastrin-releasing peptide (GRP) or the receptor therefor (GRPR, aka bombesin receptor 2 [BBR2]) or the production thereof, including but not limited to GRPR antagonists {e.g., ATBBN, MATBBN, PD-176252, RC-3095, [D-Phe⁶]bombesin(6-14) methyl ester, and [D-Phe⁶-Sta^!3-Leuⁱ⁴-NH₂]bonibesin(6-14)}, and analogs, derivatives and salts thereof; inhibitors of neuromedin B (NMB) or the receptor therefor (NMBR, aka bombesin receptor 1 [BBR1]) or the production thereof, including but not limited to NMBR antagonists (e.g , BIM-23042, BIM-23127, PD-165929, PD-168368, PD-176252 and D-Nal-Cys-Tyr-D-Trp- Lys-Val-Cys-Nal-NIT), and analogs, derivatives and salts thereof;

inhibitors of glutamate or receptors therefor (e.g., AMPA, kainate and NMDAR) or the production thereof, including but not limited to AMPA antagonists (e.g., becampanel, fanapanel [MPQX], perampanel and zonampanel), dual AMPA/kainate antagonists (e.g., cyanquixaline [CNQXj, dasolampanel, 6,7-dinitroquinoxaline-2,3-dione [DNQX], kynurenic acid, NBQX, selurampanel, tezampanel and L-theanine), uncompetitive antagonists (channel blockers) of NMDAR (e.g., memantine, nitromemantine, amantadine, lanicemine, neramexane,

dextrallorphan, dextromethorphan [DXM], dextrorphan [metabolite of DXM] and procyclidine), and analogs, derivatives and salts thereof:

anticonvulsants, including but not limited to GABA analogs (e.g., gabapentin, pregabalin and vigabatrin), GABA-A receptor positive allosteric modulators (e.g., benzodiazepines [infra]), carbamazepine, tiagabine, topiramate, valproic acid and salts thereof (e.g., sodium valproate), and analogs, derivatives and salts thereof;

inhibitors of testicular nuclear receptor 4 (TR4) or the production thereof, including but not limited to TR4 -targeting siRNAs;

kappa-opioid receptor (KOR) agonists (e.g., selective KOR agonists), including but not limited to asimadolme, bremazocine, difelikefalin (CR845), dynorphin, enadoline, ketazocme, nalfurafine (TRK-820), salvinorin A, 2-methoxymethyl salvinorin B, 2-ethoxymethyl salvinorin B, 2-fluoroethoxymethyl salvinorin B, spiradoline, tifluadom, BRL-52537, CR665, FE 200665, GR-89696, HZ-2, ICl-199,441, ICl-204,448, LPK-26, SA- 14867, U-50488, U-69593, 2- phenylbenzothiazoline-type compounds, and analogs, derivatives and salts thereof;

mu-opioid receptor (MOR) antagonists, including but not limited to alvimopan, axelopran, bevenopran, butorphanol (mixed mu antagonist/kappa agonist), cyprodime, eptazocine, levallorphan (lorfan or naloxiphan, mixed mu antagonist/kappa agonist), methylnaltrexone, naldernedine, nalmefene, nalbuphine (mixed mu antagonist/kappa agonist), nalodeine (mixed mu antagonist/kappa agonist), nalorphine (lethidrone or naltine), naloxegol, naloxone, naloxol, naltrexone (e.g., naltrexone 1% cream), 6p-naltrexol, pentazocine (mixed mu antagonist/kappa agonist), samidorphan, SK-1405, and analogs, derivatives and salts thereof; antidepressants, including but not limited to tricyclic antidepressants (e.g., amitriptyline, amitriptylinoxide, amoxapime, clomipramine, desipramine, dosulepin [dothiepin], doxepin, cidoxepin, imipramine, melitracen and nortriptyline), tetracyclic antidepressants (e.g., amoxapine, maprotiline, mazindol, mianserin, mirtazapine, esmirtazapine and setiptiline), selective serotonin reuptake inhibitors (SSRIs, e.g., citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and S-41744), serotonin-norepinephrine reuptake inhibitors (SNRJs, e.g., bicifadine, doxepin, cidoxepin, duloxetine, rnilnacipran, levomilnacipran, sibutramine, venlafaxine, desvenlafaxine and SEP-227162), inhibitors of monoamine oxidases (MAQs) {e.g., selective MAO-A inhibitors (e.g., bifemelane, moclobemide, pirlindole [pirazidol] and toloxatone), selective MAO-B inhibitors (e.g., rasagiline and selegiline), and non-selective MAO-A/MAO-B inhibitors (e.g., hydracarbazine, isocarboxazid, nialamide, phenelzine and tranylcypromine)}, and analogs, derivatives and salts thereof;

anti-anxiety agents (anxiolytics or minor tranquilizers), including but not limited to benzodiazepines (e.g., alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, midazolam, oxazepam, temazepam and triazolam), antidepressants (including tricyclic antidepressants [e.g., amitriptyline, desipramine, imipramine and nortriptyline], tetracyclic antidepressants [e.g., mirtazapine], SSRIs [e.g., fluoxetine, fluvoxamine and paroxetine], SNRIs [e.g., duloxetine and venlafaxine], and MAOIs [e.g., isocarboxazid, moclobemide, phenelzine and tranylcypromine]), first-generation HI antihistamines (e.g., hydroxyzine), anticonvulsants (e.g., pregabalin), and analogs, derivatives and salts thereof;

counterirritants and cooling agents, including but not limited to capsaicinoids (e.g., capsaicin, homocapsaicin, dihydrocapsaicin, homodihydrocapsaicm, nordihydroeapsaicim and nonivamide [pelargonie acid varhllylamidej), camphor, eucalyptol, icilin, isopulegol, mint oil (e.g., Japanese mint [. Mentha arvensis ] oil, peppermint oil and spearmint oil), menthol (e.g., menthol 1-3% cream), menthone, menthone glycerol ketal, menthy! lactate, menthyl succinate, methyl salicylate, phenol (e.g., in calamine cream and lotion), trimethylcyclohexanol, WS-23, local anesthetics, and analogs, derivatives and salts thereof;

local anesthetics, including but not limited to amides (e.g., articaine, bupivacaine, cinchocaine [dibucaine], etidocaine, levobupivacaine, lidocaine [e.g., lidocaine 2.5-5% cream], triethylaminolidocame [QX-314], prilocaine [e.g., pnlocaine 2.5% cream], EMLA [lidocaine 2.5%/prilocaine 2.5% cream], mepivacaine, ropivacaine and trimecaine), esters (e.g., benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine [larocaine], piperocame, procaine

[novocaine], proparacaine, propoxycaine, stovaine and tetracaine [amethocaine]), ethers (e.g., mexiletme, polidocanol [e.g., polidocanol 3% foam] and pramocaine [pramoxine] [e.g., pramoxine 1% cream]), naturally derived local anesthetics (e.g., cocaine, eugenol, menthol, saxitoxin, neosaxitoxin and tetrodotoxin), and analogs, derivatives and salts thereof;

moisturizers and emollients, including but not limited to aqueous moisturizers, low pH moisturizers containing an acid (e.g., lactic acid), and moisturizers containing a humectant that attracts and retains water (e.g., glycerol, sorbitol, lactate, urea, heparinoids, hyaluronic acid and salts thereof, and honey), an occlusive that prevents evaporation {e.g., oils (e.g., mineral oil and silicone oil [e.g., dimethicone]) and petroleum jelly (petrolatum)}, or/and an emollient that provides partial hydration and occlusion (e.g., oils, waxes [e.g., lanolin and paraffin], lipids [e.g., phospholipids, ceramides, triglycerides, glycol stearate, glyceryl stearate, fatty acids and squalene], and sterols [e.g., cholesterol and phytosterol]), and analogs, derivatives and salts thereof; and

other lands of antipruritic agents, including but not limited to a!lantom (e.g., 6% ai!anioin cream in SD-101), NST-141, S-adenosyl methionine, botulinum toxin (e.g., botulinum toxin types A and B, which inhibit release of acetylcholine from presynaptic nerve terminals), vitamin D (e.g., vitamin Di and vitamin Di) and analogs and derivatives thereof (e.g., calcitriol, calcipotriol [calcipotriene], paricaicitol and 1,25-dihydroxyergocaiciferol), inhibitors of lysophosphatidie acid (LPA) or receptors therefor (e.g., LPARl and 3) or the production thereof (e.g., autotaxin inhibitors such as GLPG1690, HA 130, ONO-8430506, PF 8380, S 32826 and anti-autotaxin DNA aptamers [e.g., RB011 and RB014]), bile acid absorption-reducing, ileal bile acid transporter-inhibiting or bile acid-sequestering agents (e.g., colesevelam, colestipol, colextran, and anion-exchange resins [e.g., cholestyramine and colestilan]), cholesterol absoiption-reducing or gallstone-dissolving agents (e.g., ursodeoxycholic acid [ursodiol]), antagonists of G protein-coupled bile acid receptor 1 (GPBAR1, aka TGR5), antimicrobials (including antibiotics, antifungals, antivirals and amtiparasitics, such as crotamiton and rifampin [rifampicin]), ultraviolet (e.g., ultraviolet A [UVA] and ultraviolet B [UYB]) phototherapy, laser therapy, transcutaneous electrical nerve stimulation and the like (e.g., transcutaneous electrical acupoint stimulation), acupuncture (using, e.g., electric needles) and the like (e.g., acupressure and auricular acupressure optionally with Vaccaria seed), massage, therapeutic agents that treat the underlying causes of the pruritus-associated conditions, and analogs, derivatives, fragments and salts thereof.

[0153] Non-steroidal anti-inflammatory drugs (NSAIDs) include without limitation:

acetic acid derivatives, such as aceciofenac, bromfenac, diclofenac, etodolac, indomethacin, ketorolac, nabumetone, suiindae, su!indac sulfide, sulindac sulfone and tolmetin; anthranilic acid derivatives (fenamates), such as flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid; enolic acid derivatives (oxicams), such as droxicam, isoxicam, lornoxicam, meloxicam, piroxicam and tenoxicam;

propionic acid derivatives, such as fenoprofen, flurbiprofen, ibuprofen, dexibuprofen, ketoprofen, dexketoprofen, loxoprofen, naproxen and oxaprozin;

salicylates, such as diflunisal, salicylic acid, acetylsalicyhc acid (aspirin), choline magnesium trisalicylate, salsalate and mesalazine;

COX-2-selective inhibitors, such as apricoxib, celecoxib, etoricoxib, firocoxib, fluorocoxibs (e.g., fluorocoxibs A-C), lumiracoxib, mavacoxib, parecoxib, rofecoxib, tilmacoxib (JTE-522), valdecoxib, 4-O-methylhonokiol, mflunnc acid, DuP-697, CGI 00649, GW406381, NS-398, SC-58125, benzothieno[3,2-d]pyrimidin-4-one sulfonamide thio-derivatives, and COX- 2 inhibitors derived from Tribulus terrestns;

other kinds ofNSAIDs, such as monoterpenoids (e.g., eucalyptol and phenols [e.g., carvacrol]), anrlinopyridinecarboxylie acids (e.g., clonixin), sulfonanilides (e.g., nimesulide), and dual inhibitors of lipooxygenase (e.g., 5-LOX) and cyclooxygenase (e.g., COX-2) {e.g., chebulagic acid, licofelone, 2-(3,4,5-trimethoxyphenyl)-4-(N-methylindol-3-yl)thiophene, and di- ferf-butylphenol-based compounds (e.g., DTPBHZ, DTPINH, DTPNHZ and DTPSAL)}; and analogs, derivatives and salts thereof.

[0154] To relieve pruritus and to avoid or minimize drowsiness during the day, a non sedating antipruritic agent can be used. For example, second-generation and third-generation Hi antihistamines are designed to be non-sedating or mildly sedating and to affect primarily peripheral Hi histamine receptors. Non-limiting examples of second-generation and third- generation Hi antihistamines include acnvastine, astemizole, azelastine, bepotastine, bilastine, cetirizine, cidoxepin, levocetirizine, ebastine, fexofenadine, levocabastine, loratadine, desloratadine, mizolastine, olopatadine, quifenadine, rupatadine, terfenadme, and salts thereof.

[0155] A sedating antipruritic agent can also be used, such as at night for relief of pruritus during nighttime. In most types of chronic itch, itch usually becomes more intense during nighttime, particularly in the extremities and torso. Impairment or lack of sleep increases fatigue, stress and negative mood and reduces the ability to cope or concentrate, which in turn can lead to additional stress and exacerbate the itch cycle. Sleep relieves itch for many patients.

[0156] Accordingly, sedating first-generation Hi antihistamines that cross tire blood-brain bamer can be taken at night to aid with sleep and to decrease nighttime itch and scratching. Non-limiting examples of first-generation Hi antihistamines include antazoline, azatadine, brompheniramine, buclizine, bromodiphenhydramine (bromazine), carbinoxamine,

chioreyciizine, chloropyramine, chlorpromazine, cyclizine, chlorpheniramine,

chlorodiphenhydramine, clemastine, cyproheptadine, dexbrompheniramine,

dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxepin, doxylamine, embramme, esmirtazapine, hydroxyzine, ketotifen, meclozine (meclizine), mepyramine, mirtazapine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, quetiapine, trimeprazine, tripelennamine, triprolidine, and salts thereof

[0157] In addition to or alternative to a sedating antihistamine, a sedative can be taken at night to aid with sleep and to decrease nocturnal itch and scratching. Such a sedative can be, e.g., an antidepressant (e.g., a tricyclic antidepressant) or a tranquilizer A tranquilizer can be a minor tranquilizer (aka an anxiolytic) or a major tranquilizer (aka an antipsychotic or neuroleptic).

