Resistens mot biologisk behandling ved IBD - mekanismer og klinikk. Professor Jon Florholmen, UNN

Transkript

1 Mandag 7. januar Kl. 13:00 Kl. 13:05 Kl. 13:25 Kl. 13:45 Kl. 14:10 Kl. 14:30 Kl. 14:50 Kl. 15:05 Innledning - Møteleder overlege Gustav Lehne Immunologi ved inflammatorisk hudsykdom. PhD Øystein Sandanger, OUS Resistens mot biologisk behandling ved IBD - mekanismer og klinikk. Professor Jon Florholmen, UNN Riktig behandlingsvalg til rette tid - hvem skal ha biologisk behandling? Et nytt prognostisk verktøy ved UC debut. PhD Rasmus Goll, UNN Biologisk immundempende behandling og kreft. Professor Bjørn Moum, OUS Immunterapi ved cancer. Overlege/forskningsgruppeleder ved OUS og professor II ved UiO, Åslaug Helland Paneldiskusjon Pause

2 Immunologi ved inflammatorisk hudsykdom Øystein Sandanger, MD, PhD Seksjon for hudsykdommer, OUS Institutt for indremedisinsk forksning, OUS

3 Huden er et immunologisk organ Tikoo et al, Immunology & Cell biology 2018 Alle cellene er potente inflammatoriske celler: keratinocytter, flere typer dendrittiske celler, T-celler, mastceller makrofager, endotel Dobbelt så mange T-celler i huden som i blodet (ca 2x10 10 ), de fleste er hukommelses-t-celler

4 Bolognia 4th ed.

5 Oversikt Hovedtyper av inflammatoriske responser og adaptiv immunitet Atopisk dermatitt Definisjon og kriterier Immunpatogenese Psoriasis Definisjon og kriterier Immunpatogenese

6 Hovedtyper av proinflammatoriske responser og adaptiv immunitet Respons Formål Spesifikke cytokiner Effektorer Type 1 Bekjempe intracellulære mikrober/virus IFN-γ, IL-12 Th1-celler CD8+ cytotoksiske T-celler Makrofager IgG Type 2 Bekjempe parasitter IL-4, IL-5, IL-13 Th2-celler Mastceller Eosinofile granulocytter IgE Type 3 Bekjempe ekstracellulære bakterier og sopp IL-17, IL-22, IL-23 Th17 og Th22 celler Nøytrofile granulocytter Antimikrobielle peptider IgG

7 Atopisk dermatitt (AD)

8 Definisjon Diagnosen stilles på bakgrunn av følgende hovedkriterier: Kløe ( eksem er kløen som gir utslett ) Utslett med typisk eksematøs morfologi og alderspesifikk utbredelse Kronisk tilstand/tilbakefall

9 Patogenese ved atopisk eksem Nyttig å inndele patogenetiske faktorer i 3 hovedkategorier: Epidermal barriæredysfunksjon Immundysregulering Endring i hudens mikrobiom Bolognia Dermatology, 4th ed.

10 Genetisk predisposisjon Går i familier Konkordanserate: Eneggede tvillinger: 77% Toeggede tvillinger: 15% To hovedkategorier av gener involvert i atopisk dermatitt: Epidermal barriærefunksjonen Immunologiske funksjoner

11 Epidermal barriæredysfunksjon Svekket barriærefunksjon Inflammatorisk Respons (utslett) Økt transepidermalt vanntap Kløe Tørr hud Økt permeabilitet for - Irritanter - Mikrober - Allergener

12 Bolognia Dermatology, 4th ed.

13 IL-4 har en nøkkelrolle ved atopisk dermatitt Polariserer inflammasjon mot en Th2 immunrespons Transgene mus som overuttrykker IL-4 i epidermis utvikler kløe, endret mikrobiom, økt IgE i blod og hudlesjoner forenelig med atopisk dermatitt IL-4 og IL-13 signaliserer begge gjennom reseptoren IL-4Rα Dupilumab er et monoklonalt antistoff mot IL-4Rα og brukes mot atopisk dermatitt Vatrella et al. J Asthma Allergy Sep 4;7:123-30

14 IL-31 fremmer kløe og kan bli et terapeutisk angrepspunkt ved atopisk eksem Høyt uttrykt i atopisk dermatitt-lesjoner Induseres av S. aureus, en link mellom kolonisering og kløe Reseptorer for IL-31 uttrykkes av kutane sensoriske nervefibre Nemolizumab, et monoklonalt antistoff mot IL-31 reseptor A, er vist å redusere kløe ved moderat og alvorlig atopisk eksem i en dobbel blindet randomisert placebokontrollert studie (fase 2A-B) (Ruzicka et al. N Engl J Med. 2017; Kabashima et al. J Allergy Clin Immunol 2018)

