Dienst gastro-enterologie, UZ Gent

Dienst gastro-enterologie, UZ Gent
Lentesymposium VVGE inflammatoir darmlijden Pieter Hindryckx, MD, PhD Dienst gastro-enterologie, UZ Gent Acknowledgement to Geert D’Haens AMC Amsterdam, The Netherlands Elewijt, 12 maart 2016

Inflammatory Bowel Diseases 2016
IBD innovations driving clinical decisions Amsterdam RAI EACCME applied Register online at

This year at ECCO: IBD drugs in the pipeline
Therapeutic Target population Company Phase Mesenchymal stem cells CD with complex perianal fistula TiGenix Phase 3 Toll like receptor 9 agonist (Kappaproct) Moderate to severe UC InDex Pharmaceuticals Ustekinumab (Stelara) moderate-severe CD, refractory to anti-TNFα Johnson & Johnson anti-IL6 CD refractory to anti-TNF Pfizer Phase 2 Tofacitinib (Xeljanz) selective JAK1 inhibitor Filgotinib Moderate to severe Crohn’s Disease Galapagos Moderate to severe Crohn’s Disease:

Oude farmaca in een nieuw jasje
Medicatie in de (directe) pipeline

ULCERATIVE COLITIS

111 steroid-dependent UC patients
Meteor trial, GETAID-ECCO, minstens 6 maanden UC, <75j, minstens 1 poging tot stoppen in de laatste drie maanden, actief of inactief, SC of IM, steroidvrije remissie op week 16 (totale mayo < of gelijk aan 2 111 steroid-dependent UC patients 51 placebo 60 MTX 25mg/w SC or IM Steroid-free remission at w16

MERIT-UC

FECAL MICROBIOTA TRANSPLANTATION FOR UC Moayyedi et al.1
Rossen et al.2 N of patients 75 50 Way of administration Enema Nasojejunal tube Dose regimen Weekly (6x) Every 3 weeks (2x) Placebo Water enema autologous FMT Primary endpoint Total Mayo <3 + endoscopic Mayo=0 SCCAI<3 + at least a 1-point decrease in endoscopic Mayo Study duration 7 weeks 12 weeks Concomittant anti-TNF allowed? yes no Primary endpoint reached Yes No 1Moayyedi et al. Gastroenterology 2015, 2Rossen et al. Gastroenterology 2015

Moayyedi et al. Gastroenterology 2015
130 patienten, 75 gerandomizeerd, Moayyedi et al. Gastroenterology 2015

Rossen et al. Gastroenterology 2015
TURN The ITT population consisted of all patients who received at least one treatment. The per-protocol population consisted of all patients who completed both treatments and passed the first endoscopic and clinical evaluation at week 6. Rossen et al. Gastroenterology 2015

Friday, March 18

Gut, 2016

Development and validation of new UC histo-indices
Mosli et al. Gut in press Marchal-Bressenot et al. Gut in press Bryant et al. Gut, 2016

