C0365 - Symptoms and Laboratory Values as Proxies for Endoscopic and Histologic Clinical Endpoints in Ulcerative Colitis: A Mediation Analysis Based on Upadacitinib Phase 3 Induction Trials

Monday, October 24, 2022

3:00 PM – 5:00 PM ET

Location: Crown Ballroom

Presenting Author(s)

Marla C. Dubinsky, MD

Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai
New York, New York

Marla Dubinsky, MD¹, Min Yang, MD, PhD, MS², Mirko Fillbrunn, PhD², Silvio Danese, MD, PhD³, Johan Burisch, MD, PhD⁴, Satoshi Tanida, MD⁵, Dolly Sharma, PhD⁶, Dapo Ilo, MBBS, MRCS, MSc⁶, Wen Zhou, MD, PhD⁷, Yuri Sanchez-Gonzalez, PhD⁶, Laurent Peyrin-Biroulet, MD⁸
¹Icahn School of Medicine, Mount Sinai, NY; ²Analysis Group, Inc., Boston, MA; ³IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Molise, Italy; ⁴Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Hovedstaden, Denmark; ⁵Education and Research Center for Community Medicine, Nagoya City University, and Gamagori City Hospital, Gamagori, Aichi, Japan; ⁶AbbVie, Inc., North Chicago, IL; ⁷AbbVie Inc., North Chicago, IL; ⁸University Hospital of Nancy, Lorraine University, Vandoeuvre, Franche-Comte, France

Introduction: We evaluate the extent to which commonly available measures in clinical practice (i.e., signs, symptoms, and laboratory values) mediate endoscopy-based clinical measures.

Methods: We analyzed, in the intent-to-treat population from upadacitinib’s (UPA) phase 3 induction trials (U-ACHIEVE Induction, U-ACCOMPLISH in moderately to severely active UC, relationships between deep mucosal healing (DMH), histologic endoscopic mucosal improvement (HEMI), and change from baseline in endoscopic score as outcomes, and signs/symptoms and lab values as mediators (fecal calprotectin, high sensitivity C-reactive protein [hs-CRP], abdominal pain [AP], bowel urgency [BU], and Partial Adapted Mayo Score [PA-Mayo]). The mediated proportion of effect at week (wk) 8 was calculated as the difference in mean outcomes due to a one-unit change in mediators while controlling for baseline characteristics.The effects of mediators at wks 2 and 8 were assessed. Analyses assumed mediators were unrelated to each other and used linear models for all variables. Missing values for DMH and HEMI at wk 8 were imputed via non-responder imputation per trial protocol, while other variables were analyzed as-observed. Standard errors were computed via bootstrap.

Results: A total of 878 patients were included; mean (standard deviation [SD]) age was 42.9 (14.4) years and disease duration was 8.0 (7.2) years. At wk 8, 9.0% of patients achieved DMH and 25.7% achieved HEMI, and mean (SD) change from baseline of the endoscopic score was -0.70 (0.97). All outcomes were mediated by PA-Mayo and BU (Table 1). PA-Mayo mediated around a third of the total effect for all outcomes with similar mediation at wk 2 and 8 (all P< 0.05). The proportion mediated by BU was larger at wk 8 and ranged from one to two thirds of the total effect (all P< 0.05 except for wk 2 for DMH). In contrast, hs-CRP at wk 2 only mediated 2-3% across outcomes (all P< 0.05). The predictive power of the models was similar using wk 2 and 8 mediators and explained 15% (DMH), 40% (HEMI), and 50% (endoscopic score) of variation.

Discussion: Our study found that easily accessible measures such as Partial Adapted Mayo Score and bowel urgency can mediate endoscopy-based endpoints for UC as early as wk 2 of induction, with mediation effects persisting for concurrently assessed signs and symptoms. Our findings suggests that symptom-based measures for UC in clinical practice could be useful proxies for endoscopic and histologic outcomes.

	Deep mucosal healing^c		HEMI^d		Change from baseline in endoscopic score
Variance explained	Week 2 (R²= 0.15^b)	Week 8 (R²= 0.15^b)	Week 2 (R²= 0.39^b)	Week 8 (R²= 0.40^b)	Week 2 (R²= 0.50^b)	Week 8 (R²= 0.52^b)
Bowel urgency, proportion mediated, %^a	30.2	66.2*	48.12*	49.4*	37.4*	45.1*
Partial Adapted Mayo Score, proportion mediated, %^a	33.6*	30.1*	34.6*	33.2*	27.6*	29.1*
Abdominal pain, proportion mediated, %^a	-4.3	-17.4	-13.7	0.4	-5.1	-5.0
hs-CRP (mg/L), proportion mediated, %^a	1.8*	-0.1	2.6*	1.3	2.3*	1.3
Fecal calprotectin (mg/kg), proportion mediated, %^a	-0.0	-1.7	-0.0	-1.6	-0.2	-1.9
Abbreviations: HEMI: Histologic Endoscopic Mucosal Improvement, hs-CRP: High sensitivity C-reactive protein. * denotes statistical significance (alpha < 0.05). Note: [a] Proportion mediated denotes the proportion of the mediated effect of changing one unit of the mediator relative to the total effect; for fecal calprotectin, a change of 100 mg/kg was considered. [b] The R² was calculated for the model regressing the outcome on all control variables and all mediators. [c] Deep mucosal healing was defined as endoscopic score of 0 and Geboes score < 2.0. [d] HEMI was defined as endoscopic score of 0 or 1 and Geboes score ≤ 3.1.

