Effectiveness and Safety of Risankizumab Induction Therapy for 100 Patients With Crohn's Disease

A GETAID Multicentre Cohort Study

Mathurin Fumery; Antoine Defrance; Xavier Roblin; Romain Altwegg; Benedicte Caron; Xavier Hébuterne; Carmen Stefanescu; Antoine Meyer; Maria Nachury; David Laharie; Stephane Nancey; Catherine Le Berre; Melanie Serrero; Sophie Geyl; Cyrielle Giletta; Philippe Ah-Soune; Nicolas Duveau; Mathieu Uzzan; Vered Abitbol; Amelie Biron; My-Linh Tran-Minh; Thierry Paupard; Lucine Vuitton; Yasmine Elgharabawy; Laurent Peyrin-Biroulet

Disclosures

Aliment Pharmacol Ther. 2023;57(4):426-434.

Abstract and Introduction

Abstract

Background: Phase III trials have demonstrated the efficacy of risankizumab in moderate-to-severe Crohn's disease (CD), but no real-world data are currently available. We aimed to assess the short-term effectiveness and safety of risankizumab in patients with CD.

Methods: From May 2021 to May 2022, all patients with refractory luminal CD treated with risankizumab in 22 French GETAID centres were retrospectively included. The primary endpoint was steroid-free clinical remission at week 12 (Harvey-Bradshaw [HB] score <5). Secondary endpoints included clinical response (≥3-point decrease of HB score and/or (HB) score <5), biochemical remission (CRP ≤ 5 mg/L), need for CD-related surgery and adverse events.

Results: Among the 100 patients included, all have been previously exposed to anti-TNF agents, 94 to vedolizumab, 98 to ustekinumab (all exposed to at least three biologics) and 61 had a previous intestinal resection. All but three (97%) received a 600 mg risankizumab intravenous induction at weeks 0–4–8. At week 12, steroid-free clinical remission was observed in 45.8% of patients, clinical remission in 58% and clinical response in 78.5%. In subgroup analysis restricted to patients with objective signs of inflammation at baseline (n = 79), steroid-free clinical remission at week 12 was observed in 39.2% of patients. Biochemical remission was observed in 50% of patients. Six patients discontinued risankizumab before the week 12 visit due to lack of efficacy. CD-related hospitalisation was needed in six patients, and three underwent intestinal resection. In multivariable analysis, only a history of ustekinumab loss of response (vs primary failure) (odds ratio (OR), 2.80; 95% CI: 1.07–7.82; p = 0.041) was significantly associated with clinical remission at week 12. Twenty adverse events (AE) occurred in 20 patients including 7 serious AE corresponding to 6 CD exacerbation and one severe hypertension.

Conclusion: In a cohort of highly refractory patients with luminal CD and multiple prior drug failures including ustekinumab, risankizumab induction provided a clinical response in about 3 out of 4 patients and steroid-free clinical remission in about half of patients.

Introduction

Crohn's disease (CD) is a chronic and destructive inflammatory disease of the gastrointestinal tract characterised by phases of relapse and remission.^[1] Tumour necrosis factor (TNF) antagonists, anti-integrins and anti-interleukin (IL) 12/23 are the main therapeutic agents to obtain deep remission and prevent disability.^[2] Although biologics are a major advance in the treatment of CD, many patients do not respond, lose response over time or have adverse events leading to drug discontinuation.^[3,4] There is a growing demand for novel therapeutic agents targeting alternative disease mechanisms.

Risankizumab is a fully human IgG1 monoclonal antibody targeting selectively the IL-23 p19 subunit and inhibiting its interaction with the IL-23 receptor complex.^[5] Risankizumab is currently approved for the treatment of plaque psoriasis and psoriatic arthritis.^[6] In two recent phase III trials, risankizumab demonstrated its efficacy and safety as induction therapy in patients with moderate-to-severe CD, naive or previously exposed to biologics.^[5] This robust data have driven the approval of risankizumab by the Food Drug Administration (FDA) for the treatment of patients with moderate-to-severe CD.

Few studies have reported the real-world effectiveness of risankizumab in CD. Real-world studies allow for bridging some data gaps by describing patient experiences that are lacking in clinical trials that tend to exclude certain groups of patients.^[7] The aim of this study was therefore to evaluate the effectiveness and safety of risankizumab induction therapy in a multicentre retrospective cohort of patients with CD failing conventional treatment.

