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Research Letters |

Efficacy and Safety of Topical WBI-1001 in the Treatment of Atopic Dermatitis: Results From a Phase 2A, Randomized, Placebo-Controlled Clinical Trial FREE

Robert Bissonnette, MD, FRCPC; Genhui Chen, PhD; Chantal Bolduc, MD, FRCPC; Catherine Maari, MD, FRCPC; Michael Lyle, PhD; Liren Tang, PhD; John Webster, PhD; Youwen Zhou, MD, PhD
[+] Author Affiliations

Author Affiliations: Innovaderm Research Inc, Montreal, Quebec, Canada (Drs Bissonnette, Bolduc, and Maari); Welichem Biotech Inc, Burnaby, British Columbia, Canada (Drs Chen, Lyle, Tang, and Webster); and Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada (Dr Zhou).


Arch Dermatol. 2010;146(4):446-449. doi:10.1001/archdermatol.2010.34.
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Published online

Most patients with mild to moderate atopic dermatitis (AD) are currently treated with topical therapy. However, there are safety concerns with long-term use of topical agents such as corticosteroids and calcineurin inhibitors.1,2 The novel synthetic compound WBI-1001 (2-isopropyl-5-[(E)-2-phenylethenyl] benzene-1, 3-diol) (hereinafter, “IPBD”) demonstrates nonsteroidal anti-inflammatory activities. Originally derived from metabolites of a unique group of bacterial symbionts of entomopathogenic nematodes, IPBD has been demonstrated to inhibit inflammatory cytokine secretion by activated T cells, including tumor necrosis factor α and interferon γ in vitro (data on file at Welichem Biotech Inc, Burnaby, British Columbia, Canada). Furthermore, it has been demonstrated to inhibit allergic contact dermatitis in a mouse edema model (data on file at Welichem). The objective of the present trial was to study the safety and efficacy of topical IPBD creams for the treatment of adult patients with atopic dermatitis.

This was a single-center, parallel group, randomized, double-blinded, vehicle-controlled, phase 2A study in adults with AD. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization and Good Clinical Practice guidelines and was reviewed and approved by an institutional review board. Thirty-seven men and women were randomized (1:1:1) to apply twice daily either the vehicle cream, IPBD, 0.5%, cream, or IPBD, 1.0%, cream for 4 weeks.

Safety and tolerability of topically applied IPBD were assessed by physical examinations, electrocardiography, hematologic and clinical chemical analysis, urinalysis, and by evaluating adverse events. Efficacy of IPBD was assessed by measuring the mean values and percentage changes over baseline in the Eczema Area Severity Index (EASI) scores,3 SCORing Atopic Dermatitis score (SCORAD),4 Investigator's Global Assessment (IGA),5 body surface area (BSA) involvement, and pruritus (10-cm visual analog scale). To be eligible, patients had to have a minimum of 1% and a maximum of 10% of their BSA affected with AD excluding the face, groin, scalp, and genital regions; an EASI score of less than 12; and an IGA score of 2 (mild) or 3 (moderate).

A repeated-measures analysis of variance model was used to analyze changes over time. A pairwise group comparison at each visit was performed on all efficacy parameters using a Bonferroni correction. All statistical tests were carried out at the 5% significance level. Efficacy analyses should be considered post hoc analyses because they were not planned before database lock.

Safety

At both 0.5% and 1.0% concentrations, IPBD was well tolerated by patients. There were no serious adverse events, and no patients discontinued owing to adverse events. Three patients developed mild papules on treated areas: 1 of these was randomized to vehicle, and the other 2 to IPBD, 1.0%. In all cases, the eruptions were mild, and patients continued to apply the study creams to active AD. Two patients who complained of pruritus had both been randomized to vehicle. The only other adverse event coded by the investigator as possibly related to IPBD was a nonspecific anomaly of T wave observed on electrocardiography in a patient randomized to IPBD, 1.0%. However, IPBD was not detected in the plasma samples of this patient at any time points.

