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

Results

Patients

A total of 198 patients were screened and 194 were randomly assigned to one of the following four groups: PAC-14028 cream 0·1% (n = 49), 0·3% (n = 48), 1·0% (n = 49) or vehicle cream (n = 48) (Figure 1). In total, 193 patients received at least one dose of study treatment and were analysed for safety of the materials tested. Overall, 18 patients discontinued study treatment prematurely [PAC-14028 cream 0·1% (n = 4), 0·3% (n = 4), 1·0% (n = 5) or vehicle cream (n = 5)] and 175 patients completed the study treatment. Four patients who administered major prohibited concomitant medication were excluded from the efficacy analysis and 189 patients were analysed for efficacy of the treatments.

Figure 1.

Patient disposition.

Statistically significant differences were not found for baseline characteristics and disease severity including age, sex, percentage of total BSA, IGA and total SCORAD across study treatment groups (Table 1).

Efficacy

More patients treated with PAC-14028 cream achieved success according to IGA score compared with the vehicle-treated group (Figure 2a). The IGA success rates were 14·6% for vehicle cream, 42·6% for PAC-14028 cream 0·1% (P = 0·0025 vs. vehicle), 38·3% for PAC-14028 cream 0·3% (P = 0·0087 vs. vehicle) and 57·5% for PAC-14028 cream 1·0% (P < 0·001 vs. vehicle). By week 8, the proportion of patients achieving treatment success, based on an IGA score with a two-grade improvement from baseline was significantly higher in the PAC-14028 cream 0·1% (21·3%, P = 0·0121), 0·3% (27·7%, P = 0·0017) and 1·0% (38·3%, P < 0·001) groups than in the vehicle cream (4·2%) group. In particular, the group who received PAC-14028 cream 1·0% showed a significantly greater proportion of patients that achieved success than the vehicle group. The measure of success was based on an IGA score of 0 or 1 with at least a two-grade improvement from baseline from week 3 through week 8 (Figure 2b).

Figure 2.

Treatment success rate (%) in the Investigator's Global Assessment (IGA). (a) Percentage of patients who were assessed as 0 (clear) or 1 (almost clear) according to the week-8 IGA score. (b) Percentage of patients who were assessed as 0 (clear) or 1 (almost clear) IGA score with two-grade improvement from the baseline at week 1, 3, 6 and 8 (*P < 0·05 vs. vehicle, **P < 0·01 vs. vehicle, ***P < 0·001 vs. vehicle).

Improvement in the mean change in SCORAD index was achieved by a greater number of patients in all PAC-14028 groups compared with the vehicle group. A significant improvement was observed particularly in the groups receiving PAC-14028 cream 0·1% (P < 0·05) and 1·0% (P < 0·05) at week 3 compared with those receiving vehicle cream (Figure 3a). Additionally, higher response rates in EASI 75/90 (the proportion of patients with an improvement in the EASI of at least 75% or 90%) were observed in the PAC-14028 groups than in the vehicle group, except for EASI 75 in the treatment group that received PAC-14028 cream 0·3% (Figure 3b, c).

Figure 3.

Efficacy analysis of severity Scoring of Atopic Dermatitis (SCORAD) index and Eczema Area and Severity Index (EASI) score. (a) Mean change in SCORAD index from the baseline at week 1, 3, 6 and 8 (*P < 0·05 vs. vehicle). (b) Proportion of patients achieving ≥ 75% improvement from baseline in the week-8 EASI score. (c) Proportion of patients achieving ≥ 90% improvement from baseline in the week-8 EASI score.

An assessment of the severity of pruritus-related VAS scores was conducted at each patient visit. All PAC-14028 groups showed decreased mean changes from baseline over the duration of the treatment period. In particular, by week 8, the PAC-14028 cream 1·0% (P = 0·0326 vs. vehicle) group showed a significant reduction in VAS scores from baseline (Figure 4a). A significant reduction in the sleep disturbance score was also observed in the group receiving the PAC-14028 cream 1·0% (P < 0·05 vs. vehicle) from week 3 of treatment (Figure 4b).

Figure 4.

Patient-reported outcomes based on pruritus visual analogue scale (VAS) and sleep disturbance score. (a) Mean change from baseline in pruritus VAS at 1, 3, 6 and 8 weeks. (b) Mean change from baseline sleep disturbance score at 1, 3, 6 and 8 weeks (*P < 0·05 vs. vehicle, **P < 0·01 vs. vehicle, ***P < 0·001 vs. vehicle).

Representative photographs of patients treated with PAC-14028 cream 0·1%, 0·3% or 1·0% showed marked improvement (Figure 5).

Figure 5.

Clinical photographs of three patients treated with PAC-14028 cream 1·0% (a), PAC-14028 cream 0·3% (b), PAC-14028 cream 0·1% (c) from baseline to week 8.

Safety

PAC-14028 cream demonstrated a favourable safety profile and the overall incidence of AEs was similar in the PAC-14028 and vehicle groups (Table 2). The incidence of AEs after administering the investigational product was 6·3% for PAC-14028 cream 0·1%, 12·5% in PAC-14028 cream 0·3%, 16·3% for PAC-14028 cream 1·0% and 18·8% for vehicle cream. The incidence of ADRs was 2·1% (one case of wound secretion) for PAC-14028 cream 0·3%, 6·3% (two cases of rash, one case of irritability) for vehicle cream and 0% for both PAC-14028 cream 0·1% and 1·0%. All AEs were considered mild or moderate in severity, and no clinically meaningful differences were found in the rate of incidence of AEs and ADRs among the treatment groups.

As for serious AEs (SAEs), one case of appendicitis (2·0%) without relationship to the study treatment was reported in the group receiving PAC-14028 cream 1·0%. Treatment-related SAEs were not reported.

No clinically significant abnormalities were found in patients' clinical laboratory values, vital signs, physical examinations or electrocardiograms.

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