Tradipitant: First Approval.

TREATMENT of chronic pain, particularly of neuropathic etiology, is extremely difficult and resistant to many available pharmacologic therapies. Current analgesic agents may be limited with regard to analgesic efficacy or side effects. Newer and experimental pharmacologic agents may also have significant limitations. By targeting a specific receptor or other specific protein targets, a gene therapy approach to the treatment of pain may provide greater analgesic efficacy without the limitations associated with current pharmacotherapy. Advances in the field of gene therapy, along with significant increases in our understanding of the neurobiology of nociception and knowledge of the fundamental genetic structure of many nociceptive targets, have made gene therapy for the management of pain a conceivable reality. In part I of this review, we introduced the basic concepts of gene therapy with an emphasis on the available tools (e.g., viral vectors and antisense oligonucleotides) and strategies for upregulating antinociceptive or downregulating pronociceptive targets. In part II, we summarize current knowledge regarding the nociceptive role, molecular biology, and antisense and knockout data of several novel nociceptive targets for gene therapy. We base our selection of the targets included in this review on the three aforementioned criteria. The targets selected are the best characterized and, in our opinion, most likely amenable to the gene therapeutic approach. A simple but feasible strategy and potential gene therapy targets for the management of pain are summarized in figure 1. However, the list is admittedly incomplete, and the readers are referred to other recent reviews cited in part I of this review for a broader perspective on potential targets for the management of pain.

Neurons in the rostral ventromedial medulla (RVM) project to the spinal cord and are involved in descending modulation of pain. Several studies have shown that activation of neurokinin-1 (NK-1) receptors in the RVM produces hyperalgesia, although the underlying mechanisms are not clear. In parallel studies, we compared behavioral measures of hyperalgesia to electrophysiological responses of nociceptive dorsal horn neurons produced by activation of NK-1 receptors in the RVM. Injection of the selective NK-1 receptor agonist Sar9,Met(O2)11-substance P (SSP) into the RVM produced dose-dependent mechanical and heat hyperalgesia that was blocked by coadministration of the selective NK-1 receptor antagonist L-733,060. In electrophysiological studies, responses evoked by mechanical and heat stimuli were obtained from identified high-threshold (HT) and wide dynamic range (WDR) neurons. Injection of SSP into the RVM enhanced responses of WDR neurons, including identified neurons that project to the parabrachial area, to mechanical and heat stimuli. Since intraplantar injection of capsaicin produces robust hyperalgesia and sensitization of nociceptive spinal neurons, we examined whether this sensitization was dependent on NK-1 receptors in the RVM. Pretreatment with L-733,060 into the RVM blocked the sensitization of dorsal horn neurons produced by capsaicin. c-Fos labeling was used to determine the spatial distribution of dorsal horn neurons that were sensitized by NK-1 receptor activation in the RVM. Consistent with our electrophysiological results, administration of SSP into the RVM increased pinch-evoked c-Fos expression in the dorsal horn. It is suggested that targeting this descending pathway may be effective in reducing persistent pain.NEW & NOTEWORTHY It is known that activation of neurokinin-1 (NK-1) receptors in the rostral ventromedial medulla (RVM), a main output area for descending modulation of pain, produces hyperalgesia. Here we show that activation of NK-1 receptors produces hyperalgesia by sensitizing nociceptive dorsal horn neurons. Targeting this pathway at its origin or in the spinal cord may be an effective approach for pain management.

Substance P is generally considered an excitatory neurotransmitter related to gut motor activity, although an inhibitory influence of neurokinin-1 (NK1) receptor activation on peristalsis has also been reported. With an optimized in vitro method to assess distention-induced peristalsis, our aim was to clarify the effect of NK1 receptor activation on peristaltic activity and to reveal the mechanisms by which NK1 activation alters peristalsis. Distention of the small intestine of the mouse and guinea pig induced periodic occurrence of rhythmic waves of propagating rings of circular muscle contraction, associated with slow waves and superimposed action potentials, that propelled intestinal contents aborally. Activation of NK1 receptors by Ava[l-Pro(9),N-MeLeu10] substance P(7-11) (GR 73632) and Sar(9), Met(O(2))(11) on smooth muscle cells resulted in prolongation of the activity periods and increased action potential generation occurring superimposed on the intestinal slow wave activity. Activation of NK1 receptors on interstitial cells of Cajal resulted in an increase in slow wave frequency. Slow wave amplitude increased, likely by increased cell-to-cell coupling. The NK1 antagonist (S)-1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR 140333) induced a decrease in the slow wave frequency and duration of the activity periods evoked by distention, which makes it likely that NK1 receptor activation plays a role in the normal physiological distention-induced generation of peristaltic motor patterns. In summary, NK1 receptors play a role in normal development of peristalsis and NK1 receptor activation markedly increases propulsive peristaltic contractile activity.