[0158] In some embodiments, a corticosteroid/glucocoiticoid of moderate or medium potency is used in combination with an NK-I antagonist (e.g., seriopitant) to treat chronic pruritus. Examples of corticosteroids/glueocorticoids having moderate or medium potency include Groups III, IV and V corticosteroids under the 7-group US classification system and Class II corticosteroids under the 4-class European classification sy stem:

Group III US (upper mid-strength), including but not limited to amcinonide 0.05-0 1% (e.g., Cyclocort® cream/lotion), betamethasone dipropionate 0.05% (e.g., Diprolene® ointment/cream and Diprosone® ointment/cream), betamethasone valerate 0.1% (e.g., ointment and Luxiq® foam), diflorasone diacetate 0.05% (e.g., Florone® cream and Maxiflor® cream), fiuocinonide 0.05% (e.g., Lidex-E® cream), fluticasone propionate 0.005% (e.g., Cutivate® ointment), halometasone 0.05% (e.g., cream), mometasone furcate 0.1% (e.g., Elocon® ointment), and triamcinolone acetonide 0.5% (e.g., Aristocort® cream and Kenalog® cream);

Group IV US (mid-strength), including but not limited to desoximetasone 0.05% (e.g., Topicort® LP ointment/cream), fiuocinolone acetonide 0.025-0.2% (e.g., Synalar® ointment and Synemol® cream), flurandrenolide 0.05% (e.g., Cordran® ointment), hydrocortisone butyrate 0.1 % (e.g., Locoid® ointment), hydrocortisone valerate 0.2% (e.g., Westcort® ointment), mometasone furoate 0.1% (e.g., Elocon® cream/lotion), and triamcinolone acetonide 0.1% (e.g., Aristoeort®⁾ A ointment and Kenalog® ointment/cream/spray); Group V US (lower mid-strength), including but not limited to betamethasone dipropionate 0.05% (e.g., Diprosone® lotion), betamethasone valerate 0.1% (e.g., Valisone® cream/lotion), desonide 0.05% (e.g., DesQwen® ointment and Tridesilon® ointment), fluocinolone acetonide 0.025/0.03% (e.g., Synalar® cream and Synemol® cream), fluocinolone acetonide 0.01 % (e.g., Synalar® cream), flurandrenolide 0.05% (e.g., Cordran®

cream/lotion/tape), fluticasone propionate 0.05% (e.g., Cutivate® cream/lotion), hydrocortisone butyrate 0.1% (e.g., Locoid® cream), hydrocortisone valerate 0.2% (e.g., Westcort® cream), prednicarbate 0.1 % (e.g., DermAtop® cream), and triamcinolone acetonide 0.1% (e.g., Kenalog® lotion); and

Class II EU (moderate), including but not limited to clobetasone butyrate 0.05% (e.g., Eumovate® cream), and triamcinolone acetonide 0.1-0.5% (e.g., Aristocort® ointment/cream, Kenacomb® ointment/cream, Kenalog® cream/spray and Viaderm® KC ointment/cream).

[0159] In other embodiments, a potent or very potent corticosteroid/glucocorticoid is used in combination with an NK-1 antagonist (e.g., serlopitant) to treat chronic pruritus. A potent or very potent topical corticosteroid can be used to treat, e.g., more severe or more resistant puritus or pruritus-associated conditions. Examples of potent or very potent corticosteroids/ glucocorticoids include Groups I and II corticosteroids under the 7-group US classification system and Classes III and IV corticosteroids under tire 4-class European classification system:

Group I US and Class IV EU (very' potent), including but not limited to betamethasone dipropionate 0.25% (e.g., Diprolene® ointment/cream, Diprosone® OV ointment/cream and Diprovate® cream), clobetasol propionate 0.05% (e.g., Clobex® lotion/spray, Cormax® cream/solution, Dermovate® ointment/cream, Exel® cream, Olux® foam and Temovate® ointment/cream/solution), desoximetasone 0.25% (e.g., Topicort® topical spray), diflorasone diacetate 0.05% (e.g., Psorcon® ointment), fluocinonide 0.1% (e.g., Vanos® cream), and halobetasol propionate 0.05% (e.g., Halox® lotion and Ultravate® ointment/cream/lotion); and

Group II US and Class III ELI (potent), including but not limited to amcinonide 0.05- 0.1% (e.g., Cyclocort® ointment), desoximetasone 0.25% (e.g., Topicort®⁾ ointment/cream and Topisolon® ointment/cream), desoximetasone 0.05% (e.g., Topicort® gel), diflorasone diacetate 0.05% (e.g., Florone® ointment, Maxiflor® ointment and Psorcon® cream), fluocinonide 0.05% (e.g., Index® ointment/cream/gel), ha!cinonide 0.05-0.1% (e.g., Halog® ointment/cream), and halometasone 0.05% (e.g., ointment). [0160] In still other embodiments, a corticosteroid/glucocorticoid of low potency is used in combination with an NK-1 antagonist (e.g., seriopitant) to treat chronic pruritus. A low-potency topical corticosteroid can be used to treat, e.g., mild to moderate puritus or pruritus-associated conditions, more sensitive skin areas (e.g., the face and the genital area), or young patients (e.g., infants and young children). Examples of low-potency corticosteroids/glucocoriicoids include Groups VI and VII corticosteroids under the 7-group US classification system and Class I corticosteroids under the 4-class European classification system:

Group VI US (low potency), including but not limited to aiclometasone dipropionate 0 05% (e.g., Aclovate® ointroent/cream), betamethasone valerate 0.1% (e.g., lotion), clocortolone pivalate 0.1% (e.g., Cloderm® cream), desonide 0.05% (e.g., Desonate® gel, Desowen® ointmeni/cream/lotion, Lokara® lotion and Verdeso® foam), fluocinolone acetonide 0.01% (e.g., Derma-Smoothe/FS oil and Synalar® cream), hydrocortisone butyrate 0.1% (e.g., Locoid® cream), and triamcinolone acetonide 0.025% (e.g., cream/lotion); and

Group VII US (lowest potency) and Class I EU (mild), including but not limited to hydrocortisone 0.5%/!%/2%/2.5% (e.g., Cetaeort® lotion, DermAid® cream, DP-HC lotion, Hytone® cream/lotion, MiCort-HC cream, Nutracort® lotion, Pimafucort® ointment/cream and Synacort® cream).

[0161] In certain embodiments, a very potent or potent topical corticosteroid is used continuously for no more than about 3, 2 or 1 week(s), or a topical corticosteroid of

moderate/medium or low potency is used continuously for no more than about 3, 2 or 1 month(s), to minimize potential side effects such as skin atrophy and impairment of epidermal barrier function. For example, a very potent topical corticosteroid can be applied daily (e.g., once daily) for about 3 consecutive days and then not applied for about 3 or 4 consecutive days, or a medium-potency topical corticosteroid can be applied daily (e.g., once daily) for about 1 month and then not applied for about 1 week, and the cycle can be repeated for the duration of the treatment regimen. The treatment regimen of the topical corticosteroid can be based on, e.g., the nature and severity of pruritus or the pruritus-associated condition, the bodily area(s) affected and the potency of the corticosteroid. If the pruritus or the condition is, e.g., more severe or more widespread, a corticosteroid can also be administered systemicaily (e.g., orally or parenterally) for a more rapid or more systemic action, although there may be a greater risk of side effects.

[0162] In some embodiments, an NK-1 antagonist (e.g., seriopitant) is used in combination with an inhibitor of BNP or the receptor therefor (NprA), an inhibitor of GRP or the receptor therefor (GRPR), an inhibitor of glutamate or a receptor therefor (e.g., AMP A, kainate or NMDAR), or a GABAergic agent, or any combination or ail thereof, to treat chrome pruritus. In further embodiments, an NK-1 antagonist (e.g., serlopitant) is used in combination with a TRPA1 antagonist or/and a TRPV! antagonist or desensitizer to treat chronic pruritus. In additional embodiments, an NK-1 antagonist (e.g., serlopitant) is used in combination with an Mrgpr (e.g., MrgprX2) antagonist, a PAR (e.g., PAR2) antagonist or a TLK (e.g., TLR3, TLR4 or TLR7) antagonist, or any combination or all thereof, to treat chronic pruritus.

[0163] In some embodiments, an NK-1 antagonist (e.g., serlopitant) is used in combination with a kappa-opioid receptor (KQR) agonist (e.g., nalfurafme), a mu-opioid receptor (MOR) antagonist (e.g., naltrexone or naloxone), an anticonvulsant (e.g , gabapentin or pregabalin), or an antidepressant (e.g., an SSRI such as paroxetine, fluvoxamine or sertraline, a tricyclic antidepressant such as doxepin or amitriptyline, or a tetracyclic antidepressant such as mirtazapine), or any combination or all thereof, to treat chronic pruritus. In further embodiments, an NK-1 antagonist (e.g., serlopitant) is used in combination with a corticosteroid/glucocorticoid (e.g., a topical corticosteroid of low to medium potency), an immunosuppressant (e.g., a topical calcmeurin inhibitor or systemic azathioprine), an immunomodulator (e.g., thalidomide), an inhibitor of an inflammatory cytokine (e.g., IL-31) or a receptor therefor (e.g., IL-3 ! R ).. or an Hi or Bi antihistamine, or any combination thereof, to treat chronic pruritus. In additional embodiments, an NK-1 antagonist (e.g., serlopitant) is used in combination with a topical counterirritant or/and cooling agent (e.g., capsaicin), a topical local anesthetic (e.g., pramoxine), a moisturizer or emollient, or UV phototherapy (e.g , NB-UVB, BB-UVB or PUVA), or any combination or all thereof, to treat chronic pruritus.

[0164] In certain embodiments, the additional antipruritic agent(s) comprise a kappa-opioid receptor (KOR) agonist (e.g., nalfurafme) for treatment of, e.g., chronic prurigo nodularis (PN)- related, uremic, ESRD-related, dialysis-related, cholestatic or paraneoplastic pruritus. In further embodiments, the additional antipruritic agent(s) comprise a mu-opioid receptor (MOR) antagonist (e.g., naltrexone, naloxone or nalmefene) for treatment of, e.g., chronic atopic dermatitis (AD)-related, PN-related, urticaria-related, postbum, dialysis-related, cholestatic, CTCL (e.g., mycosis fungoides)-related, opioid-induced, hydroxyethyl starch-induced or idiopathic pruritus. In still further embodiments, the additional antipruritic agent(s) comprise an anticonvulsant (e.g., gabapentin or pregabalin) for treatment of, e.g., chronic PN-related, uremic, CKD-related, dialysis-related, neuropathic, neurogenic or idiopathic pruritus. [0165] In other embodiments, the additional antipruritic agent(s) comprise an antidepressant (e.g., a tricyclic antidepressant such as doxepin, a tetracyclic antidepressant such as mirtazapine, or an SSRT such as paroxetine, sertraline or fluvoxamine), or/and a selective KOR agonist (e.g , nalfurafine), a selective MOR antagonist (e.g., naloxone or naltrexone) or a mixed KOR agonist/MOR antagonist (e.g., butorphanol or nalbuphine), for treatment of chronic pruritus associated with, e.g., CKD, ESRD, PBC, a cutaneous or systemic lymphoma, or a carcinoma. In still other embodiments, the additional antipruritic agent(s) comprise an immumomoduiator (e.g., thalidomide) for treatment of, e.g , chronic PN-related, uremic or PBC-related pruritus. In yet other embodiments, the additional antipruritic agent(s) comprise an antihistamine (e.g., a sedating Hi antihistamine such as doxepin, hydroxyzine or diphenhydramine) for treatment of, e.g., chrome urticaria-related, drug-induced or nocturnal itch

[0166] For treatment of chronic pruritus associated with dermatitis or eczema (e.g., atopic dermatitis), in some embodiments an NK-l antagonist (e.g , serlopitant) is used in combination with one or more of the following antipruritic agents:

1) in general one or more anti-inflammatory agents that can be administered topically (e.g , dennally or transderm ally) or/and systemica!ly (e.g., orally or parenterally);

2) a topical corticosteroid, or a systemicaliy (e.g., orally or parenterally) administered corticosteroid for more severe or more widespread dermatitis;

3) a topical immunosuppressant (e.g., a calcineurin inhibitor such as pimecrolimus [e.g., about 1% pimecrolimus] or tacrolimus [e.g., about 0.1% tacrolimus]), or a systemicaliy (e.g., orally or parenterally) administered immunosuppressant (e.g., mycophenolic acid or a derivative thereof [e.g., mycophenolate mofetil], an antimetabolite such as an antifolate [e.g., methotrexate] or a purine analog [e.g., azathioprine], a calcineurin inhibitor such as ciclosporin, or interferon- gamma) for more severe or more widespread dermatitis;

4) an inhibitor of a pro-inflammatory cytokine or a receptor therefor or the production thereof (e.g., an inhibitor of IL-2 or IL-2R such as basiliximab or daclizumab, an inhibitor of IL- 4 or IL-4R such as dupilumah, an inhibitor of IL-31 or IL-31R such as nemolizumab, or a PDE4 inhibitor such as apremilast or crisaborole), which can be administered topically (e.g., dermally or transdermally) or systemicaliy (e.g., orally or parenterally);

5) an antihistamine (e.g., an Hr antihistamine such as JNJ-7777120 or ZPL-389, or/and a sedating first-generation Hi antihistamine such as clemastine or diphenhydramine for, e.g., nighttime use), which can he administered topically (e.g., dermally or transdermally) or systemicaily (e.g., orally);

6) a mu-opioid receptor antagonist (e.g., naltrexone), which can be administered topically (e.g., dermally or transdermally) or systemicaily (e.g., orally or parenteral ly);

7) a cannabinoid receptor agonist (e.g., palmitoylethanolamide or S-777469), which can be administered topically (e.g., dermally or transdermally) or systemicaily (e.g., orally);

8) an antidepressant (e.g., an SSRI such as fluvoxamine or paroxetine or a tricyclic antidepressant such as doxepin or cidoxepin), which can be administered topically (e.g., dermally or transdermally) or systemicaily (e.g., orally');

9) a moisturizer or emollient (e.g., one containing an occlusive such as an oil, or a humectant such as urea); or

10) UVB phototherapy (e.g., narrow-band UVB [NB-UVB] at 311-313 nm or broad-band UVB [BB-UVB] in the range of about 280-315 nm) or/and UVA phototherapy (e.g., in the range of about 315-400 nm) with a skin photosensitizer (e.g., psoralen in PUVA); or

11) any combination of the above.

