Z Gastroenterol 2019; 57(05): e136
DOI: 10.1055/s-0039-1691868
POSTER
CED
Georg Thieme Verlag KG Stuttgart · New York

Molecular Response to Ustekinumab in Moderate-to-severe Ulcerative Colitis by Serum Protein and Biopsy Gene Expression Analysis: Results from the UNIFI Phase 3 Induction Study

K Li
1   Janssen Research & Development, LLC, Spring House, United States
,
F Yang
1   Janssen Research & Development, LLC, Spring House, United States
,
K Hayden
1   Janssen Research & Development, LLC, Spring House, United States
,
D Strawn
1   Janssen Research & Development, LLC, Spring House, United States
,
E Wadman
1   Janssen Research & Development, LLC, Spring House, United States
,
S Bhagat
1   Janssen Research & Development, LLC, Spring House, United States
,
C Marano
1   Janssen Research & Development, LLC, Spring House, United States
,
JR Friedman
1   Janssen Research & Development, LLC, Spring House, United States
› Author Affiliations
Further Information

Publication History

Publication Date:
16 May 2019 (online)

 

Background:

IL-12 and IL-23 are elevated in ulcerative colitis (UC) and genetic association suggests that they play causative roles in the disease. Ustekinumab (UST) blocks both cytokines and is an effective therapy for moderate-to-severe UC, but its molecular effects in UC patients remain unknown.

Methods:

Colonic biopsy mRNA and serum samples from ˜60% of patients (UNIFI phase 3 induction study) were analyzed, with equal representation of patients with a history of biologic therapy failure (BF) and those without (BN) (Tab. 1). Biopsy and serum samples from healthy subjects were analyzed as controls.

Results:

Colon biopsies from UC pts had a gene expression disease profile of 4095 probe sets, including genes involved in inflammatory response, tissue remodeling and wound healing, host-microbe interaction, intestinal permeability, and solute transport. BF and BN UC pts shared almost identical disease profiles. At Week 8 after UST induction therapy, the disease profile was significantly normalized in responders to UST. A smaller magnitude of normalization was observed in responders to PBO. No significant change in disease signature occurred in non-responders. At baseline, BF and BN UC pts had similar serum profiles, with significantly elevated levels of IFNγ, IL-17A, IL-22, SAA, NGAL, MMPs, and TNF versus healthy controls. Normalization of IFNγ, SAA, IL-17A, and IL-22 was first detected in responders to UST at Week 4, the earliest time point in our assessment, and continued to improve through Week 8. A trend of normalization of MMPs, IL-10, and NGAL was observed in UST responders; it was weaker or absent in UST non-responders and PBO-treated patients. TNF was elevated in UC prior to treatment and was not normalized by UST induction therapy.

Tab. 1:

Biopsy mRNA and serum protein assessments in UNIFI

Biopsy mRNA

(550 UC and 18 healthy controls)

Serum Protein

(574 UC and 50 healthy controls)

Time points

Screening, Week 8, Week 16

Screening, Week 4, Week 8, Week 16

Methods

Generalized linear model (GLM) & Gene Set Variation Analysis

GLM

Significance cutoffs

|fold change| > 1.5x and p < 0.05

|fold change| > 1.5x and p < 0.05

Analytes

Affymetrix HG U133 PM arrays

12 serum markers:

· Matrix metalloproteinases: MMP-1,3,9

· Cytokines and cytokine receptors: IFNγ, IL-17A, IL-22, IL-10, IL-2R, TNFα, TNFR1

· Acute Phase Reactant: SAA

· Inflammatory marker: NGAL

Conclusions:

Transcriptomic and protein analyses demonstrated the suppression of IL-12 (IFNγ) and Il-23 (IL-17A) pathways and normalization of the UC disease gene expression profile in response to UST.