Inflammatory bowel disease: cause(s), cure(s) and prediction of disease flare NZ Society of GI: 21 st November 2018

Transcription

1 Inflammatory bowel disease: cause(s), cure(s) and prediction of disease flare NZ Society of GI: 21 st November 2018 Dr Charlie Lees Consultant Gastroenterologist From the Edinburgh IBD Unit at the Western General Hospital

2 Disclosures & Disclaimer I, Charlie Lees, have received Speaker, Advisory Board Consultant and/or Clinical Trial honoraria from the following companies: Abbvie, MSD, Janssen, Takeda, Pfizer /Hospira, Gilead, Vifor Pharma, Cellgene, GSK, Shire 2

3 IBD 2018 (q4): what are the issues? How many people have (will get) IBD? and WHY? Can we prevent IBD? Can we cure IBD? and if not can we prevent disease flare? and stop disease progression? How do we address the unmet therapeutic need? How to stratify patients early by risk and biology? Drug pipeline Choosing the right treatment for the right patient at the right time Can we get it right first time? and if not, what s the next best alternative strategy? What can patients do to improve outcomes? How do we empower patients with their own healthcare records with signposting to information and education?

4 Incidence and prevalence CD < 1960 Molodecky et al., Gastroenterology Volume 142, Issue e42

5 Incidence and prevalence CD Molodecky et al., Gastroenterology Volume 142, Issue e42

6 Incidence and prevalence CD Molodecky et al., Gastroenterology Volume 142, Issue e42

7 Incidence and prevalence CD Molodecky et al., Gastroenterology Volume 142, Issue e42

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10 This non-promotional meeting has been organised and funded by AbbVie 10

11 This non-promotional meeting has been organised and funded by AbbVie 11

12 This non-promotional meeting has been organised and funded by AbbVie 12

13 Lothian population = 834,648 Prevalence = 0.83% This non-promotional meeting has been organised and funded by AbbVie 13

14 This non-promotional meeting has been organised and funded by AbbVie 14

15 This non-promotional meeting has been organised and funded by AbbVie 15

16 SCENARIO IBD_PREVENT: detect those patients at risk of developing IBD, intervene and prevent disease from developing 1. Can we detect biomarkers for preclinical disease? YES 2. Can we then intervene to prevent disease development? YES Can we maintain this state? This requires large unbiased cohorts sampled before disease development (e.g. GEM) It needs a strategy to intervene that works and is implementable and is durable How long does the at-risk state last? How long do we need to keep the patient in prevent mode?

17 This non-promotional meeting has been organised and funded by AbbVie 17

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20 1980s ~200 independent IBD susceptibility loci

21 Blood vessel Pathogen Intestinal lumen Lamina propria Dendritic cell AMG 139 Risankizumab LY IEL Etrolizumab Laquinimod PF Tofacitinib Filgotinib Upadacitinib Peficitinib Ustekinumab IL-6R JAKs STATs IL-12/23R SMADs SMAD7 TGF-βRI/II Mongersen IL-10 IL-6 TNF-α IL-17A/F IL-12 (p40/p35) TGF-β1 IL-23 (p40/p19) Ozanimod T E Estrasimod Amiselimod S1P 1 S1P gradient Lymph node TNFR NF- B Transcription of target genes Macrophages Infliximab Adalimumab Golimumab Certolizumab pegol PF α4β1 MAdCAM-1 Natalizumab AJM 300 α4β7 Vedolizumab AMG 181 Etrolizumab αeβ7 VCAM-1 S1P T-cells Endothelial cell 21 Figure adapted from Coskun M, et al. Trends Pharmacol Sci. 2017;38:

22 Crohn s disease 23,339 Ulcerative colitis 19,208 Healthy controls 19,544

23 Proportion (%) Crohn s disease is progressive Inflammatory window of opportunity Inflammatory (B1) Stricturing (B2) Penetrating (B3) Time after diagnosis of Crohn s disease (years) N=16,902 patients with Crohn s disease Cleynen I, et al. Lancet 2016;387:

24 Cleynen I, et al. Lancet 2016;387:

25 Cleynen I, et al. Lancet 2016;387:

26 Cleynen I, et al. Lancet 2016;387:

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29 Moeller et al PNAS 2014 Nov 3 [early view]

30 PC2 Ulcerative colitis Effect PC1 p=0.031 Crohn s disease Healthy Figure amended from reference 1 Cause 1. Qin J, et al. Nature 2010;464:59 65

31 This non-promotional meeting has been organised and funded by AbbVie 31

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34 what components of diet? It s the Sugar It s the Fat It s the Protein It s low Fiber It s low fruit intake Low intake Fiber ( fruit; veggies)? Western Diet? It s the Western Diet It s Vitamin D HELP! Ananthakrishnan et al 2015 D Souza et a l 2008

