Efficacy and Safety of Tradipitant in Diabetic and Idiopathic Gastroparesis: A Randomized, Placebo-Controlled Study

Abstract

Background and Aims: There is a high unmet need for the treatment of gastroparesis and studies of NK1-R antagonists suggest potential benefit in reducing the symptoms of nausea and vomiting. We hypothesized that tradipitant, an NK1-R antagonist, would be effective in treating patients with idiopathic or diabetic gastroparesis. Methods: In a randomized, double-blind, placebo-controlled study across 47 U.S. sites, 152 gastroparesis patients were randomized to receive oral 85mg BID tradipitant (n=77) or placebo (n=75) daily for four weeks. Symptoms were assessed using a daily symptom dairy, Gastroparesis Cardinal Symptom Index (GCSI), and other patient reported questionnaires. Results: Patients receiving tradipitant had a significant decrease in nausea score at Week 4 compared to placebo (-1.2 improvement vs -0.7, respectively, p=0.0099), and a significant increase in nausea-free days (28.8% increase on tradipitant vs 15.0% on placebo p=0.0160). Patients with both nausea and vomiting at baseline (n=101) showed an even greater decrease in nausea score (-1.4 improvement on tradipitant vs -0.4 on placebo p<0.0001) and an increase in nausea free days (32.3% improvement on tradipitant vs 7.6% on placebo p=0.0003). 32.9% of patients treated with tradipitant were nausea responders (average nausea score ≤ 1 at week 4) compared to 11.8% of patients on placebo (p=0.0013). 46.6% of patients treated with tradipitant had a greater than 1-point improvement in GCSI score compared to 23.5% of patients on placebo (p=0.0053). Conclusions: Tradipitant treatment resulted in statistically and clinically meaningful improvements in nausea and overall gastroparesis symptoms. These robust efficacy results suggest tradipitant has the potential to become a useful pharmacological treatment for gastroparesis.

Drug Design Strategies, Modes of Action, Synthesis and Industrial Challenges Behind Trifluoromethylated New Chemical Entities

“…Tradipitant (261) (VLY-686) is a potent selective inhibitor of NK1R and is hypothesized to treat gastroparesis by acting centrally in the nausea-vomiting centers of the brain and peripherally in the smooth muscle of the intestines. Gastroparesis is a severe illness characterized by delayed gastric emptying and chronic symptoms of nausea, vomiting, bloating, fullness, and abdominal pain [189]. NK1 receptor (NK1R) antagonists are approved to treat nausea and vomiting in chemotherapy and the mechanism has been investigated in gastroparesis, which showed positive eff ects on nausea [189].…”

“…Gastroparesis is a severe illness characterized by delayed gastric emptying and chronic symptoms of nausea, vomiting, bloating, fullness, and abdominal pain [189]. NK1 receptor (NK1R) antagonists are approved to treat nausea and vomiting in chemotherapy and the mechanism has been investigated in gastroparesis, which showed positive eff ects on nausea [189]. In 2020, Welsh and coworkers reported the effi cacy and safety of Tradipitant (261) in the reduction of chronic pruritus in adults with mild to severe Atopic Dermatitis (AD) (Phase III clinical trial).…”

“…According to the authors, future studies are needed to confi rm the effi cacy results and refi ne treatment recommendations for AD patients who despite having mild lesions, experience signifi cant pruritus [190]. In 2021, Carlin and co-workers investigated the safety and effi cacy of Tradipitant (261), in patients with idiopathic or diabetic gastroparesis [189]. The results of this Phase II study further validate the NK1 receptor as a useful target for symptom relief in diabetic and idiopathic gastroparesis [189].…”

Farmacoterapia atual das náuseas e vômitos induzidos por antineoplásicos

“…Um estudo recente, mostrou que o tradipitanto é um potente inibidor dos receptores NK-1, com a hipótese de atuar de forma central (centro do vômito) e periférica (músculo liso do intestino), sendo bem tolerado e com efeitos adverso semelhantes ao grupo placebo (Carlin et al, 2021). No entanto, mais estudos devem ser realizados.…”

Motion Sifnos: A randomized, double-blind, placebo-controlled study demonstrating the effectiveness of tradipitant in the treatment of motion sickness

“…Tradipitant (VLY-686) is a novel NK1 receptor antagonist in development for the treatment of gastroparesis and atopic dermatitis. Tradipitant was shown to be effective in the treatment of nausea and vomiting in gastroparesis in a 4-week randomized study [12]. Given this evidence to support the use of tradipitant as an NK1 receptor antagonist to treat nausea and vomiting and specifically in motion sickness, we designed and conducted the Motion Sifnos Study.…”