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Abstract and Introduction
Patients and Methods
Results
Discussion
References

Table 1. Demographic, disease characteristics and medication histories of the 100 patients with Crohn's disease at risankizumab initiation
Characteristic	n = 100
Age, years (median, IQR)	36.9 (30.2–48.5)
Male gender, n	46
BMI, kg/m² (median, IQR)	21.5 (19.3–24.7)
Smoking habits, n
Active smoker	14
Duration of disease, years (median, IQR)	14.8 (9.4–21.7)
Location (n)
Ileal	20
Colonic	20
Ileocolonic	59
Isolated upper gastrointestinal tract	1
Disease behaviour
Inflammatory	32
Stricturing	41
Penetrating	27
Perianal involvement	36
Extra-intestinal manifestations (n)	37
Articular	23
Cutaneous	15
Ocular	3
Others	3
Prior medications exposure (n)
Immunosuppressant	92
Thiopurines	89
Methotrexate	61
Anti-TNF therapy	100
Adalimumab	94
Infliximab	97
Vedolizumab	94
Ustekinumab	98
Exposition to 3 biologics	17
Exposition to 4 biologics	83
Previous intestinal resection	61
Mode of failure of ustekinumab (n)
Primary failure	55
Loss of response	35
Intolerance	6
Unknown	2
Disease activity at week 0
Harvey-Bradshaw index (median, IQR)	8 (5–11)
CRP, mg/L (median, IQR)	8.1 (3.0–30.4)
CRP > 5 mg/L n (%)	62 (63.9%)
Calprotectin, μg/g (median, IQR)	877 (178–1992)
Calprotectin > 250 μg/g n (%)	28 (66.6%)
Haemoglobin, g/dl (median, IQR)	12.9 (11.8–14.2)
Concomitant medications
Steroids	48
Immunosuppressants	11
Ustekinumab therapy
Intravenous 600 W0–W4–W8	97
Subcutaneous 150 mg W0–W2–W12	2
Subcutaneous 150 mg W0–W4–W8	1

Abbreviations: BMI, body mass index; CRP, high sensitivity C-reactive protein; TNF, tumour necrosis factor-α.

Table 2. Predictors of steroids-free clinical remission at week 12.
Risk factors	Univariate analysis		Multivariate analysis
Risk factors	OR (95% CI)	p value	OR (95% CI)	p value
Age	0.98 (0.95–1.01)	0.172	0.98 (0.95–1.01)	0.3
Male gender	1.31 (0.59–2.94)	0.5	–	–
Disease duration	1.01 (0.99–1.02)	0.544	–	–
Body mass index >25	1.02 (0.94–1.11)	0.608	–	–
Previous intestinal resection	1.82 (0.80–4.21)	0.154	1.67 (0.66–4.28)	0.3
Non-smoker at baseline	2.64 (0.82–9.49)	0.103	3.11 (0.93–11.6)	0.072
Localisation			–	–
Ileal (L1)	–
Colonic (L2)	1.21 (0.34–4.37)	0.764
Ileocolonic (L3)	1.35 (0.48–3.84)	0.565
Behaviour			–	–
Inflammatory (B1)	–
Stricturing (B2)	1.27 (0.50–3.27)	0.614
Fistulizing (B3)	1.68 (0.59–4.94)	0.334
Perianal Crohn's disease	0.84 (0.37–1.93)	0.680	–	–
Harvey-Bradshaw at risankizumab initiation	1.38 (0.59–3.25)	0.461	–	–
C reactive protein at risankizumab initiation	1.00 (0.99–1.01)	0.487	–	–
Prior exposition to vedolizumab	0.85 (0.09–5.80)	0.864	–	–
Mechanism of ustekinumab failure
Primary failure	–		–	–
Intolerance	1.20 (0.19–7.52)	0.842	1.16 (0.19–7.26)	0.09
Loss of response	3.39 (1.37–9.00)	0.008	2.80 (1.07–7.82)	0.041
Steroids at risankizumab initiation	0.87 (0.39–1.93)	0.728
Concomitant immunosuppressant therapy	2.24 (0.59–11.4)	0.246	–	–

Abbreviations: OR, odds ratio; CI, confidence interval.