Drug development in IBD
Deze afbeelding geeft een overzicht van verschillende middelen die onderzocht zijn in trialverband. De middelen aangegeven in blauw zijn succesvol gebleken, tenminste in fase 2, 3 of zijn zelfs geregistreerd. Links ziet u vooral anti-lichamen gericht tegen specifieke interleukinen, rechts onderaan ziet u de integrinen-remmers en in het midden de anti-TNFs. Infliximab was de eerste anti-TNF die werd goedgekeurd door de FDA, dit was naar aanleiding van de ACCENT studies die lieten zien dat IFX effectief was in induceren en het in stand houden van remissie, in therapierefractaire Crohn patienten. Daarnaast bleek het effectief in de behandeling van complexe fistelende ziekte. DE ACT1- en ACT2 studie lieten zien dat IFX veilig en effectief was in de behandeling van colitis ulcerosa, IFX werd goedgekeurd voor colitis in 2006. Zowel infliximab als de latere introductie van Adalimumab, goedgekeurd voor de behandeling van UC en CD in 2012 heeft grote gevolgen gehad voor de behandeling van IBD. Certolizumab pegol is alleen goed gekeurd voor CD in Zwitserland, Etanercept interfereert met TNF-IgG fusie, echter dit was niet effectief. Onercept interfereerde met de TNFa receptor, echter deze was niet ook niet effectief in klinische trials. Veel van de abstracts tijdens de DDW over anti-TNF richtten zich op geindividualiseerde behandeling of therapeutic drug monitoring. Golimumab is almost one of the latest introduced anti-TNF antibodies. It has demonstrated a higher affinity than adalimumab. Therefore, it is associated with promising efficacy in patients with moderately to severely active UC during Phase II and III of clinical trials, as expected. Golimumab has been approved by FDA in 2013 for treatment of moderately to severely active UC. Infliximab is the first approved TNF-a inhibitor for CD by inducing and maintaining remission in steroid- refractory, steroid-dependent and immunomodulator- refractory inflammatory CD as demonstrated during ACCENT studies (A Crohn’s Disease Clinical Trial Evaluat- ing Infliximab in a New Long-Term Treatment Regimen in Patients with Fistulizing Crohn’s Disease). It is demonstrated to exert its beneficial effects via treating complex fistula and preventing postoperative recurrence. Furthermore, as a new indication for anti-TNF drugs, it has been approved in 2006 for UC based on the results of the acute ulcerative colitis treatment trial (ACT)-I and -II trials that evaluated the safety and efficacy of infliximab for induction and maintenance therapy in adult patients with moderately to severely active UC [32-34]. New biologic therapeutics for ulcerative colitis and Crohn’s disease Shilan Mozaffari, Shekoufeh Nikfar, Amir Hossein Abdolghaffari & Mohammad Abdollahi† †Tehran University of Medical Sciences, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran, Iran 2012 BMJ Publishing Group Ltd & British Society of Gastroenterology

Expected Selectivity of Hypothetical Single JAK Specific Inhibitors
Receptors sharing γ-chain1 Type I IFNR1 IL-10R family1 IFN-α/β/κ/ω/ε IL-10†, IL-20, IL-22 Receptors sharing gp130 subunit1,2* IL-6, IL-11, IL-27, G-CSF Type II IFNR1 IFN-γ IL-12R family sharing p40 subunit1 IL-12, IL-23 Hormone receptors1 IL-3R family1 IL-3, IL-5 IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 EPO, TPO, GH, PRL TYK2* JAK1 TYK2 JAK1 JAK1 JAK2 JAK1 JAK3 JAK2* JAK2 TYK2 JAK2 JAK2 + - JAK1 inhibitor The JAK-STAT system consists of three main components: (1) a receptor (green), which penetrates the cell membrane (2) Janus kinase (JAK) (yellow), which is bound to the receptor and (3) Signal Transducer and Activator of Transcription (STAT) (blue), which carries the signal into the nucleus and DNA. The red dots are phosphates. After the cytokine binds to the receptor, JAK adds a phosphate to (phosphorylates) the receptor. This attracts the STAT proteins, which are also phosphorylated and bind to each other, forming a pair (dimer). The dimer moves into the nucleus, binds to the DNA, and causes transcription of JAK2 inhibitor JAK3 inhibitor TYK2 inhibitor TOFACITINIB (XeljanzR) 15

JAK inhibitors: Tofacitinib in UC
A. Clinical response B. Clinical remission p<0.001 p<0.001 p=0.10 78 p<0.001 p=0.55 61 p=0.01 p=0.39 48 p=0.76 Patients (%) Patients (%) 48 42 41 32 10 13 33 4/31 5/48 11/33 16/33 20/49 20/48 10/31 16/33 20/33 38/49 C. Endoscopic response p=0.001 D. Endoscopic remission p=0.07 p<0.001 p=0.30 78 p<0.001 Klinische respons op week 8 (drop in Mayo minstens 3, 30% reductie en zeker 1 punt drop of score van 0 of 1 voor rectal bleeding) p=0.64 67 p=0.01 58 52 p=0.14 Patients (%) 46 Patients (%) 30 10 27 2 18 3/31 22/48 16/31 19/33 22/33 38/49 1/48 10/33 13/49 6/33 Sandborn WJ, et al. New Engl J Med 2012