[0167] For treatment of chronic pruritus associated with mild to moderate dermatitis or eczema (e.g., atopic dermatitis), in certain embodiments the one or more additional antipruritic agents are or comprise a topical corticosteroid of low or medium potency (e.g., about 1-2.5% hydrocortisone or about 0.1% hydrocortisone butyrate), a topical calcineurin inhibitor (e.g., about 1% pimecrolimus or about 0.1% tacrolimus) or a PDE4 inhibitor (e.g., apremilast or crisaborole), or any combination or all thereof.

[0168] For treatment of chronic pruritus associated with mild to moderate psoriasis (e.g., plaque psoriasis), in some embodiments an NK-1 antagonist (e.g., serlopitant) is used in combination with one or more topically (e.g., dermally or transdermally) administered antipruritic agents. In certain embodiments, the one or more topical antipruritic agents are or comprise a corticosteroid (e.g., about 0.1% betamethasone valerate, about 0.05%

desoximetasone, about 0.05% fluocinonide or about 1% hydrocortisone acetate), an agent that inhibits keratinocyte proliferation (e.g., hydroxyurea, 5-fluorouracil, salicylic acid or coal tar), a retinoid (e.g., tazarotene), an anthrone derivative (e.g., dithranol [anthralin]), vitamin D (e.g., vitamin Eh or vitamin D ) or an analog or derivative thereof (e.g., caicitriol, calcipotriol or paricaieitol), or a moisturizer or emollient (e.g., one containing an occlusive such as mineral oil or petroleum jelly, or a humectant such as urea), or any combination thereof. If response to the one or more topical antipruritic agents is not sufficient, UVB (e.g., NB-UVB or BB-UVB) phototherapy or/and UVA (e.g., PUVA) phototherapy can be employed.

[0169] In other embodiments, an NK-l antagonist (e.g., serlopitant) is used in combination with one or more systenncaliy (e.g., orally or parenterally) administered antipruritic agents, or/and UVB or PUVA phototherapy, to treat chronic pruritus associated with moderate to severe psoriasis (e.g., plaque psoriasis), including psoriasis with widespread lesions and psoriasis with localized but disabling lesions (e.g., on the palm of the hands or/and the sole of tire feet). In certain embodiments, the one or more systemic antipruritic agents are or comprise a retinoid (e.g , acitretin or etretinate [acitretin ethyl ester]), an immunosuppressant (e.g., methotrexate, ciclosporin, alefacept or a furnaric acid ester [e.g., dirnethylfumarate]), an inhibitor of a pro- inflammatory cytokine or a receptor therefor (e.g., an inhibitor of TNF-a [e.g., adalimumab, infliximab or etanercept], an inhibitor of IL-12 [e.g., ustekinumab] or IL-12R, an inhibitor of IL- 17 [e.g., ixekizumab or secukinumab] or IL-17R [e.g., brodalumab], an inhibitor of IL-22 [e.g., fezakinumab] or IL-22R, or an inhibitor of IL-23 [e.g., guselkumab, risankizumab, tildrakizumab or ustekinumab] or IL-23R), an inhibitor of the production of a pro-inflammatory cytokine or a receptor therefor (e.g., apilimod, a PDE4 inhibitor [e.g., apremilast or crisaborole], a JAK inhibitor [e.g., tofacitinib] or a PKC inhibitor [e.g., sotrastaurin]), or any combination thereof

[0170] For treatment of chronic pruritus associated with prurigo (e.g., prurigo nodularis), in some embodiments an NK-l antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) a topical corticosteroid (e.g., betamethasone or a derivative thereof), or a systemically (e.g., orally or parenterally) administered corticosteroid (e.g., prednisone or a derivative thereof);

2) an immunomodu!ator (e.g., thalidomide), winch can be administered, e.g., systenncaliy (e.g., orally or parenterally);

3) a topical immunosuppressant (e.g., a calcineurin inhibitor such as pimecrolimus or tacrolimus), or a systemically (e.g., orally or parenterally) administered immunosuppressant (e.g., an antimetabolite such as an antifolate [e.g., methotrexate] or a purine analog [e.g., azathioprine], or a calcineurin inhibitor such as ciclosporin); 4) an antihistamine (e.g., an Hi antihistamine such as ioratadine or cetirizine), which can be administered topically (e.g., dermaliy or transdemialiy) or systemicaily (e.g., orally or parenterally);

5) a rnu-opioid receptor antagonist (e.g., naloxone or naltrexone), which can be administered topically (e.g., dermaliy or transdermally) or systemicaily (e.g., orally or parenterally);

6) a kappa-opioid receptor agonist (e.g., nalfiirafine), which can be administered, e.g., systemicaily (e.g., orally or parenterally);

7) an anticonvulsant (e.g., gabapentin or pregabalin), which can be administered, e.g., systemicaily (e.g., orally or parenterally):

8) an antidepressant (e.g., a tricyclic antidepressant such as amitriptyline, doxepin or cidoxepin, or an SSRI such as fluvoxamine or paroxetine), which can be administered topically (e.g., dermaliy or transdermally) or systemicaily (e.g., orally or parenterally);

9) a topical counterirritant (e.g., capsaicin) or/and a cooling agent (e.g., a local anesthetic); or

10) UVB (e.g., NB-UVB or BB-UVB) phototherapy or/and UV A (e.g., PUVA) phototherapy; or

11) any combination of the above.

[0171] In certain embodiments, the one or more additional antipruritic agents are or comprise an antihistamine (e.g., an Hi antihistamine such as Ioratadine or cetirizine).

[0172] For treatment of chronic pruritus associated with urticaria (e.g., chronic idiopathic urticaria), in some embodiments an NK-1 antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) in general one or more anti-inflammatory agents that can be administered topically (e.g., dermaliy or transdermally) or/and systemicaily (e.g., orally or parenterally);

2) an antihistamine (e.g., a second-generation Hi antihistamine such as cetirizine, cidoxepin, Ioratadine or desloratadine, or/and a first-generation Hi antihistamine such as diphenhydramine, doxepin, hydroxyzine or mirtazapine, and optionally an H2 antihistamine such as cimetidine [e.g., cidoxepin or/and hydroxyzine, or hydroxyzine and cimetidine]), which can be administered topically (e.g., derrnally or transderrnally) or systemically (e.g., orally or parenteraily);

3) an inhibitor of a leukotriene or a receptor therefor or the production thereof (e.g., a leukotriene receptor antagonist such as montelukast or zafirlukast);

4) a corticosteroid, which can be administered topically (e.g., dermal iy or transderrnally) or systemically (e.g., orally or parenteraily);

5) an immunosuppressant (e.g., myeophenolate, a calcineurin inhibitor such as cyclosporine or tacrolimus, or an mTOR inhibitor such as rapamycin);

6) an IgE inhibitor (e.g., an anti-IgE antibody such as omalizumab);

7) a DMARD (e.g., sulfasalazine);

8) another kind of anti-inflammatory_' agent (e.g., dapsone or/and hydroxychloroquine); or

9) a rnu-opioid receptor antagonist (e.g., naloxone or naltrexone), which can be administered topically (e.g., derrnally or transderrnally) or systemically (e.g., orally or parenteraily); or

10) any combination of the above.

[0173] In certain embodiments, the one or more additional antipruritic agents are or comprise one or more antihistamines (including, e.g., an Hi antihistamine).

[0174] For treatment of chronic pruritus associated with a kidney disorder (e.g., CKD,

ESRD, uremia, uremic pruritus or pruritus associated with dialysis [e.g., hemodialysis]), in some embodiments an NK-1 antagonist (e.g., seriopitant) is used in combination with one or more of the following antipruritic agents:

1) a selective KOR agonist (e.g., nalfurafine, asimadoline or difelikefalin [CR845]) or/and a selective MQR antagonist (e.g., naltrexone, naloxone or SK-1405), or a mixed KOR agonist/MOR antagonist (e.g., butorphanol or nalbuphine);

2) an anticonvulsant (e.g., gabapentin or pregabalin);

3) an antidepressant (e.g., an SSRI such as paroxetine or sertraline, a tricyclic antidepressant such as doxepin, or a tetracyclic antidepressant such as mirtazapine);

4) an immunomodulator (e.g., thalidomide or pentoxifylline); 5) an immunosuppressant (e.g., a calcineurin inhibitor such as pirnecroiimus or tacrolimus), which can be administered, e.g., topically (e.g., dermally or transdermally);

6) an inhibitor of the complement system or a component thereof (e.g., a C3 inhibitor such as neurotropin);

7) an inhibitor of a pro-inflammatory cytokine or a receptor therefor or the production thereof (e.g., an antibody or a fragment thereof targeting IL-31 or IL-31R, such as nemolizumab);

8) a mast ceil stabilizer (e.g., cromolyn or a salt thereof [e.g., topical about 4% cromolyn sodium], ketotifen or a salt [e.g., fumarate salt] thereof, or zinc sulfate), which can be administered topically (e.g., dermally or transdermally) or systemically (e.g., orally);

9) an antihistamine (e.g., a sedating first-generation Hi antihistamine such as doxepin or ketotifen);

10) an inhibitor of a leukotriene or a receptor therefor or the production thereof (e.g., a leukotriene receptor antagonist such as montelukast or zafirlukast, or a 5-LOX inhibitor such as g-imolenic acid or a salt thereof an omega-3 fatty acid or an ester thereof [e.g., EPA or fish oil], or zileuton), which can be administered topically (e.g., dermally or transdermally) or

systemically (e.g., orally);

11) an antagonist of a PAR (e.g., PAR2) or an inhibitor of an activating protease (e.g., an inhibitor of a serine protease such as trypsin or tryptase), winch can be administered topically (e.g., dennally or transdermally) or systemically (e.g., orally, intravenously or subcutaneously);

12) an agent that binds to uremic toxins (e.g., activated charcoal or a carbonaceous adsorbent [e.g., carbonaceous particles such as AST-120]);

13) a phosphate-binding agent (e.g., bixalomer, sevelamer hydrochloride or carbonate, or calcium carbonate or acetate);

14) an anion -exchange resin (e.g., cholestyramine or colestilan [colestimide]);

15) vitamin D or an analog or derivative thereof (e.g., calcipotriol), which can be administered topically (e.g., dennally or transdermally) or systemically (e.g., orally);

16) a topical counterirritant or/and cooling agent (e.g., capsaicin [e.g., about 0.025% capsaicin ointment, gel or cream], camphor, menthol or phenol, or any combination thereof); 17) a topical local anesthetic (e.g., pramocaine [pramoxine], such as an about 1% pramoxine hydrochloride lotion):

18) a moisturizer or emollient (e.g., one containing a humectant [e.g., urea or a heparinoid] or an occlusive [e.g., petrolatum], such as an about 2.5% L-arginine hydrochloride ointment or an about 10% Urea ISD1N® plus dexpanthenoi [Ureadin Rx 10] lotion, or one containing a structured lipid and a cannabinoid);

19) UVB (e.g., NB-UVB or BB-UVB) phototherapy or/and UVA phototherapy (e.g., long-wave UVA, high-dose UVA [e.g., about 20-25 J/cm² per treatment], or PUVA); or

20) acupuncture (using, e.g., electric needles) or the like (e.g., acupressure or auricular acupressure optionally with Vaccaria seed): or

21) any combination of the above.

[0175] For treatment of uremic pruritus or pruritus associated with dialysis (e.g., hemodialysis), in certain embodiments the one or more additional antipruritic agents are or comprise a KOR agonist (e.g., nalfurafme), a sedating Hi antihistamine (e.g., doxepin or ketotifen) or an anticonvulsant (e.g., gabapentin or pregabalin), or any combination or ail thereof. In further embodiments, the one or more additional antipruritic agents are or comprise a topical counterirritant (e.g., capsaicin, which also depletes neuropeptides such as substance P in peripheral sensory neurons), a moisturizer or emollient, or UVB (e.g., BB-UVB) phototherapy, or any combination or all thereof.

