Nieuwe biologicals in IBD

Nieuwe biologicals in IBD Ph.Van Hootegem Symposium AZ St-Lucas Brugge 22 september 2015

Nieuwe biologicals in IBD Werkingsmechanisme Veiligheid Praktische aspecten

IBD therapie (1) Crohn (CD) Colitis ulcerosa (UC) de Klassiekers Inductie Onderhoud Inductie onderhoud 5-ASA (Pentasa, Asacol, Colitofalk) +/- - + + Corticoïden Metylprednisolone (Medrol) Budesonide (Budenofalk, Entocort) + - + - + - +/- - Beclomethasone-dipropr. (Clipper) Immunomodulatoren +/- - + - Azathioprine (Imuran) +/- + +/- + Methotrexaat (Ledertrexaat) +/- + +/- +

Crohn (CD) Colitis ulcerosa (UC) IBD therapie (2) Inductie Onderhoud Inductie onderhoud de Biologicals Anti-TNF medicatie Infliximab (Remicade) iv Adalimumab (Humira) sc + (combo) + + (combo) + + + + + Golimumab (Simponi) sc Anti-adhesie molecules Vedolizumab (Entyvio) iv - - + + + + + + In studie + + + +

IBD: Imbalance of inflammatory response results in accumulation of excess infiltrating lymphocytes 1,2 Gut lumen Infiltrating lymphocytes Inappropriate and sustained recruitment of inflammatory cells 1. Hanauer SB. Inflamm Bowel Dis. 2006;12 Suppl 1:S3 S9; 2. Xavier RJ, et al. Nature. 2007;448:427 434.

α4β7 Integrin MAdCAM-1 interactions help mediate selective lymphocyte trafficking to the gut 1 MAdCAM-1 MAdCAM-1 Lymphocyte α4β7 integrin α4 integrin β7 integrin α4β7 MAdCAM-1 interactions likely mediate migration of lymphocytes into the gut, which can cause inflammation that is characteristic of UC and CD 1 MAdCAM-1, mucosal addressin cell adhesion molecule-1 1. Briskin M, et al. Am J Pathol. 1997;151:97 110.

Vedolizumab is a gut-selective α4β7 integrin receptor antagonist 1 Endothelial cell MAdCAM-1 Vedolizumab: A humanised monoclonal antibody (mab) that binds to the α4β7 integrin 1 Vedolizumab binding blocks α4β7 binding to MAdCAM-1 1 α4 integrin β7 integrin α4 integrin β7 integrin Memory T-lymphocyte 1. Entyvio (vedolizumab) Summary of Product Characteristics, Takeda, May 2014.

Vedolizumab prevents migration of lymphocytes into the gut 1 Vedolizumab Lymphocyte adhesion blocked Migration of gut-homing lymphocytes blocked with vedolizumab 1 Vedolizumab prevents lymphocyte migration into the gut, without affecting other lymphocyte subtypes 1 1. Entyvio (vedolizumab) Summary of Product Characteristics, Takeda, May 2014.

Overview of the vedolizumab GEMINI phase 3 clinical programme 1 4 Study no. Status Study design/population GEMINI I 1 UC GEMINI II 2 CD GEMINI III 3 CD GEMINI LTS 4 UC & CD Completed Completed Completed Ongoing (2009 2016) Induction and maintenance Moderate to severe UC Induction and maintenance Moderate to severe CD Induction Moderate to severe CD & failed Anti-TNFα and/or immunomodulators Long-term safety UC or CD & participated in a prior VDZ study CD, Crohn s disease; LTS, long-term study; PBO, placebo; TNF, tumour necrosis factor; UC, ulcerative colitis; VDZ, vedolizumab 1. Feagan BG, et al. N Engl J Med. 2013;369:699 710; 2. Sandborn WJ, et al. N Engl J Med. 2013;369:711 721; 3. Sands B, et al. J Crohns Colitis. 2013;7 Suppl 1:S5 S6; 4. Millennium Pharmaceuticals, Inc. NCT00790933. Available at http://www.clinicaltrials.gov [last accessed May 2014].

Patients, % GEMINI I: A significantly greater percentage of patients achieved clinical response, remission and mucosal healing at week 6 with vedolizumab 1 Primary Outcome Secondary Outcomes 60 50 40 30 20 10 0 p<0.001 25.5 47.1 p=0.001 16.9 5.4 p=0.001 40.9 24.8 Clinical Response Clinical Remission Mucosal Healing Placebo (n=149) Vedolizumab (n=225) Adapted from: 1. Feagan BG, et al. N Engl J Med. 2013;369:699 710.