Friday, March 18

Lobaton T, APT 2014

Gut, in press >4000PY

Colombel et al. Gut in press
Enteric infections Placebo Vedolizumab CMV 0/504 73/2830 Clostridium 15/2830 Streptococcus 1/2830 36/2830 Colombel et al. Gut in press

ETROLIZUMAB IN ULCERATIVE COLITIS ERTROLIZUMAB IN ULCERATIVE COLITIS
Vermeire et al., Lancet 2014 ANTI-MADCAM IN ULCERATIVE COLITIS Week 12 remissie D’Haens et al., ECCO 2015

Efficacy of AJM300, an Oral Antagonist of α4 Integrin,
in induction therapy for patients with active ulcerative colitis. AJM300 (960 mg) or placebo 3 times daily for 8 weeks. The primary end point was a clinical response at week 8, defined as a decrease in Mayo Clinic score of at least 3 points and a decrease of at least 30% from baseline, with a decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Yoshimura et al. Gastroenterology 2015

S1P1R Modulation Results in Sequestration of Select Lymphocyte subsets
S1P1R modulators induce S1P1R internalization so a subset of auto-reactive lymphocytes (central memory T cells) are retained in the lymph node. Protective immunity is generally preserved by effector memory T cells that do not circulate trough the lymph nodes. Ozanimod (RCP1063) is a next generation oral S1P receptor touchstone Ozanimod (RCP1063) is a next generation oral S1P receptor modulator. Increased selectivity for the S1P1R and S1P5R as compared to teh S1P3R that may be realted to saftey concerns of fingolimod. Improved pharmacokinetic properties of enhanced tissue penetration and faster clearance from teh body. Demonstrated efficacy and safety in Phase 2 trial in Relapsing MS patients. Clinical trial experience to date has demonstrated and improved cardiovascular safety profile, reduced LFT elevations, no macular edema and rapid lymphocyte recovery.

Proportion of Patients in Remission
OZANIMOD in UC Remission at week 8 Mayo ≤ 2 points + no subscore > 1 point Δ = 10.8% p = Δ = 7.8% p = Proportion of Patients in Remission touchstone Sandborn et al. ECCO 2015

CONCLUSIONS: UC 2016/17 Deze afbeelding geeft een overzicht van verschillende middelen die onderzocht zijn in trialverband. De middelen aangegeven in blauw zijn succesvol gebleken, tenminste in fase 2, 3 of zijn zelfs geregistreerd. Links ziet u vooral anti-lichamen gericht tegen specifieke interleukinen, rechts onderaan ziet u de integrinen-remmers en in het midden de anti-TNFs. Infliximab was de eerste anti-TNF die werd goedgekeurd door de FDA, dit was naar aanleiding van de ACCENT studies die lieten zien dat IFX effectief was in induceren en het in stand houden van remissie, in therapierefractaire Crohn patienten. Daarnaast bleek het effectief in de behandeling van complexe fistelende ziekte. DE ACT1- en ACT2 studie lieten zien dat IFX veilig en effectief was in de behandeling van colitis ulcerosa, IFX werd goedgekeurd voor colitis in 2006. Zowel infliximab als de latere introductie van Adalimumab, goedgekeurd voor de behandeling van UC en CD in 2012 heeft grote gevolgen gehad voor de behandeling van IBD. Certolizumab pegol is alleen goed gekeurd voor CD in Zwitserland, Etanercept interfereert met TNF-IgG fusie, echter dit was niet effectief. Onercept interfereerde met de TNFa receptor, echter deze was niet ook niet effectief in klinische trials. Veel van de abstracts tijdens de DDW over anti-TNF richtten zich op geindividualiseerde behandeling of therapeutic drug monitoring. Golimumab is almost one of the latest introduced anti-TNF antibodies. It has demonstrated a higher affinity than adalimumab. Therefore, it is associated with promising efficacy in patients with moderately to severely active UC during Phase II and III of clinical trials, as expected. Golimumab has been approved by FDA in 2013 for treatment of moderately to severely active UC. Infliximab is the first approved TNF-a inhibitor for CD by inducing and maintaining remission in steroid- refractory, steroid-dependent and immunomodulator- refractory inflammatory CD as demonstrated during ACCENT studies (A Crohn’s Disease Clinical Trial Evaluat- ing Infliximab in a New Long-Term Treatment Regimen in Patients with Fistulizing Crohn’s Disease). It is demonstrated to exert its beneficial effects via treating complex fistula and preventing postoperative recurrence. Furthermore, as a new indication for anti-TNF drugs, it has been approved in 2006 for UC based on the results of the acute ulcerative colitis treatment trial (ACT)-I and -II trials that evaluated the safety and efficacy of infliximab for induction and maintenance therapy in adult patients with moderately to severely active UC [32-34]. New biologic therapeutics for ulcerative colitis and Crohn’s disease Shilan Mozaffari, Shekoufeh Nikfar, Amir Hossein Abdolghaffari & Mohammad Abdollahi† †Tehran University of Medical Sciences, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran, Iran 2018/20 Etrolizumab Ozanimod 2012 BMJ Publishing Group Ltd & British Society of Gastroenterology