[0176] For treatment of chronic pruritus associated with a hepato-biliary disorder (e.g., a cholestatic disorder such as cholestasis or primary biliary cholangitis [PBC]), in some embodiments an NK-l antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) a bile acid-/bile salt-chelating or -sequestering agent (e.g., an ion-exchange resm [e.g., cholestyramine], colesevelam or colestipol);

2) a cholesterol absorption-reducing or gallstone-dissolving agent (e.g., ursodeoxycholic acid [ursodiol] or ehenodeoxyebohe acid);

3) an agonist of the farnesoid X receptor (FXR, aka bile acid receptor) (e.g., cafestol, chenodeoxycholic acid, obeticholic acid or fexaramme);

4) a pregnane X receptor (PXR) agonist (e.g., rifampicin); 5) an inhibitor of lysophosphatidic acid (LPA) or a receptor therefor or the production thereof (e.g., an autotaxin inhibitor);

6) an antidepressant (e.g., an SSRI such as sertraline, paroxetine or fluvoxamine, a tricyclic antidepressant such as doxepin, or a tetracyclic antidepressant such as rnirtazapine);

7) a selective KOR agonist (e.g., nalfurafine) or/and a selective MOR antagonist (e.g., nalmefene, naloxone, naltrexone or methylnaltrexone), or a mixed KOR agonist/MOR antagonist (e.g., butorphanoi or nalbuphine):

8) an immunomodulator (e.g., thalidomide);

9) UVB (e.g., NB- or BB-UVB) phototherapy or/and UVA (e.g., PUVA) phototherapy; or

10) transcutaneous electrical nerve stimulation; or

11) any combination of the above.

[0177] For treatment of cholestatic pruritus or pruritus associated with a cholestatic disorder (e.g., cholestasis or PBC), in certain embodiments the one or more additional antipruritic agents are or comprise rifampicin, cholestyramine, ursodeoxycholic acid or obetiehoiic acid, or any combination or all thereof.

[0178] For treatment of chronic pruritus associated with a solid cancer or paraneoplastic pruritus, in some embodiments an NK-1 antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) an antidepressant (e.g., an SSRI such as paroxetine or a tetracyclic antidepressant such as rnirtazapine);

2) a 5-HT₃ antagonist (e.g., gramsetron or rnirtazapine);

3) an immunomodulator (e.g., thalidomide); or

4) a kappa-opioid receptor agonist (e.g., nalfurafine); or

5) any combination of the above.

[0179] For treatment of chronic pruritus associated with a lymphoma (e.g., Hodgkin’s lymphoma or non-Hodgkin’s lymphoma), in some embodiments an NK-1 antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) an anticonvulsant (e.g., carbamazepine or gabapentin); 2) an antidepressant (e.g., a tetracyclic antidepressant such as mirtazapine, a tricyclic antidepressant such as doxepin, or an SSR1 such as paroxetine, sertraline or fluvoxamine);

3) a selective KOR agonist (e.g., nalfurafme) or/and a selective MOR antagonist (e.g., naloxone or naltrexone), or a mixed KOR agonist/MOR antagonist (e.g., butorphanol or nalbuphine);

4) an H₂ antihistamine (e.g., cimetidine):

5) a corticosteroid, which can be administered, e.g., systemically (e.g., orally); or

6} UVB (e.g., NB- or BB-UVB) phototherapy or/and UVA (e.g., PUVA) phototherapy; or

7) any combination of the above.

[0180] For treatment of chronic pruritus associated with cutaneous T-cell lymphoma (CTCL, such as mycosis fungoides), in some embodiments an NK-l antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) a selective KOR agonist (e.g., nalfurafme) or/and a selective MOR antagonist (e.g., naloxone or naltrexone), or a mixed KOR agonist/MOR antagonist (e.g., butorphanol or nalbuphine), which can be administered topically (e.g., dermally or transdermally) or systemically (e.g., orally or parenterally);

2) an antidepressant (eg., a tetracyclic antidepressant such as mirtazapine, a tricyclic antidepressant such as doxepin, or an SSRI such as paroxetine, sertraline or fluvoxamine), which can be administered topically (e.g., dermally or transdermally) or systemically (eg., orally);

3) an anticonvulsant (e.g., gabapentin or pregabalin), which can be administered systemically (e.g., orally);

4) a corticosteroid, which can be administered topically (e.g., dermally or transdermally) or systemically (e.g., orally or parenterally);

5) an immune-response modifier (e.g., gardiquimod, imiquimod or resiquimod), wdiich can be administered, e.g., topically (e.g., dermally or transdermally);

6) an anti-cancer agent (e.g., a retinoid X receptor agonist such as a retinoid [e.g., bexarotene], or a histone deacetylase inhibitor [e.g., panobinostat, vorinostat or romidepsin]), which can be administered topically (e.g , dermally or transdermally) or systemically (e.g., orally or parenterally); or 7) UVB (e.g., NB- or BB-UVB) phototherapy or/and UVA (e.g., PUVA) phototherapy; or

8) any combination of the above.

[0181] For treatment of chronic pruritus associated with polycythemia vera, in some embodiments an NK-1 antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) a Janus kinase inhibitor (e.g., a JAK2 inhibitor such as a dual JAK1/JAK2 inhibitor [e.g., ruxolitinib]);

2) a cytoreductive agent (e.g., interferon-alpha);

3) aspirin;

4) an SSRI (e.g. paroxetine);

5) an tfc antihistamine (e.g., cimetidine);

6) a mu-opioid receptor antagonist (e.g., naltrexone);

7} a b; adrenergic receptor antagonist (e.g., atenolol); or

8) UVB (e.g., NB- or BB-UVB) phototherapy or/and UVA (e.g., PUVA) phototherapy; or

9) any combination of the above.

[0182] For treatment of chrome aquagenic pruritus in general, in some embodiments an NK-

1 antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) an Hi antihistamine (e.g., loratadme or doxepin) or/and an Hz antihistamine (e.g., cimetidine);

2) a mu -opioid receptor antagonist (e.g., naloxone or naltrexone);

3) an anticonvulsant (e.g , gabapentin or pregabalin);

4) a topical corticosteroid of low to medium potency (e.g., hydrocortisone):

5) a beta-adrenergic receptor antagonist (e.g., a b: -antagonist such as atenolol or a dual pi-/p?.-antagonist such as propranolol, both of w hich are also anxiolytic); or

6) UVB (e.g., NB- or BB-UVB) phototherapy or/and UVA (e.g., PUVA) phototherapy, or

7) any combination of the above. [0183] For treatment of chronic HIV-associated pruritus, in some embodiments an NK-1 antagonist (e.g., serlopitant) is used in combination with a COX inhibitor (e.g., a dual CQX- l/COX-2 inhibitor such as indomethacin) or/and UVB (e.g., NB- or BB-UVB) phototherapy or UV.4 (e.g. PUV.4) phototherapy.

[0184] For treatment of chronic neuropathic itch, m some embodiments an NK-1 antagonist

(e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) an anticonvulsant (e.g., gabapentin or pregabalin);

2) a tricyclic antidepressant (e.g., amitriptyline);

3) botulinum toxin A, which can be administered, e.g., subcutaneously; or

4) a topical local anesthetic (e.g., pramoxme or lidocaine/prilocaine eutectic mixture); or

5) any combination of the above.

[0185] For treatment of chronic neurogenic itch, in certain embodiments an NK-1 antagonist

(e.g., serlopitant) is used in combination with a mu-opioid receptor antagonist (e.g., nahnefene, naloxone, naltrexone or methylnaltrexone) or/and an anticonvulsant (e.g., gabapentin or pregabalin).

[0186] For treatment of chronic psychogenic itch, in some embodiments an NK-1 antagonist

1) an anticonvulsant (e.g., gabapentin or pregabalin);

2) an antidepressant (e.g., an SSRJ such as paroxetine, an SNRI such as venlafaxine, or a tetracyclic antidepressant such as mirtazapine);

3) an anxiolytic (e.g., pregabalin or a benzodiazepine such as alprazolam or lorazepam);

4) an antipsychotic/neuroleptic (e.g., pimozide); or

5) UVB (e.g., NB- or BB-UVB) phototherapy; or

6) any combination of the above.

[0187] For treatment of pruritus that persists despite treatment of the pruritus in view' of a suspected underlying cause or condition, in some embodiments an NK-1 antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) a topical calcineurin inhibitor (e.g., pirnecrolimus or tacrolimus); 2) a topical counterirritant or/and cooling agent (e.g., capsaicin);

3) UVB (e.g., NB- or BB-UVB) phototherapy or/and UV A (e.g., PUV A) phototherapy;

4) a mu-opioid receptor antagonist (e.g., naloxone, naltrexone or methylnaltrexone), which can be administered systemicaliy (e.g., orally or parenteraily);

5) an anticonvulsant (e.g., gabapentin or pregabalin), which can be administered systemicaliy (e.g., orally); or

6) an antidepressant (e.g., an SSRI such as paroxetine or fluvoxamine, a tricyclic antidepressant such as doxepin or amitriptyline, or a tetracyclic antidepressant such as mirtazapine), which can be administered systemicaliy (e.g., orally); or

7) any combination of the above.

[0188] In certain embodiments, one or more topical antipruritic agents or/and UV phototherapy are used prior to the use of one or more systemic antipruritic agents, if any.

[0189] For treatment of chronic idiopathic pruritus, in some embodiments an NK-1 antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) an antidepressant (e.g., an SSRI such as paroxetine or fluvoxamine, a tetracyclic antidepressant such as mirtazapine, or a tricyclic antidepressant such as amitriptyline), which can be administered systemicaliy (e.g., orally) or topically (denna!ly or transderm ally);

2) an anticonvulsant (e.g., gabapentin or pregabalin), which can be administered systemicaliy (e.g., orally);

3) a selective MOR antagonist (e.g., naloxone, naltrexone or methylnaltrexone) or a mixed KOR agonist/MOR antagonist (e.g., butorphanol or nalbuphine), which can be administered systemicaliy (e.g., orally or parenteraily);

4) a non-sedating or mildly sedating Hi antihistamine (e.g., fexofenadine, loratadine or cetirizine), which can be administered systemicaliy (e.g., orally);

5) a topical first-generation Hi antihistamine (e.g., doxepin, diphenhydramine or mirtazapine);

6) an immunosuppressant (e.g., azathioprine), which can be administered systemicaliy (e.g., orally); 7) a topical corticosteroid of low to medium potency (e.g., about 0.05% clobetasone butyrate):

8) a topical counterirritant or/and cooling agent (e.g., menthol);

9) a topical local anesthetic (e.g., chloroethane or polidocanol):

10) a moisturizer or emollient (e.g., one containing an occlusive such as petroleum jelly or a humectant such as urea);

1 1) UVB (e.g.. NB- or BB-TJVB) phototherapy; or

12) acupuncture (using, e.g., electric needles) or the like (e.g., acupressure or auricular acupressure optionally with Vaccaria seed); or

13) any combination of the above.

[0190] For treatment of chronic idiopathic pruritus in the elderly, in certain embodiments an NK-1 antagonist (e.g., serlopitant) is used in combination with one or more of the following antipruritic agents:

1) an anticonvulsant (e.g., gabapentm or pregabalin), which can be administered systemicaliy (e.g., orally);

2) a non-sedating or mildly sedating Hi antihistamine (e.g., fexofenadine, loratadine or cetirizine), which can be administered systemicaliy (e.g., orally);

3) a topical corticosteroid of low to medium potency; or

4) a moisturizer or emollient (e.g., one having a high lipid content); or

5) any combination of the above.

[0191] It is understood that a KOR agonist can be a selective KOR agonist and a MOR antagonist can be a selective MOR antagonist, or either can be, e.g., a mixed KOR agonist/MOR antagonist. It is further understood that an antipruritic agent can be used in non-salt form or in the form of a pharmaceutically acceptable salt.

[0192] The optional additional antipruritic agent(s) can be administered to a subject suffering from chronic pruritus concurrently with (e.g., in the same composition as the NK-1 antagonist or in separate compositions) or sequentially to (before or after) administration of the NK-1 antagonist. The optional additional antipruritic agent(s) independently can be administered in any suitable mode, including without limitation oral, topical (e.g., dermal/epicutaneous, transdermal, rnucosal, transmucosal, intranasal [e.g., by nasal spray or drop], pulmonary [e.g., by oral or nasal inhalation], ocular [e.g., by eye drop], bucal, sublingual, rectal [e.g., by suppository] and vaginal [e.g., by suppository]), and parenteral (e.g., intramuscular, subcutaneous, intradermal, intravascular, intravenous, intraarterial, intraperitoneal, intramedullary, intrathecal and topical). In some embodiments, an antipruritic agent is administered topically (e.g., derrnally or transdermally) if the pruritus or the pruritus-associated condition is localized or/and less severe, and is administered systemica!ly (e.g., orally or parenterally such as intravenously or subcutaneously) if the pruritus or the pruritus-associated condition is widespread (generalized), has a systemic cause or/and is more severe. In certain embodiments, an optional additional antipruritic agent (e.g., a counterirritant or cooling agent such as capsaicin, a local anesthetic, a corticosteroid, a calcineurin inhibitor such as pimecrolimus or tacrolimus, or a cannabinoid such as N-palmitoylethanolamine) is administered locally (e.g., topically such as derrnally or transdermally). In other embodiments, an optional additional antipruritic agent (e.g., an immunosuppressant [e.g., azathioprine or eielosporin], an antihistamine, an anticonvulsant, an antidepressant, a KOR agonist or a MOR antagonist) is administered systemical!y (e.g., orally or parenterally such as intravenously or subcutaneously).