It has been shown that anxiety and stress responses are modulated by substance P (SP) released within the amygdala. However, there is an important gap in our knowledge concerning the mechanisms regulating extracellular SP in this brain region. To study a possible self-regulating role of SP, we used a selective neurokinin-1 (NK1) receptor antagonist to investigate whether blockade of NK1 receptors results in altered basal and/or stress-evoked SP release in the medial amygdala (MeA), a critical brain area for a functional involvement of SP transmission in enhanced anxiety responses induced by stressor exposure. In vitro binding and functional receptor assays revealed that L-822429 represents a potent and selective rat NK1 receptor antagonist. Intra-amygdaloid administration of L-822429 via inverse microdialysis enhanced basal, but attenuated swim stress-induced SP release, while the low-affinity enantiomer of L-822429 had no effect. Using light and electron microscopy, synaptic contacts between SP-containing fibres and dendrites expressing NK1 receptors was demonstrated in the medial amygdala. Our findings suggest self-regulatory capacity of SP-mediated neurotransmission that differs in the effect on basal and stress-induced release of SP. Under basal conditions endogenous SP can serve as a signal that tonically inhibits its own release via a NK1 receptor-mediated negative feedback action, while under stress conditions SP release is further facilitated by activation of NK1 receptors, likely leading to high local levels of SP and activation of receptors to which SP binds with lower affinity.

Basic and clinical studies suggest that neurokinin 1 (NK1) receptor antagonists have efficacy in the treatment of affective disorders through effects on the dorsal raphe nucleus (DR), a source of forebrain-projecting serotonin (5-HT) neurons that has also been implicated in affective disorders. To investigate the regulation of the DR-5-HT system by NK1 receptors, the effects of substance P (an NK1 agonist) on rat DR neuronal activity were characterized. Most of the DR neurons (83%; n = 47 total) were inhibited by substance P microinfusion into the DR, and in some cases (17%) this was preceded by a brief activation. Pure excitation was observed in a small population of neurons (17%) that were localized in the dorsal DR, where NK1 receptors are most dense. Sendide, a selective NK1 antagonist, attenuated the effects of substance P, indicating that they were mediated by NK1 receptor activation. The selective 5-HT1A antagonist, WAY 100635, administered systemically or into the DR, prevented the inhibitory effects of substance P, implicating DR 5-HT1A receptors in this response. Finally, microinfusion of the excitatory amino acid antagonist, kynurenic acid, into the DR prevented both excitatory and inhibitory effects. The results suggest that NK1 receptor activation in the DR excites a population of 5-HT neurons via glutamatergic transmission. This results in 5-HT release throughout the DR, activation of 5-HT1A receptors, and subsequent inhibition. Interactions between NK1 and 5-HT1A receptors within DR neural networks may contribute to the mechanism of action of novel antidepressants acting at NK1 receptors.