15 Endring i hudens mikrobiom Friske har stor diversitet S. aureus dominerer hos atopikere, særlig lesjonelt Svekket barriærefunksjon Mindre antimikrobielle peptider Økt ph Th2-polarisert inflammasjon Sekundærinfeksjon forverrer hudbarriæren, inflammasjon og kløe Antibiotika og/eller oksiderende bad ofte nødvendig ved behandling av uttalt atopisk dermatitt Biotika (tilførsel av konkurrerende stafylokokker) er en mulig terapeutisk strategi AMT: Autologous micro-biome transplant Nakatsuji T et al. Sci Transl Med. 2017

16 Barriæredysfunksjon Fuktighetskrem Oljebad Immundysregulering Kortikosteroider Calcineurinhemmere Lysbehandling Metotreksat Anti-IL-4 JAK-hemmere? Anti-IL-31? Endret mikrobiom Antiseptisk bad Antibiotika Biotika?

17 Psoriasis

18 Definisjon og kriterier for psoriasis Kronisk inflammatorisk hudsykdom preget av velagrensde erytematøse skjellende plakk med fortykket epidermis En (trolig) autoimmun T-celle-drevet type 3 immunrespons (IL-17, IL-23) Tre autoantigener beskrevet så langt: LL37, ADAMTSL5 og PLA2G4D

19 Genetisk predisposisjon Går i familier Hovedgrupper gener assosiert med psoriasis Epidermal barriærefunksjonen Immunologiske funksjoner Antigenpresentasjon (HLA-Cw6 sterkest assosiert med psoriasis) Medfødt immunitet Adaptiv immunitet

20 Bolognia Dermatology, 4th ed.

21 Sentrale aspekter ved patogenesen ved psoriasis Utløsende årsak (triggere) hos genetisk predisponerte individer: Skade Infeksjoner Medikamenter Lymfocytter γδ-t17 Keratinocyttstress: Autoantigener og nukleinsyrer frigjøres LL37 pdc IFN-α mdc Antigenpresentasjon IL-23 (CD8 + )Tc17 Th17 IL-17 Keratinocytt Nøytrofil influx DNA RNA TNF-α IL-1β IL-6 TNF-α IL-1β IL-6 IL-6 TGFβ Th22 IL-22 ILC3 IL-17: Pro-inflammatoisk feedback Cytokiner (inkl. TNF og IL-36), kjemokiner og vekstfaktorer IL-22 (via STAT3): Fortykket epidermis: proliferasjon, hyperplasi, migrasjon, redusert differensiering. Antimikrobielle peptider IL-36: forsterker det hele med positiv feedback

22 Chiricozzi et al, Int. J. Mol. Sci. 2018

23 Chiricozzi et al, Int. J. Mol. Sci. 2018

24 Takk for oppmerksomheten

25 Effektive effektorceller fjerner infeksjon Type 1: Intracellulære mikrober: bakterier protozo virus Spesifikke PAMPs Sensorer Spesifikke mediatorer IL-12, IFNγ Antigenpresentasjon Klonal ekspansjon Th1 IFN-ү IL-12 CD4 + IFN-ү CD8 + Type 2: Ekstracellulære parasitter Spesifikke PAMPs IL-4, IL-5, IL-13 Th2 IL-5 Eosinofile granulocytter MBP Parasittdrap Type 3: Ekstracellulære bakterier og sopp Spesifikke PAMPs TGF-β, IL-6 IL-23 Naive T-celler Th17 Antigen-spesifikke effektor T-celler IL-17, IL-22 Nøytrofile granulocytter (IL-17) Epitel: antimikrobielle peptider, proliferasjon (IL-22)

26 Failure against biological agents in inflammatory bowel disease Advanced study Inflammatory Bowel Disease (ASIB) The Resistance Project: Health Finnmark Health UNN Health Vestre Viken

27 Failure against biological agents in inflammatory bowel disease Definition and incidence Resistance project in ASIB Mechanisms

28 Failure against biological therapy in IBD Non-immune-mediated pharmacokinetic issues due to insufficient drug doses resulting in inadequate tissue concentrations for proper drug efficacy Immune-mediated pharmacokinetic development of antidrug antibodies causing rapid degradation of the drug and/or allergic reactions Pharmacodynamic issues predominant inflammatory pathways not being targeted by the drug.