[0193] The optional additional antipruritic agent(s) independently can be administered in any suitable frequency, including without limitation daily (1, 2, 3 or more times per day), once every' two or three days, twice weekly, once weekly, once every two weeks, once e very three weeks or once monthly, or can be administered in an irregular manner or on an as-needed basis, which can be determined by the treating physician. The dosing frequency can depend on, e.g., the mode of administration chosen. For example, a dermal formulation of an antipruritic agent can be applied to the skin of a subject 1, 2, 3, 4 or more times a day. The length of treatment of chronic pruritus with the optional additional antipruritic agent(s) can be determined by the treating physician and can independently be, e.g., at least about 6 weeks, 2 months, 3 months, 4 months, 5 months,

6 months, 1 year, 2 years, 3 years, 4 years, 5 years or longer (e.g., at least about 6 weeks,

3 months, 6 months or 1 year).

[0194] The following embodiments of the disclosure are provided by way of example:

1. A method of treating chronic pruritus hav ing a duration of at least abo ut 6 months,

comprising administering to a subject in need of treatment a therapeutically effective amount of a neurokinin- 1 (NK- 1 ) antagonist. The method of embodiment 1, wherein the chronic pruritus has a duration of at least about 1 year, 2 years or 3 years.

The method of embodiment 1 or 2, wherein the chronic pruritus has a duration of at least about 4 years, 5 years or 10 years.

The method of any one of the preceding embodiments, wherein the chronic pruritus is characterized by sensitization or hypersensitization of the central nervous system (e.g., dorsal root ganglion neurons, spinal dorsal hom neurons or spinal trigeminal nucleus [e.g., medullary dorsal hom] neurons, or any combination or all thereof).

The method of any one of the preceding embodiments, wherein the chronic pruritus is characterized by sensitization or hypersensitization of the peripheral nervous system (e.g., unmyelinated C fibers, thinly myelinated Ad fibers or myelinated A |3 fibers, or any combination or all thereof).

The method of any one of the preceding embodiments, wherein the chronic pruritus is characterized by spontaneous itch, alloknesis or hyperknesis, or any combination or all thereof.

The method of embodiment 5, wherein the NK-l antagonist inhibits spontaneous itch, alloknesis or hyperknesis, or any combination or all thereof

The method of embodiment 6, wherein tire NK-l antagonist reduces the frequency or/and the intensity of spontaneous itch, alloknesis or hyperknesis, or any combination or all thereof, by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% (e.g., by at least about 30% or 50%), as measured by a visual analog scale (VAS) score or a numerical rating scale (NRS) score, for example.

The method of any one of the preceding embodiments, wherein the NK-l antagonist is a selective NK-l antagonist.

The method of any one of the preceding embodiments, wherein the NK-l antagonist is selected from aprepitant (L-754030 or MK-(0)869), fosaprepitant (L-758298), befetupitant, burapitant (SSR-240600), casopitant (GW-679769), dapitant (RPR-100893), ezlopitant (CJ-1 1974), figopitant (BIIF-1149), lanepitant (LY-303870), maropitant (CJ- 11972), netupitant, fosnetupitant, nolpitantium (SR-140333), orvepitant (GW-823296), rolapitant (SCH-619734), SCH-720881 (active metabolite of rolapitant), serlopitant (MK- (0)594 or VPD-737), tradipitant (VLY-686 or LY-686017), vestipitant (GW-597599), vofopitant (GR-205171), hydroxyphenyl propamidobenzoic acid, maltooligosaccharides (e.g., maltotetraose and maltopeniaose), spaniides (e.g., spantide I and II), AV-608, AY- 818, AZD-2624, CGP-49823, CJ-17493, CP-96345, CP-99994, CP-122721, DNK-333 (NK1/NK2), FK-224 (NK1/NK2), FK-888, GR-82334, GR-203040, GR-205171, GSK- 424887, HSP-117, KRP-103, L-703606, L-733060, L-736281, L-759274, L-76Q735, LY- 686017, M516102, MDL-105212 (NK1/NK2), MK-0303 (L-001182885), MK-8478 (L- 001983867), NKP-608, PD-154075, R- i 1603 ! . R-116301, RP-67580, S-41744, SCH- 206272 (NK-1/NK-2/NK-3), SCH-388714, SCH-900978, SLV-317, T-2328, TA-5538, TAK-637, TKA-731, WIN-51708, ZD-4974, ZD-6021 (NK1/NK2), and analogs, derivatives, prodrugs, metabolites, salts and stereoisomers thereof

The method of any one of the preceding embodiments, wherein the NK-1 antagonist is serlopitant or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof.

The method of any one of the preceding embodiments, wherein the NK-1 antagonist is not aprepitant or fosaprepitant.

The method of any one of the preceding embodiments, wherein the therapeutically effective amount (e.g., per day or per dose) of the NK-1 antagonist is about 0.25 or 1 to 200 mg, 0.25 or 1 to 150 mg, 0.25 or 1 to 100 mg, 0.25 or 1 to 50 mg, 0.25 or 1 to 10 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-100 mg, 100-150 mg or 150-200 mg. The method of any one of the preceding embodiments, wherein the therapeutically effective amount of the NK-1 antagonist is administered one or more times a day, once every two days, once ever}' three days, twice a week or once a week (e.g., once or twice daily).

The method of any one of the preceding embodiments, wherein the NK-1 antagonist is serlopitant, and the therapeutically effective amount of serlopitant is about 0.25 or 1 to 5 mg or 5-10 mg, or about 0.25 mg, 0.5 mg, 1 mg, 5 mg or 10 mg, once or twice daily. Tire method of embodiment 15, wherein the therapeutically effective amount of serlopitant, or a pharmaceutically acceptable salt or stereoisomer thereof, is about 5 mg once daily.

The method of any one of the preceding embodiments, wherein the therapeutically effective amount of the NK-1 antagonist is administered over a period of at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years or longer (e.g., at least about 6 weeks, 3 months, 6 months or 1 year).

The method of any one of the preceding embodiments, wherein the NK-1 antagonist is administered orally (e.g., as a tablet or capsule).

The method of any one of embodiments 1 to 17, wherein the NK-1 antagonist is administered parenterally (e.g., intravenously, subcutaneously or intramuscularly).

Tire method of any one of embodimen ts 1 to 17, wherein the NK-1 antagonist is administered topically (e.g., transdermally, transmucosally, pulmonarily, buccally or sublingually).

The method of any one of the preceding embodiments, wherein the NK-1 antagonist is serlopitant, or a pharmaceutically acceptable salt or stereoisomer thereof, and serlopitant, or a pharmaceutically acceptable salt or stereoisomer thereof, is administered orally (e.g., as a tablet) in a dose of about 0.25, 0.5, 1 , 5 or 10 mg (e.g., about 5 mg) once daily for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years or longer (e.g., at least about 6 weeks, 3 months, 6 months or 1 year)

The method of any one of the preceding embodiments, wherein at least one loading dose of the NK-1 antagonist is first administered, and a therapeutically effecti ve maintenance dose of the NK-1 antagonist is subsequently administered.

The method of embodiment 22, wherein the therapeutically effective maintenance dose (e.g., per day or per dose) of the NK-1 antagonist is about 0.25 or 1 to 200 mg, 0.25 or 1 to 150 mg, 0.25 or 1 to 100 mg, 0.25 or 1 to 50 mg, 0.25 or 1 to 10 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-100 mg, 100-150 mg or 150-200 mg.

The method of embodiment 22 or 23, wherein the at least one loading dose of the NK-1 antagonist is about 1.5, 2, 3, 4 or 5 times (e.g., about 3 times) larger than the

therapeutically effective maintenance dose of the NK-1 antagonist.

The method of any one of embodiments 22 to 24, wherein the therapeutically effective maintenance dose of the NK-1 antagonist is administered one or more times a day, once every two days, once every three days, twice a week or once a week (e.g., once or twice daily). The method of any one of embodiments 22 to 25, wherein the NK-1 antagonist is serlopitant, or a pharmaceutically acceptable salt or stereoisomer thereof, and the therapeutically effective maintenance dose of serlopitant, or a pharmaceutically acceptable salt or stereoisomer thereof, is about 0.25 or 1 to 5 mg or 5-10 mg, or about 0.25 mg, 0.5 mg, 1 mg, 5 mg or 10 mg, once or twice daily, such as about 5 mg once daily.

The method of any one of embodiments 22 to 26, wherein the therapeutically effective maintenance dose of the NK-1 antagonist is administered over a period of at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years or longer (e.g., at least about 6 weeks, 3 months, 6 months or 1 year).

The method of any one of embodiments 22 to 27, wherein the NK-1 antagonist is serlopitant, or a pharmaceutically acceptable salt or stereoisomer thereof, and serlopitant, or a pharmaceutically acceptable salt or stereoisomer thereof, is administered in a loading dose of about 3-15 mg or 15-30 mg once or twice on day 1, followed by a maintenance dose of about 1-5 mg (e.g., about 1, 3 or 5 mg) or about 5-10 mg (e.g., about 5, 7.5 or 10 mg) once or twice daily for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years or longer (e.g., 15 mg on day 1 followed by 5 mg once daily for at least about 6 weeks, 3 months, 6 months or 1 year), where the loading dose is three times larger than the maintenance dose and serlopitant, or a pharmaceutically acceptable salt or stereoisomer thereof, is administered orally (e.g., as a tablet or capsule).

The method of any one of the preceding embodiments, wherein the NK-1 antagonist is administered at bedtime or in the morning.

The method of any one of the preceding embodiments, wherein the NK-1 antagonist is administered without food (e.g., at least about 1 or 2 hours before or after a meal, such as at least about 2 hours after an evening meal or at least about 2 hours before or after a meal in the morning).

The method of any one of the preceding embodiments, wherein the chronic pruri tus is, or is associated with a condition or disorder, selected from xerosis/xeroderma (dry skin), demiatitis/eczema (e.g., xerotic/asteatotic eczema, atopic dermatitis, contact dermatitis, exfoliative dermatitis [erythroderma], seborrheic dermatitis, stasis dermatitis, neurodermatitis [lichen simplex chronicus] and dermatitis herpetiformis j Duhhng s disease]), lichen planus, lichen sclerosus, psoriasis (e.g., plaque psoriasis and

erythrodermic psoriasis), prurigo (e.g., prurigo nodularis, prurigo simplex and actinic prurigo), urticaria (e.g., chronic idiopathic urticaria), hidradenitis suppurativa, acamtholytic disorders {e.g., Grover’s disease and pemphigus (e.g., pemphigus vulgaris and familial benign chronic pemphigus [Hailey-Hailey disease])}, connective tissue disorders (e.g., dermatomyositis, epidermolysis bullosa [e.g., EB simplex], lupus erythematosus [e.g., systemic LE and discoid LE], pemphigoid [e.g., bullous pemphigoid], scleroderma and Sjogren’s syndrome), mastocytosis (cutaneous and systemic), bums (e.g., thermal bums, third-degree bums and major bums), wounds (e.g., venous ulcers), scars (e.g., keloids and hypertrophic scars), endocrine disorders (e.g., hyperthyroidism [e.g., Graves’ disease], hypothyroidism and hyperparathyroidism), metabolic disorders (e.g., diabetes mellitus [including types 1 and 2]), hyperuricemia, iron deficiency, iron overload (due to, e.g., hemochromatosis or hyperferritinemia), malabsorption disorders (e.g., iron-deficiency anemia, celiac disease and inflammatory_' bowel disease [e.g., Crohn’s disease]), kidney disorders (e.g., diabetic nephropathy, glomerulonephritis, chronic kidney disease [CKD], chronic kidney failure [CKF], end-stage renal disease [ESRD], pruritus associated with dialysis [e.g., hemodialysis, peritoneal dialysis, hemofiltration and hemodiafiltration], uremia and uremic pruritus [which may or may not be caused by uremia]), hepato-biliary disorders (e.g., Alagille syndrome, cholestatic pruritus, cholestasis, primary biliary cholangitis [PBC, aka primary biliary cirrhosis], primary sclerosing cholangitis, choledocholithiasis, cholangiocarcinoma, hepatitis [e.g., chronic hepatitis B and C and autoimmune hepatitis], alcoholic liver disease, chronic liver disease [CLD], cirrhosis and chronic liver failure [other than complete liver failure]), cardiovascular disorders (e.g., heart failure [e.g., congestive heart failure] and venous insufficiency), benign and malignant neoplasms {e.g., solid tumors (e.g., those of the breast, cervix, lung, thymus [e.g., thymoma], stomach [e.g., gastric carcinoid], colon, pancreas [e.g., insulinoma], prostate, testicle and rectum), metastatic solid tumors, carcinomas (e.g., those of the breast, lung, stomach, colon, liver, bile duct, pancreas and prostate), adenocarcinomas (e.g., lung adenocarcinoma), sarcomas (e.g., soft-tissue sarcomas), melanoma, neurofibromatosis, and hematological neoplasms (including myelodysplastic syndrome, myeloproliferative neoplasms such as polycythemia vera, chronic myelogenous leukemia, chrome neutrophilic leukemia and systemic mastocytosis, and iymphoproliferative neoplasms such as lymphomas [including Hodgkin’s lymphoma and non-Hodgkin’s lymphoma such as cutaneous T-cell lymphoma {CTCL, such as mycosis fungoides, erythrodennic MF and Sezary syndrome} and cutaneous B-cell lymphoma], chrome lymphocytic leukemia, multiple myeloma, plasmacytoma and lymphocyte-variant hypereosmopbila)}, paraneoplastic pruritus (e.g., itch due to paraneoplastic syndromes [e.g., carcinoid syndrome] and paraneoplastic skin disorders [e.g., erythroderma, Grover's disease, malignant acanthosis nigricans, generalized granuloma annulare, Bazex syndrome and dermatomyositis]), infections (e.g. fungal infections [e.g., candidiasis such as vulvovaginal candidiasis] and viral infections [e.g., HIV/AIDS and hepatitis A, B, C and E]), drug- induced pruritus {e.g., itch due to chloroquine, hydroxethyl starch, androgens, estrogens, angiotensin-converting enzyme (ACE) inhibitors, analgesics (e.g., acetaminophen and opioids), antiarrhythmic drugs (e.g., amiodarone and quinidine), anticoagulants, antibiotics (e.g., carbapenems, sulfonamides, erythromycin, flucloxacillin, isoniazid, neomycin, nitrofurantoin, penicillin, tnmethoprim/sulfamethoxazoie and vancomycin), antifungals (e.g., fluconazole, griseofulvin, itraconazole and ketoconazole), antidiabetics (e.g., antihyperglycemics), calcium channel blockers, chemotherapeutics (e.g., tamoxifen, epidermal growth factor receptor [EGFR] inhibitors such as erlotinib and cetuximab, and anti-CTLA-4 antibodies such as ipiiimumab), diuretics (e.g., thiazides such as

