Jessica Philptt MD PhD Digestive Diseases Institute Cleveland Clinic
Objectives Review the Crhn s and Clitis Fundatin Challenges t Research Gals 2018 Review data in envirnment and genetics as cntributing t disease develpment Review rle f bacterial flra in IBD Discuss new paradigms in assessing therapeutic utcmes Discuss nvel technlgies
Challenges in IBD Research 2018* Preclinical human factrs Envirnmental factrs Nvel technlgies Precisin Medicine Clinical Research Gal: Identify unmet areas f knwledge t imprve utcmes fr patients
Challenges in IBD Research 2018* Preclinical human factrs What makes sme peple get IBD and makes their IBD severe? Genetics Immunlgy Envirnmental factrs-culd we change what we eat r are expsed t in rder t cure r avid IBD? Diet Intestinal flra Fd additives Nvel technlgies-what else d we need t better treat IBD? Unmet needs Precisin Medicine Hw can we best tailr treatment t each individual patient? Clinical Research-Hw can we make sure studies are dne that we can quickly apply t ur patients? Pragmatic studies
Interactin f multiple factrs impact develpment f IBD
Preclinical Factrs: Genetics Ye et al,expert Rev Clin Immunl. 2016 Oct; 12(10): 1091 1107.
Preclinical factrs: envirnment Csnes, Gastr Vlume 140, Issue 6, Pages 1785-1794.e4 (May 2011)
Suspects Diet Hygiene thery Tbacc use Vaccines Change in micrbita
Randmized cntrlled trials
Envirnment: Diet Exclusive enteral nutritin has been shwn t reduce inflammatin in children with Crhn s disease, but is inferir t sterids The Specific Carbhydrate Diet (SCD) is ne that restricts all carbhydrates except mnsaccarides Uncntrlled study in children shwed imprvement in mucsal healing with SCD Other carbhydrate restricted diets such as the AIP (Autimmune prtcl-pale) have been studied in small grups already n ther treatment with imprvement but few with strictures suffered frm bwel bstructin In 2018 we dn t have adequate evidence t recmmend a diet t treat inflammatin but we hpe t sn CARBs prbably key ***Lewis and Abreu, Gastrenterlgy 152:398 414 Knijieti, Inflamm Bwel Dis. 2017 Nv; 23(11): 2054 2060.
Envirnment: bacteria in the intestines Dysbisis: an unfavrable alteratin f the cmpsitin and gut micrbita Rle f bacteria in the intestines Nutrient synthesis and delivery Immune system regulatin and develpment Hst defense Nishida et al Clinical Jurnal f Gastrenterlgy February 2018, Vlume 11, Issue 1, pp 1 10
Davenprt et al, Inflamm Bwel Dis. 2014 Apr; 20(4): 723 731.
Shuld we try t change the bacterial micrbita and if s, hw? Are the bacteria altered because the gut is injured/the immune system dysfunctinal r d the altered flra CAUSE disease?(chicken r the egg) Antibitics: n data suggesting strng effect t directly treat Crhn s and Ulcerative clitis Prbitics: insufficient data,? Rle in additin t traditinal therapy in UC Fecal micrbacteritherapy (FMT) Diet
Precisin medicine An emerging apprach fr disease treatment and preventin that takes int accunt individual variability in genes, envirnment, and lifestyle fr each persn Tailr IBD therapy t each individual patient t ptimize their clinical utcmes Predict risk f medicines used and risk f disease prgressin Predict respnse t medicatin Detect respnse t medicatin and detect when medicatin change in needed
What is ur treatment target? What shuld be ur gal: nt just treat symptms but als attempt t heal mucsal inflammatin Mucsal healing has been shwn t be assciated with lwer risk f need fr sterids, surgery and cancer Treating t target is a attempt at using bjective data t guide therapy and t adjust therapy based n evidence f inflammatin Neurath, Gut, / Vlume 61, Issue 11;Buguen, Clinical Gastrenterlgy and Hepatlgy 2015;13:1042 1050
CALM study Attempt t cmpare escalatin f therapy n schedule based n lab parameters suggesting nging inflammatin cmpared t adjusting therapy based n clinical symptms The primary utcme is mucsal healing and sterid free remissin is a secndary utcme at 48 mnths. We dn t knw hw these patients will d lng term. What makes these patients different that the average Crhn s patient They have never been treated with bilgics r immunsuppressives befre
CALM study Clumbel et al Lancet. 2018 Dec 23;390(10114):2779-2789
Nvel technlgies Bimarkers: when can we d a stl r bld test t avid endscpy t find ut if the disease is effectively treated? Endscpic therapy fr IBD: when can we safely intervene endscpically t avid a surgery -Dysplasia in UC-can precancerus areas be resected? -Strictures in CD and puchitis Use f drug level mnitring
FDA apprvals fr IBD meds
Many pathways t target Valatas AJP Gastr Liver Phys 2013
Multitude f pathways targeted by new medicatins JAK/STAT Anti IL23/ p19 (psriasis) Tfacitinib (Xeljanz) Brazikumab (CD) Filgtinib (CD) Risankizumab (CD) Upadacitinib Mirikizumab (UC) Upadacitinib Sphingsine-1- Cell trafficking/antiintegrin phsphate receptr inhibitin Finglimd Etrlizumab Ozanimd Etrasimd Befre 2014 the nly FDA apprved bilgics we had targeted just ne pathway: TNF-alpha
Rates f Primary and Majr Secndary End Pints at 8 Weeks in the Mdified Intentin-t-Treat Ppulatin, Accrding t Study Grup. Sandbrn WJ et al. N Engl J Med 2012;367:616-624
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