29 Failure against biological agents in IBD- definitions Primary nonresponse (PNR) Primary nonremission Secondary loss of response (LOR) Intolerant to agent

30 Failure against antitnf agents in IBD Incidence

31 Failure against antitnf agents in IBD Primary nonresponse Up to % Additional partial response Primary nonremission % Papamichael et al. Inflamm Bowel Dis 2015

32 Failure against biological agents in IBD Primary nonrespons Infliximab- after 3 infusions- 0,2 and six weeks Adalimumab- after 3-5 bi-weekly D Haens et al Amer J Gastroenterol 2011, 106: Vedolizumab- 10 (UC), 14 (CD), 20 weeks?

33 Failure against antitnf agents in IBD Secondary loss of response (LOR) or Intolerant to antitnf 30 40% Papamichael et al. Inflamm Bowel Dis 2015

34 Resistance against biological agents in ibd Exclusion criteria in ASIB To be excluded: not adequate drug concentration no bacterial nor viral inflammation

35 AntiTNF resistance project preliminary results ASIB - molecular mechanisms 27; 16 UC and 11 CD inclusive 7 with subsequent vedulizumab treatment Vedolizumab - clinical effect

36 Resistance project ASIB Ulcerative colitis/crohn s disease TNF, IL-17 and IL-23 Comparisons against - Debut UC-later antitnf treated - Remission UC on antitnf treatment - Healthy control

37 Molecular immune profile in antitnf resistance Ulcerative colitis

38 S e m i - q u a n t i t a t i v e l o g - s c a l e U C I L 1 7 * * n s N o r m a l R e m i s s i o n R e s i s t a n t D e b u t S e v e r e

39 S e m i - q u a n t i t a t i v e l o g - s c a l e U C I L 2 3 * * n s N o r m a l R e m i s s i o n R e s i s t a n t D e b u t S e v e r e

40 S e m i - q u a n t i t a t i v e l o g - s c a l e U C T N F * * * N o r m a l R e m i s s i o n R e s i s t a n t D e b u t S e v e r e

41 S e m i - q u a n t i t a t i v e l o g - s c a l e U C T N F * * * N o r m a l R e m i s s i o n R e s i s t a n t D e b u t S e v e r e

42 S e m i - q u a n t i t a t i v e l o g - s c a l e I L 1 7 i n U C r e s i s t a n t * * N o r m a l I L 1 7 T N F - l o I L 1 7 T N F - h i

43 S e m i - q u a n t i t a t i v e l o g - s c a l e I L 2 3 i n U C r e s i s t a n t * * N o r m a l I L 2 3 T N F - l o I L 2 3 T N F - h i

44 Molecular immune profile in antitnf resistance Crohn s disease

45 S e m i - q u a n t i t a t i v e l o g - s c a l e I L 1 7 i n C D r e s i s t a n t * N o r m a l I L 1 7 T N F - l o I L 1 7 T N F - h i

46 S e m i - q u a n t i t a t i v e l o g - s c a l e I L 2 3 i n C D r e s i s t a n t * N o r m a l I L 2 3 T N F - l o I L 2 3 T N F - h i

47 Failure against antitnf agents in IBD Molecular mechanisms?

48 Figure 4 Proinflammatory immune cells and their crosstalk in patients with IBD antitnfs T cells Neurath, M. F. (2016) Current and emerging therapeutic targets for IBD Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro

49 Figure 4 Potential pathophysiological mechanisms: failure of T cell apoptosis antitnfs Lack of apoptosis Neurath, M. F. (2016) Current and emerging therapeutic targets for IBD Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro

50 Apoptosis John E. Sulston Nobel Price 2002

51 Overview of signal transduction pathways in apoptosis John E. Sulston Nobel Price 2002

52 Overview of signal transduction pathways in apoptosis Bcl 2 John E. Sulston Nobel Price 2002

53 Failure of effect Potential mechanisms Anti TNF: induces T cell apoptosis Heat shock protein A4 (apoptose gene 2) induces Bcl-2 and IL-23/IL-17: reduced apoptosis of T cells (T-helper IL-17 producing cell) and monocytes Refractary CD and UC Upregulation of Bcl-2 and IL-17 by HSPA4 Adachi T et al. Inflamm Bowel Dis 2015 Vedolizumab resistance Increased IL-6, higher soluble CD40 ligand (scd40l), osteocalcin Soendergaard C et al. BMJ Open Gastroenterol 2018

54 Contribution to personalyzed medicine in IBD? Expression of heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, is induced by several forms of stress. Upregulation of Bcl-2 and IL-17 by HSPA4 would control apoptosis of inflammatory cells and immune response in the gut, which might develop treatment resistance in IBD. HSPA4 and Bmi1 would be a useful biomarker for refractory clinical course and a promising approach for a therapeutic strategy in patients with IBD. Adachi T et al. Inflamm Bowel Dis 2015

