Drugs in Clinical Pipeline: Tradipitant

Tradipitant [{2-[1-{[3,5-bis(trifluoromethyl)phenyl]methyl}-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl]pyridin-3-yl}(2-chlorophenyl)methanone] is an  Neurokinin 1 Receptor (NK-1R) antagonist which is currently in clinical development for chronic pruritus in patients with atopic dermatitis.

Tradipitant is licensed by Vanda from Eli Lilly and Company in April 2012. Previous research at Lilly focused on the potential of tradipitant as a novel therapeutic in alcohol dependence. The patent describing Tradipitant as a new chemical entity expires worldwide in April 2023, except in the United States, where it expires in June 2024, absent any applicable patent term adjustments.

Common Name: Tradipitant

Synonyms: VLY-686; LY686017
IUPAC Name: {2-[1-{[3,5-bis(trifluoromethyl)phenyl]methyl}-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl]pyridin-3-yl}(2-chlorophenyl)methanone

CAS Number: 622370-35-8
Mechanism of Action: NK-1R antagonist

Indication: Treatment-resistant pruritus
Development Stage: Phase II

Company: Vanda Pharma

Chronic pruritus affects millions of people worldwide and represents a serious and unmet medical need.  The itch sensation is believed to be induced at least in part through the action of the endogenous neuropeptide substance P, through the binding at NK-1Rs expressed on multiple skin cells.

VP-VLY-686-2101 Study

In the Phase II proof of concept clinical study (VP-VLY-686-2101), Vanda studied the effects of tradipitant in chronic pruritus in patients with atopic dermatitis.  Patients with a Visual Analog Scale (VAS) score of greater than 70mm during one of the two days preceding inclusion into the study were randomized to receive orally either 100 mg of tradipitant (N=34) or placebo (N=35) once a day in the evening.  Baseline VAS scores were 76.1 and 77.2 for the tradipitant and placebo arms respectively. Patients received treatment for 4 weeks and efficacy was evaluated through a number of clinical research instruments.

In addition, at the time of efficacy evaluation blood samples were collected for PK analysis in order to determine the plasma levels of tradipitant. A PK-PD analysis in the tradipitant treatment arm showed a significant correlation between blood levels of tradipitant and the VAS change from baseline (p less than 0.05).

A separate PK analysis of the time of pruritus assessment revealed that approximately half the patients in the study came in for morning (AM group, ~12 hours post-dose) visits for their pruritus assessments and that these patients also had higher blood levels of tradipitant than those who came in the afternoon (PM group, ~18 hours post-dose).

Higher concentrations of tradipitant were associated with higher efficacy in treating chronic pruritus in the study. A similar analysis in the PM group showed no significant differences between tradipitant and placebo. Data reported is consistent with the hypothesis that Tradipitant, an NK-1R antagonist, may offer symptomatic relief in patients with pruritus (VAS, VRS, SCORAD subjective).

References:
1. ClinicalTrial: Study of Itch Control by VLY-686 in Healthy Volunteers After Intradermal Injections of Substance P. NCT01919944