TY - JOUR
T1 - Crisaborole and atopic dermatitis skin biomarkers
T2 - An intrapatient randomized trial
AU - Bissonnette, Robert
AU - Pavel, Ana B.
AU - Diaz, Aisleen
AU - Werth, John L.
AU - Zang, Chuanbo
AU - Vranic, Ivana
AU - Purohit, Vivek S.
AU - Zielinski, Michael A.
AU - Vlahos, Bonnie
AU - Estrada, Yeriel D.
AU - Saint-Cyr Proulx, Etienne
AU - Ports, William C.
AU - Guttman-Yassky, Emma
N1 - Funding Information:
Supported by Pfizer .
Funding Information:
Supported by Pfizer.Disclosure of potential conflict of interest: R. Bissonnette is an investigator, consultant, advisory board member, and speaker for and/or receives honoraria from Aquinox Pharma, Antiobix, Asana, Astellas, Brickell Biotech, Dermavant, Dermira, Dignity Sciences, Eli Lilly, Galderma, Glenmark, GSK-Steifel, Hoffman-La Roche, Kiniksa, LEO Pharma, Neokera, Pfizer, Regeneron, Sanofi, Sienna, and Vitae and is also an employee and shareholder of Innovaderm Research. J. L. Werth, C. Zang, I. Vranic, V. S. Purohit, M. A. Zielinski, B. Vlahos, and W. C. Ports are employees and shareholders of Pfizer. E. Guttman-Yassky is an employee of Mount Sinai and has received research funds (grants paid to the institution) from AbbVie, Celgene, Eli Lilly, Janssen, Dermavant, DS Biopharma, Novartis, Pfizer, Regeneron, Glenmark, Galderma, Asana Biosciences, Innovaderm, Dermira, LEO Pharma, Novan, Kyowa Kirin, Concert, Union Therapeutics, and Ralexar and is also a consultant for Sanofi, Regeneron, Celgene, Dermira, Galderma, Glenmark, Novartis, Pfizer, LEO Pharma, AbbVie, Eli Lilly, Kyowa Kirin, Mitsubishi Tanabe, Asana Biosciences, Union Therapeutics, Allergan, Amgen, Concert, DS Biopharma, EMD Serono, Escalier, and Flx Bio. The rest of the authors declare that they have no relevant conflicts of interest.We thank the patients, investigators, and investigational site for their participation in this study, as well as Karl Nocka, PhD, and Maudeline Louis for their critical review of the manuscript. Editorial/medical writing support under the guidance of the authors was provided by Madeline L. Pfau, PhD, and Jennifer C. Jaworski, MS, at ApotheCom, San Francisco, California, and was funded by Pfizer, New York, NY, in accordance with Good Publication Practice (GPP3) guidelines. On request and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual deidentified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the United States, European Union, or both or (2) in programs that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data can be requested from Pfizer trials 24 months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research criteria and other conditions and for which an exception does not apply through a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.
Publisher Copyright:
© 2019
PY - 2019/11
Y1 - 2019/11
N2 - Background: Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined. Objective: This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD. Methods: Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15. Results: Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10−15) that was sustained until day 15 (92.90% vs 49.59%, P < 10−15). Crisaborole significantly modulated key AD biomarkers versus vehicle, including TH2 and TH17/TH22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function. Conclusion: Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD.
AB - Background: Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined. Objective: This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD. Methods: Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15. Results: Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10−15) that was sustained until day 15 (92.90% vs 49.59%, P < 10−15). Crisaborole significantly modulated key AD biomarkers versus vehicle, including TH2 and TH17/TH22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function. Conclusion: Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD.
KW - Atopic dermatitis
KW - biomarker
KW - crisaborole
KW - gene expression
KW - inflammation
KW - phosphodiesterase 4
KW - pruritus
KW - transcriptome
KW - transepidermal water loss
UR - http://www.scopus.com/inward/record.url?scp=85072066608&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2019.06.047
DO - 10.1016/j.jaci.2019.06.047
M3 - Article
C2 - 31419544
AN - SCOPUS:85072066608
SN - 0091-6749
VL - 144
SP - 1274
EP - 1289
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 5
ER -