55 Failure of effect Potential target drugs TYK2 and JAK1 inhibition inhibits IL-22 and IL-23/IL-17 pathways Works MG et al. J Immunol 2014 Ustekinunab inhibits IL-12 and IL-23 Deepak Gastroenterol Clin North Am 2017

56 Taken home message Avoid resistance to treatment Personalized medicine: treatment to Documented REMISSION- not only response Improves prognosis and patient s well-being near the cure? Biological agents

57 Conclusion Resistance to antitnf treatment in IBD beyond that of antibodies against the drug is a great challange IL17 and IL23 are one of several mechanisms mediating the resistance A subgroup of patients with antitnf resistance have normal TNF in mucosa but still high IL17 and IL23

58 Personalized Medicine in IBD Rasmus Goll Overlege, Gastromedisinsk avd UNN/Tromsø

59 Definition - Wikipedia Personalized medicine, precision medicine, or theranostics is a medical model that separates people into different groups with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted response or risk of disease.

60 Evidence from Rheumatology Monti S, et al. RMD Open 2015

61 Why Personalized Medicine in IBD? Solberg et al Scand J Gastroenterol 2009

62 Step-up vs Top-down Can we change the natural course of he disease?

63 Why not just use Top-down for all patients? Expensive Potent drugs proportional side effects >55% of the UC patients don t need biologics Liernett.no

64 ASIB transcriptome ulcerative colitis Predictive biomarkers Patophysiology Registrations Clinical data Behaviour Food Quality Life Transcriptome Debut Outcome Time to relapse Resistance 5ASA Immunosupp Biologic Surgery Debut Remission Debut Resistance Remission Normal controls Debut Normal controls Remission Proteome Metabolome Epigenome Normal controls Resistance

65

66 Prediction of response to biologics Pre-ASIB

67 Conclusion High TNF gene expression predicted less likelihood of response to a standard 3-dose course of infliximab Later experience yield remission rates approaching 80% using intensified induction regimes on demand Work in progress on primary resistance

68 Treatment algorithm in Tromsø 1. Induction to endoscopic remission (IFX) 0, 2, 6 then 4 week interval 2. 6 months maintenance 3. Stop of biologics Two outcomes: 1. Long term remission 2. Relapse restart

69 ASIB

70 Prospective data Withdrawal of biologics at normal TNF

71 Conclusion Normalized TNF gene expresion in colon mucosa predict longer remission time after biologic drug withdrawal Prospective RCT study in preparation in collaboration with King s College, London (prof Bu Hayee) Comparison of relapse rates using TNF based withdrawal vs standard care according to NICE guidelines

72 UC outcomes Endpoints Surgery/proctocolectomy Remission/active disease at a given time? No consensus

73 Step-up treatment Surgery Biological Prednisolone Budesonide Immunosuppressant 5-aminosalicylates/sulfasalazine Local steriod enamas Local 5-ASA enemas and suppositories

74 Our proposal for UC outcome def: At 1 year after debut: Which medications were needed to achieve remission using standard step-up care according to ECCO guidelines? Outcome types by maximal treatment level during 1 st year: 1. Mild: 5-ASA, local steroids 2. Moderate: Oral steroids, thiopurine 3. Severe: Biologics, surgery

75 Prediction factors for 1-year outcome ASIB Prospective inclusion of UC patients at debut of disease Retrospective outcome definition based on maximal treatment level Extensive data collection before any treatment is given

76 Patient groups Mild Moderate Severe N=79 n=38 n=24 n=17 Age med(iqr) 41 (25-51) 30 (23-37) 27 (20-56) Proctitis 13% 4% 0% Left side 66% 46% 47% Extensive 18% 46% 53% UCDAI med(iqr)* 7 (5-9) 9 (8-10) 10 (8-11) Calprotectin med(iqr)* 540 ( ) 915 ( ) 1200 ( ) Geboes score med(iqr)* 5 (4-8) 7 (4-10) 11 (8-14)

77 TNF gene expression at debut

78 Prediction of Severe Outcome

79 Test spec s for prediction of severe outcome Baseline predictor Youden's J Cutt off value Sensitivity Specificity PPV NPV % DOR TNF copies/µg mrna 0.63 > Geboes score 0.51 > UCDAI score 0.50 > Mayo endo score 0.19 > Calprotection step TNF Geboes and >