Patients, % GEMINI I: Rates of durable clinical response, clinical remission, and mucosal healing were significantly higher in vedolizumab-treated patients at 52 weeks 1 60 50 p<0.001 p<0.001 56.6 52.0 p<0.001 p<0.001 51,6 56.0 Vedolizumab/Placebo (n=126) Vedolizumab Q8W (n=122) 40 Vedolizumab Q4W (n=125) p=0.001 30 20 23,8 19,8 p=0.008 20,5 24.0 10 8,7 0 Durable Clinical Response Mucosal Healing Durable Clinical Remission Adapted from: 1. Feagan BG, et al. N Engl J Med. 2013;369:699 710.

Patients, % GEMINI II: A high proportion of Anti-TNFα failure vedolizumab responders achieved clinical remission and CDAI-100 response at week 52 1 Maintenance ITT Population 70 60 50 40 30 20 10 Patients With Prior Anti-TNFα Failure VDZ/PBO (n=237) VDZ Q8W VDZ Q4W 12.8 28.0 27.3 29.3 20.5 37.7 Patients Without Prior Anti-TNFα Failure (n=224) 59.7 51.4 53.2 45.5 40.0 30.7 0 Mean % (95% CI) vs VDZ Q8W: VDZ Q4W: Clinical Remisson CDAI-100 Response Clinical Remission CDAI-100 Response 15.2 (3.0, 27.5) 14.5 (2.0, 26.9) 8.8 ( 4.6, 22.1) 17.1 (3.1, 31.2) 20.7 (5.2, 36.3) 14.8 ( 0.5, 30.0) 19.7 (3.9, 35.6) 13.2 ( 2.5, 29.0) CDAI, Crohn s Disease Activity Index; ITT, intention-to-treat; PBO, placebo; VDZ, vedolizumab Adapted from: 1. Colombel JF, et al. Presentation at UEGW 2012; Abstract OP139B.

Veiligheid Infusiereacties : 4% (placebo 3%) Neveneffecten : nausea, moeheid, hoofdpijn, nasopharyngitis, arthralgie Infecties : nasopharyngitis, bovenste luchtweginfecties, urinaire infecties (ernstige infecties : 0,07 /patiëntjaar; 0,06 bij placebo) Zwangerschap / borstvoeding :? Progressieve multifocale leuco-encephalopathie (PML) : niet

Praktische aspecten Terugbetaling sinds 1 september 2015 in CD en UC 300 mg IV infuus om de 8 weken

Entyvio dosage and administration 1 WEEK 0 2 6 Recommended IV infusion schedule 10 Induction Maintenance Q8W* Entyvio 300mg Entyvio 300mg Entyvio 300mg Entyvio 300mg Entyvio 300mg Entyvio 300mg Entyvio 300mg 30-minute, single-vial infusion at weeks 0, 2 and 6, then Q8W thereafter Patients with CD who have not shown a response may benefit from an additional dose at week 10 Entyvio must be reconstituted and diluted prior to administration. Do not administer as an intravenous push or bolus ~6 infusions per year after induction Patients receive one 300mg dose at regular 8- week intervals For patients who have a decrease in response, dosing may be escalated to 4-week intervals *Clinical data are available only up to 52 weeks 1. Takeda Pharmaceuticals International GmBH. Entyvio (vedolizumab). Summary of Product Characteristics. June 2014. Last accessed June 2014.

Praktische aspecten Voorafgaande tuberculose screening Uitstellen bij acute infectie Vaccinatie

Vaccinaties bij IBD-patiënten via GE dikwijls suboptimaal huisarts IBD-verpleegkundige mevr.patsy Vlieghe tel 050 36 51 92

Immunosuppressive characteristics of IBD drugs 1,2 Immunosuppressive: Non-immunosuppressive: - Prednisone > 20mg/day for > 2 weeks - Azathioprine + 6-mercaptopurine - Methotrexate - Tacrolimus, Ciclosporine,... - Anti-TNF therapies, other biologicals - 5-ASA - Prednisone < 10mg/day or cumulative dose < 700mg 3 - Beclomethasone dipropionate - Budesonide 6mg/day, immunosuppressive characteristic of higher doses is unknown - Any treatment above, within the past 3 months, except for corticosteroids (within the past month) 1. Rahier JF, et al. Vaccinations in patients with immune-mediated inflammatory diseases. Rheumatology 2010; 49: 1815-1827. 2. Belgian Superior Health Council Advisory report 8561 regarding the vaccination of immunocompromised children and adults - 19/10/2011 (http://tinyurl.com/hgr-8561-vacc-immuno = Dutch; http://tinyurl.com/css-8561-vacc-immuno = French; http://tinyurl.com/shc-8561-vacc-immuno =English). 3. Stuck AE, et al. Risk of infectious complications in patients taking glucocorticosteroids. Review of infectious diseases 1989; 11(6): 954-963. 18

