Tomalin, Lewis E, Kolbinger, Frank, SUprun, M, Wharton, KA Jr., Hartmann, Nicole, Peters, Thomas, Glueck, Anton, Milutinovic, Marina, Krueger, James G. and Suárez-Fariñas, Mayte (2024) Deep resolution of clinical, cellular, and transcriptomic inflammatory markers during 52 weeks of IL-17A inhibition by secukinumab. Clinical and experimental dermatology, 00. pp. 1-9. ISSN 1365-2230

Abstract

Background
Secukinumab, an anti-IL-17A monoclonal antibody, induces histological and molecular resolution of psoriatic plaques by 12 weeks. However, the long-term effects of secukinumab on molecular resolution of psoriatic inflammation remain unknown.

Objective
To investigate the molecular resolution of psoriasis following 52-weeks of secukinumab treatment.

Methods
NCT01537432 was a two-part Phase 2, randomised, double-blinded, placebo-controlled, 52-week study of patients with moderate to severe psoriasis receiving secukinumab 300 mg. Psoriatic lesional and non-lesional skin biopsies were obtained at baseline, Week 12, and Week 52, and the composition of the residual disease genomic profile (RDGP, i.e., “molecular scar”) of biopsies from secukinumab-responders was analysed.

Results
After 52 weeks of treatment, 14/24 enrolled patients were considered clinical responders (≥75% improvement in Psoriasis Area and Severity Index [PASI]; PASI75), 4/24 were considered non-responders (<PASI75), and 6/24 patients were lost to follow-up; both histological and transcriptomic profiles of PASI75 responders improved from Week 12–52. RDGP transcripts of histological responders only partially overlapped between Week 12 and 52, despite similar number of transcripts in each RDGP; specifically, four novel transcript subsets showed distinct expression dynamics between Week 12 and 52 (slow-resolving, recurring, persistent, and resolved), with anti-inflammatory and immunomodulatory genes (e.g., SOCS1, CD207, IL-37) notably restored at Week 52. Shorter disease duration prior to secukinumab treatment coincided with greater transcript improvements at Week 12 and Week 52.

Conclusions
Secukinumab improves the histological and molecular phenotype of psoriatic lesional skin up to 52 weeks of treatment; these results suggest possible mechanisms that drive long-term control of psoriasis.

Item Type:	Article
Keywords:	AIN457, Cosentyx, Psoriasis, disease modification, transcriptomics
Date Deposited:	23 Jul 2024 00:46
Last Modified:	23 Jul 2024 00:46
URI:	https://oak.novartis.com/id/eprint/53152