80 Proposed biomarker for severe 1-year outcome at debut of disease Two-step test: 1. TNF gene expression >12800 copies/ug RNA 2. Geboes score >9 Yields diagnostic odds-ratio of 53 - odds for correct positive classification 53 times higher than for incorrect positive classification

81 Conclusion I 1. Personalized medicine is feasible in IBD, and has the potential to streamline treatment algorithms 2. Personalized medicine can help our patients to achieve remission faster and may have the potential to change the individual phenotype in a favourable direction 3. Potential to decrease overall spendings on IBD treatment

82 Conclusion II 1. Biomarkers for response to biologics can be identified work in progress 2. Proposed biomarker for identifying patients with severe outcome at debut: mucosal TNF gene expression combined with Geboes histologic score 3. Biomarker for identifying patients who can safely stop biologics: normalization of mucosal TNF gene expression. To be evaluated in a prospective study (RCT in collaboration with King s college, London)

83 Study proposal Multicenter prospective open-label RCT on UC patients at debut Intervention: Top-down treatment for patients with positive test at debut Control: Regular step-up regimen Primary end point: colectomy rate at 3 years Secondary endpoints Time in remission first 3 years QoL Drug expenditures during study period Safety profile

84 Inflammatorisk tarmsykdom (IBD); Biologiske legemidler, immunhemmende behandling og kreft Bjørn Moum Gastromedisinsk avdeling, OUS Ullevål

85 Problemstillinger : Biologiske legemidler, IMM og kreftrisiko ved IBD 1. gir behandlingen (IMM, Bio) økt risiko for kreft? 2. påvirkes tumorvekst av TNFalfa hemmere 3. øker risikoen for residiv av kreft hos ferdigbehandlede pasienter når det gis biologisk behandling 4. er det forskjell i kreftrisiko ved biologisk behandling hos unge og gamle 5. er det forskjell i en evt. kreftrisiko ved biologiske legemidler og TOFA

86 Noen fakta ved IBD uavhengig av biologisk behandling

87

88

89 Cancer sekundært til kronisk intestinal inflammation (IBD) Cancer type Colorektalcancer Tynntarmsadenocarcinom Intestinal lymfom Analcancer Kolangiocarcinom ved UC SIR 5.7 (95%CI: ) 27.1 (95%CI: ) 17.5 (95%CI: ) Ingen data (95%CI: ) World J Gastroenterol 2016 May 28; 22(20):

90 Medikamentell behandling av IBD Behandling Kirurgi Alvorlig sykdom: antitnfalfa,vdz, UST, TOFA Prednisolon, Aza, MTX, AB Moderat sykdom: Prednison, Aza, MTX Entocort, Cortiment, 5ASA, AB Mild sykdom: 5ASA, Entocort, Cortiment

91 Kombinasjon IMM & TNFalfa gir bedre effekt ved oppstart UC study feb 2014, CD study NEJM 2010,362,1383

92 Kombinasjon IMM & TNFalfa vedlikeholder effekt

93 TNFa hemming øke tumorvekst : pro-tumor cytokine (NO-DNA mutasjon), fremme vekstsignal and angiogenesis øke tumor spredning: fremme matrix metalloproteinaser reduserer effekten av cytotoksiske medikamenter tumor-hemmende egenskaper (behandling av melanoma og sarcoma Shaji S, Ther Adv Gastroenterology 2019, in press.

94 Vurderinger ved behandling med. TNFalfa (IFX, ADA, GOL) Intoleranse (allergisk inf hud ledd alment) Behandlingssvikt primær sekundær partiell - full Antistoffer TNFalfa Bunnkonsentrasjon lav («placebo») Risiko Gjennomgått cancerbehandling Dysplasi (f ex kolon, cervix) Hjertesvikt g 3-4 Demyeliniserende sykdom (MS) Varicella % - vac 6u/ EBV* neg. & menn <35år (+IMM & >2 års beh); HTCL Kvinner / HPV** vaksinasjon & ktr. Pt ønske Reise (IFX/VEDO -> ADA,UST) Pris * Ebstein Barr virus **Herpes papilloma virus

95 30 år, UC proktitt ASA og pred X 3 (2014,2015,2017) 2016 cervix-dysplasi - beh gynekolog - ktr 2018 tilbakefall UC; blodig diare, smerter. Fecaltest 1250 mg/l Kolonoskopi moderate proktitt (MS 2 ; 14cm) 5ASA po & eller lokal / GCS lokalt Cortiment Prednisolon Biologisk Biologisk + Aza/MTX

96 Kvinne F år, Crohn kolon 2006 Kolonoskopi 2015: t.ileitt/kolitt & Fecaltest 1800 Entocort / Prednisolon kur x IFX 300mg /8.u + Aza 125mg IFX-trough 5-8, Fecaltest 388mg/l (<250) Klinisk remission Feb 2018 Mai 2018 : Mamma-cancer operert Kolonoileoskopi juni -18: lett inflam v B & hø kolon Fecaltest 615mg/l?