Table 3. Adverse events affecting 100 patients with Crohn's disease treated with risankizumab
Event	n = 100
Adverse events
Headaches	3
Injection site reaction	1
Arthralgia	4
IBD exacerbation	6
Otitis	1
Skin rash	1
Bronchitis	1
Alopecia	1
Mastodynia	1
Hypertensive flare-up	1
Serious adverse event
IBD exacerbation	6
Hypertensive flare-up	1
Cancer	0
Death	0

Authors and Disclosures

Mathurin Fumery¹, Antoine Defrance², Xavier Roblin³, Romain Altwegg⁴, Benedicte Caron⁵, Xavier Hébuterne⁶, Carmen Stefanescu⁷, Antoine Meyer⁸, Maria Nachury⁹, David Laharie¹⁰, Stephane Nancey¹¹, Catherine Le Berre¹², Melanie Serrero¹³, Sophie Geyl¹⁴, Cyrielle Giletta¹⁵, Philippe Ah-Soune¹⁶, Nicolas Duveau¹⁷, Mathieu Uzzan¹⁸, Vered Abitbol¹⁹, Amelie Biron²⁰, My-Linh Tran-Minh²¹, Thierry Paupard²², Lucine Vuitton²³, Yasmine Elgharabawy² and Laurent Peyrin-Biroulet⁵

¹Department of Gastroenterology, Amiens University Hospital, and PeriTox, Université de Picardie, Amiens, France
²Groupe d'étude des Affections Inflammatoires du tube Digestif, GETAID, Paris, France
³Department of Gastroenterology, CHU of Saint-Etienne, Saint-Etienne, France
⁴Department of Gastroenterology, CHU of Montpellier, Montpellier, France
⁵Department of Gastroenterology and Inserm NGERE U1256, Nancy University Hospital, University of Lorraine, Vandoeuvre-lès-Nancy, France
⁶Department of Gastroenterology and Clinical Nutrition, CHU of Nice and University Côte d'Azur, Nice, France
⁷Department of Gastroenterology, CHU Beaujon, APHP, Clichy, France
⁸Department of Gastroenterology, CHU Kremlin-Bicetre, APHP, Kremlin-Bicetre, France
⁹Department of Gastroenterology, CHU of Lille, Lille, France
¹⁰Service d'Hépato-Gastroentérologie et Oncologie Digestive, CHU de Bordeaux, Hôpital Haut-Lévêque, Université de Bordeaux, Bordeaux, France
¹¹Department of Gastroenterology, CHU of Lyon, Lyon, France
¹²Hépato-Gastro-Entérologie et Assistance Nutritionnelle, Inserm CIC 1413, Inserm UMR 1235, Institut des Maladies de l'Appareil Digestif (IMAD), Nantes Université, CHU Nantes, Nantes, France
¹³Department of Gastroenterology, CHU of Marseille, Marseille, France
¹⁴Department of Gastroenterology, CHU of Limoges, Limoges, France
¹⁵Department of Gastroenterology and Pancreatology, CHU of Toulouse RANGUEIL, Toulouse, France
¹⁶Department of Gastroenterology, CH of Toulon, Toulon, France
¹⁷Department of Gastroenterology, CH of Roubaix, Roubaix, France
¹⁸Gastroenterology Department, Henri Mondor Hospital, Fédération Hospitalo-Universitaire TRUE InnovaTive theRapy for immUne disordErs, Paris Est Créteil University UPEC, Assistance Publique-Hôpitaux de Paris (AP-HP), Créteil, France
¹⁹Department of Gastroenterology, Hopital Cochin, Paris, France
²⁰Department of Gastroenterology, CHU of Reims, Reims, France
²¹Department of Gastroenterology, Hopital Saint-Louis, Paris, France
²²Department of Gastroenterology, Centre Hospitalier de Dunkerque, Dunkirk, France
²³Department of Gastroenterology, UMR 1098, University of Franche-Comté, Besançon, France

Correspondence
Mathurin Fumery, Department of Gastroenterology, Amiens University hospital, and PeriTox, Université de Picardie, France. Email: fumery.mathurin@chu-amiens.fr

