Efficacy and Safety of PAC-14028 Cream – a Novel, Topical, Nonsteroidal, Selective TRPV1 Antagonist in Patients With Mild-to-moderate Atopic Dermatitis

A Phase IIb Randomized Trial

Y.W. Lee; C.-H. Won; K. Jung; H.-J. Nam; G. Choi; Y.-H. Park; M. Park; B. Kim

Disclosures

The British Journal of Dermatology. 2019;180(5):1030-1038. 

In This Article

Abstract and Introduction

Abstract

Background: Transient receptor potential vanilloid subfamily, member 1 (TRPV1) may play an important role in pruritus and inflammation induction in atopic dermatitis (AD). The treatment effect of TRPV1 antagonist via topical application in patients with AD remains unknown.

Objectives: To assess the clinical efficacy and safety of PAC-14028, a TRPV1 antagonist, via topical application in patients with AD.

Methods: In this 8-week, phase IIb, randomized, double-blind, multicentre, vehicle-controlled study, patients with mild-to-moderate AD were randomized to receive PAC-14028 cream 0·1%, 0·3%, 1·0% or vehicle cream twice daily. The primary efficacy end point was the Investigator's Global Assessment (IGA) success rate defined as the percentage of patients with an IGA score of 0 or 1 at week 8. The secondary efficacy end points included the severity Scoring of Atopic Dermatitis (SCORAD) index and Eczema Area and Severity Index (EASI) 75/90.

Results: A total of 194 patients were enrolled. IGA success rates at week 8 were 14·58% for vehicle cream, 42·55% for PAC-14028 cream 0·1% (P = 0·0025 vs. vehicle), 38·30% for PAC-14028 cream 0·3% (P = 0·0087 vs. vehicle) and 57·45% for PAC-14028 cream 1·0% (P < 0·001 vs. vehicle). In particular, statistically significant differences were found between the vehicle and treatment groups in the IGA success rates with two-grade improvement. The SCORAD index, EASI 75/90, sleep disturbance score and pruritus visual analogue scale showed a trend towards improvement. No significant safety issues were reported.

Conclusions: PAC-14028 cream may be an effective and safe treatment modality for the treatment of patients with mild-to-moderate AD.

Introduction

Atopic dermatitis (AD) is a chronic, relapsing inflammatory disease characterized by intolerable pruritus, an impaired epidermal barrier and eczematous lesions.[1,2] The prevalence ranges are about 15–30% in children and 2–10% in adults in industrialized countries.[3,4]

In an effort to alleviate AD, topical therapies such as topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs) have long been the mainstay of AD flare treatment. However, TCSs may provoke significant risk of adverse events (AEs), such as skin atrophy and rebound phenomenon in some patients requiring long-term application. Several issues related to steroid phobia have been raised.[1] TCIs are also associated with AEs, such as skin burning sensation and pruritus, and a boxed warning about a theoretical risk of malignancy (including lymphoma) has been added to TCI product labels.[5] In addition, emerging targets of interest in the treatment of AD include intracellular enzyme phosphodiesterase (PDE)-4 inhibitors and Janus kinase (JAK) inhibitors. Crisaborole is a small molecule that inhibits PDE-4 activity and is the first in its class to be approved by the Food and Drug Administration.[1,5] Although crisaborole showed significant clinical efficacy and an acceptable safety profile across two phase III trials, the conclusions on its efficacy should be cautiously interpreted because the minimal clinically important difference was not defined for the reported outcome measure.[1] The JAK inhibitors also have potential risk for AEs caused by immunosuppression, with nasopharyngitis and upper respiratory infections as the most commonly reported AEs.[5,6] Therefore, given the chronicity of AD and the need for long-term pharmacological therapy, new treatment options with better benefit–risk profiles are still needed.

Transient receptor potential vanilloid subfamily, member 1 (TRPV1) is expressed not only on sensory nerves but also on keratinocytes, dendritic cells and sebocytes in the skin.[7] It is directly activated by pain-producing stimuli such as capsaicin, heat, and acid, or activated when intracellular signal transduction is conducted by pruritogens.[8] The selective TRPV1 antagonist, PAC-14028 (Asivatrep, C21H22F5N3O3S), has shown antipruritic effects, improved skin barrier function, and suppressed allergic inflammation in AD-like murine models by blocking the secretion of neuropeptides, such as substance P, modulating epidermal differentiation markers and suppressing T helper 2 cytokines.[9–11]

A phase IIa trial of PAC-14028 cream was conducted in patients with AD. The efficacy of PAC-14028 cream was superior to that of the vehicle, and similar to pimecrolimus. Furthermore, PAC-14028 cream showed a good safety profile with a far lower incidence of treatment-related AEs than pimecrolimus. Safety findings in the treatment arms were comparable with those in the vehicle group, and there was no other safety concern requiring further investigation (ClinicalTrials.gov: NCT02583022). Based on these results, this phase IIb clinical trial aimed to evaluate the safety and efficacy of PAC-14028 cream in patients with mild-to-moderate AD and to determine the optimal dosage by reviewing the responses to PAC-14028 cream 0·1%, 0·3% and 1·0% by dose step (NCT02757729).

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