Efficacy

After 4 weeks of treatment both 0.5% and 1.0% concentrations, IPBD demonstrated significant reduction in EASI (59.3% and 54.9%, respectively, compared with 7.1% for vehicle) (P = .03) (Figure 1A), SCORAD (56.2% and 50.1%, respectively, compared with 18.4% for vehicle) (P = .04) (Figure 1B), IGA (38.9% and 45.8%, respectively, compared with 5.6% for vehicle (P = .003) (Figure 1C), and pruritus scores (74.0% and 56.0%, respectively, compared with 30.2% for vehicle) (P = .04) (Figure 1D) and significant reduction in affected BSA (64.4% and 57.7%, respectively, compared with 10.8% for vehicle) (P = .03) (Figure 1E). At week 4, 50% of subjects in both active treatment arms (n = 23) had an IGA of 0 (clear) or 1 (almost clear) compared with 8.3% for the vehicle arm (n = 12) (Figure 2).

Place holder to copy figure label and caption
Figure 1.

Percentage reduction from the baseline in mean skin evaluation scores in patients with atopic dermatitis treated with topical placebo (vehicle), IPBD, 0.5%, and topical IPBD, 1.0%, creams. A, EASI; B, SCORAD; C, IGA; D, pruritus; and E, affected BSA. For all abbreviation expansions see the introduction and “Methods” section herein. Treatment was discontinued in all cases at week 4; the dotted lines indicate the scores 1 week after discontinuation of treatment. The points at which the data reached a level of statistical significance compared with the placebo cream.

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Place holder to copy figure label and caption
Figure 2.

Representative patients with atopic dermatitis before and during treatment. Patients with atopic dermatitis were photographed at baseline and at weeks 1, 2, and 4 of the treatment regimen with placebo cream (A), IPBD, 0.05%, cream (B), or IPBD, 1.0%, cream (C). IPBD indicates novel synthetic compound WBI-1001 (2-isopropyl-5-[(E)-2-phenylethenyl] benzene-1, 3-diol).

Graphic Jump Location
Pharmacokinetics

Pharmacokinetic analyses showed that IPBD was minimally absorbed. For patients randomized to 0.5% and 1.0% IPBD concentrations, plasma levels of IPBD 8 hours after application ranged from below the lower limit of quantification (0.10 ng/mL) to a maximum of 5.97 ng/mL after the first cream application and 0.44 ng/mL at week 4.

Topical IPBD at 0.5% and 1.0% in a cream formulation was well tolerated when used to treat patients with AD. Both 0.5% and 1.0% IPBD were superior to vehicle in improving AD at week 4 as demonstrated by the significant decrease in the EASI, SCORAD, IGA, and BSA scores. These results need to be confirmed by larger clinical trials.

Correspondence: Dr Bissonnette, Innovaderm Research Inc, 1851 Sherbrooke St E, Ste 502, Montreal, QC H2K 4L5, Canada (rbissonnette@innovaderm.ca).

Author Contributions: Drs Bissonnette, Chen, Lyle, Tang, Webster, and Zhou had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bissonnette, Chen, Lyle, Tang, and Webster. Acquisition of data: Bissonnette, Bolduc, and Maari. Analysis and interpretation of data: Bissonnette, Lyle, Tang, Webster, and Zhou. Drafting of the manuscript: Bissonnette, Webster, and Zhou. Critical revision of the manuscript for important intellectual content: Bissonnette, Chen, Bolduc, Maari, Lyle, Tang, Webster, and Zhou. Statistical analysis: Zhou. Obtained funding: Webster. Administrative, technical, and material support: Bolduc, Lyle, Tang, and Webster. Study supervision: Bissonnette, Bolduc, Maari, Lyle, Tang, and Webster.