CROHN DISEASE

Corticosteroidvrije remissie na 12 maanden (HBI less or equal than 4)

Khanna R et al. Lancet 2015

Vande Casteele N et al. Gastroenterology 2015
TAXIT Vande Casteele N et al. Gastroenterology 2015

Vande Casteele N et al. Gastroenterology 2015

IL12 → Th1 T cells → IFN γ IL-23 → TH17 T-cell → IL-17 → chronic inflammatory and autoimmune diseases Il 12 en IL23 zijn van belang in de pathogenese van Crohn, eerst lag de focus op IL12. IL-23R signaling may profoundly affect the innate immune response; IL-23 is also expressed on the surface of macrophages and dendritic cells and may thereby control barrier function and immune response against the commensal microflora in the gut. De rol van Il12 is mogelijk overschat. Ustekinemab targets IL12/IL23 MedImmune only targets IL23 Neurath MF. Nat Med 2007; Sandborn WJ et al. Gastroenterology 2008

Anti-p40 and p19-antibodies
Ustekinumab Medi 2070 L. Steinman. Nature Immunology 2010

Response to Ustekinumab in Psoriasis
At Least 75% Improvement in PASI Physician’s Global Assessment of Clear or Excellent 100 100 80 80 60 60 Patients (%) Patients (%) 40 40 20 20 2 5 8 12 16 20 24 28 32 2 5 8 12 16 20 24 28 32 Weeks Weeks At Least 50% Improvement in PASI At Least 90% Improvement in PASI 100 100 Placebo 4 x 45 mg 45 mg 4 x 90 mg 80 Week 12 320 80 90 mg 60 60 Patients (%) Patients (%) 40 40 20 20 2 5 8 12 16 20 24 28 32 2 5 8 12 16 20 24 28 32 Weeks Weeks Krueger, G. et al. NEJM 2007

Overall UNITI Phase 3 Crohn’s Program
Two Induction Studies One Maintenance Study UNITI-1: αTNF Failure Population Placebo IV (N=225)* IM-UNITI Randomized Withdrawal Maintenance Study Stelara 130 mg IV (N=225)* R Stelara ~6 mg/kg IV (N=225)* Responders 90 mg SC q8 wks 44 Week maintenance study: Followed by (up to) 4 yr LTE UNITI-2: Failed Convent. Therapy R 90 mg SC q12 wks Uniti 2 Patients w/ mod - severely active Crohn’s (CDAI score ) of > 3 months duration who had NOT previously demonstrated inadequate response or intolerance to 1 or more TNF antagonist therapies Active CD confirmed by either elevated CRP, fecal calprotectin > 250 mg/kg, or endoscopic evidence of active inflammation Required prior inadequate response or failure to tolerate corticosteroids or immunomodulators Placebo SC Stelara 130 mg IV (N=200)* Responders Stelara ~6 mg/kg† IV (N=200)* R Placebo IV (N=200)* * Subjects randomized to placebo and subjects who are non-responders to Stelara are eligible for non-randomized maintenance dosing after completion of the induction study. Feagan B, et al. UEGW 2015.