97 Cancer sekundært til antiinflammatorisk behandling ved IBD Økt risiko på thiopurin* Non-Hodgkin lymphom Akutt myeloid leukemia og myelodysplastisk syndrom Ikke melanom hudkreft Urinveiscancer Økt risiko på TNF-α hemmer Økt risiko på kombinert TNF-α hemmer og thiopurin Melanom Hepatosplenic T-cell lymfom * Azathioprin (Imurel) World J Gastroenterol 2016 May 28; 22(20):

98 Rettningslinjer: Immunosuppressiv behandling ved IBD med krefthistorie Type kreft Unngå Bruk med forsiktighet Kan brukes Lymfom Akutt myeloid leukemi, annen myelodysplastisk sykdom Melanom Ikke-melanom hudkreft Urinveiskreft Andre svulster Thiopuriner* Thiopuriner Anti-TNF Thiopuriner Thiopuriner Anti-TNF, MTX** Anti-TNF, steroider Thiopuriner, steroider Anti-TNF, steroider Anti-TNF Thiopuriner, Anti-TNF MTX, steroider MTX MTX MTX, steroider Journal of Crohn's and Colitis, 2015, NGF (4) 2018 * Azathioprin (Imurel) ** Metothrexat

99 Matrise: Malignitet-risiko ved medikamentell behandling for IBD Shaji S, Ther Adv Gastroenterology 2019, in press.

100 Oppsummert biologisk behandling ved IBD & kreft Økt forekomst av kreft ved IBD behandlet med biologiske legemidler, men ingen årsakssammenheng mellom TNF-α hemmere og kreft De fleste pasienter som behandles med TNF-α hemmere krever samtidig bruk av immunmodulerende legemiddel ved oppstart Risikoen for lymfom og hudkreft (NMSC) med TNF-α hemmer er hovedsakelig forårsaket av samtidig thiopurinbehandling Et sjeldent T-celle lymfom (HSTL) hos unge menn med Crohns sykdom behandlet med kombinasjon infliximab og thiopurin

101 Oppsummert biologisk behandling ved IBD & kreft nyere IBD behandling.. Risiko for lymfom og hudkreft med vedolizumab & ustekinumab ser ut til å være som ved TNF-α hemmere (data basert på ikke-ibd eller IBD-data med kort oppfølging): inklusive tofacitinib ingen alarmsignaler men sparsomme data «Ingen» antistoffer ved vedolizumab, ustekinumab & tofacitinib IMM unødvendig/kontraindisert

102

103 The Danish experience on switching from originator to biosimilars for non-medical reasons including subsequent back-switching Prof Merete L Hetland, MD, DMSc, PHD Head of the DANBIO steering committee Rigshospitalet, University of Copenhagen, Denmark

104 Background Agenda Experiences with biosimilars in Denmark 1. Infliximab, the first non-medical switch from originator to biosimilar 2. Etanercept, to switch or not to switch from originator to biosimilar (and back again) 3. Adalimumab one becomes two 4. Infliximab, multiple switches are here Concluding remarks

105 Health care in Denmark Biological treatments tax paid Provided free of charge to the patient Provided through hospitals 20 hospital departments of rheumatology SC treatments are dispensed to the patients every 8 weeks

106 Expensive drugs, regulation Tender based sysem Recommendations regarding choice of bdmard Naïve, switchers, non-medical switches Audits if guidelines are not followed, reasons must be explained by the physician responsible for treatment Expert panel, independent of pharmaceutical industry

107 Non-medical switch Medical Council for use of expensive drugs, guidelines Nov 2018 Regarding use of biosimilar infliximab, etanercept and adalimumab Originator bdmards and their biosimilars should be considered equal in patients - who start first line treatment - who switch bdmard treatment - unless specific patient related matters exist, patients on stable treatment with originator should switch to cheapest drug (i.e. the biosimilar) Originator no longer available

108 Current recommendations In bionaive and in switchers 1: Biosimilar infliximab 2: Biosimilar etanercept (1 in mono therapy) 3 etc: other (originator) bdmards

109 New recommendations 1: Biosimilar adalimumab In two regions: Hymiroz (Sandoz) In three regions: Imraldi (Biogen) 2: Biosimilar infliximab (Zessly)... Biosimilar rituximab (Rixathon) All adult Danish patients with inflammatory diseases (rheumatology, dermatology, gastroenterology)

