Patent Description:
Motion sickness is a disorder defined by a constellation of symptoms that can result from real or perceived sickness-inducing motion. Such motion may include, e.g., motion involving the head of a subject that can produce one or more symptoms characteristic of motion sickness. The sickness-inducing motion that gives rise to motion sickness may commonly include riding in any form of transportation such as, e.g., automobiles, buses, trains, other ground or rail transportation, boats under power, ferries, cruise ships, sailboats, personal water craft, canoes, kayaks, row boats, airplanes and helicopters, amusement rides, and certain gymnastic maneuvers such as somersaults. The symptoms of motion sickness typically can include, but are not limited to, nausea, vomiting, dizziness, headache, fullness, cold sweats, sweating, pallor, disorientation, and anorexia. Motion sickness has been reported to affect up to <NUM>% of the general population under ordinary travel conditions that include sea, air, and land travel. The prevalence of motion sickness in one epidemiological study during bus travel found <NUM>% of passengers reporting feeling ill while <NUM>% reported experiencing nausea.

Under the sensory conflict theory, motion sickness is described as arising due to a mismatch between the perceptions of motion, or lack thereof, by the visual, vestibular, and somatosensory systems. A discrepancy between actual body position and perceived body position is believed to trigger the maladaptive response of motion sickness. Motion sickness is one of the most prevalent episodic disorders in the world, and its prevalence has dramatically increased with world population mobility. Despite the increasing prevalence of the disorder, the treatments available today, which are primarily antihistamines and anticholinergics, were first discovered in the <NUM>'s.

The mammalian tachykinins (neurokinins [NKs]) are a family of peptide neurotransmitters that share a common C-terminal sequence. This group includes substance P (SP), neurokinin-A (NKA), and neurokinin-B (NKB). SP, the most abundant NK, preferentially binds to the neurokinin type-<NUM> (NK-<NUM>) receptor and is involved in the regulation of many physiological processes. NK-<NUM> receptors have been mapped in the central nervous system and were found to have a broad distribution in the brain, including the mid-brain, basal ganglia, hypothalamus, and limbic system. Neurokinin receptors are also widely distributed in the gut, the bronchial tree, and the vascular system.

The NK-<NUM> receptor has been identified as a potential therapeutic target for the treatment of motion sickness. Maropitant, another neurokinin <NUM> receptor antagonist, is approved for the prevention of vomiting due to motion sickness in dogs and cats. A crossover study showed that the therapy reduced the occurrence of vomiting in over <NUM>% of dogs as compared to placebo. This data supports the exploration of the effects of NK-<NUM> antagonists on motion sickness in humans, though maropitant has a different molecular composition and pharmacokinetics from other NK-<NUM> antagonists. Another NK1-receptor antagonist, aprepitant, is approved for postoperative nausea and vomiting (PONV) in adults, and for use with other medications in children and adults to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines. Currently, tradipitant is being tested in clinical trials for the treatment of nausea and vomiting in patients with gastroparesis. Currently, available therapies are not effective for all patients and some of the medications used have significant side effect profiles.

Tradipitant is a highly potent, selective, centrally penetrating, and orally active neurokinin-<NUM> (NK-<NUM>) receptor antagonist, depicted below as the compound of Formula (I)
<CHM>.

Tradipitant is disclosed in <CIT>, and contains six main structural components: the <NUM>,<NUM>-bis-trifluoromethylphenyl moiety, two pyridine rings, the triazol ring, the chlorophenyl ring, and the methanone. Tradipitant is known by the chemical names: <NUM>-[<NUM>-[[<NUM>,<NUM>-bis(trifluoromethyl)phenyl]methyl]-<NUM>-(<NUM>-pyridinyl)-<NUM>-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl]-<NUM>-pyridinyl](<NUM>-chlorophenyl)-methanone, and {<NUM>-[<NUM>-(<NUM>,<NUM>-bistrifluoromethylbenzyl)-<NUM>-pyridin-<NUM>-yl-<NUM>-[<NUM>,<NUM>,<NUM>]triazol-<NUM>-yl]-pyridin-<NUM>-yl}-(<NUM>-chlorophenyl)-methanone, and has also been known as LY686017 and as VLY-<NUM>. Crystalline Forms IV and V of tradipitant are disclosed in <CIT>, and a process for preparing crystalline f <NUM>-[<NUM>-(<NUM>,<NUM>-bistrifluoromethylbenzyl)-<NUM>-pyridin-<NUM>-yl-<NUM>-[<NUM>,<NUM>,<NUM>]triazol-<NUM>-yl]-pyridin-<NUM>-yl}-(<NUM>-chlorophenyl)-methanone, Form IV is disclosed in US Pats. <NUM>,<NUM>,<NUM>; <NUM>,<NUM>,<NUM>; and <NUM>,<NUM>,<NUM>.