Proportion of Subjects (%)
UNITI-2 Primary Endpoint: Clinical Response at Week 6 (≥100 Point CDAI Reduction) p=0.001 p<0.001 ∆ 23.0% (13.83%, 32.11%)* p<0.001 ∆ 24.9% (17.10%, 32.66%)* % % % Proportion of Subjects (%) % Ustekinumab *95% CI **Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight >55 mg and ≤85 kg), 520 mg (weight >85 kg). Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis time point are considered not to be in clinical response, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at designated analysis endpoint are considered not to be in clinical response. Feagan B, et al. UEGW 2015.

Secondary Endpoint: CRP Concentration
UNITI-2 Secondary Endpoint: CRP Concentration Summary of Mean Change From Baseline in CRP Concentration (mg/L) at Weeks 3, 6, & 8a,b All p-values <0.001 Mean Change from Baseline in CRP (mg/L) *Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight >55 mg and ≤85 kg), 520 mg (weight >85 kg). aSubjects who, prior to the designated analysis timepoint, had a prohibited Crohn’s disease-related surgery or had prohibited concomitant medication changes, had their baseline value carried forward bSubjects who had insufficient data at the designated analysis timepoint had their last value carried forward Feagan B, et al. UEGW 2015.

Summary of Key Safety Events Through Week 8
UNITI-2 Summary of Key Safety Events Through Week 8 Placebo Ustekinumab 130 mg ~6 mg/kg Combined Treated subjects 208 212 207 419 Avg. duration of follow-up (weeks) 7.88 7.89 7.90 Subjects with ≥1, n (%) Death AE 113 (54.3%) 106 (50.0%) 115 (55.6%) 221 (52.7%) SAE 12 (5.8%) 10 (4.7%) 6 (2.9%) 16 (3.8%) Infection 48 (23.1%) 31 (14.6%) 44 (21.3%) 75 (17.9%) Serious infection 3 (1.4%) 1 (0.5%) 4 (1.0%) AEs during/<1hr post-Infusion 5 (2.4%) 8 (1.9%) Malignancy MACE* * Major Adverse Cardiovascular Events Feagan B, et al. UEGW 2015.

UNITI-1 P=.002 P=.003 Response at week 6 (%) P=.001 P=.003
Ustekinumab P=.001 P=.003 Phase 2b (certifi) confirmed Remission at week 6 (%) Ustekinumab Sandborn W et al. Inflamm Bowel Dis. 2016 Mar;22 Suppl 1:S1 (2015 Advances in Inflammatory Bowel Disease; December , 2015; Orlando, Florida. Abstract O-001

PSOLAR REGISTRY Papp et al., J Drugs Dermatol 2015

MEDI2070 – ‘MedImmune’ Phase 2 Multicenter, Randomized, Double-Blind, Placebo Controlled Study 12 weeks 100 week Open-Label Period Placebo (N=60) MEDI 2070 (N=59) 700 mg IV At week 0 and week 4 MEDI2070 210 mg SC q4wk (26 doses) randomization Patienten kregen MedImmune op week 0 en week 4 CRP ≥ 5 mg/L, FCP ≥ 250 µg/g and/or endoscopic evidence of inflammation within 12 weeks of screening Primary endpoint: proportion of patients achieving CDAI clinical effect defined as ≥100 point CDAI reduction from baseline or CDAI <150. Sands et al., DDW 2015

MEDI2070 – ‘MedImmune’ Sands et al., DDW 2015

SMAD7 Signaling Blocks TGF-β signaling
Smad7, an intracellular protein that inhibits TGF-β1-driven Smad-dependent signalling. In CD and UC, TGF-β1 is highly produced but unable to signal through Mongersen is an oral Smad7 antisense oligonucleotide with negligible systemic absorption Modified-release tablet → active substance into lumen terminal ileum and right colon. nucleus Monteleone et al. N Engl J Med 2015

Study design Phase 2 Multicenter, Randomized, Double-Blind, Placebo Controlled Study 2 weeks baseline D 14 D 28 D 84 Follow up placebo 10 mg Mongersen 40 mg Mongersen 160 mg Mongersen Maintenance of remission after cessation Mongersen Monteleone et al. N Engl J Med 2015

Proportion of pts in remission at d15
28 van 43 patiënten die 160 mg Mongersen kregen per dag, was in klinische remissie gedefinieerd als een CDAI score < 150. Dit was significant verschillend ten opzicht van de patienten die placebo kregen. 22 van de 40 patienten die 40 mg Mongersen kregen per dag, was in klinische remissie gedefinieerd als een CDAI score < 150. Dit was significant verschillend ten opzicht van de patienten die placebo kregen.