Motion sickness affects millions of people with common symptoms, including nausea and vomiting. Medications used for management of motion sickness since 1870 predominately have anticholinergics and antihistamines properties. For the past 40 years, there have been no advances in medication options for motion sickness until recently, a novel agent, tradipidant received the Food and Drug Administration approval for symptoms related to motion sickness. Tradipitant is a selective neurokinin-1 (NK-1) receptor antagonist, blocking the actions of substance P, a neurotransmitter from the tachykinin family. It has high affinity for NK-1 receptors that are present throughout the emetic pathway. The 4 major metabolites of this drug (ie, M2, M3, M4, and M8) have shown a similar affinity to the NK-1 receptor as the parent drug. Pharmacokinetic data have revealed that tradipitant absorption is delayed when administered with food. The volume of distribution is 1956 L and is highly plasma protein bound (∼96%). The half-life is 34 hours. Tradipitant is predominately metabolized by CYP450-mediated pathways and through glucuronidation. Approximately 80% of excretion of tradipitant occurs in the feces. Two phase 3 pivotal trials, Motion Syros (N = 365) and Motion Serifos (N = 316), randomized, double-blinded, placebo-controled, showed significant efficacy for tradipitant in preventing vomiting associated with motion sickness. In Motion Syros, tradipitant groups experienced significantly lower incidences of vomiting than placebo (170 mg tradipitant = 18.3%, 85 mg tradipitant = 19.5%, placebo = 44.3%). In Motion Serifos, 10.4% of the 170-mg tradipitant group and 18.3% of the 85-mg tradipitant group experienced vomiting, compared with 37.7% of the placebo group (P = 0.00002 and P = 0.0014, respectively). The results of the 2 trials validated tradipitant as an effective NK-1 receptor antagonist for motion sickness prevention. The drug was well tolerated with a favorable safety profile and no serious adverse events. Tradipitant works by blocking the NK-1 receptors found in the emetic pathway and it has been proven in pivotal trials effective for prevention of vomiting due to motion sickness. It reduces motion sickness symptoms in 2 phase 3 trials and offers a revolutionary new treatment option for people who experience motion sickness.

1. Following induction of acute inflammation by intraarticular injection of kaolin and carrageenan into the knee joint in rats, there was a significant decrease in the withdrawal latency to radiant heat applied to the paw (i.e. heat hyperalgesia), an increased joint circumference and increased joint temperature. 2. A neurokinin1 (NK1) receptor antagonist (CP-99,994, 10 mM) had no effect on the paw withdrawal latency when it was administered spinally through a microdialysis fibre before the induction of inflammation. Pretreatment with a NK2 receptor antagonist (SR48968, 1 mM) administered spinally through the microdialysis fibre prevented the heat hyperalgesia from developing in the early stages of the inflammation. 3. Post-treatment through the microdialysis fibre with the NK1 receptor antagonist (0.01-10 mM) was effective in reversing the heat hyperalgesia. In contrast, post-treatment spinally with the NK2 receptor antagonist (0.01-1 mM) had no effect on the heat hyperalgesia. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 4. Pretreatment systemically with the NK1 receptor antagonist (30 mg kg-1) had no effect on the heat hyperalgesia or pain-related behaviour ratings where 0 is none and 5 is non weight bearing and complete avoidance of limb contact. Pretreatment with a NK2 receptor antagonist (10 mg kg-1) systemically prevented the heat hyperalgesia and pain-related behaviour ratings from developing in the early stages of the inflammation. The inactive stereoisomers of NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 5. Post-treatment systemically with either the NK1 (0.1-30 mg kg-1) or the NK2 (0.1-10 mg kg-1) receptor antagonist resulted in a dose-dependent reversal of the heat hyperalgesia. Pain-related behaviour ratings were reduced by post-treatment only with the NK1 receptor antagonist. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the behavioural responses. 6. Direct pretreatment of the knee joint with either the NK1 (30 mg) or the NK2 (10 mg) receptor antagonist prevented the heat hyperalgesia from developing without affecting joint swelling. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 7. There appears to be a differential role for the spinal tachykinin receptors in the development and maintenance of the heat hyperalgesia associated with acute joint inflammation. The NK2 receptors appear to be activated early in the development of the heat hyperalgesia and NK1 receptors are involved in the maintenance of the heat hyperalgesia. 8. Peripherally, both NK1 and NK2 receptors are involved in the development of heat hyperalgesia and pain-related behaviour ratings induced by acute inflammation.

Activation of central neurokinin-1 receptors induces reinstatement of cocaine-seeking behavior

