Dott.ssa Maria Cappello

UOC Gastroenterologia ed Epatologia

Azienda Ospedaliera Universitaria Policlinico Palermo

Vecchi e nuovi biologici nelle MICI: criteri di scelta oggi

Disclosures

•  Lecture fees: MSD, AbbVie, Takeda, Janssen, Chiesi, Pharmanutra

•  Advisory Board Member: MSD, AbbVie, Takeda, Janssen, Shire,

BIOLOGICS IN IBD

IFX

ADA

GOLI

VEDO

USTE

•  Targetingleukocytetrafficking

anti-MAdCAM1,etrolizumab-anti-β7,CCR9antagonist,antiIP-10,

S1P1receptormodulator

•  TargetingT-celldifferentiation(antiIL23p19)

•  TargetingJAK-STATpathway(tofacitinibanti-JAK1/3,anti-JAK1)

•  Cell-basedtherapy(autologusHSCtransplantation,MSC

transplantation,tolerogenicimmunecells)

Future perspectives

TheJAK-STATpathway

ShuaiKetal.NatRevImmunol2003

CytokinebindingtoitscellsurfacereceptorleadstoreceptorpolymerizationandactivationofassociatedJAKs

ActivatedJAKsphosphorylatethereceptorsthatdocksSTATs

ActivatedJAKsphosphorylateSTATswhichdimerizeandmovetonucleustoactivateproinflammatorygenetranscription

How to choose a biologic: the sources

•  Pivotal RCTs •  Guidelines •  SMPC •  Pharmacoeconomic studies •  Indirect comparison studies Ø Network metaanalyses Ø Real-world experiences •  Direct comparison: head-to-head RCTs

Infliximab CDP 571 Adalimumab CDP 870 Etanercept

Anti-TNFs in Crohn’s disease

ACCENTI,2002 CHARM,2007

Efficacy of anti-TNFs in Crohn’s disease in pivotal RCTs

ClassicI,2006Targan,1997

Efficacyofanti-TNFsinCrohn’sdisease:fistulizingdisease

ACCENTII CHARM

GUT,2011 Gastroenterology2012

Efficacy of anti-TNFs in UC in pivotal RCTs

NEJMed,2005

ACT1&2NEnglJMed2005)

ULTRA2ULTRA1

GUT,2011 Gastroenterology2012

Efficacy of anti-TNFs in UC in pivotal RCTs

NEJMed,2005

ACT1&2

ULTRA2ULTRA1

Golimumab in UC

Anti-TNF biosimilars §  Infliximab Biosimilars:

§ Remsima or Inflectra (CT-P13, Celltrion) § Flixabi (SB2, Samsung Bioepis) § Zessly (L04AB02, Sandoz) positive CHMP opinion in March

2018

§ Adalimumab Biosimilars: § ABP-501 (Amgevita, Amgen) FDA approval in Sept 2016 § Amgevita and Solymbic (Amgen) positive CHMP opinion in

Jan 2017 §  Imraldi (Samsung Bioepis) positive CHMP opinion in Aug

2017 § Cyltezo (Boehringer Ingelheim) FDA approval in Sept 2017

*DaneseS,etal,NatRevGastroenterolHepatol.2016Oct12.doi:10.1038/nrgastro.2016.155.

Biosimilars pipeline

The Vedolizumab GEMINI programme

UlcerativeColitis Crohn’sdisease

Tofacitinib registration program

Safetyconcern:herpeszoster,lipidchanges,bowelperforation,thromboembolism.

Tofacitinib,anoralJanusKinaseinhibitor,inactiveUC

SandbornWetal.NEJM2012

194activeUC(Mayo≥6),8-weektreatmentdouble-blind,placebo-controlled,phase2trial

Indicazioni farmaci biotecnologici secondo scheda tecnica nelle IMID

Indicazioni in scheda tecnica: il vedolizumab

Colite ulcerosa Entyvio è indicato per i l t rat tamento di pazient i adult i con colite ulcerosa attiva da moderata a grave, che hanno manifestato una risposta inadeguata, hanno perso la risposta o sono risultati intolleranti alla terapia convenzionale o alla somministrazione di un antagonista del fattore di necrosi tumorale alfa (TNFα). Malattia di Crohn Entyvio è indicato per i l t rat tamento di pazient i adult i con malattia di Crohn attiva da moderata a grave, che hanno manifestato una risposta inadeguata, hanno perso la risposta o sono risultati intolleranti alla terapia convenzionale o alla somministrazione di un antagonista del fattore di necrosi tumorale alfa (TNFα).