hydrochlorothiazide), NSAIDs (e.g., aspirin, diclofenac and sulindac), statins (e.g., simvastatin}, and xanthine oxidase inhibitors (e.g., allopurinol}}, neuropathic itch (e.g., itch due to peripheral neuropathy, small fiber neuropathy [due to, e.g., diabetes, Fabry disease, HIV infection, shingles, lupus, rheumatoid arthritis and cutaneous sarcoidosis], diabetic neuropathy, postherpetic itch, vulvodynia, Guiliain-Barre syndrome,

polyneuropathy, nerve, nerve root and ganglion injuries and lesions, radiculopathy, brachioradiai pruritus, notaigia paresthetica, trigeminal trophic syndrome, aneurysms, ischemic stroke, cerebral infarction, myelopathy, multiple sclerosis, neuromyelitis optica, cavernous hemangiomas [cavernomas] of the spinal cord, syringomyelia, tumors and abscesses in and near tire spinal cord and the brain, neurofibromatosis type 1 and neurosarcoidosis), neurogenic itch, psychogenic itch (e.g., itch due to stress, anxiety disorders, depression, obsessive-compulsive disorders, substance abuse and delusional parasitosis/infestation), pruritus in the elderly (e.g., elderly patients with xerosis, diabetes, chronic renal insufficiency or chronic venous insufficiency), and chronic idiopathic pruritus. The method of embodiment 31, wherein the chronic pruritus is associated with xerosis or xeroderma (dry skin).

Tire method of embodiment 31, wherein the chronic pruritus is associated with dermatitis or eczema, such as atopic dermatitis.

The method of embodiment 31, wherein the chronic pruritus is associated with psoriasis, such as plaque psoriasis (aka psoriasis vulgaris).

The method of embodiment 34, wherein the plaque psoriasis is present in any anatomic location of the subject and covering at most 30%, at most 25%, at most 20%, at most 15%, at most 10% or at most 5% of body surface area in total.

The method of embodiment 34 or 35, wherein the duration of plaque psoriasis (e g., prior to beginning treatment) is at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years. Tire method of embodiment 34 or 35, wherein the subject was diagnosed with plaque psoriasis at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years prior to beginning treatment.

The method of embodiment 31, wherein the chronic pruritus is associated with prurigo, such as prurigo nodularis.

The method of embodiment 31, wherein the chronic pruritus is associated with urticaria, such as chronic idiopathic urticaria.

The method of embodiment 31 , wherein the chronic pruritus is associated with a connective tissue disorder, such as dermatomyositis.

The method of embodiment 31, wherein the chronic pruritus is post-bum pruritus.

The method of embodiment 31, wherein the chronic pruritus is associated with a kidney disorder, such as CKD, CKF or ESRD.

The method of embodiment 31 or 42, wherein the chronic pruritus is uremic pruritus or is associated with dialysis (e.g., hemodialysis).

Tire method of embodiment 31, wherein the chronic pruritus is associated with a hepato biliary disorder, such as hepatitis (e.g., chronic hepatitis B or C), CLD or cirrhosis. The method of embodiment 31 or 44, wherein the chronic pruritus is cholestatic pruritus or is associated with a cholestatic disorder (e.g., cholestasis or PBC).

Tire method of embodiment 31, wherein the chronic pruritus is associated with a benign or malignant neoplasm, such as a solid tumor, a carcinoma or a hematological neoplasm (e.g., Hodgkin’s lymphoma, non-Hodgkin’s lymphoma [e.g., CTCL such as mycosis fungoides or Sezary syndrome], or polycythemia vera).

The method of embodiment 31, wherein the chronic pruritus is induced by a medication. Tire method of embodiment 31, wherein the chronic pruritus is neuropathic itch, such as brachioradial pruritus or notalgia paresthetica.

The method of embodiment 31, wherein the chronic pruritus is neurogenic itch.

The method of embodiment 31, wherein the chronic pruritus is pruritus in the elderly (over

65 years of age)

Hie method of embodiment 31, wherein the chronic pruritus is chronic idiopathic pruritus. The method of any one of embodiments 31 to 51 , wherein the pruritus-associated condition or disorder is chronic.

The method of any one of the preceding embodiments, wherein:

i) tire subject is about 40 years of age or older;

ii) the chronic pruritus is associated with a condition or disorder of mild to moderate severity; or/and

iii) the chronic pruritus is not characterized by or associated with:

a) stinging or/and burning;

b) inflammation; or/and

c) neuropathy.

The method of embodiment 53, wherein the chronic pruritus is associated with dermatitis/eczema (e.g., atopic dermatitis), psoriasis (e.g., plaque psoriasis) or prurigo (e.g., prungo nodularis), or is chronic idiopathic pruritus. The method of embodiment 54, wherein the dermatitis or eczema (e.g., atopic dermatitis) has mild to moderate severity (e.g., an Investigator’s Global Assessment [IGA] score of 2 [mild] to 3 [moderate] on a 0 to 5 scale).

The method of embodiment 54, wherein the psoriasis (e.g., plaque psoriasis) has mild to moderate severity (e.g., a IGA score of 2 [mild] to 3 [moderate] on a 0 to 5 scale, a Psoriasis Area and Severity Index [PASI] score of about 10 or less, or/and affected body surface area [BSA] of about 10% or less).

The method of any one of the preceding embodiments, wherein the chronic pruritus is refractory or resistant to other antipruritic therapies without an NK-1 antagonist.

The method of any one of the preceding embodiments, further comprising administering one or more additional antipruritic agents.

The method of embodiment 58, wherein the one or more additional antipruritic agents are or comprise an inhibitor of brain natriuretic peptide (BNP) or the receptor therefor (NprA), an inhibitor of gastrin-releasing peptide (GRP) or the receptor therefor (GRPR), an inhibitor of glutamate or a receptor therefor (e.g., AMPA, kainate or NMDAR), or a GABAergic agent, or any combination or all thereof.

The method of embodiment 58 or 59, wherein the one or more additional antipruritic agents are or comprise a TRPA1 antagonist or/and a TRPV1 antagonist or desensitizer. Tire method of any one of embodimen ts 58 to 60, wherein the one or more additional antipruritic agents are or comprise an Mrgpr (e.g., MrgprX2) antagonist, a PAR (e.g., PAR2) antagonist or a TLR (e.g., TLR3, TLR4 or TLR7) antagonist, or any combination or all thereof.

The method of any one of embodiments 58 to 61, wherein the one or more additional antipruritic agents are or comprise a kappa-opioid receptor agonist (e.g., nalfurafme), a mu-opioid receptor antagonist (e.g., naltrexone or naloxone), an anticonvulsant (e.g., gabapentin or pregabalin) or an antidepressant (e.g., an SSRI such as paroxetine, fluvoxamine or sertraline, a tricyclic antidepressant such as doxepin or amitriptyline, or a tetracyclic antidepressant such as mirtazapine), or any combination or all thereof.

The method of any one of embodiments 58 to 62, wherein the one or more additional antipruritic agents are or comprise a corticosteroid/glucocorticoid (e.g., a topical corticosteroid of low to medium potency), an immunosuppressant (e.g., a topical calcineurin inhibitor or systemic azathioprine), an immunomodulator (e.g., thalidomide), an inhibitor of an inflammatory cytokine (e.g., IL-31) or a receptor therefor (e.g., IL-31R), or an Hi or Hr antihistamine, or any combination thereof.

Hie method of any one of embodiments 58 to 63, wherein the one or more additional antipruritic agents are or comprise a topical counterirritant or/and cooling agent (e.g., capsaicin), a topical local anesthetic (e.g., pramoxine), a moisturizer or emollient, or UV phototherapy (e.g., NB-UVB, BB-UVB or PUVA), or any combination or all thereof. The method of any one of embodiments 58 to 64, wherein the one or more additional antipruritic agents are administered locally (e.g., topically such as dermally or

transdermally).

The method of any one of embodiments 58 to 65, wherein the one or more additional antipruritic agents are administered systemically (e.g., orally or parenterally such as intravenously or subcutaneously).

A neurokinin- 1 antagonist (e.g., serlopitant) for use in the treatment of chronic pruritus having a duration of at least about six months or one year, optionally in combination with an additional antipruritic agent.

A composition comprising a neurokinin- 1 antagonist (e.g., serlopitant) for use in the treatment of chronic pruritus having a duration of at least about six months or one year, optionally in combination with an additional antipruritic agent.

Use of a neurokinin-1 antagonist (e.g., serlopitant) in the preparation of a medicament for the treatment of chrome pruritus having a duration of at least about six months or one year, optionally in combination with an additional antipruritic agent.

The method of claim 1, wherein the NK-1 antagonist is serlopitant, or a pharmaceutically acceptably salt or stereoisomer thereof, and the serlopitant or the pharmaceutically acceptably salt or stereoisomer thereof is administered at about 5 to 40 mg once a week. A kit comprising:

a neurokinin-1 antagonist (e.g., serlopitant); and

instructions for administering or using the neurokinin- 1 antagonist to treat chronic pruritus having a duration of at least about six months or one year. Examples

[0195] The following examples are intended only to illustrate the disclosure. Other assays, studies, protocols, procedures, methodologies, materials, substances, reagents and conditions may alternatively be performed or used as appropriate. All of the inactive pharmaceutical ingredients in the examples below comply with United States Pharmacopeia and The National Formulary requirements and are tested and released according to the monograph for each ingredient specified m the IJSP/NF compendium.

Example 1. Preparation of Serlopitant Tablets

[0196] The NK-1 antagonist serlopitant can be formulated as a tablet for oral use. Table 1 shows qualitative/quantitative composition of exemplary dosages. Minor variations in the excipient quantities (+/-10 %) may occur during the drug development process.

Table 1

[0197] Tablet potencies of 0.25 mg, 1 mg and 5 mg are prepared as a compressed tablet formulation. The tablet manufacturing process is the same for ail potencies. The process comprises the following steps: 1) serlopitant, mannitol and sodium lauryl sulfate are blended; 2) the remaining mannitol is added to the blender and mixed; 3) microcrystalline cellulose, croscarmellose sodium and colloidal silica are added to the blender containing the mixture above to complete the mixing, and the blend is de-agglomerated if necessary; 4) the blend is lubricated with magnesium stearate that has been previously screened, if necessary; 5) the lubricated blend is roller-compacted and milled, and then lubricated with magnesium stearate that has been previously screened, if necessary ; and 6} the mixture is compressed into tablets of the appropriate weight.

[0198] Similar tablets can be prepared for other NK-1 antagonists.

Example 2. Preparation of Serlopitant Capsules

[0199] Serlopitant can also be formulated as liquid-filled capsules. Table 2 shows qualitative/quantitative composition of exemplary dosages. Minor variations in the excipient quantities (+/-10 %) may occur during the drug development process.

Table 2

* Capsules are provided by Capsugel (Morristown, New Jersey) and contain gelatin and titanium dioxide

** Approximate weight of empty capsule shell

* **As needed to seal the capsule shells [0200] The formulation is prepared by dissolving the drug substance in mono- and di glycerides. Furthermore, 0.1 wt% butylated hydroxyanisoie is added as an antioxidant.

Initial capsule strengths are dispensed into hard gelatin capsules and sealed by spraying with a 1 : 1 (wt/wt) water: ethanol solution. Subsequent potencies, including 0.25 mg, 1 mg and 4 mg, are dispensed into hard gelatin capsules and sealed with a band of gelatin/poly sorbate 80. Corresponding placebo formulations are prepared in a similar manner, but without the addition of the drug substance and the antioxidant.

[0201] The capsule manufacturing process is the same for all potencies. The process comprises the following steps: 1) the mono- and di-glycerides are melted at 40 °C, if necessary;

2) the mono- and di -glycerides are added to an appropriately sized, jacketed vessel and mixing is initiated; 3) the butylated hydroxyanisoie is added to the mono- and di-glycerides and mixed until dissolved (minimum of 10 min); 4) serlopitant is slowly added to the mixture and mixed until dissolved (visual confirmation); 5) the solution is filled into hard gelatin capsules; 6) the filled capsules are sealed with a mixture of gelatin and polysorbate 80; 7) the sealed capsules are allowed to dry overnight and then the capsules are visually inspected for leaking; 8) the acceptable capsules may be weight-sorted, if necessary: and 9) the finished product is packaged in appropriate containers.

[0202] Similar capsules can be prepared for other NK-l antagonists.