Proportion of pts in clinical response
Clinical response = a decrease in CDAI score ≥ 100 Op dag 15 ziet u dat het aantal patienten dat in klinische remissie 65 % was in de groep die 160 mg mongersen kreeg tov van 26 % in de placebo groep. OP dag 28 ziet u dat alle drie de doseringen significant verschilden tov van de placebo groep wat betreft klinische response

CONCLUSIONS: CD 2016/17 2019/20 Mongersen Deze afbeelding geeft een overzicht van verschillende middelen die onderzocht zijn in trialverband. De middelen aangegeven in blauw zijn succesvol gebleken, tenminste in fase 2, 3 of zijn zelfs geregistreerd. Links ziet u vooral anti-lichamen gericht tegen specifieke interleukinen, rechts onderaan ziet u de integrinen-remmers en in het midden de anti-TNFs. Infliximab was de eerste anti-TNF die werd goedgekeurd door de FDA, dit was naar aanleiding van de ACCENT studies die lieten zien dat IFX effectief was in induceren en het in stand houden van remissie, in therapierefractaire Crohn patienten. Daarnaast bleek het effectief in de behandeling van complexe fistelende ziekte. DE ACT1- en ACT2 studie lieten zien dat IFX veilig en effectief was in de behandeling van colitis ulcerosa, IFX werd goedgekeurd voor colitis in 2006. Zowel infliximab als de latere introductie van Adalimumab, goedgekeurd voor de behandeling van UC en CD in 2012 heeft grote gevolgen gehad voor de behandeling van IBD. Certolizumab pegol is alleen goed gekeurd voor CD in Zwitserland, Etanercept interfereert met TNF-IgG fusie, echter dit was niet effectief. Onercept interfereerde met de TNFa receptor, echter deze was niet ook niet effectief in klinische trials. Veel van de abstracts tijdens de DDW over anti-TNF richtten zich op geindividualiseerde behandeling of therapeutic drug monitoring. Golimumab is almost one of the latest introduced anti-TNF antibodies. It has demonstrated a higher affinity than adalimumab. Therefore, it is associated with promising efficacy in patients with moderately to severely active UC during Phase II and III of clinical trials, as expected. Golimumab has been approved by FDA in 2013 for treatment of moderately to severely active UC. Infliximab is the first approved TNF-a inhibitor for CD by inducing and maintaining remission in steroid- refractory, steroid-dependent and immunomodulator- refractory inflammatory CD as demonstrated during ACCENT studies (A Crohn’s Disease Clinical Trial Evaluat- ing Infliximab in a New Long-Term Treatment Regimen in Patients with Fistulizing Crohn’s Disease). It is demonstrated to exert its beneficial effects via treating complex fistula and preventing postoperative recurrence. Furthermore, as a new indication for anti-TNF drugs, it has been approved in 2006 for UC based on the results of the acute ulcerative colitis treatment trial (ACT)-I and -II trials that evaluated the safety and efficacy of infliximab for induction and maintenance therapy in adult patients with moderately to severely active UC [32-34]. New biologic therapeutics for ulcerative colitis and Crohn’s disease Shilan Mozaffari, Shekoufeh Nikfar, Amir Hossein Abdolghaffari & Mohammad Abdollahi† †Tehran University of Medical Sciences, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran, Iran 2012 BMJ Publishing Group Ltd & British Society of Gastroenterology

Take home summary Insights from previous FMT studies (optimal treatment regimen, donor selection) may improve outcome in future trials Postoperative treatment in CD: according to risk stratification + follow-up endoscopy Increasing role for therapeutic drug monitoring and dose optimization Anti-integrins may become first choice biologic for moderate UC Ustekinumab will be the next big asset for CD Tofacitinib may come ahead of biologics in UC Mongersen for CD promising, but uncertain

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