110 Non-medical switches in Denmark May 2015: originator IFX, Remicade biosimilar CT-P13, Remsima April 2016: originator ETA, Enbrel biosimilar SB4, Benepali 2017: biosimilar CT-P13, Remsima biosimilar CT-P13, Inflectra Nov 2018: originator ADA, Humira biosimilar Inflectra originator RTX, MabThera biosimilar Hyrimoz and Imraldi biosimilar Zessly (multiple switches) biosimilar Rixathon

111 Costs, infliximab, Denmark Time period Price per 100 mg, DKK Saving* Remicade Remsima Inflectra /1-30/ /4-30/ % 1/7-30/ % 1/8-31/ % /7-31/ % /1-31/ % 31/3-1/ % 1/7-31/ % /1-30/ % * Biosimilar versus originator Thanks to Dorte Klitgaard, Region H Pharmacy

112 Costs, etanercept, Denmark Time period Price per 50 mg, DKK Benepali Saving Enbrel pen Enbrel syringe Benepali pen/syringe /1-29/ /3-30/ % 1/5-30/ % 1/7-30/ % 1/10 31/ % /1-31/ % 31/3-1/ % 1/7-31/ % /1-30/ %

113 Costs, adalimumab, Denmark Time period Price per 40 mg, DKK Saving Humira pen Humira syringe Hyrimoz /Imraldi pen/syringe Nov /11-18 to 31/ % 35%

114 Costs, rituximab, Denmark Time period Price per 500 mg, DKK Saving MabThera Rixathon Nov /11-18 to 31/ %

115 Information to patients Leaflets from The Danish Medicines Agency You can be completely safe when you use an originator or biosimilar drug The biosimilars and originators work in the same way No differences in treatment effects You may be changed to a different pen or syringe

116 Monitoring of adverse events Mandatory to report all side effects during treatment with biosimilars to The Danish Medicines Agency (by use of online system, DANBIO or safety officers) Patients may report (online system) Reports available online

117 RCT vs. observational studies Observational postmarketing studies may contribute important knowledge regarding the effectiveness of biosimilars To facilitate making informed decisions about therapeutic substitution with biosimilars, healthcare providers are encouraged to gather pharmacovigilance data in registries about the outcome of such switches made in the context of clinical practice. Kay et al, ARD, Online first 2018 Available data from real-world clinical practice, somewhat conflicting with those of RCTs, seem to suggest that it is premature to formulate recommendations on the switching strategy from the bio-originator to its biosimilar. Cantini et al, ARD, online first 2018 Crucially, the real-world experience that is being proactively gathered through post-marketing studies (including the NOR-SWITCH study) and patient registries will add to our knowledge concerning biosimilars, and may further enhance confidence in the use of these products in clinical practice. Uhlig et at, Rheumatology, online first 2017

118 Background, DANBIO In year 2000, the DANBIO registry was set up by the rheumatological society to monitor patients with inflammatory arthritis receiving biological treatments Online data entry in the clinic by patients and physicians Nationwide, >95% coverage of biological treatments >40,000 patients currently registered in DANBIO

119 Background, DANBIO Approved by authorities as a quality and research database Part of the patient file Online system, Funding: Hospital owners, pharmaceutical industry, private and public funds Pharma: Quarterly aggregated postmarketing data (numbers of pts). No impact on organization, data collection, analysis or publication

120 Dept of rheumatology Private practitioner > 400 professionel users > patients are users DANBIO, Copenhagen University Hospital at

121 Glintborg B et al. Ann Rheum Dis, 2017;76(8):

122 Remicade-Remsima switch 250 Number of patients switch patients May June July Aug Sept Oct Nov Dec Jan Feb March April

123 Objectives To investigate the impact of the nationwide non-medical switch from originator infliximab (Remicade) to biosimilar (CT-P13, Remsima) on 1) 3 months disease activity and flare rates 2) 1 year retention rates In adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or axial spondyloarthrits (AxSpA)

124 Methods Observational study as part of routine care All patients were monitored prospectively in the DANBIO registry prior to and after the switch All Danish departments of rheumatology were invited to validate their data regarding Dates for treatment start and stop (Remicade, Remsima) Disease activity at baseline (switch) and during follow-up Reasons for withdrawal of Remsima

125 Baseline demographics

126 Disease activity and flares

127 Disease activity and flares

128 Disease activity and flares

129 Disease activity and flares During the 3 months prior to the switch compared to the 3 months after the switch Disease activity remained largely unchanged The proportions of patients with disease flare were similar