Example 3. Topical Formulations Containing Serlopitant

[0203] Table 3 shows various topical formulations containing serlopitant. The formulations contain Vanicream^iM Moisturizing Skin Cream (“VM”), Vanicream™ Lite Lotion (“VLL”) or Aquaphor® Healing Ointment (“AP”, from Eucerin) as the base or carrier. VM and VLL are oil- in-water emulsion and AP has an oil base. A stock solution of free base serlopitant (Compound 1, or“Cpd 1”, in Tables 3 and 4) in ethanol (EtOH) was prepared by dissolving free base serlopitant in ethanol to the maximum extent and then filtering the resulting solution through an Anotop® 25 inorganic filter having a 0.02 micron pore size. Free base serlopitant has a maximum solubility in ethanol of 64.5 mg/g EtOH, or 6.45% w/w. To prepare a topical formulation, the stock solution of serlopitant/ ethanol was added to a tared tube containing a particular amount of the base until the resulting mixture weighed 25.0 g. The mixture was mixed vigorously for 2 minutes using a vibration stand and then was rotated slowly for 4 days. For the “C” formulations, ethanol containing no serlopitant was added so that the“B” and“C” formulations would contain the same amount of base and ethanol. Table 3

[0204] AP was determined to be an unsuitable base for an ethanol solution containing serlopitant because of ethanol insolubility in that base. The VM base appeared stable/unchanged under 15x microscopic magnification after 4 days of mixing with 15.5% ethanol. The VLL base showed some aggregation of lamellar structures under 15x microscopic magnification after 4 days of mixing with 15.5% ethanol, but the overall change to the base appeared minor. The VM and VLL formulations can be tested, e.g., for the skin permeation of serlopitant.

[0205] Similar topical formulations can be prepared for other antipruritic agents.

Example 4, in Vitro Skin Permeation of Serlopitant in Topical Formulations

[0206] Topical formulations A-D used in the in vitro skin permeation studies are shown in Table 4. The bases“VM” and“VLL” of formulations A-D are described in Example 3.

Formulations A-D were prepared according to the procedures described in Example 3. Table 4

[0207] In vitro skin permeation of serlopitant in topical formulations A-D was evaluated using a Franz diffusion cell. FIG. 1 illustrates a Franz diffusion cell. A Franz diffusion cell having a circular permeation area of 4.15 cm² and a receptor chamber volume of 19 mL was set up with a thermo-regulated outer water jacket to maintain the temperature at 37 °C. The receptor chamber was filled with 19 mL lxPBS (pH 7.5) containing 10% ethanol and 1% Tween® 80. Solubility test indicated that serlopitant remained soluble at concentrations of 0.5, 5 and 50 ug/mL in this solution after 1 hour of incubation at 37 °C. The solubility of serlopitant decreased significantly if Tween® 80 was not used and decreased slightly if ethanol was not used.

[0208] Human skin was pre-treated to remove all subcutaneous fat and was cleaned with 70% ethanol before use. The skin was visually inspected to ensure that it was free of any surface irregularity or small holes and was equally divided into four pieces. The skin was then mounted onto the receptor chamber with the stratum corneum side facing up. About 100 mg of topical formulation A, B, C or D was applied to the skin (actual weight: A, 103.8 mg; B, 101.3 mg; C, 103.2 mg; and D, 103.8 mg), which was then covered with parafdm to avoid evaporation.

[0209] About 0.5 mL of solution was withdrawn through the sampling port of the Franz diffusion cell at 0.5, 1, 2, 4, 6, 18 and 22 hours. The receptor chamber was replenished with equal volume of fresh diffusion buffer after each sampling. At the end of the experiment (after 22 hours of incubation), the skin was wiped clean with methanol, and the formulation-treated area was weighed and frozen for cryoseetioning.

[0210] All samples were processed by solid-phase extraction (SPE) before LC-MS/MS analy sis. Briefly, a Strata-X 33 um Polymeric Reverse-Phase column with 30 mg sorbent mass H ml volume (Phenomenex) was conditioned with 1 mL of methanol and equilibrated with 1 mL of water. 300 uL of sample was loaded to the column followed by a wash with 1 mL of 30% methanol. Seriopitant was eluted with 2% formic acid in acetonitrile. The sample then was concentrated by blow drying with nitrogen and re-suspended in 50 uL of 50% methanol. A working standard was first generated by spiking the diffusion buffer with known concentrations of seriopitant, which was then processed using the same SPE method. A sensitivity of 0.1 ng/mL was achieved. Seriopitant concentrations in samples resulting from formulations A-D were determined by comparison to the standard. Seriopitant was not detected in samples resulting from topical formulations A and D, as expected. FIG, 2 shows the cumulative release of seriopitant from topical formulations B and C into the receptor chamber at 0.5, 1, 2, 4, 6, 18 and 22 hours. After an initial lag, seriopitant was detected by LC-MS/MS in the receptor chamber at 6 hours. FIG. 2 indicates that topical formulation B resulted in greater penetration of seriopitant through the skin than topical formulation C in this in vitro study.

[0211] The amount of seriopitant retained in th e skin was determined at the end of the experiment. The skin was wiped and washed with methanol. Tire formulation-treated area was cut into horizontal sections of 25 um using a cryostat. Every 10 sections were pooled, placed in Eppendorf tubes, weighed and digested with twice the volume of 1 mg/mL hberase at 37 °C for 1 hour. Digested skin sections were further homogenized with a probe sonieator. To 25 uL of the skin homogenate were added 25 uL of 50% methanol and 100 uL of acetonitrile/methanol to extract seriopitant. For spiked standards, 25 uL of a solution of seriopitant in 50% methanol (from 5 ng/mL to 5000 ng/mL) was added to 25 uL of blank skin homogenate followed by 100 uL of acetonitrile/methanol. Extracted seriopitant was quantified by LC-MS/MS. FIG. 3 show's the amount of seriopitant (called“VPD737” in FIG. 3) retained in the skin at the end of the experiment. Each bar represents ug of seriopitant/g of skin in 250 um skin layers. For each of topical formulations B and C, the bars from left to right represent the amount of seriopitant retained in skin layers from the stratum comeum to the dermis.

[0212] Similar in vitro skin permeation studies can be conducted for other antipruritic agents.

Example 5. Representative Topical Formulations Containing an Antipruritic Agent

[0213] Table 5 provides non-limiting examples of topical fonnulations that can be prepared with an antipruritic agent (e.g., an NK-1 antagonist).

Example 6. Clinical Study of Serlopitant for Chronic Pruritus

[0214] A well-controlled human clinical trial assessing the efficacy of serlopitant in the treatment of chronic pruritus was approved by an Institutional Review Board and was conducted in accordance with the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practices, the U.S Code of Federal Regulations, the Health insurance Portability and Accountability Act (HIPAA), and any local regulatory requirements. The study was a Phase II randomized, double-blind, parallel-group, placebo-controlled, multicenter trial designed to evaluate the efficacy and safety of serlopitant versus placebo in subjects with chronic pruritus. Tire study subject population was adult males and females 18 to 65 years old who had pruritus of at least 6-week duration which was unresponsive or inadequately responsive to current therapies such as topical steroids or oral antihistamines, and who had a baseline Visual Analog Scale (VAS) pruritus score of at least 7 on a 10-point scale.

[0215] Subjects were randomized to receive a 0.25 mg, 1 mg or 5 mg tablet of serlopitant or a matching placebo tablet. Subjects took one tablet of serlopitant or placebo once daily by mouth for a total of 6 -weeks following a loading dose of 3 tablets on the first day of treatment. The maximum study duration for each subject was about 12 weeks and included a screening period of up to 2 weeks, a treatment period of 6 weeks, and a follow-up period of 4 weeks. The screening period was extended up to 44 days if a washout period from any prohibited medications was required. The study parameters are summarized in Table 6.

Table 6

[0216] Table 7 shows the least squares mean percent change from Baseline/Day 1 in average VAS pruritus score in subjects with chronic pruritus who took orally placebo or 0.25 mg, 1 mg or 5 mg of serlopitant once daily for 6 weeks. Compared to placebo, a once-daily 1 mg dose and a once -daily 5 mg dose of serlopitant provided statistically significant improvement in relief of itch at Weeks 4, 5 and 6 in the VAS score (the primary efficacy endpoint; Table 7). Similarly, at Week 6 {he 1 mg serlopitant group and the 5 mg serlopitant group showed an improvement in live NRS itch score (a secondary efficacy endpoint) of 39.4% and 39.0% from Baseline, respectively, both of which were statistically significantly (p < 0.05) superior to the placebo group improvement of 28.7%. In addition, a once-daily 1 mg dose and a once-daily 5 mg dose of serlopitant resulted in a 4-point responder rate (the proportion of subjects achieving > 4-point improvement on a 10-point scale) of 42% and 53%, respectively, in the average VAS itch score at Week 6 compared to a 4-point responder rate of 26% for placebo at Week 6. All three doses of serlopitant were well tolerated and exhibited an excellent safety profile, with the most common treatment-emergent adverse events being diarrhea, somnolence and headache in the low single-digit percent, and all adverse events being of mild or moderate intensity.

Table 7. Least squares mean % change from baseline in average VAS itch score

*p < 0.05 vs placebo

Example 7. Clinical Study of Serlopitant for Chronic Pruritus in Prurigo Nodularis

[0217] A well-controlled human clinical trial assessing the efficacy of serlopitant in the treatment of pruritus associated with prurigo nodularis (PN) was approved by an Institutional Review Board and was conducted in accordance with the ICH Guidelines for Good Clinical Practices, German regulations on recordkeeping of subject information, and any local regulatory requirements. The study was a Phase 11 randomized, double-blind, placebo-controlled, multicenter trial designed to evaluate the efficacy and safety of serlopitant versus placebo in subjects with PN Tire study subject population was adult males and females 18 to 80 years of age who had both PN (lesions on both arms, both legs or/and the trunk of tire body) and pruritus of more than 6-week duration which were unresponsive or inadequately responsive to topical glucocorticoid or oral antihistamine therapies, and who had a Visual Analog Scale (VAS) pruritus score of at least 70 on a 0 to 100 mm scale within 72 hours of baseline. The subjects had chronic pruritus due to PN.

[0218] Subjects were randomized to receive either a 5-mg tablet of serlopitant or a matching placebo tablet. Subjects took a tablet of serlopitant or placebo once daily by mouth for 8 weeks following a loading dose of 3 tablets on the first day of treatment. The maximum study duration for each subject was about 14 weeks and included a screening period of up to 4 weeks, a treatment period of 8 weeks, and a follow-up period of 2 weeks. The study parameters are summarized in Table 8.

Table 8

[0219] Regarding the primary efficacy endpoint, Table 9 shows the mean difference in change of the average itch VAS score from Baseline at Weeks 2, 4, and 8 between subjects with chronic pruritus due to prurigo nodularis who took orally 5 mg of serlopitant or placebo once daily for 8 weeks. At Baseline, the average itch VAS score (average itch over the past 24 hours) for the serlopitant group and the placebo group was 7.88 and 7.92, respectively. Compared to placebo, a once-daily 5 mg dose of serlopitant resulted in a statistically significant improvement (a statistically significantly greater decrease) in the average itch VAS score from Baseline at Weeks 2, 4, and 8. Furthermore, a once -daily 5 mg dose of serlopitant led to a 4-point responder rate (the proportion of subjects achieving > 4-point improvement on a 10-point scale) of 54% with respect to the average itch VAS score at Week 8 compared to 25% for placebo.

Table 9, Mean difference between 5 mg serlopitant and placebo in change of average itch VAS score from baseline by repeated measures analysis

SE = standard error

[0220] Treatment with serlopitant alleviated pruritus to a greater extent in subjects with PN of longer duration. The mean difference in change of the average itch VAS score from Baseline at Week 8 between the 5 mg serlopitant group and the placebo group was -2.19 {95% Cl of (- 3.57, -0.81 )} in subjects with PN for > 5 years, while it was -0.78 {95% Cl of (-2.17, 0.61 )} in subjects with PN for < 5 years.

[0221 ] A once-daily 5 mg dose of serlopi tant also demonstrated efficacy in secondary endpoints compared to placebo in subjects with chronic pruritus due to PN. First, there was a greater proportion of subjects reporting“no/mild pruritus^’’ on the VRS, and improvement in pruritus on the PGA, at Week 8 in the serlopitant group (54.4% and 82.5%, respectively) than in the placebo group (28.9% and 54.3%, respectively). Second, serlopitant provided a statistically significantly greater improvement in the worst itch VAS score from Baseline to Week 8 than placebo (p ^::: 0.0024). Third, serlopitant provided a statistically significantly greater decrease in the average itch NRS score from Baseline to Week 8 than placebo (p =^: 0.0069). Fourth, a once- daily 5 mg dose of serlopitant resulted in a 4-point responder rate of 47% with respect to the worst itch NRS score at Week 8 compared to 26% for placebo. Fifth, serlopitant provided greater improvement in pruritus on the IGA than placebo.

[0222] Serlopitant was well tolerated and safe in the study, and no significant safety signal was detected. Treatment-emergent adverse events were generally mild or moderate. The most common adverse events were nasopharyngitis (17%) and diarrhea (11%).