The Motion Syros study was a multicenter, randomized, double-blind placebo-controlled study to evaluate the efficacy and safety of tradipitant for motion sickness. Motion sickness is a common disorder affecting approximately 30% of travelers under usual circumstances. The sensory mismatch theory postulates that motion sickness is induced by a discordance between the visual, vestibular, and kinesthetic systems, leading to a constellation of symptoms including nausea and vomiting. Substance P activates NK1 receptors in the nucleus tractus solitarius inducing a cascade of symptoms. Tradipitant is a novel NK1 receptor antagonist being studied for the treatment of nausea and vomiting associated with motion sickness. The Motion Syros study was a multicenter, randomized, double-blind, placebo-controlled study where 365 participants embarked on boat trips under varied sea conditions and received tradipitant 170 mg, tradipitant 85 mg, or placebo. Participants evaluated their symptoms at thirty-minute intervals during the expedition. Participants on tradipitant 170 mg or 85 mg had a significantly lower incidence of vomiting as compared to those on placebo across all boat trips (tradipitant 170 mg = 18.3%, tradipitant 85mg = 19.5%, placebo = 44.3%, p < .0001 for both dose comparisons against placebo, n = 365). A range of wave heights was represented across the various boat trips, eliciting variable degrees of severity of motion sickness and differing responses to tradipitant. Tradipitant has been confirmed to be effective in the reduction of vomiting associated with motion sickness across varied sea conditions with a range of wave heights. Motion sickness remains a significant unmet medical need, given existing treatments' limitations in alleviating symptoms and their frequent adverse effects. Disclosure: Dr. Polymeropoulos has received personal compensation for serving as an employee of Vanda Pharmaceuticals. An immediate family member of Dr. Polymeropoulos has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Vanda. Dr. Polymeropoulos has stock in Vanda. Miss Bushman has received personal compensation for serving as an employee of Vanda Pharmaceuticals. Miss Bushman has stock in Vanda Pharmaceuticals. Mr. Morgan has stock in Vanda Pharmaceuticals. Ms. Sutherland has received personal compensation for serving as an employee of Vanda Pharmaceuticals. Ms. Sutherland has stock in Vanda Pharmaceuticals. Mr. Davis has received personal compensation for serving as an employee of Vanda Pharmaceuticals, Inc.. Mr. Davis has stock in Vanda Pharmaceuticals, Inc.. Mr. Pham has received personal compensation for serving as an employee of Vanda Pharmaceuticals. Mr. Pham has stock in Vanda Pharmaceuticals. Miss Kiely has received personal compensation for serving as an employee of Vanda Pharmaceuticals Inc.. Miss Kiely has stock in Vanda Pharmaceuticals Inc.. Ms. Goldberg has received personal compensation for serving as an employee of Vanda Pharmaceuticals Inc. Ms. Goldberg has stock in Vanda Pharmaceuticals Inc. Miss Mourad has received personal compensation for serving as an employee of Vanda Pharmaceuticals Inc.. Miss Mourad has stock in Vanda Pharmaceuticals Inc.. Miss Miller has received personal compensation for serving as an employee of Vanda Pharmaceuticals . Miss Miller has stock in Vanda Pharmaceuticals. Dr. Xiao has received personal compensation for serving as an employee of Vanda pharma. Dr. Xiao has stock in Vanda pharma. Dr. Polymeropoulos has received personal compensation for serving as an employee of Vanda Pharmaceuticals Inc. An immediate family member of Dr. Polymeropoulos has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Vanda Pharmaceuticals Inc. Dr. Polymeropoulos has stock in Vanda Pharmaceuticals Inc. Mr. Birznieks has received personal compensation for serving as an employee of Vanda Pharmaceuticals. Dr. Polymeropoulos has received personal compensation for serving as an employee of Vanda Pharmaceuticals. Dr. Polymeropoulos has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Vanda Pharmaceuticals .

Convergent data suggest that SP, through the activation of neurokinin1 receptors (NK1-R), may be involved in anxiety. In particular, NK1-R antagonists have been reported to exert anxiolytic-like effects in a variety of animal procedures in which anxiety-related behaviour is induced by novelty. The present study investigated the effects of acute blockade of NK1-R in conflict paradigms, another category of anxiety-related procedures, in which positively reinforced responses are suppressed by contingent punishment. For this purpose, three selective antagonists with nanomolar affinity for rat NK1-R, GR205171, RP67580 and [2-cyclopropoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)benzyl]-(2-phenylpiperidin-3-yl)amine (Compound L), were tested in the safety signal withdrawal operant paradigm. In this procedure, suppression of lever pressing for food was induced by the withdrawal of a conditioned signal for safety, with no presentation of a conditioned signal for punishment, and no punishment. Compound L was also tested in the punished drinking test, which consists of the contingent delivery of electric footshocks upon water drinking. As expected, the reference compound, diazepam (2 mg/kg s.c.), induced an anxiolytic-like effect, as indicated by significant increases of the number of responses emitted during conflict period in the operant procedure, and footshocks received in the drinking test. In contrast, GR205171 (10 mg/kg s.c.), RP67580 (0.25-8 mg/kg s.c.) and Compound L (10 and 30 mg/kg s.c.) failed to release lever pressing during the operant conflict period. In addition, punished drinking was not affected by Compound L (3-30 mg/kg s.c.). These data show that NK1-R blockade has no anxiolytic-like effects in conflict paradigms, thereby suggesting that the anxiolytic properties of NK1-R antagonists are less broad than those reported for benzodiazepines.