130 Withdrawal 132/802 patients (16%) stopped Remsima treatment during 1 year of follow-up Prior Remicade treatment duration: 5.9 ( ) years

131 Treatment retention 1 year treatment retention was compared to that of a historic cohort of all patients in DANBIO receiving treatment with Remicade by January 1 st 2014 Adjusted* absolute rates: Historic: 86.8% ( ) Switch: 83.4% ( ) (p=0.03) corresponding to an absolute difference of 3.4%. *Age, gender, diagnosis, methotrexate (yes no), comorbidities(number), patient s global score

132 Health care resources Glintborg B et al, RMD Open 2018

133 Conclusion In this observational nationwide study of 802 patients with RA, PsA or AxSpA treated with Remicade for >6 years who conducted a non-medical switch to biosimilar Remsima: Disease activity and flare rates 3 months after the switch were comparable to those 3 months prior to switch 16% stopped treatment during 1 year of follow-up mainly due to lack of effect or adverse events Withdrawal rate was similar to a historic cohort of Remicade treated patients No evidence of increased use of health care resources

134 Glintborg et al, ARD Nov 5th 2018

135

136 Baseline characteristics Compared to non-switchers, switchers had More often received conc MTX (in RA and PSA) Longer ETA treatment history Received fewer previous bdmard Lower disease activity

137 Date of Enbrel-Benepali switch Number of patients 1621 switchers 2016

138 Treatment retention

139 Backswitchers (LOE)

140 Backswitchers (AE) Arthralgia (1) Bladder dysfunction (1) Blurred vision (1) Diarrhoea (4) Dizziness (2) Dyspnoea (2) Erectile dysfunction (1) Hair loss (1) Headache/migraine (4) Hyperhidrosis (2) Hypertension (1) Hypotension (1) Infections (2) Leg cramps (1) Local injection problems (3) Myalgia (1) Nausea (2) Neuropathies (1) Psoriasis worsening (1) Rash/itching (9) Not stated (21)

141 Conclusion In this observational nationwide study of 2061 patients switching from Enbrel to Benepali - The outcomes (retention, remission) were influenced by patients and physicians choice to comply with the guideline (i.e. switch) or not (i.e. not switch), which was reflected in differences in baseline characteristics - Other factors than the switching alone may have influenced the outcome - Withdrawal was most common in patients not in remission - Switch outcome in routine care is affected by non-specific drug effects and patientrelated factors

142 Overall conclusion A tender based system that rates bsdmard equal to bodmard have resulted in significant reductions of drug costs Mandatory switching from originator to biosimilar drugs is associated with increased drug withdrawal This may in part be explained by non-specific and patient-related factors For infliximab and etanercept no major safety concerns have been raised Future non-medical switches (bs adalimumab, bs rituximab and multiple switching of bs infliximab) stress the importance of continued monitoring of biosimilars in real-world registries

143 Current recommandations Bio-naive Switch Rheumatoid arthritis + csdmard 1. Biosimilar IFX (50%) 2. Biosimilar ETA (30%) 1. Biosimilar IFX (50%) 2. Biosimilar ETA (30%) 3. Rituximab 4. s.c. Abatacept -- Rheumatoid arthritis mono Biosimilar ETA 1. Biosimilar ETA 2. Tocilizumab s.c 3. Tocilizumab i.v. 4. Certolizumab 5. Adalimumab Psoriatic arthritis and mild PsO Psoriatic artrhitis and severe PsO 1. Biosimilar IFX (60%) 2. Biosimilar ETA (30%) 1. Biosimilar IFX (60%) 2. Secukinumab (30%) 1. Biosimilar IFX 2. Biosimilar ETA 3. Secukinumab 4. Golimumab Biosimilar IFX 2. Secukinumab 3. Adalimumab --

144 Current recommandations Bio naive Ankylosing spondylitis* 1. Biosimilar IFX (50%) 2. Biosimilar ETA (30%) Nr-AxSpA* 1. Biosimilar IFX (50%) 2. Biosimilar ETA (30%) Switch 1. Biosimilar IFX 2. Biosimilar ETA 3. Secukinumab 4. Golimumab Biosimilar IFX 2. Biosimilar ETA 3. Golimumab 4. Certolizumab 5. Adalimumab *Specific recommandations for uveitis, IBD

145 Kaplan-Meier plots of crude treatment retention rates among SB4 switch patients. Bente Glintborg et al. Ann Rheum Dis doi: /annrheumdis by BMJ Publishing Group Ltd and European League Against Rheumatism

146 Infliximab, 2015 The Nordic countries T Kvien

147