In preclinical and clinical studies, tradipitant produces a long-lasting blockade of brain NK-<NUM> receptors. Although the distinct pathways of nausea and vomiting are largely undetermined, a definitive role of SP acting at NK-<NUM> receptors in the nucleus tractus solitarus has been confirmed. Previous clinical studies have demonstrated the efficacy of NK-<NUM> antagonism in the prevention of chemotherapy induced and postoperative nausea and vomiting (CINV and PONV).

Tradipitant has been shown to be useful in treating nausea and vomiting associated with chemotherapy (<NPL> and <CIT>), in the treatment of pruritus (<CIT>) an in the treatment of depression, anxiety, Alzheimer's disease and inflammatory diseases (<CIT>).

<CIT> describes <NUM>-phenylpyridine derivatives as substance P antagonists (NK1 receptor antagonists) for the treatment of various diseases including motion sickness and emesis.

In the following description, where reference is made to the invention encompassing a method of treating a disease using a compound, we intend such references to be interpreted as relating to said compounds for use in said methods of treating said disease.

A first aspect of the invention provides tradipitant for use in the treatment or prevention of motion sickness or a symptom thereof, in an individual, the individual being a human, wherein the treatment or prevention comprises administration of the tradipitant to said individual in an amount effective to prevent or treat the motion sickness or the symptom thereof in the individual. In practicing the foregoing use, the amount of tradipitant that is effective to prevent motion sickness or a symptom thereof may be, e.g., <NUM>-<NUM>, <NUM>-<NUM>, or <NUM>-<NUM>. For example, the effective amount can be about <NUM>. The effective amount may be administered in a single dose, such as a single oral dose, and may or may not be in a single dosage unit form. The dose may be administered in advance of engaging in a sickness-inducing motion, typically about <NUM> minutes before commencing such motion. Administration of such an effective amount prior to commencing sickness-inducing motion can prevent or reduce the severity or frequency of one or more symptoms of motion sickness, including the prevention of nausea, vomiting, dizziness, headache, fullness, cold sweats, sweating, pallor, or disorientation.

Treatment of motion sickness may be considered to include a reduction in severity of symptoms, the prevention of progression, or the complete resolution of one or more symptoms of motion sickness after such symptom or symptoms have manifest in the individual. In practicing the foregoing use, the amount of tradipitant that is effective to treat motion sickness or a symptom thereof may be, e.g., <NUM>-<NUM>, <NUM>-<NUM>, or <NUM>-<NUM>. For example, the effective amount can be about <NUM>. The effective amount may be administered in a single dose, such as a single oral dose, and may or may not be in a single dosage unit form. The dose may be administered after the onset of at least one symptom of motion sickness, preferably soon after the onset of the at least one symptom, and more preferably, immediately after the onset of the at least one symptom. Administration of such an effective amount after motion sickness has begun to manifest can reduce the severity of the symptom(s), eliminate the symptom(s), prevent the progression or intensification of the symptom(s) of motion sickness, for example from dizziness to nausea, from nausea to vomiting, etc..

Another aspect of the invention provides a pharmaceutical composition for use in the treatment or prevention of motion sickness or a symptom thereof in an individual, the individual being a human, wherein the pharmaceutical composition comprises tradipitant or a pharmaceutically acceptable salt thereof, and at least one excipient, wherein the treatment or prevention comprises: administration of the pharmaceutical composition to the individual in an amount effective to prevent or treat the motion sickness of the symptom thereof in the individual.

Herein also disclosed, although not forming part of the claimed invention, is tradipitant for use in the manufacture of a pharmaceutical composition comprising tradipitant for use in the treatment or prevention described in the preceding aspects.

