A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis

G Berstein, Y Zhang, Z Berger, E Kieras, G Li, A Samuel, T Yeoh, H Dowty, K Beaumont, W Wigger-Alberti, Y von Mackensen, U Kroencke, R Hamscho, S Garcet, J G Krueger, C Banfield, B Oemar, G Berstein, Y Zhang, Z Berger, E Kieras, G Li, A Samuel, T Yeoh, H Dowty, K Beaumont, W Wigger-Alberti, Y von Mackensen, U Kroencke, R Hamscho, S Garcet, J G Krueger, C Banfield, B Oemar

Abstract

Background: Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms.

Aim: To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis.

Methods: This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint.

Results: In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions.

Conclusion: Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.

Conflict of interest statement

GB, YS, EK, GL, AS, TY, HD, KB, CB and BO are employees of Pfizer Inc. and hold stock in the company. ZB was an employee of Pfizer Inc. and held Pfizer stock at the time the study was conducted and continues to hold stock in the company; ZB is currently an employee of Biogen and holds Biogen stock. WW‐A, YvM and UK are employees of Bioskin GmbH. RH is Medical Director of Rothhaar Studien GmbH. SG has no conflicts of interest to disclose. JGK declares grants/personal fees from AbbVie, Akros, Allergan, Almirall, Amgen, Arena Pharmaceuticals, Aristea Therapeutics, Asana BioSciences, Aurigene, Avillion, Biogen, Boehringer Ingelheim, Botanix Pharmaceuticals, Bristol‐Myers Squibb, Celgene, Eli Lilly, Escalier Biosciences, Exicure, Incyte Corporation, Innovaderm, Janssen Pharmaceutica, Leo Pharma, Menlo Therapeutics, Nimbus Therapeutics, Novan, Novartis, Parexel, Pfizer Inc., Regeneron Pharmaceuticals, Sanofi, Sienna Biopharmaceuticals, Sun Pharmaceutical Industries, UCB, Valeant Pharmaceuticals and Vitae Pharmaceuticals.

© 2020 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British.

Figures

Figure 1
Figure 1
Study design. CRU, Clinical Research Unit; F/U, follow‐up; V1, first visit.
Figure 2
Figure 2
Mean (95% CI) psoriatic skin infiltrate thickness shown by echo‐poor band (EPB) in the full analysis set.
Figure 3
Figure 3
Quantitative real‐time reverse transcription PCR analysis of the (a) interleukin (IL)‐17A and (b–d) retinoic acid‐related orphan receptor (RORC) isoform expression levels in psoriatic skin biopsies at baseline from an independent repository (study NCT02310750). ***P < 0.0001. Patient numbers: (a,b) n = 25; (c) n = 24; (d) n = 21. The data are normalized to harmonin‐interacting, ankyrin repeat‐containing protein (hARP) and represent least squares mean ± SE. The box represents the 25th–75th percentiles.
Figure 4
Figure 4
Expression of psoriasis‐related genes in psoriatic lesions treated with PF‐06763809 or the vehicle at Day 19. The data are normalized to harmonin‐interacting, ankyrin repeat‐containing protein (hARP) and represent least squares mean ± SE from 34 biopsy samples [2.3% PF‐06763809 (n = 13), 0.23% PF‐06763809 (n = 4) and PF‐06763809 vehicle (n = 17)] with fold‐change between groups. The box represents the 25th−75th percentiles. IL, interleukin; KRT16, keratin 16; RORC, retinoic acid‐related orphan receptor.

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