Table: Table 1. Proportion mediated as estimated from mediation analyses for week 8 outcomes using week 2 or week 8 mediators

Disclosures:

Marla Dubinsky: AbbVie – Consultant. Allergan – Consultant. Amgen – Consultant. Boehringer Ingelheim – Consultant. Celgene – Consultant. Eli Lilly – Consultant. Gilead – Consultant. Janssen – Consultant. Pfizer – Consultant. Prometheus Labs – Consultant. Roche – Consultant. Takeda – Consultant. Trellus Health – Share holder. UCB – Consultant.

Min Yang: Analysis Group, Inc. – Employee, Analysis Group has received consulting fees from Ferring Pharmaceuticals.

Mirko Fillbrunn: Analysis Group, Inc. – Employee, Analysis Group has received consulting fees from Ferring Pharmaceuticals.

Silvio Danese: AbbVie – Consultant, Speakers Bureau. Allergan – Consultant, Speakers Bureau. Amgen – Consultant, Speakers Bureau. AstraZeneca – Consultant, Speakers Bureau. Athos Therapeutics – Consultant, Speakers Bureau. Biogen – Consultant, Speakers Bureau. Boehringer Ingelheim – Consultant, Speakers Bureau. Celgene – Consultant, Speakers Bureau. Celltrion – Consultant, Speakers Bureau. Eli Lilly – Consultant, Speakers Bureau. Enthera – Consultant, Speakers Bureau. Ferring – Consultant, Speakers Bureau. Gilead – Consultant, Speakers Bureau. Hospira – Consultant, Speakers Bureau. Inotrem – Consultant, Speakers Bureau. Janssen – Consultant, Speakers Bureau. Johnson & Johnson – Consultant, Speakers Bureau. MSD – Consultant, Speakers Bureau. Mundipharma – Consultant, Speakers Bureau. Mylan – Consultant, Speakers Bureau. Pfizer – Consultant, Speakers Bureau. Roche – Consultant, Speakers Bureau. Sandoz – Consultant, Speakers Bureau. Sublimity Therapeutics – Consultant, Speakers Bureau. Takeda – Consultant, Lecture fees. TiGenix – Consultant, Speakers Bureau. UCB Inc – Consultant, Speakers Bureau. Vifor – Consultant, Speakers Bureau.

Johan Burisch: AbbVie – Consultant. Bristol-Myers Squibb(BMS) – Consultant, Grant/Research Support. Celgene – Consultant. Ferring – Consultant. Galapagos – Consultant. Janssen-Cilag – Consultant, Grant/Research Support. MSD – Consultant, Grant/Research Support. Novo Nordisk – Grant/Research Support. Pfizer – Consultant. Pharmacosmos – Consultant. Samsung Bioepis – Consultant. Takeda – Consultant, Grant/Research Support. Tillots Pharma – Consultant, Grant/Research Support.

Satoshi Tanida: AbbVie – Grant/Research Support. EA Pharma – Grant/Research Support.

Dolly Sharma: AbbVie – Employee, Stock-publicly held company(excluding mutual/index funds).

Dapo Ilo: AbbVie – Employee, Stock Options.

Wen Zhou: AbbVie – Employee, Stock Options.

Yuri Sanchez-Gonzalez: AbbVie – Employee, Stock Options.

Laurent Peyrin-Biroulet: AbbVie – Grant/Research Support, Personal Fees. Allergan – Personal Fees. Alma Bio Therapeutics – Personal Fees. Amgen – Personal Fees. Arena – Personal Fees. Biogen – Personal Fees. Boehringer-Ingelheim – Personal Fees. Celgene – Personal Fees. Celltrion – Personal Fees. Clementia Pharmaceuticals – Stock Options. Enterome – Personal Fees. Ferring – Personal Fees. Genentech – Personal Fees. Gilead – Personal Fees. Hikma – Personal Fees. InDex Pharmaceuticals – Personal Fees. Janssen – Personal Fees. Merck/MSD – Grant/Research Support, Personal Fees. Nestle – Personal Fees. Pfizer – Personal Fees. Pharmacosmos – Personal Fees. Roche – Personal Fees. Samsung Bioepis – Personal Fees. Sandoz – Personal Fees. Sterna Biological – Personal Fees. Takeda – Grant/Research Support, Personal Fees. Tillots Pharma – Personal Fees.