ECCO guidelines

UC, 2017

CD, 2016

Moderate-to-severeUC Moderate-to-severeCD

DLD2016

Positioning USTEKINUMAB: Italian consensus

DLD2018

No statistically significant difference was observed between anti–TNFs and anti-integrin agents during induction or maintenance. Same results for infections and withdrawal due to AEs

Induction

Maintenance

In anti-TNF experience only vedo and ada could be compared: no difference in induction; During maintenance vedo proved superior.

Only anti-TNFs naive

VDZ proved to be the safest drug

IFX and vedolizumab ranked first in bio-naive pts

Vedolizumab ranked first as far as concerns safety included infections

Tofacitinib ranked first in anti-TNFs exposed pts

DLD 2018

A further analysis considering adalimumab optimization as treatment failure showed that the difference between adalimumab and golimumab was not significant.

Propensity score weighting analysis confirmed the higher clinical benefit achieved with ADA compared to GOL at 8 weeks(p = 0.009, OR = 2.88, 95% CI 1.31–6.33) and the lower risk of dis-continuing treatment in ADA compared to GOL group (p = 0.006,HR = 0.49, 95% CI 0.30–0.81) at the end of follow up

Anti-TNF naive

Anti-TNF non-naive

M.Bohmetal.-ECCO2018–OP025

12months

(VICTORYConsortium)

538pts

12months

D.Falecketal.–ECCO2018–OP026

(VICTORYConsortium)

659pts

ComparativesafetyprofileofVDZandTNF-antagonisttherapyforIBD:Amulticentrepropensityscore–matchedanalysis

(VICTORYConsortium)

•  CD,Crohn’sdisease;CI,confidenceinterval;IBD,inflammatoryboweldisease;OR,oddsratio;SAE;seriousadverseevents;SI,seriousinfection;TNF,tumournecrosisfactor;UC,ulcerativecolitis;US,UnitedStates;VDZ,vedolizumab.

•  Boldtextindicatessignificance.

LukinD,etal.JCrohnsColitis2018;12(suppl1):S036–S036.

4,1 4,7

10,1

14,5

0

5

10

15

20

SI SAE

VDZ TNF-antagonist

Results(cont’d):Ra

teofe

vents,%

Safetyprofile:biologicmonotherapy(n=247;VDZ=142)

SIOR0.37,

95%CI0.13-1.02OR0.29,

95%CI0.12-0.73

SAE

RatesofSIandSAEswerelowerwithVDZthanwithTNF-antagonisttherapyinbiologicmonotherapy

Vedolizumabshowsafavourablesafetyprofileinarealworldsetting

ECCO2019-OP34

Thefirsttrialhead-to-headinIBD

Varsity study design

Active vedolizumab 300 mg iv (0,2,6 and every 8 wk) and placebo sc (every other wk) N=385

OR Active adalimumab 160/80 sc 0,2 and 40 sc every other wk and iv placebo 0,2,6 and every 8 wk N=385

•  Primary endpoint: clinical remission (Mayo < 2) at wk 52

•  Secondary end-points: •  Mucosal healing (Mayo <

1) at wk 52 •  Steroid-free remission at

wk 52

Endoscopy at wk 0, 14 and 52

40

The Varsity trial: inclusion and exclusion criteria

Inclusion criteria 1.  Has a diagnosis of ulcerative colitis established at least 3

months prior to screening by clinical and endoscopic evidence and corroborated by a histopathology report.

2.  Has moderately to severely active ulcerative colitis as determined by a Mayo score of 6 to 12 with an endoscopic subscore greater than or equal to >=2 within 14 days prior to the randomization.

3.  Has evidence of ulcerative colitis proximal to the rectum (>=15 centimeter [cm] of involved colon).

4.  With extensive colitis (up to the hepatic flexure) or pancolitis of >8 years duration or left-sided colitis of >12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit (may be performed during the Screening Period).