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

The use of tradipitant as described herein requires administering an amount of tradipitant that is effective to prevent or treat motion sickness or a symptom thereof. The amount administered to a subject being treated depends upon a number of factors, including the species being treated, the weight of the subject being treated, and the subject's condition otherwise. The use specifically involves the prevention and amelioration of motion sickness in human beings, including adult human beings. In adult human beings the typical dose effective to prevent motion sickness or a symptom thereof is <NUM>-<NUM>, <NUM>-<NUM>, or <NUM>-<NUM>. One specific regime involves administration of about <NUM>-<NUM>, or more particularly about <NUM>.

As used herein, the terms "patient," "subject," and "individual" refer to a mammal who is administrated tradipitant.

The subject is a human being. The term "effective amount," i.e., dose, of tradipitant refers to an amount that is effective in treating or preventing the disorders described herein, or symptoms thereof.

As indicated above, a use is provided herein for preventing motion sickness or a symptom thereof, in an individual anticipating experiencing sickness-inducing motion. Such use comprises prophylactically administering tradipitant to said individual in an amount effective to prevent the manifestation of motion sickness or one or more symptoms thereof. The effective amount of tradipitant to prevent motion sickness or a symptom thereof may be, e.g., <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, or <NUM>-<NUM>, and may particularly be about <NUM>. The effective amount may be administered in a single dose such as, e.g., a single oral dose, and may or may not be in a single dosage unit form. The dose may be administered in advance of engaging in a sickness-inducing motion, for example, in advance of boarding an airplane, train, boat, or other vehicle, or getting into an automobile, or before an anticipated airplane takeoff or commencement of motion on board any other type of vehicle. Particularly, the dose may be administered about thirty (<NUM>) minutes prior to commencement of the potentially motion sickness-inducing motion or activity. Such administration of an effective amount of tradipitant can prevent the manifestation of one or more symptoms of motion sickness, including the prevention of nausea, vomiting, dizziness, headache, fullness, or disorientation, or may limit the symptom(s) experienced by the individual and the severity thereof.

A use is also provided herein for treating motion sickness or a symptom thereof after such motion sickness has already manifest or begun to manifest in the individual. Such use includes administering tradipitant to said individual in an amount effective to treat the motion sickness or the symptom thereof. Treatment of motion sickness in the present context includes all processes in which there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of motion sickness and/or symptoms thereof. For example, such treatment may include the prevention of progression, or the partial or complete resolution of one or more symptoms of motion sickness after such symptom or symptoms have manifest in the individual. In practicing the foregoing use, the amount of tradipitant that is effective to treat motion sickness or a symptom thereof may be, e.g., <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, or particularly about <NUM>. The effective amount may be administered in a single dose, including a single oral dose, which may or may not be in a single dosage unit form. The effective amount of tradipitant may be administered after the onset of at least one symptom of motion sickness. Preferably, the effective amount is administered soon after the onset of the at least one symptom, for example up to thirty (<NUM>) minutes after the onset of the at least one symptom, and more preferably, the effective amount is administered immediately or substantially immediately after the onset of the at least one symptom. Administration of such an effective amount after motion sickness has begun to manifest can reduce the severity of the symptom(s), eliminate the symptom(s), or prevent the progression or intensification of the symptom(s) of motion sickness, for example from dizziness to nausea, from nausea to vomiting, etc..

Tradipitant is a selective neurokinin-<NUM> (NK-<NUM>) receptor antagonist. In vitro, tradipitant potently inhibits NK-<NUM> receptor binding and antagonizes the effects of an NK-<NUM> agonist in a functional assay. No significant activity is observed in a panel of <NUM> additional receptors, enzymes, and ion channels including the NK-<NUM> and NK-<NUM> receptors. By <NUM> different measures, tradipitant is also a potent centrally active NK-<NUM> antagonist in vivo.

Tradipitant inhibits [<NUM>I]substance P (SP) binding to the NK-<NUM> receptor expressed by IM-<NUM> cells with a Ki of <NUM> and inhibits the SP-induced mobilization of intracellular calcium in U373 cells with a Kb of <NUM> (Table <NUM>).

These potencies are similar to those observed with the NK-<NUM> antagonists aprepitant (MK-<NUM>) and CP-<NUM>. In addition, results from tradipitant evaluation in a panel of <NUM> other receptors, enzymes, and ion channels indicate that, at a test concentration of <NUM>, tradipitant does not exhibit any inhibition of binding greater than <NUM>%. At the NK-<NUM> and NK-<NUM> receptors, the compound produces no significant inhibition. Therefore, tradipitant is a highly selective NK-<NUM> antagonist in vitro.

