Il Valore dei Farmaci Biologici nell’Evoluzione della Gestione del Paziente Il punto di vista del gastroenterologo Paolo Gionchetti, MD IBD unit University of Bologna, Italy

Conflitto di Interessi

• Il dott Gionchetti è stato consulente per la Alfa-Wasserman e Athlantic Pharmaceuticals

Long term evolution of Crohn’s disease behaviour

100 90 80 70 60 50 40 30 20 10 Inflammatory Penetrating Stricturing 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Patients at risk: n = 2,002 552 Months 229 95 37 Cosnes J, et al. Inflamm Bowel Dis 2002;8:244 –50

3

“Simple” rules in IBD management • have a long-term strategy !

• treat lesions and not only symptoms! (use surrogate markers as CRP, faecal markers…) • Use time-bound approaches : “accelerated step-up” (or top down in selected cases) • optimize dosing of drugs • Give therapy long enough but if not efficacious discontinue

Changes in treatment goals

Goal Clinical Parameters Outcomes Response Improved symptoms Improved QoL Remission Deep remission No symptoms Normal labs Normal endoscopy Histological remission SUSTAINED Decreased hospitalisation No surgery Minimal/no disability

Which patients could benefit from receiving biologicals?

Steroid/Azathioprine “incomplete control” patients:

1. steroid-dependent /resistant patients 2. azathioprine resistant patients (patients with frequent need of additional treatments - with continous biological activity – without steroid-sparing effect) 3. patients who suffer from steroid or azathioprine side effects

Patients with high risk of disabling disease

Possible approaches to achieve and sustain deep remission in clinical practice?

• Identify patients likely to have a poor prognosis who may benefit from intensive therapy • Introduce anti-TNF therapy in a timely manner to appropriate patients 8

Possible approaches to achieve and sustain deep remission in clinical practice?

• Identify patients likely to have a poor prognosis who may benefit from intensive therapy • Introduce anti-TNF therapy in a timely manner to appropriate patients 9

Crohn’s disease management must be tailored to the individual patient

IBSEN study: Patients choosing 1 of 4 theoretical, predefined disease courses (n=197) n=85 (43%) Decrease in symptom severity 0 Years from diagnosis 10 n=37 (19%) Chronic continuous symptoms 0 Years from diagnosis 10 n=6 (3%) Increase in symptom severity 0 Years from diagnosis 10 Missing data: n=6 (3%) Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430 –8 n=63 (32%) Chronic relapsing symptoms 0 Years from diagnosis 10

10

Bad prognostic factors for Crohn’s disease •

Disease location and behaviour

– Rectal disease – Extensive small bowel disease – Severe upper gastro-intestinal disease – Perianal lesions – Early stricturing/penetrating disease – Deep ulcers •

Worsening factors

– Smoking – Young age at diagnosis – Genetic and serological profile (for the future?) Lakatos P,

et al

. Munkholm P,

et al

.

Scand JGastroenterol

1995;30:699 –700; Louis E,

et al. Gut

2003;52:552 –7;

World J Gastroenterol

2009;15:3504 –10; Henckaerts L,

et al. Clin Gastroenterol Hepatol

2009;7:972 –80; Romberg MJ,

et al. Am J Gastroenterol

2009;104:371 –83; Chow D,

et al

.

Inflamm Bowel Dis

2009;15:551 –7; Hellers G,

et al

.

Gut

1980;21:525 –7; Beaugerie L,

et al. Gastroenterol

2006;130:650 –6; Loly C,

et al. Scand J Gastroenterol

2008;43:948 –54; Allez M,

et al

.

Am J Gastroenterol

2002;97:947 –53

Possible approaches to achieve and sustain deep remission in clinical practice?

• Identify patients likely to have a poor prognosis who may benefit from intensive therapy • Introduce anti-TNF therapy in a timely manner to appropriate patients 12

The evolution of Crohn’s disease therapy in the era of biologics Treating Early to Increase the Rate of Primary Response

2008 Earlier treatment 1998-2007 Later treatment Natural course of disease Later intervention 2010 – Future treatment at diagnosis

S U S T A I N A B L E

Intervention at diagnosis Time Disease onset

80 70 60 20 10 0 90 80 70 60 50 40 30 20 10 0 50 40 30 When to start biological therapy? Early Treatment is better

response 73.1

remission response remission

q8 q12

Disease Duration years 63.5

59.6

55.8

47.1

REACH 2007 Mean (SD) 2.0 (+1.4) 35.3

33.3

23.5

47 39 36 28 ACCENT I 2002 Median (range) 7.9 (3.9-14.7) Week 30 Week 54

CHARM: disease duration and clinical remission* rates

60 Placebo 51 All adalimumab 44 40 35 20 0 17 4/23 20/39 <2 years 11 4/36 25/57 2 to <5 years Disease duration 11 12/111 82/233 ≥5 years *Clinical remission defined as CDAI <150 All patients received adalimumab 80/40mg induction therapy, before responders (