35 what components of diet? High fat diet (PUFA, omega-6 & meat) High fruit & fiber diet High vegetable diet Emulsifiers carboxymethylcellulose Risk of UC & CD Risk of CD Risk of UC Develop IBD in healthy mice & polysorbate-80 Hou JK et al. Am J Gastroenterol. 2011;106(4): Chassaing B et al. Nature. 2015;519(7541):92-96

36 Devkota S et al Nature 2012;487: David LA et al Nature 2013;505:

37 The dietary road to colitis

38 This non-promotional meeting has been organised and funded by AbbVie 38

39 This non-promotional meeting has been organised and funded by AbbVie 39

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41 Crohn s disease activity Pattern of bowel symptom severity in Crohn s disease varies among patients IBSEN study (N = 237) 10-year follow-up Diagnosed a 3% Increase in symptom severity 19% Chronic continuous symptoms 0 10 Years 32% Chronic relapsing symptoms a From 1990 to 1994, patients with inflammatory bowel disease were enrolled in southeastern Norway and systematically followed up for up to 10 years after diagnosis. Grey line: 43% decrease in severity of bowel symptoms during follow-up. CD, Crohn s disease; IBSEN, Inflammatory Bowel South-Eastern Norway. Adapted from Solberg IC, et al. Clin Gastroenterol Hepatol. 2007;5:

42 While mucosal inflammation fluctuates over time, structural damage to the luminal GI tract may continue to progress 42

43 IBD 2018 (q4): what are the issues? How many people have (will get) IBD? and WHY? Can we prevent IBD? Can we cure IBD? and if not can we prevent disease flare? and stop disease progression? How do we address the unmet therapeutic need? How to stratify patients early by risk and biology? Drug pipeline Choosing the right treatment for the right patient at the right time Can we get it right first time? and if not, what s the next best alternative strategy? What can patients do to improve outcomes? How do we empower patients with their own healthcare records with signposting to information and education?

44 History of treatment for IBD 1950s 1st use of steroids st MTX study in CD 2015 Start of biosimilar era 2017 Ustekinumab launched for CD st use of thiopurines 1990s 1st approval of anti-tnfαs 2014 Vedolizumab launched; 1st gut-selective agent for IBD Tofacitinib approved for UC/ JAK inhibitors CD, Crohn s disease; IBD, inflammatory bowel disease; JAK, Janus kinase; MTX, methotrexate; TNF, tumour necrosis factor; UC, ulcerative colitis. Mulder DJ, et al. J Crohns Colitis 2014;8:

45 IBD_Treat-to-target: optimised Identify risk factors for progressive disease Stratify therapy by RISK NOD2; FOXOa1 Microbial signature Smoking/diet/environment NORMAL quality of life COMPLETE MUCOSAL HEALING PREVENTION OF BOWEL DAMAGE NO TOXICITY FROM DRUGS Identify dominant biological pathway Stratify therapy by BIOLOGY Anti-TNF Anti-integrin Anti-p40/p19 Anti-SP1 JAK inhibition PDE4 inhibition FMT Optimize with TDM & pharmacogenomics TREAT TO TARGET MONITORING = symptoms + inflammation Adjust therapy to reach target NB. This slide contains details of pipeline therapies that are not approved by regulatory authorities. Safety and efficacy have not been established FMT: faecal microbiota transplantation; FOXO: forkhead box O; IBD: inflammatory bowel disease; JAK: janus kinase; NOD: nucleotide-binding oligomerization domain-containing protein; PDE: phosphodiesterase; SP: service pack; TNF: tumour necrosis factor Image source: Lees C

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48 SCENARIO IBD_NO FLARES: induce remission, maintain remission, prevent flare, & therefore disease progression 1. Can we accurately and appropriately phenotype and classify our patients for RISK and BIOLOGY? YES 2. Can we target the appropriate pathway(s) to completely induce remission YES The strategy may be an achievable target IBD could no longer be a chronic illness 3. Can we prevent disease flare? (aka maintain remission) This requires large unbiased cohorts studying drug response Right drug, for the right patient first time We need methods to reliably maintain remission

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50 PREdiCCt: - recruit 3100 patients with IBD in clinical remission - detailed baseline demographics and phenotyping - dietary survey & environmental questionnaire - stool: metagenomics, calpro & SCFAs - saliva: whole-genome sequencing Primary endpoint 2 years of follow-up: monthly questionnaires

51 PREdiCCt: - recruit 3100 patients with IBD in clinical remission - detailed baseline demographics and phenotyping - dietary survey & environmental questionnaire - stool: metagenomics, calpro & SCFAs - saliva: whole-genome sequencing The primary objectives are to test associations with: 1. Total animal protein intake 2. Dietary fibre To determine which aspects of a) baseline habitual diet, b) the environment, c) genetic variation and d) the gut microbiota, predict disease flare in Crohn s disease and /or ulcerative colitis. Primary endpoint 3. N-6 polyunsaturated fatty acids 4. Dietary emulsifiers 5. Total bacterial gene count in stool 2 years of follow-up: monthly questionnaires