Author Contributions
Antoine Defrance: Data curation (equal); project administration (equal); supervision (equal). Xavier Roblin: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Romain Altwegg: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Benedicte CARON: Data curation (equal); investigation (equal); writing – review and editing (equal). Xavier Hebuterne: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Carmen Stefanescu: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Antoine Meyer: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). maria nachury: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). David Laharie: Data curation (equal); investigation (equal); supervision (equal); writing – review and editing (equal). stephane Nancey: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Catherine Le Berre: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Melanie Serrero: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Sophie Geyl: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Cyrielle Gilletta: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Philippe Ah Soune: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Nicolas Duveau: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Mathieu Uzzan: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Vered Abitbol: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Amelie Biron: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). My-Linh Tran-Minh: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Thierry Paupard: Data curation (equal); investigation (equal); validation (equal); writing – review and editing (equal). Lucine Vuitton: Data curation (equal); investigation (equal); supervision (equal); writing – review and editing (equal). Yasmine Elgharabawy: Conceptualization (equal); methodology (equal); software (equal); validation (equal); writing – review and editing (equal). Laurent Peyrin-Biroulet: Conceptualization (equal); data curation (equal); investigation (equal); methodology (equal); supervision (equal); validation (equal); writing – original draft (equal).

Conflict of Interest
Mathurin Fumery has received lecture and consulting fees from Abbvie, MSD, Boehringer, Pfizer, Takeda, Fresenius, Celgene, Gilead, Celltrion, Sandoz, CTMA, Amgen, Biogen, Viatris, Lilly, Celgene, Gilead, Tillots, Galapagos, Janssen and Ferring. Xavier Roblin reported a relationship with Abbvie, MSD, Janssen Cilag and Takeda. David Laharie received counselling, boards or transports fees from Abbvie, Biogaran, Biogen, Ferring, HAC-pharma, Janssen, MSD, Novartis, Pfizer, Prometheus, Roche, Takeda, Theradiag and Tillots. Romain Altwegg received board or lecture fees from Abbvie, Janssen, Pfizer and Takeda. B Caron reports lecture and/or consulting fees from Abbvie, Amgen, Celltrion, Ferring, Galapagos, Janssen and Takeda. Xavier Hébuterne reports clinical research funding from Abbvie, Abivax, Alphasigma, Arena, Gilead, Eli Lilly, Enterome, Fresenius-Kabi, Janssen, InDex Pharmaceuticals, Pfizer, Prometheus Biosciences, Sangamo, Takeda, Theravance, serving on advisory boards for Abbvie, Abivax, Boehringer Ingelheim, Celltrion, Fresenius-Kabi, Galapagos, Janssen, Nestlé Health Sciences, Nordic Pharma and participating in lectures and educational activities for Abbvie, Amgen, Celltrion, Fresenius-Kabi, Janssen, MSD, Nordic Pharma, Nestlé Health Sciences, Nutricia, Pfizer, Tillots, Takeda, Viatris. Vered Abitbol received lecture fees from Biogen Amgen Sandoz Mylan Pfizer Takeda Janssen, Gilead, Tillots. Melanie Serrero has received lecture fees from Abbvie, Ferring. Cyrielle Gilletta received lecture fees from Abbvie, Takeda, Pfizer and Janssen and consulting fees from Abbvie, Janssen and Celltrion. Stephane Nancey received consulting fees from Merck, Abbvie, Takeda, Ferring, Norgine, Vifor Pharma, Novartis, Janssen-Cilag, Hospira, Takeda and HAC-Pharma. M Uzzan reports lecture and/or consulting fees from Abbvie, Celltrion, Galapagos, Janssen and Takeda. Thierry Paupard received consulting fees from Abbvie, Ferring, Janssen, Celltrion, Tillots and Novartis. L Vuitton has received fees from Amgen, Abbvie, Celltrion, MSD, Ferring, Pfizer, Janssen, Takeda, Galapagos and Biogen. Laurent Peyrin-Biroulet received consulting fees from Merck, Abbvie, Janssen, Genentech, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-Pharma, Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer and HAC-Pharma. This author also received lecture fees from Merck, Abbvie, Takeda, Janssen Cilag, Ferring, Norgine, Tillots, Vifor, Therakos, HAC-Pharma and Mitsubishi. No conflict of interest is claimed by the remaining authors.