Until late 1994, research on the neurokinin-3 (NK3) receptor, compared with that on neurokinin-1 (NK1) and neurokinin-2 (NK2) receptors, received little attention, due, to a large extent, to the absence of potent and selective non-peptide NK3 receptor antagonists. During 1995 and 1996, the disclosure of non-peptide antagonists led to a marked increase in research activities aimed at clarifying the physiological and pathophysiological role of the NK3 receptor. This review addresses the recent highlights and developments in this area, with particular emphasis on non-peptide NK3 receptor antagonists. Focus has been given to the various strategies utilised by several pharmaceutical companies to identify NK3 receptor antagonist prototypes and on the chemical optimisation processes which led to the potent and selective peptide-derived PD 161182 (8), the dichlorophenylalkylpiperidine SR 142,801 (9) and the quinoline derivative SB 223412 (27), which are representative compounds of the three distinct chemical classes of non-peptide NK3 receptor antagonists disclosed to date. The human NK3 (hNK3) receptor was cloned and stably expressed in 1992, and studies on the distribution in rodents and humans revealed that it is present in the central nervous system (CNS) and periphery. Based on receptor distribution and on the pharmacological effects of selective NK3 receptor agonists, a number of potential therapeutic indications for NK3 receptor antagonists are suggested, including CNS disturbances, pain and inflammation, pulmonary and skin diseases. Overall, although evidence indicates a noticeable increase in interest and research on NK3 receptors in the last few years, extensive additional medicinal chemistry and pharmacology studies, including preclinical and clinical evaluation of appropriate compounds from distinct structural classes, are required to delineate the pathophysiological role of NK3 receptors and to establish more firmly potential therapeutic utilities of potent and selective NK3 receptor antagonists.

Introduction: Novel therapies are needed for the treatment of motion sickness given the inadequate relief and bothersome and dangerous adverse effects of currently approved therapies. Neurokinin-1 (NK1) receptor antagonists have the potential to be effective in improving the symptoms of motion sickness, given the involvement of Substance P in nauseogenic and emetic pathways and the expression of NK1 receptors in the gastrointestinal system. Here we evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preventing motion sickness in variable sea conditions.Methods: A total of 126 adults participated in the Motion Sifnos study. Groups of participants were assigned to one of seven boat trips lasting ~4 h on the Pacific Ocean. Participants were randomized 1:1 to tradipitant 170 mg or placebo and completed the Motion Sickness Severity Scale (MSSS) every 30 min, in addition to other assessments. Severity of motion sickness was assessed with the incidence of vomiting and the MSSS.Results: Participants on tradipitant had a significantly lower incidence of vomiting as compared to those on placebo across all boat trips (tradipitant = 17.5%, placebo = 39.7%, p = 0.0039). For trips exposed to rough sea conditions, the difference in the incidence of vomiting between the groups was more dramatic (tradipitant = 15.79%, placebo = 72.22%, p = 0.0009). Across these trips, motion sickness symptoms were significantly lower in the tradipitant group compared to the placebo group (tradipitant = 3.19, placebo = 4.57, p = 0.0235).Discussion: Tradipitant has the potential to be an effective therapy for the prevention of vomiting and treatment of nausea in people with motion sickness.