5.  The participant: 1.  Has had previous treatment with tumor necrosis factor-

alpha (TNF-alpha) antagonists without documented clinical response to treatment (example, due to lack of response [primary nonresponders], loss of response, or intolerance [secondary nonresponders]), or

2.  Has previously used a TNF-alpha antagonists (except adalimumab), and discontinued its use due to reasons other than safety, or

3.  Is naïve to TNF-alpha antagonist therapy but is failing current treatment (example, corticosteroids, 5-aminosalicylate [5-ASA], or immunomodulators).

Exclusion criteria 1.  Clinical evidence of abdominal abscess or toxic megacolon at Screening. 2.  Has had an extensive colonic resection, subtotal or total colectomy. 3.  Has had ileostomy, colostomy, or known fixed symptomatic stenosis of the

intestine. 4.  Has a diagnosis of Crohn's colitis or indeterminate colitis, ischemic colitis,

radiation colitis, diverticular disease associated with colitis, or microscopic colitis.

5.  Has received any of the following for the treatment of underlying disease within 30 days of randomization:

1.  Non-biologic therapies (example, cyclosporine, tacrolimus, thalidomide) other than those specifically listed in Section Permitted Medications For Treatment of UC.

2.  An approved non-biologic therapy in an investigational protocol. 6.  Has received any investigational or approved biologic or biosimilar agent within

60 days or 5 half lives prior to the screening (whichever is longer). 7.  Has previously received natalizumab, efalizumab, adalimumab, AMG-181, anti-

mucosal addressin cell adhesion molecule-1 antibodies, or rituximab. 8.  Has previously received vedolizumab. 9.  Has history or evidence of adenomatous colonic polyps that have not been

removed, or colonic mucosal dysplasia. 10.  Evidence of an active infection during Screening. 11.  Evidence of, or treatment for, Clostridium difficile (C. difficile) or other intestinal

pathogen within 28 days prior to the 1st dose of study drug. 12.  Has chronic hepatitis B virus (HBV) infection* or chronic hepatitis C virus (HCV)

infection (* HBV immune participants, ie, being hepatitis B surface antigen [HBsAg], may participate).

13.  Has active or latent TB, regardless of treatment history. 14.  Has used a topical (rectal) treatment with (5-ASA) or corticosteroid enemas/

suppositories within 2 weeks of the administration of the 1st dose of study drug. 15.  Has a positive progressive multifocal leukoencephalopathy (PML) subjective

symptom checklist prior to the administration of the first dose of study drug.

Varsity patients recruitment

•  330 study sites, 37 countries •  Eligible pts 1285, randomized 771 •  386 in the adalimumab arm, 239 completed treatment •  385 in the vedolizumab arm, 287 completed treatment •  Randomized patients •  Prior anti-TNF use: 20% •  UC duration: 6,35 (ada) vs 7,25 (vedo) •  Concomitant IM: 25 vs 26% •  Concomitant steroids: 36% •  Severe disease (Mayo score 9 -12): 54 s 56%

42

Varsity:results

43

VARSITY Results: Overall Clinical Remission at week 52

22,5 24,3

16,0

31,334,2

20,3

05

10152025303540

OverallPrimaryAnalysis

Anti-TNFNaiveSubgroupAnalysis

Anti-TNFExposure/FailureSubgroup

Analysis

AdalimumabSC160/80/40VedolizumabIV300mg

=8,8%p=0,0061

=9,9% =4,2%p=0,0070 p=0,4948

%Patients

IV=Intravenous;SC=subcutaneous;TNF=TumorNecrosisFactorClinicalremission:CompleteMayoScoreof≤2pointsandnoindividualsubscore>1point.FullAnalysisSet:includesallrandomisedpatientswhoreceivedatleastIdoseofstudydrug.Anti-TNFsubgroupanalysiswasprespecifiedandproducednominalpvalues.

Varsity:results

45

VARSITYResults:MucosalHealingatWeek52

27,7 29,5

21,0

39,743,1

26,6

05

101520253035404550

OverallPrimaryAnalysis

Anti-TNFNaiveSubgroupAnalysis

Anti-TNFExposure/FailureSubgroup

Analysis

AdalimumabSC160/80/40VedolizumabIV300mg

=12,0%p=0,0005

=13,6% =5,6%p=0,0005 p=0,4136

%Patients

IV=Intravenous;SC=subcutaneous;TNF=TumorNecrosisFactorClinicalremission:CompleteMayoScoreof≤2pointsandnoindividualsubscore>1point.FullAnalysisSet:includesallrandomisedpatientswhoreceivedatleastIdoseofstudydrug.Anti-TNFsubgroupanalysiswasprespecifiedandproducednominalpvalues.