Example 8. Clinical Study of Serlopitant for Chronic Idiopathic Pruritus

[0223] A well-controlled human clinical trial assessing the efficacy of serlopitant in the treatment of chronic idiopathic pruritus (CIP) is conducted in accordance with the ICH

Guidelines for Good Clinical Practices, the U.S. Code of Federal Regulations, HIPAA and any local regulatory requirements. The study is a Phase II randomized, double-blind, placebo- controlled, multicenter trial designed to evaluate the efficacy, tolerability and safety of serlopitant versus placebo in subjects with CIP. The study subject population includes adult males and females 18-65 years of age. The subjects have CIP of at least 6-month duration despite treatment with standard-of-care antipruritic therapies such as oral Hi antihistamines, topical corticosteroids and emollients.

[0224] Subjects are randomized to receive either a 5 -mg tablet of serlopitant or a matching placebo tablet. Subjects take a tablet of serlopitant or placebo once daily by mouth for a total of 6 weeks following a loading dose of 3 tablets on the first day of treatment. Tire maximum study duration for each subject is about 12-14 w¾eks and includes a screening period of 2-4 weeks, a treatment period of 6 weeks, and a follow-up period of 4 weeks. The study parameters are summarized in Table 10.

Table 10

[0225] Other primary efficacy endpoints can also be used, including without limitation the WI-NRS and AI-NRS 4-point responder rates at Week 6. Moreover, other secondary efficacy- endpoints can also be used, including without limitation the WI-NRS and AI-NRS 4-point responder rates at the midpoint of the treatment period (Week 3), the WI-NRS and AI-NRS 3- point responder rates at Weeks 3 and 6, the change in WI-NRS and AI-NRS from Baseline to Weeks 2 and 4, the change in mean Visual Analog Scale (VAS) pruritus score from Baseline to Week 6, the change in mean Verbal Rating Scale (VRS) pruritus score from Baseline to Week 6, the change in 5-D Pruritus Scale from Baseline to Week 6, the change in Static Patient Global Assessment of Itch Severity (sPGA) from Baseline to Week 6, the change in Patient Global Impression of Change in Itch Severity (PGIC) from Baseline to Week 6, the change in the number of nighttime scratching events per hour from Baseline to Week 6, and the change in sleep and activity actigraphy from Baseline to Week 6.

Example 9, Clinical Study of Serlopitant for Pruritus Associated with Psoriasis

[0226] A well-controlled human clinical trial assessing the efficacy of serlopitant in the treatment of pruritus in adults with plaque psoriasis was conducted in accordance with the ICH Guidelines for Good Clinical Practices, the U.S. Code of Federal Regulations, H1PAA and any local regulatory requirements. The study was a Phase II randomized, double-blind, placebo- controlled, multicenter trial designed to evaluate the efficacy and safety of serlopitant versus placebo in subjects with pruritus associated with plaque psoriasis. The study subject population was adult males and females 18 to 80 years of age wire had pruritus of at least 4-week duration and plaque psoriasis of at least 6-month duration, and who had plaques covering at most 10% of the body surface ares and a screening worst itch numerical rating scale (WI-NRS) score >7 in the 24-hour period prior to the initial screeining visit. Mean age for subjects was 47.5 years, 54.2% were female, and 85.2% were Caucasian .

[0227] Subjects were randomized in a 1 : 1 ratio to receive either a 5 -mg tablet of ser!opitant or a matching placebo tablet. Subjects took a tablet of seriopitant or placebo once daily by mouth for a total of 8 weeks, following a 3-tablet loading dose on the first day of the treatment period . The maximum study duration for each subject was about 12-14 weeks and includes a screening period of 2-4 weeks, a treatment period of 8 weeks, and a follow-up period of 2 weeks. The study parameters are summarized in Table 1 1.

[0228] Regarding the primary efficacy endpoint, Table 12 shows the mean difference in change of the WI-NRS 4-point response rate at Weeks 4 and 8 between subjects with pruritus associated with plaque psoriasis who took orally 5 mg of serlopitant or placebo once daily for 8 weeks following a 3-tablet loading dose on the first day of the treatment period. At Baseline, the WI-NRS 4-point response rate for the serlopitant group and the placebo group was 8.3% and 8.1 %, respectively. Compared to placebo, a once-daily 5 mg dose of serlopitant resulted in a statistically significant improvement (a statistically significantly greater increase) in the WI-NRS 4-point response rate from Baseline at Weeks 4 and 8. Furthermore, a once-daily 5 mg dose of serlopitant led to a WI-NRS 4-point response rate (the proportion of subjects achieving > 4-point improvement on a 10-point scale) of 20.8% at Week 4 compared to 11.5% for placebo (p = 0.039), and 33.3%% at Week 8 compared to 21.1 % for placebo (p ------ 0.028). At corresponding timepoints, the WI-NRS 3-point responder rates for serlopitant were 42.1% and 31.9%.

Additionally, treatment-related adverse events were reported for 4.9% of serlopitant-treated patients compared to 4.0% of placebo-treated patients.

Table 12. WI-NRS 4-point response rates for pa· cm is with pruritus associated with psoriasis in the 5 mg serlopitant and placebo treatment groups

[0229] Serlopitant significantly reduced pruritus associated with psoriasis, as demonstrated by 4-point improvement on Wl-NRS at Weeks 4 and 8. This corresponds to clinically meaningful improvement in itching for this patient population.

[0230] Differences in 4-point responder rate between serlopitant and placebo were also compared across different subgroup populations. Generally, the differences in 4-point responder rate between serlopitant and placebo, respectively, were maintained with some variance across age groups (36.9% vs 22.1% in those <47 years; 30.5% vs 19.9% in those >47 years), by gender (38.2% vs 21.7% in females; 29.0% vs 20.0% in males), by weight (36.9% vs 19.8% for <85.7 kg; 29.6% vs 22.3% for >85.7 kg), by baseline body surface area (33.2% vs 21.2% for <5%; 33 5% vs 20.8% for >5), by baseline WI-NRS score (32.7% vs 22 9% for <9; 34.6% vs 15.0% for >9), and by baseline Physician Global Assessment (34.8% vs 22.0% for mild/moderate;

22.3% vs 15.5% for severe/very severe).

[0231] Additional or different clinical trials according to a similar study design can be conducted to study, e.g., different dosages (e.g., about 1 mg or 10 mg once daily), different dosing schedules (e.g., about 1 mg or 5 mg twice daily) or different modes of administration (e.g , oral inhalation) of serlopitant, or different lengths of treament (e.g., about 2 months,

3 months, 6 months or 1 year) with serlopitant. Furthermore, the efficacy of serlopitant in specific subject populations, such as children, adolescents, the elderly, and in treating pruritus of a longer duration (e.g , at least 1 year, 2 years, 3 years or 5 years) or pruritus associated with a particular type of pruritic condition (e.g., cholestatic, uremic or neuropathic pruritus), can be determined in additional or different clinical trials conducted in a similar fashion.

[0232] it is understood that, while particular embodiments have been illustrated and described, various modifications may be made thereto and are contemplated herein. It is also understood that the disclosure is not limited by the specific examples provided herein. The description and illustration of embodiments and examples of the disclosure herein are not intended to be construed in a limiting sense. It is further understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein, which may depend upon a variety of conditions and variables. Various

modifications and variation s in form and detail of the embodim ents and examples of the disclosure will be apparent to a person skilled in the art. It is therefore contemplated that the disclosure also covers any and all such modifications, variations and equivalents.

Claims

1. A method of treating chronic pruritus havi ng a duration of at least about six m onths, comprising administering to a subject in need of treatment a therapeutically effective amount of 3-[(3aR,4R,5S,7aS)-5-[( lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-fluorophenyl)- l,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-l-one (serlopitant) or a

pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof.

2. The method of claim 1, wherein the chronic pruritus has duration of at least about 1 year, 2 years, 3 years, 4 years, 5 years, or 10 years.

3. lire method of claim 1 or 2, wherein the chronic pruritus is characterized by spontaneous itch, alloknesis or hyperknesis, or any combination or all thereof.

4. The method of claim 3, wherein serlopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof reduces the frequency or/and the intensity of spontaneous itch, alloknesis or hyperknesis, or any combination or all thereof, by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, as measured by a visual analog scale (VAS) score or a numerical rating scale (NRS) score.

5. The method of any one of the preceding claims, wherein the therapeutically effective amount of serlopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoi somer thereof is adm inistered one or more times a day, once every' two days, once every three days, twice a week or once a week.

6. lire method of any one of claims 1-5, wherein the therapeutically effective amount of serlopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is about 0 25 or 1 to 5 mg or 5-10 mg, or about 0.25 mg, 0.5 mg, 1 mg, 5 mg or 10 mg, once or twice daily.

7. The method of any one of claims 1-5, wherein the therapeutically effective amount of serlopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is about 5 mg once daily.

8. The method of any one of claims 1-5, wherein the therapeutically effective amount of serlopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is about 5 to 40 mg once a week.

9. The method of any one of the preceding claims, wherein the therapeutically effective amount of seriopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is adm inistered over a period of at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years.

10. The method of any one of the preceding claims, wherein seriopitant or the

pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is administered orally, parenterally or topically.

11. The method of any one of the preceding claims, wherein seriopitant or the

pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is administered orally in a dose of about 0.25, 0.5, 1, 5 or 10 mg once daily for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years.

12. The method of any one of the preceding claims, wherein at least one loading dose of seriopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is first administered, and a therapeutically effective maintenance dose of seriopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is subsequently administered.

13. The method of claim 12, wherein the at least one loading dose of seriopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is about 1.5, 2, 3, 4 or 5 times larger than the therapeutically effective maintenance dose.

14. The method of claim 12 or 13, wherein the therapeutically effective maintenance dose of seriopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is about 0.25 or 1 to 5 mg or 5-10 mg, or about 0.25 mg, 0.5 mg, 1 mg, 5 mg or 10 mg, once or twice daily.

15. The method of any one of claims 12-14, wherein seriopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is administered in a loading dose of about 3-15 mg or 15-30 mg once or twice on day 1, followed by a maintenance dose of about 1-5 mg or about 5-10 mg once or twice daily for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months. 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years or longer, where the loading dose is three times larger than the maintenance dose, and serlopitant or the pharmaceutically acceptable salt, solvate, hydrate, clathrate, polym orph, prodrug, metabolite or stereoisomer thereof is administered orally.

16. The method of any one of the preceding claims, wherein serlopitant or the

pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug, metabolite or stereoisomer thereof is administered at bedtime or in the morning.

17. The method of any one of the preceding claims, wherein serl opitant or the

pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrag, metabolite or stereoisomer thereof is administered without food at least about 2 hours before or after a meal.

18. The method of any one of the preceding claims, wherein the chronic pruritus is associated with xerosis, xeroderma, dermatitis, atopic dermatitis, eczema, or psoriasis.

19. The method of any one of the preceding claims, wherein the chronic pruritus is associated with plaque psoriasis.

20. The method of claim 19, wherein the plaque psoriasis is present in any anatomic location of the subject and covering at most 30%, at most 25%, at most 20%, at most 15%, at most 10% or at most 5% of body surface area in total.

21. The method of any one of claims 1-17, wherein the chronic pruritus is chronic idiopathic pruritus

22. The method of any one of the preceding claims, wherein any one or more of i) - iii) apply:

i) the subject is about 40 years of age or older;

ii) the chronic pruritus is associated with a condition or disorder of mild to moderate severity; and

iii) the chronic pruritus is not characterized by or associated with one or more of stinging, burning, inflammation, and neuropathy

23. The method of any one of the preceding claims, further comprising administering one or more additional antipruritic agents.

24. The method of claim 23, wherein the one or more additional antipruritic agents comprise: a) an inhibitor of brain natriuretic peptide (BNP) or the receptor therefor (NprA), an inhibitor of gastrin-releasing peptide (GRP) or the receptor therefor (GRPR). an inhibitor of glutamate or a receptor therefor, or a GABAergic agent, or any combination or all thereof;

b) a TRPA1 antagonist or/and a TRPYl antagonist or desensitizer;

e) an Mrgpr antagonist, a PAR antagonist or a TLR antagonist, or any combination or all thereof;

d) a kappa-opioid receptor agonist, a mu -opioid receptor antagonist, an anticonvulsant or an antidepressant, or any combination or all thereof;

e) a corticosteroid/glucocorticoid, an immunosuppressant, an inhibitor of an inflammatory cytokine or a receptor therefor, or an Hi or Hr antihistamine, or any combination thereof; or f) a topical counterirritant or/and cooling agent, a topical local anesthetic, a moisturizer or emollient, or UV phototherapy, or any combination or all thereof.

25. Serlopitant or a pharmaceutically acceptable salt, solvate, hydrate, dathrate, polymorph, prodrug, metabolite or stereoisomer thereof for use in the treatment of chronic pruritus having a duration of at least about six months, optionally in combination with an additional antipruritic agent

26. A composition comprising serlopitant or a pharmaceutically acceptable salt, solvate, hydrate, dathrate, polymorph, prodrug, metabolite or stereoisomer thereof for use in the treatment of chronic pruritus having a duration of at least about six months, optionally in combination with an additional antipruritic agent.

27. Use of serlopitant or a pharmaceutically acceptable salt, solvate, hydrate, dathrate, polymorph, prodrug, metabolite or stereoisomer thereof in the preparation of a medicament for the treatment of chronic pruritus having a duration of at least about six months, optionally m combination with an additional antipruritic agent.

28. A kit comprising:

serlopitant or a pharmaceutically acceptable salt, solvate, hydrate, dathrate, polymorph, prodrug, metabolite or stereoisomer thereof; and

instructions for administering or using serlopitant or the pharmaceutically acceptable salt, solvate, hydrate, dathrate, polymorph, prodrug, metabolite or stereoisomer thereof to treat chronic pruritus having a duration of at least about six months.