As shown in Table <NUM>, several of the major metabolites of tradipitant have an affinity for the NK-<NUM> receptor based on a binding assay. These metabolites have high affinity for the NK-<NUM> receptor.

Differences in species selectivity of NK-<NUM> receptors pose challenges to characterization of NK-<NUM> receptor antagonists in vivo. Gerbil NK-<NUM> receptors have previously been shown to be similar to those in humans. Gerbils exhibit a characteristic stereotypic foot-tapping behavior in response to distress, fear, or aversive stimuli. Intracerebroventricular (icv) administration of substance P or a selective NK-<NUM> receptor agonist such as GR73632 produces rapid rhythmic tapping of the hind feet lasting approximately <NUM> minutes, which can be inhibited by systemic administration of a brain penetrating antagonist of the NK-<NUM> receptor. This response is selective for NK-<NUM> agonists, since selective NK-<NUM> and NK-<NUM> agonists do not elicit a similar response. This behavioral response is further characterized and modified to enable identification and optimization, in vivo, of potent NK-<NUM> receptor antagonists including tradipitant.

Male Mongolian gerbils (Harlan Sprague Dawley, Indianapolis, IN) weighing <NUM> to <NUM> grams are administered the selective neurokinin-<NUM> receptor agonist GR73632 (<NUM> pmol) via direct, vertical, free-hand intracerebroventricular (icv) injection to a depth of <NUM> below bregma with a cuffed <NUM>-gauge needle attached to a <NUM>µl Hamilton syringe. Immediately after injection, animals are placed individually into isolated chambers with pressure-sensitive velocimeter platform floors (San Diego Instruments acoustic startle apparatus) that detect and quantify vibration. The San Diego Instruments "SR" DOS-based computer program is used on a PC to record the number of foot-taps over the following <NUM> to <NUM> minutes, beginning <NUM> seconds after the floor is lightly tapped. Raw data are converted with a Microsoft® Excel® (Microsoft® and Excel® are registered trademarks of Microsoft Corp. , Redmond, WA) macro that determines the number of events over threshold (<NUM>) in each <NUM>-millisecond time bin over the <NUM> minutes following onset of observation. The total number and average intensity of events over the duration is determined. Total number of taps is analyzed with one-way ANOVA and post-hoc Dunnett's test using JMP statistical software.

A dose-response curve (with doses of <NUM>, <NUM>, <NUM> and <NUM> pmols, icv) is initially generated with the NK-<NUM> agonist GR73632. Maximal foot-tapping behavior is achieved with <NUM> and <NUM> pmol doses; the <NUM> pmol dose is subsequently chosen as the dose of choice for antagonism experiments.

NK-<NUM> antagonists are tested for their ability to attenuate GR73632-induced foot tapping. NK-<NUM> antagonists are administered (po) via oral feeding tube at doses and time points specified in each experiment. All animals receive only one dose of NK-<NUM> antagonists in all tests.

NK-<NUM> antagonists are administered at multiple doses (at least <NUM>; one dose per animal) and response to GR73632 is measured.

NK-<NUM> receptor antagonists are administered at multiple pre-treatment times (one administration per animal) including at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> hours prior to GR73632 injection. GR73632 (Peninsula Labs, CA) is dissolved in saline. Tradipitant is dissolved in <NUM>% CMC/<NUM>% SLS/<NUM>% PVP vehicle. CP-<NUM> and aprepitant are synthesized at Lilly Laboratories and dissolved in <NUM>%ethanol/emulphor and <NUM>% CMC/<NUM>% SLS/<NUM>% PVP respectively.

As shown in <FIG>, orally administered tradipitant potently inhibits NK-<NUM> agonist-induced foot-tapping behavior in gerbils <NUM> hours after administration of drug in a dose-dependent manner, with an ED<NUM> of <NUM> ± <NUM>/kg (*p < <NUM> compared to vehicle for <NUM>/kg and <NUM>/kg doses). Data shown in <FIG> are expressed in number of foot-tapping events occurring in five (<NUM>) minutes.