3 scenarios for vaccinating IBD patients For optimal immunological response: vaccinate prior to administering any immunomodulator. 1 1. Peetermans W, et al. Vaccinaties bij immuungecompromitteerde en chronisch zieke patiënten. Tijdschrift voor Geneeskunde 2013; 69: nr. 22, 1113-1116. 19

Vaccinaties bij IBD-patiënten basisvaccinaties IBD-specifieke niet-levende vaccins : griep, pneumococcen, hepatitis B IBD-specifieke levende afgezwakte vaccins : mazelen,bof, rubella / varicella / (gele koorts)

Can non-live vaccines be performed while starting immunosuppressive therapy? However, for optimal immunization -and if time allows- it is preferable to complete (or at least start) the vaccinations before the start of immunosuppressive therapies. 1 1. Peetermans W, et al. Vaccinaties bij immuungecompromitteerde en chronisch zieke patiënten. Tijdschrift voor Geneeskunde 2013; 69: nr. 22, 1113-1116. 21

Can live vaccines be performed while starting immunosuppressive therapy? 1 - Varicella zoster virus - Measles, Mumps and Rubella - Yellow fever and typhoid fever* - (BCG) A minimum of 3 weeks delay after the last injection of the live vaccine is necessary before starting immunosuppressive therapies. * For typhoid fever, both a live and non-live vaccine are available. 1. Belgian Superior Health Council Advisory report 8561 regarding the vaccination of immunocompromised children and adults - 19/10/2011 (http://tinyurl.com/hgr-8561-vacc-immuno = Dutch; http://tinyurl.com/css-8561-vacc-immuno = French; http://tinyurl.com/shc-8561-vacc-immuno =English). 22

SCENARIO 3 Live vaccines recommended timelines 23

Toediening van vaccins TIJDENS een behandeling met anti-tnf Niet toegelaten Levende afgezwakte vaccins Toegelaten/aanbevolen Niet-levende vaccins Gele koorts: Stamaril Tuberculose: BCG (niet meer gebruikt in België) Buikyphus (PO) : Vivotif Berna Mazelen-bof-rubella Varicella Polio (PO) Rotavirus Buiktyphus (IM): Typhim Tetanos, difterie (herhaling om de 10j) Kinkhoest: 1 herhaling als volwassen (enkel ter beschikking in de combinatievorm met tetanos, difterie) Griep (Influenza): jaarlijks Pneumococcen (pneumonie): Pneumo 23, Prevenar 13 Polio (IM). Hépatitis A en B. Bronnen van deze informatie: EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Van Assen et al, ARD 2011; 70:414-422 Vaccinations in patients with immune-mediated inflammatory diseases. Rahier et al, Rheumatology 2010; 49:1815-1827 Website van het Belgisch centrum voor farmacotherapeutische informatie (www.bcfi.be) Website van het Instituut voor tropische geneeskunde (ww.itg.be) ABBVIE SA/NV - BEGEN150247 - JUN 2015

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TRAVEL A Live vaccines Immunosuppressive therapy in general must be stopped 3 months before vaccination and performed at least 10 days before departure to ensure immunity. Shortest recommended timeline Yellow Fever (Stamaril ): Typhoid Fever (Vivotif ): Live vaccine is not used in patients under immunosuppressive therapy. See further for typhoid fever non-live vaccination. 27

TRAVEL B Non-live vaccines (1/3) Immunosuppressive therapy can be continued. Shortest recommended timeline Hepatitis A (Havrix, Epaxal, Vaqta, Twinrix *): It is recommended to check immunity 4 to 8 weeks after the 2nd injection in immunosuppressed patients. In case lack of time, give 2 injections (double dose) in one time or give injections with 1 month time interval, and do serology. If negative, consult infectious disease/vaccine specialist. * Twinrix is a combination vaccine for hepatitis A en B and only contains half a dose of hepatitis A. 28

Pneumococcen (pneumonie): Pneumo 23, Prevenar 13 schema MMWR Morb Mortal Wkly Rep. 2012 Oct 12;61(40):816-9. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP).