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

Discussion

Cutaneous neurogenic inflammation is inflammation that is induced in the skin by the release of neuropeptides such as substance P and calcitonin gene-related peptide from sensory nerve endings, which leads to mainly sensory and vascular disorders such as pruritus, erythema and oedema.[16,17] TRPV1 is a nonselective cation channel known to participate specifically in pain and cutaneous neurogenic inflammation.[18] Indeed, TRPV1 activation regulates communication between sensory nerve endings and skin nonimmune and immune cells, increasing the release of inflammatory mediators including cytokines and neuropeptides. Several new insights have been gained regarding the control of epidermal barrier function, inflammation and chronic pruritus in the animal models of AD using a TRPV1 antagonist.[10,11,19,20]

In this phase IIb trial, the TRPV1 antagonist PAC-14028, applied topically as a 0·1%, 0·3% or 1·0% (wt/wt) cream, significantly improved the signs and symptoms of patients with AD. The positive efficacy of treatment with PAC-14028 cream for 8 weeks was based on the multiple outcome measures reflecting the objective signs of AD and the subjective symptoms (e.g. pruritus, sleep disturbance). We found improvement in the primary efficacy outcome of IGA score of 0 or 1 for all groups that applied PAC-14028 cream, compared with the vehicle cream, among patients with mild-to-moderate AD. At week 8, more patients treated with PAC-14028 cream showed a significant two-grade improvement in IGA from the baseline score compared with those who received vehicle treatment. Although a direct comparison study with PDE-4 inhibitor has not been performed, PAC-14028 cream 1·0% demonstrated a higher success rate in two-grade reduction from the baseline IGA score at week 8 than the vehicle cream (38·3% vs. 4·2%), compared with the success rate based on the IGA score at day 29 as reported for the crisaborole ointment (32·1% vs. 21·7%).[21] In addition, meaningful improvement was observed with regard to scores for both SCORAD and EASI following treatment with PAC-14028 cream. However, the treatment effects were not statistically significant owing to the relatively small sample size and the lack of children included in the study. The typical forms of clinical presentations of AD in adults differ from those in children and generally include inflammatory eczema with a larger area of lichenification, nummular eczema, and/or prurigo and are more resistant to topical therapy.[22] Successful treatment of AD with tacrolimus 0·03% or crisaborole was achieved in a greater proportion of patients in paediatric groups than those in adult groups.[23,24]

Treatment with PAC-14028 cream was also associated with improvements in patient-reported symptoms of AD including the effect on pruritus and sleep in the 1·0% formulation relative to the vehicle. Pruritus, a hallmark of AD, can lead to skin damage by excoriation and the development of secondary infection, which further aggravates AD and negatively affects patients' quality of life.[25–27] The mechanism through which TRPV1 plays a key role in mediating pruritus signalling in AD is well understood. Histaminergic itch signalling pathways excite sensory neurons, predominantly C-fibres by phospholipase A2 and 12-lipoxygenase-stimulated activation of TRPV1.[28] This directly leads to increased release of substance P and calcitonin gene-related peptide, which increase pruritogens. Although TRPV1 is an ion channel expressed on C-fibre neurons that is associated with the itch sensation, pruritus VAS scores in patients treated with PAC-14028 cream remained continuously and substantially decreased after treatment, however, the differences were statistically significant only at week 8 compared with baseline. The observed trend may be due to greater experimental deviations resulting from the small sample size, vehicle effects related to emollient bases, the transdermal administration route and/or a relative effect size caused by disruptions of skin barrier function. However, we previously reported that orally administered PAC-14028 exhibited immediate antipruritic effects in murine scratching models evoked by diverse pruritogens.[9] Therefore, this evidence indicates that PAC-14028 cream has a positive and direct impact on controlling pruritus, while simultaneously decreasing inflammation in the affected skin.

Twice-daily application of PAC-14028 cream for 8 weeks demonstrated a favourable tolerability profile in this study. The nature and number of AEs, combined with the negligible systemic exposure after PAC-14028 cream application, indicated that the novel topical formulation of PAC-14028 allows a targeted therapy at the inflammation site. Hyperthermia, which has been observed with oral TRPV1 antagonists, was not reported in patients treated with PAC-14028. The incidence and types of AEs that were associated with PAC-14028 cream were similar to those in the vehicle group. Patients treated with PAC-14028 cream did not show cutaneous TCS- or TCI-induced AEs, such as application site burning or stinging. Additionally, PAC-14028 cream 1·0% exhibited much lower rates of treatment-related AEs than the vehicle cream (0·0% vs. 6·3%) compared with the rates of treatment-related AEs reported in crisaborole ointment (4·4% vs. 1·2%).[9] However, our study has limitations owing to the relatively small sample size, and the lack of direct comparison with TCSs, TCIs or crisaborole. Moreover, further investigations in paediatric patient populations will be needed.

In conclusion, PAC-14028 cream is a promising new treatment option for patients with mild-to-moderate AD based on the favourable tolerability profile and the improved efficacy in treating AD observed in the present study. Based on these results, a phase III programme is underway to assess the efficacy and safety of PAC-14028 topical cream 1·0% in adolescent and adult patients with mild-to-moderate AD (NCT02965118).

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