52 PREdiCCt: - recruit 3100 patients with IBD in clinical remission - detailed baseline demographics and phenotyping - dietary survey & environmental questionnaire - stool: metagenomics, calpro & SCFAs - saliva: whole-genome sequencing Primary endpoint 2 years of follow-up: monthly questionnaires

53 PREdiCCt: - recruit 3100 patients with IBD in clinical remission - detailed baseline demographics and phenotyping - dietary survey & environmental questionnaire - stool: metagenomics, calpro & SCFAs - saliva: whole-genome sequencing Primary endpoint 2 years of follow-up: monthly questionnaires

54 - recruiting 3100 patients with IBD in clinical remission - detailed baseline demographics and phenotyping - dietary survey & environmental questionnaire - stool (posted from home): metagenomics, calprotectin & SCFAs - saliva: whole-genome sequencing Medication history (Antibiotics/NSAIDs/OTC/complementary medicines) Drug Compliance (MMASv8) SF-12 general quality of life (QoL) questionnaire IBD QoL and CUCQ-8 questionnaires Primary endpoint Anxiety & Depression (HADS) / Somatisation/ PHQ15 Grit and resilience (CD-RISC 25) Sleep (Pittsburgh Sleep quality index) Stressful life events (Holmes and Rahe Top20) Exercise (Global physical activity questionnaire GPAQv2) Weight loss (MUST score) Travel (planes, trains and cars) Alcohol (FAST questionnaire) & Smoking 2 years of follow-up: monthly questionnaires

55 PREdiCCt: - recruit 3100 patients with IBD in clinical remission - detailed baseline demographics and phenotyping - dietary survey & environmental questionnaire - stool: metagenomics, calpro & SCFAs - saliva: whole-genome sequencing Primary endpoint 2 years of follow-up: monthly questionnaires

56 PREdiCCt Primary/Secondary endpoint Primary outcome Clinical flare - Determined by patient answering no to the following question Do you think your disease has been well controlled in the past 1 month? Secondary outcome Hard clinical flare The occurrence of a clinical flare (defined above) plus commencement of any new medication; altered dosing of existing medication for the treatment of IBD flare, with an increase in CRP (>5mg/L) and / or faecal calprotectin (>250mcg/g). Total number of clinical flares and hard flares in the 24 months follow-up period.

57 PREdiCCt Patient Recruitment N= 3,100 (50/50 Crohn s/uc) Recruited at clinic (letters, posters, pamphlets provided) Willing volunteers via social media/publicity Broad inclusion and exclusion criteria Inclusion criteria Confirmed Crohn s disease or ulcerative colitis Clinical remission > 6 months since diagnosis > 2 months since any change in therapy for CD or UC Six years of age at study entry Written informed consent obtained from patient or parent/guardian Exclusion criteria Patient unwilling to take part in all aspects of the study Unable to obtain written informed consent Systemic corticosteroids within the last two months Thiopurines/methotrexate/biologic therapy started in the preceding two months

58 PREdiCCt Patient Recruitment N= 3,100 (50/50 Crohn s/uc) Recruited at clinic (letters, posters, pamphlets provided) Willing volunteers via social media/publicity Broad inclusion and exclusion criteria

59 PREdiCCt Patient Recruitment N= 3,100 (50/50 Crohn s/uc) Recruited at clinic (letters, posters, pamphlets provided) Willing volunteers via social media/publicity Broad inclusion and exclusion criteria

60 Introducing Oshi Health! Oshi Health, Inc. is: An NYC based startup Takeda is majority investor Oshi Health App is: IBD disease management tool Planned US launch: June 2 nd at DDW UK launch: ~August Data capture tool of PREdiCCt clinical study DDW: Digestive Disease Week; IBD: inflammatory bowel disease; NYC: New York city; UK: United Kingdom; US: United States of America

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63 HCP patient interaction EMR (TRAK) Data manually extracted and input by research nurse/doctor Curated real-time summary of disease phenotype PRO PREdiCCt OSHI Hyper-personalised care UK IBD Bioresource Data shared through REDCap Empowering patients with their medical records IBD registry Signposting

64 PREdiCCt app key features Sign-in Screen: Sign in with password or 6-digit PIN Home Screen: Displays any in progress questionnaires as well as an option to view past archived questionnaires Questionnaires: Questions have branching logic. Also has ability to save and exit allowing participant to return Unanswered Questions: Lists any incomplete questions for participants to finish before submission Archived Questions: Participants will be able to access their answers for previous archived questionnaires

65 PREdiCCt app responsive design The UI will be responsive and accessible directly through web browsers on phones, tablets and PCs UI: user interface

66 Twitter: Website: Facebook: YouTube: This non-promotional meeting has been organised and funded by AbbVie 66

67 QUESTIONS?