Financial Disclosure: Dr Bissonnette has served as a consultant to Welichem, Astellas, and Leo Pharma. He has also received honoraria from Astellas and Leo Pharma and grants from Novartis, Astellas, Leo Pharma, and Advitech. Drs Chen, Lyle, Tang, and Webster are employed by Welichem. Drs Bolduc and Maari have received grants from Novartis, Astellas, Leo Pharma, and Advitech. Dr Zhou has served as a consultant to Welichem and received honoraria from Astellas and Leo Pharma. He has received grants from Asperiva, Astellas, Leo Pharma, Biogen-Idec, Wyeth/Amgen, Abbott, EMD-Serono, Merck, and Galderma.

Funding/Support: This study was supported in part by Welichem.

Role of the Sponsors: The sponsors participated in the design of the study and in the analysis and interpretation of the data and in the preparation, review, and approval of the manuscript.

Additional Contributions: Nathalie Rodrigue, PhD, and Michel Guillet, PhD, provided statistical analysis and critical review of efficacy analysis. Bin Li, PhD, and Yangsheng Wanggui, PhD, revised the manuscript.

Langley  RGLuger  TACork  MJSchneider  DPaul  C An update on the safety and tolerability of pimecrolimus cream 1%: evidence from clinical trials and post-marketing surveillance. Dermatology 2007;215 ((suppl 1)) 27- 44
PubMed Link to Article
Callen  JChamlin  SEichenfield  LF  et al.  A systematic review of the safety of topical therapies for atopic dermatitis. Br J Dermatol 2007;156 (2) 203- 221
PubMed Link to Article
Hanifin  JMThurston  MOmoto  MCherill  RTofte  SJGraeber  MEASI Evaluator Group, The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001;10 (1) 11- 18
PubMed Link to Article
European Task Force on Atopic Dermatitis, Severity scoring of atopic dermatitis: the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis. Dermatology 1993;186 (1) 23- 31
PubMed Link to Article
Bernard  LAEichenfield  LF Topical immunomodulators for atopic dermatitis. Curr Opin Pediatr 2002;14 (4) 414- 418
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Percentage reduction from the baseline in mean skin evaluation scores in patients with atopic dermatitis treated with topical placebo (vehicle), IPBD, 0.5%, and topical IPBD, 1.0%, creams. A, EASI; B, SCORAD; C, IGA; D, pruritus; and E, affected BSA. For all abbreviation expansions see the introduction and “Methods” section herein. Treatment was discontinued in all cases at week 4; the dotted lines indicate the scores 1 week after discontinuation of treatment. The points at which the data reached a level of statistical significance compared with the placebo cream.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Representative patients with atopic dermatitis before and during treatment. Patients with atopic dermatitis were photographed at baseline and at weeks 1, 2, and 4 of the treatment regimen with placebo cream (A), IPBD, 0.05%, cream (B), or IPBD, 1.0%, cream (C). IPBD indicates novel synthetic compound WBI-1001 (2-isopropyl-5-[(E)-2-phenylethenyl] benzene-1, 3-diol).

Graphic Jump Location

Tables

References

Langley  RGLuger  TACork  MJSchneider  DPaul  C An update on the safety and tolerability of pimecrolimus cream 1%: evidence from clinical trials and post-marketing surveillance. Dermatology 2007;215 ((suppl 1)) 27- 44
PubMed Link to Article
Callen  JChamlin  SEichenfield  LF  et al.  A systematic review of the safety of topical therapies for atopic dermatitis. Br J Dermatol 2007;156 (2) 203- 221
PubMed Link to Article
Hanifin  JMThurston  MOmoto  MCherill  RTofte  SJGraeber  MEASI Evaluator Group, The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001;10 (1) 11- 18
PubMed Link to Article
European Task Force on Atopic Dermatitis, Severity scoring of atopic dermatitis: the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis. Dermatology 1993;186 (1) 23- 31
PubMed Link to Article
Bernard  LAEichenfield  LF Topical immunomodulators for atopic dermatitis. Curr Opin Pediatr 2002;14 (4) 414- 418
PubMed Link to Article

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