Substance P binds to the Neurokinin-1 (NK-1) receptors found in the emetic center of the central nervous system (CNS) to induce emesis. Maropitant is a selective NK-1 receptor antagonist that inhibits the binding of substance P to NK-1 receptors and is commonly used to prevent and treat vomiting in dogs. This review study aimed to discuss and analyze the therapeutic potential of substance P (Neurokinin-1 receptor) antagonist with a particular focus on the drug maropitant in canine medicine. A systematic literature review was performed to identify the existing literature on the subject during the past 20 years (2001-2021) using such databases as ScienceDirect, PubMed, Scopus, and Google Scholar. The initial search identified 173 articles; however, 41 articles were selected for further analysis, based on the specific inclusion and exclusion criteria. Studies have already confirmed the role of substance P and NK-1 receptors in central pain processing, intestinal smooth muscle contraction, vasodilation, and neurogenic inflammation. Maropitant is one of the most effective veterinary antiemetic drugs that work well against peripheral and central stimuli that trigger the vomiting center. It has been already demonstrated that the therapeutic efficacy of maropitant for managing acute vomiting in dogs is associated with pancreatitis, gastritis, and parvoviral enteritis. It can also prevent and treat chemotherapy-induced emesis and delay the signs of nausea and adverse gastrointestinal effects. Regarding the broad-spectrum antiemetic activity of maropitant, it can be recommended for managing uremic vomiting in dogs. In addition, it has also exhibited an anesthetic sparing effect since the dogs treated with maropitant require a slightly lower percentage of isoflurane as an inhalational anesthetic. The NK-1 receptors are also identified in different areas of the pain pathways. Therefore, NK-1 receptor antagonists might be effective for managing visceral pain. However, further studies are required to establish the broad therapeutic potential of NK-1 receptor antagonist drugs, such as maropitant in canine medicine. It has been shown that the pain associated with the subcutaneous administration of maropitant is due to metacresol, a preservative used in some formulations. Therefore, the side effects can be eliminated by developing novel maropitant formulations specifically for dogs.

Substance P and neurokinin-1 (NK-1) receptor antagonists respectively induce cell proliferation and cell inhibition in human cancer cell lines. In acute lymphoblastic leukemia (ALL), substance P is expressed in human blast cells. However, the possible presence of NK-1 receptors in human ALL and the issue of whether the antitumor action of NK-1 receptor antagonists is exerted or not on human ALL (T-ALL BE-13 and B-ALL SD-1 cell lines) remain unknown. An immunoblot analysis was performed and an in vitro study of the cytotoxicity of three NK-1 receptor antagonists (L-733,060, L-732,138, aprepitant) was carried out on both cell lines. NK-1 receptors were found in those cell lines, and both expressed mRNA for this receptor. Using a knockdown method, we demonstrate that NK-1 receptors are involved in the viability of tumor cells. TAC1R cDNA was detected in the ALL cell lines by real-time quantitative RT-PCR. We also observed that the three NK-1 receptor antagonists elicited the inhibition of ALL cell growth; that the specific antitumor action of the NK-1 receptor antagonists occurs through the NK-1 receptor, and that ALL cell death is due to apoptosis. These findings suggest that NK-1 receptor antagonists could be considered as new antitumor drugs for the treatment of human ALL.

Motion sickness has afflicted travelers since ancient times. Neurokinin-1 (NK1) receptor antagonists have therapeutic potential as treatments for the symptoms of motion sickness due to the widespread expression of NK1 receptors throughout important locations in the emetic pathway in the network of brainstem nuclei and the gut. This study evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preventing motion sickness symptoms in variable sea conditions. A total of 365 adult participants with a history of motion sickness embarked on boat trips under variable sea conditions. Study participants were distributed across 34 boat trips that took place between November 2021 and April 2023 in coastal waters of the United States. Participants were randomized 1:1:1 and received 170 mg tradipitant (n = 120), 85 mg tradipitant (n = 123) or placebo (n = 122). The symptoms of vomiting and nausea were evaluated with questionnaires every 30 min during the approximately four-hour trips. The primary efficacy endpoint for the study was the percentage of vomiting during vehicle travel. Statistical hypothesis testing was performed at the two-sided alpha level of 0.05 unless specified otherwise. Tests were declared statistically significant if the calculated p-value was ≤ 0.05. The incidence of vomiting in both dosing arms of tradipitant was significantly lower than the placebo group across all boat trips (170 mg tradipitant = 18.3%, 85 mg tradipitant = 19.5%, placebo = 44.3%, p < 0.0001 for both dose comparisons against placebo). Tradipitant prevented severe nausea and vomiting as compared to participants taking placebo (tradipitant = 18.03%, placebo = 37.70%, p < 0.0001). Tradipitant 170 mg and 85 mg have been confirmed to be effective in the prevention of vomiting associated with motion sickness across varied sea conditions. ClinicalTrials.gov, identifier NCT04327661.