<FIG> depicts a comparison of the efficacy of tradipitant to that of other NK-<NUM> antagonists, with data expressed as percent control of vehicle (vehicle response to <NUM> pmol GR73632). Tradipitant is found to be more potent than aprepitant (Merck, ED<NUM> = <NUM>/kg ± <NUM>/kg) and CP-<NUM> (Pfizer, ED<NUM> =<NUM>/kg ± <NUM>/kg).

<FIG> depicts the effects of tradipitant over a time course on NK-<NUM> agonist (GR <NUM>, <NUM> pmol, icv)-induced foot-tapping behavior after oral administration, compared with that of NK-<NUM> antagonists aprepitant and CP-<NUM>. Tradipitant (<NUM>/kg, po) is found to significantly inhibit foot-tapping behavior up to <NUM> hours after administration but the effect is significantly diminished by <NUM> hours after administration at this dose. However, at a higher dose of <NUM>/kg, tradipitant shows greater than <NUM>% inhibition of foot-tapping behavior <NUM> hours after administration. The duration of effect of tradipitant is longer than that of CP-<NUM> (up to <NUM> hours after administration, <NUM>/kg) while aprepitant (<NUM>/kg) shows inhibition of foot-tapping behavior up to <NUM> hours after administration. Data are expressed as percent control of vehicle (vehicle response to <NUM> pmol GR73632).

The effect of tradipitant on NK-<NUM> agonist-induced foot-tapping behavior in gerbils suggests that tradipitant is a very potent, centrally acting NK-<NUM> receptor antagonist in vivo in the gerbil with a relatively long duration of action.

Five male dogs are administered a single oral dose of <NUM>/kg aprepitant (a positive control), or tradipitant at <NUM>, <NUM>, and <NUM>/kg in a Latin-square design. An intravenous injection of <NUM>/kg apomorphine, a known emetic, is given alone, or <NUM> hours after administration of tradipitant or aprepitant. Each animal is administered a different dose on a particular dosing day, so that each dose of tradipitant, aprepitant, and apomorphine alone is represented. Over the five (<NUM>) weeks of the study, each animal receives each of the treatments, but only one per week. The purpose of this study is to determine if tradipitant suppresses apomorphine-induced emesis.

The low dose of tradipitant is <NUM> times the ED<NUM> in the gerbil foot-tapping model of NK-<NUM> receptor antagonism (Example <NUM>. The high dose is <NUM> times this efficacious dose, and is also the dose of aprepitant that has previously been determined to be efficacious against apomorphine-induced emesis in the dog. The mid dose of tradipitant is the approximate half-log interval between the low and high doses.

The oral route of administration is selected for tradipitant because this is the route proposed or currently used clinically. The intravenous route is typically used for experimental apomorphine administration. The beagle dog is considered an effective species for demonstration of antagonism of apomorphine-induced emesis.

A single oral dose of <NUM>, <NUM>, <NUM>, or <NUM>/kg tradipitant, or <NUM>/kg aprepitant is administered to each male dog once a week in gelatin capsules. All animals are dosed over a period of five (<NUM>) weeks, with each dog receiving one of five different treatments on each day of dosing. A dose of <NUM>/kg apomorphine is administered by intravenous injection approximately two (<NUM>) hours after each administration of tradipitant or aprepitant. In cases where apomorphine is administered alone, without prior treatment with tradipitant or aprepitant, apomorphine is given at approximately the same time as when given in combination with tradipitant or aprepitant.

All dogs are fasted overnight prior to each treatment day and then fed approximately one (<NUM>) hour after oral dosing (approximately one (<NUM>) hour prior to administration of apomorphine). Individual doses are adjusted weekly for changes in body weight.

The dose regimen consists of a 5x5 Latin square design, in which each subject receives <NUM> dose or dose combination per week (<NUM> day washout) as shown in Table <NUM> below.

The number of emetic episodes is recorded for approximately one hour following the injection of apomorphine, and plasma concentrations at anticipated Tmax of tradipitant (<NUM> hours post-dosing) are evaluated.

Table <NUM> provides individual and mean and standard deviation values for the <NUM> hour plasma concentrations of tradipitant. All animals administered tradipitant have measurable levels at <NUM> hours post-dose. In general, plasma concentrations at <NUM> hours post-dose increase with increasing dose in a sub-proportional manner. As observed in other studies in dogs, the exposure to tradipitant is variable between animals. Individual animal data reveal no relationship between plasma concentrations and week of administration.