Varsity study conclusions

•  Superiority of vedo vs ada both in terms of clinical remission and mucosal healing

•  Superiority of vedo most pronounced in naive to anti-TNFs

•  Treatment differences emerge between wk 6 and 14

•  Both drugs safe and well tolerated; serious infections rate higher (NS) in the ADA group

•  Results support the use of vedo before anti-TNFs

Biologics in IBD: factors influencing therapeutic choices

Diseasesiteandactivity

Comorbidities

Druginteractions

Age

Adherence

Previoussurgery

EIM

How to choose a biologic in IBD: this the problem

Patient- related factors •  Age •  Comorbidity •  Special situations: pregnancy,

breastfeeding, previous or concomitant neoplasia

•  Smoking habit •  Previous anti-TNF failure •  Adherence

Disease-related factors •  Disease activity •  Disease site and extent •  Type of IBD •  Disease behaviour •  Response to steroids •  Previous surgery •  Complications (perianal disease,

EIM)

Regulatory constraints •  First-line approved •  Second-line in case of first-line

failure or intolerance

Costs

IFX (n=2475) or ADA (n=604) in IBD patients (16 centers)

Severe Cancer Death Infections >65 yrs Anti-TNFs (n= 95) 11% 3% 10% >65 yrs other drugs (n=190) 0.5% 2% 2% <65 yrs anti-TNFs (n=190) 2.6% 0% 1%

Clin Gastroenterol Hepatol 2011;9(1):30-5

*

* p=n.s.

2011

Older anti-TNF users were 4 fold more likely to stop therapy

Similar clinical benefit in all age groups

Choosing a biologic in obese pts

IV route Dose titration

Comorbidity in IBD: elderly patients Older age is associated with greater comorbidity and polypharmacy, which can add to the risk for medication interactions and adverse effects due to iatrogenesis.

Parian. Inflamm Bowel Dis 2015;21:1392–1400

Older IBD were Taking 9 medications On average Severe polypharmacy in 43% 73% had at least 1 Potential medical Interaction 35% were receiving At least 1 inappropriate medication

Infliximab in prevention of postoperative recurrence

*(i.e., Rutgeerts score of ≥i2 at the anastomotic site)

•  297 CD patients included after surgery, randomized to PBO or IFX 5 mg/kg w0 and then q8w

RegueiroM,etal.Gastroenterology2016;150(7):1568-78

20%25%

51%

13%18%

22%

0%

10%

20%

30%

40%

50%

60%

Clinicalrecurrencew76 Clinicalrecurrencew104 Endoscopicrecurrencew76

PBO IFX

NNT=1.68(0.90-3.15)

NNT=1.58(0.90-2.77)

NNT=3.64(2.20-6.02)

*

DeCruzP,etalLancet2014

•  174 CD patients randomized after surgery active/standard caresubgroups,stratabasedonhigh/lowrisksofrecurrence

Conventional vs endoscopy-driven treatment: THE POCER STUDY

ProfilingIBDpatients:futureperspectives

Positioning biologics in UCAnti-TNF Anti-integrin Tofacitinib

SevereUC Infliximab No No

Patientprofile EIM>2EIMsChildren

RiskofinfectionsElderly

EIM(arthritis)

Moderate-to-severeRefractoryUC

InfliximabAdalimumabGolimumab

Yes Yes(secondline?)

Steroid-dependentUC

InfliximabAdalimumabGolimumab

Yes Yes(secondline?)

Take-home messages

•  Old and new biologics have enriched the therapeutic armamentarium in IBD

•  The choice of the appropriate drug is and will be the ultimate «challenge» for IBD specialists

•  RCTs, guidelines, SMPCs, regulatory rules, indirect comparison studies are the sources that guide decision-making in view of the paucity of head-to-head RCTs

•  Identication of predictive factors for response is an important issue which should be addressed by clinical researchers

•  Waiting for molecular profiles and omics revolution…