As shown in Table <NUM>, emesis occurs after each treatment, with the largest incidence of emesis occurring in the apomorphine alone group. One dog (Dog <NUM>) has a single episode of emesis at each dose of tradipitant and aprepitant; this dog also has the greatest number of emetic episodes with apomorphine alone (<NUM>). No emesis occurs in the remaining four (<NUM>) dogs at any dose of tradipitant or aprepitant. These dogs have an average of four (<NUM>) emetic episodes with apomorphine alone. The antiemetic effect of aprepitant supports the validity of this model.

Results of this study indicate that tradipitant is effective against apomorphine-induced emesis at each dose tested (<NUM>, <NUM>, and <NUM>/kg).

When introduced into the brain, the NK-<NUM> receptor agonist substance P (SP) elicits distress vocalizations in the guinea pig that can be inhibited by NK-<NUM> antagonists. This behavioral assay is used to demonstrate potency and CNS penetration of NK-<NUM> antagonists in the guinea pig, a species that has receptor affinity for NK-<NUM> antagonists that is similar to humans.

Male Dunkin/Hartley guinea pigs (<NUM> to <NUM> grams) are orally administered either vehicle or an NK-<NUM> antagonist. Approximately <NUM> minutes later (for dose response studies), the animals are anesthetized and <NUM> nmol of GR73632 (SP analog) in a vehicle volume of <NUM>µl is injected into the cerebral ventricle at the intersection of bregma and the midline of the skull. Animals are placed in a dark testing chamber located inside of a sound attenuation cubicle and vocalizations are recorded for <NUM> minutes following recovery from anesthesia. The time spent vocalizing is quantified for each animal. In the duration of action study, <NUM>/kg of tradipitant or vehicle solution is administered orally and then <NUM>, <NUM>, or <NUM> hours later, <NUM> nmol of GR73632 is administered into the cerebral ventricle as described above. Vocalizations are recorded and quantified as indicated above. Vehicle solutions are either CMC (<FIG> data) or an ethanol/emulphor solution (<FIG> and <FIG>). Data is analyzed using onetailed t-tests.

As shown in <FIG>, oral administration of tradipitant produces significant inhibition of agonist-induced vocalization at doses of <NUM>/kg (p<. <NUM>), <NUM>/kg (p < <NUM>), <NUM>/kg (p<. <NUM>), and <NUM>/kg (p<. Data shown parenthetically in <FIG> indicate percent of control response. Activity of tradipitant does not wane at the lower doses, indicating that even lower doses would be required to produce a dose response function.

As shown in <FIG>, the effect of <NUM>/kg tradipitant is significantly active in suppressing agonist-induced vocalization at <NUM> hours following oral administration of the antagonist compound.

A second dose-response study compares potencies of tradipitant, aprepitant, and CP-<NUM>. As shown in <FIG>, all NK-<NUM> antagonists tested produce significant inhibition of vocalization at <NUM>/kg. Only tradipitant retains significant inhibitory activity at and below <NUM>/kg. The minimum effective dose of tradipitant is found to be <NUM>/kg which produces highly significant (p<. <NUM>) inhibition of vocalization compared to controls. (Vehicle was ethanol/emulphor; vehicle groups were n=<NUM>-<NUM> per compound.

Tradipitant significantly inhibits NK-<NUM> agonist-induced vocalization in guinea pigs, indicating that this compound is an orally available and brain-penetrant NK-<NUM> antagonist. The minimum effective dose (MED) that produces this effect is <NUM>/kg. Tradipitant, administered orally, is shown to have a duration of activity that exceeds <NUM> hours. In this experimental paradigm, tradipitant is substantially more potent than aprepitant and CP-<NUM>.

A tracer NK-<NUM> antagonist compound (GR205171) is used to evaluate the ability of other NK-<NUM> antagonists to occupy the brain NK-<NUM> receptors. In these studies, the test compounds are administered orally and the tracer compound is administered intravenously afterward. The occupancy of the NK-<NUM> receptors is evaluated by quantitating the amount of the tracer compound bound to the brain NK-<NUM> receptors after increasing doses of the test compounds. Using this paradigm, tradipitant has an estimated ED<NUM> of <NUM>/kg p. and is substantially more potent than the other antagonists evaluated.

A single-center, randomized, double-blind, placebo-controlled study is conducted to investigate the effect of tradipitant on small bowel transit time. A total of <NUM> healthy subjects, including <NUM> men and <NUM> women between the ages of <NUM> and <NUM> years, are enrolled in the study and receive at least <NUM> dose of study medication. A total of <NUM> subjects complete the study. Subjects are randomized to receive <NUM> of tradipitant, <NUM> of tradipitant, or placebo as a single oral dose within each of <NUM> periods, co-administered with a capsule radiolabeled with a maximum of 1MBq <NUM>In. Four hours post-dose, all subjects also receive a second capsule radiolabeled with a maximum of 4MBq <NUM>Tc. Each subject receives all <NUM> doses during the study. For all dosing regimens, in vivo gamma scintigraphic studies are performed at predetermined intervals, and the following scintigraphic parameters are analyzed: onset and completion of gastric emptying, onset and completion of colon arrival, initiation and completion of small bowel transit, and initial and complete disintegration of the capsule (anatomical location and time).

A statistically significant effect of tradipitant on small bowel transit time is observed in the study. No effect on gastric emptying is observed in this study. However, the study is underpowered with respect to this parameter.

A randomized, double blind, placebo-controlled clinical study of motion sickness is conducted, in which <NUM> human subjects ("study participants"), each having a prior history of motion sickness, are subjected to sea travel in the Pacific Ocean under varied weather conditions.

Study participants are distributed over seven boat trips off the coast of Los Angeles, California, USA. For each trip, sea conditions and participant selfevaluation of symptoms of motion sickness are recorded. Among the seven trips, three are under "rough" sea conditions, conducive to producing motion sickness with wave heights above one meter. The remaining four trips are made under "calm" conditions, with wave heights less than one meter, and are less likely to produce motion sickness. Under "rough" sea conditions, <NUM>% of the placebo treated patients experience vomiting compared to only <NUM>% under "calm" conditions.

Subjects are randomized to receive either tradipitant <NUM> or placebo by mouth in a blinded fashion, prior to travel initiation. Participants report their symptoms at predetermined time intervals during the travel period. Primary end points of the study include: percentage of participants vomiting, and Motion Sickness Severity Scale (MSSS) Worst score. The MSSS is a <NUM> point scale ranging from <NUM> ("no symptoms") to <NUM> ("vomiting"). An exploratory analysis is also performed to evaluate the effects of tradipitant under "calm" and "rough" seas.

Results are reported in Table <NUM> below. In the overall intent to treat (ITT) population (n=<NUM>), a significantly higher percentage of participants experience vomiting in the placebo arm of the study (<NUM>%) as compared to the tradipitant arm (<NUM>%), p value = <NUM>. The MSSS Worst score endpoint also favors tradipitant (<NUM>) vs. placebo (<NUM>), although the difference does not reach statistical significance, p value = <NUM>. Under "calm" sea conditions, only a small percentage of participants in either arm experience vomiting, <NUM>% in the placebo arm and <NUM>% in the tradipitant treatment arm (not significant). A similar MSSS Worst score is seen between the two groups under "calm" conditions, <NUM> (placebo arm) and <NUM> (tradipitant treatment arm) (not statistically significant). Under "rough" sea conditions, <NUM>% of the placebo treated patients vomit as compared to <NUM>% of those treated with tradipitant, p value = <NUM>. A significant effect is also seen under "rough" conditions in the MSSS Worst score, <NUM> (placebo) and <NUM> (tradipitant), p value = <NUM>.

The foregoing data show that treatment with <NUM> tradipitant by mouth prior to travel initiation provides a significant reduction in the incidence of vomiting and in MSSS Worst score during travel under rough sea conditions and in overall conditions, as well as modest (not statistically significant) reductions during travel under calm conditions. These findings show that tradipitant at a dose of <NUM> provides an effective treatment for motion sickness.

Claim 1:
Tradipitant for use in the treatment or prevention of motion sickness or a symptom thereof in an individual, the individual being a human, wherein the treatment or prevention comprises:
administration of the tradipitant to the individual in an amount effective to prevent or treat the motion sickness or the symptom thereof in the individual.