70 decrease in CDAI by Week 4) randomised to adalimumab 40mg either eow or ew or to placebo Data for randomised responders CDAI: Crohn’s disease activity index; ew: every week; eow: every other week Schreiber S, et al. Gastroenterol 2007;132(Suppl 2):A147

15

EXTEND: disease duration and complete mucosal healing rates

50 45 40 35 30 25 20 15 10 5 0 0 44 4/9 7 1/14 40 4/10 Placebo Adalimumab 40mg eow 18 7/39 21 9/43 <2 years 2 to <5 years Disease duration



5 years † *Complete mucosal healing was defined as absence of mucosal ulceration on endoscopic exam †

p

=0.029 for adalimumab vs placebo for disease duration <5 years vs ≥5years All patients (n=135) received adalimumab 160/80mg induction therapy, before randomisation (n=129) to adalimumab 40mg eow or to placebo; data for patients with ulceration at baseline (n=123) eow: every other week Sandborn WJ , et al. J Crohn’s Colitis 2010; 4:S36

16

EXTEND: disease duration and deep remission rates

40 Placebo Adalimumab 40 mg eow 33 30 20 18 16 10 0/9 3/9 0/15 2/11 0/41 7/44 0 <2 years 2 to <5 years Disease duration ≥5 years *Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND p<0.001 for adalimumab vs placebo, adjusted for baseline disease duration (Cochran-Mantel-Haenszel test) All patients (n=135) received adalimumab 160/80mg induction therapy, before randomisation (n=129) to adalimumab 40mg eow or to placebo CDAI: Crohn’s disease activity index; eow: every other week Colombel JF, et al. Gut 2010;59(Suppl 3):A188: P400 at UEGW 2010

17

Mucosal Healing Must Be Our Current End point in Crohn’s Disease?

Endoscopic healing with steroids at 7 weeks in Crohn

’

s disease

100 80 71%

Complete MH with Steroids 13%

60 93/131 40 29% 20 38/131 9% 12/131 Worsened 0 Remission No Remission

Endoscopic Status *Among patients with clinical remission, n=131 Modigliani R, et al. Gastroenterology 1990

Endoscopy in CD Patients Treated with Azathioprine

45 patients examined (out of 83 enrolled) Clinical remission on azathioprine for ≥42 months No ulcers

53%

Lémann M, et al, Gastroenterology 2005; 128: 1812-8.

Mucosal healing and long term outcome of infliximab maintenance therapy (Leuven)

MH in 183 responders of 214 CD 32,2 45,4 22,4 Complete MH (n=83) Partial MH (n=41) No MH (n=59)

Schnitzler F, et al. IBD 2009

Endoscopic healing reduces the Risk of surgery and hospitalization ACCENT I patients who demonstrated healing at one or both control visits had a lower incidence of hospitalization or surgery 50 40 30 46 25 20 10 0 0 Hospitalization Patients with no healing 8 0 0 Surgery Patients with healing at one visit (wk. 10 or 54) Patients with healing at both visits (wk. 10 and 54) Rutgeerts et al. Gastroenterology 2004

Adalimumab – EXTEND Trial

Endoscopic Healing & Remission Among patients treated with anti-TNF, the best endoscopic response a w12 is associated to highest chances of clinical remission at 1 year (CDAI<150 alla w52)

OR 19.6

p<0.0001

(95%CI 4.79-80.2) 100% 90% 75% 68% Remission Activity 50% 32% 25% 10% 0% 21/31 SES-CD<5 10/31 3/31 28/31 SES-CD>5 Rutgeerts P, et al. ECCO 2010

Adalimumab – EXTEND Trial

Patients who achieved deep remission* with adalimumab at Week 12 and hospitalisation rates

All-cause hospitalisation through Week 52 20 17 CD-related hospitalisation through Week 52 20 15 15 9 10 10 5 5 0 0/11 Deep remission* (Week 12) 9/53 Non-deep remission* (Week 12) 0 0/11 Deep remission* (Week 12) 5/53 Non-deep remission* (Week 12) *Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND CD: Crohn’s disease; CDAI: Crohn’s disease activity index

Colombel JF, et al. Gut 2010;59(Suppl 3):A80: OP371 (UEGW 2010)

Adalimumab – EXTEND Trial

Patients who achieved deep remission* with adalimumab at Week 12 and activity impairment

Activity impairment at Week 52 Work productivity impairment at Week 52 p<0.05

50 50 44 43 40 40 30 30 23 20 18 20 10 10 n=11 n=53 n=11 n=53 0 0 Deep Non-deep Deep Non-deep remission* (Week 12) remission* (Week 12) remission* (Week 12) remission* (Week 12) *Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND CDAI: Crohn’s disease activity index; LS: least squares; WPAI: Work Productivity and Activity Impairment

Colombel JF, et al. Gut 2010;59(Suppl 3):A80: OP371 at UEGW 2010

Perianal Fistulas in CD: classification

Simple fistula

Inter-sphincteric / low trans-sphincteric with one primary track and NO extensions or abscesses

Complex fistulas carry a worse prognosis in relation to the need for and extent of surgery. Complex fistula

Inter-sphincteric / trans sphincteric with extensions or abscesses; extra sphincteric; supralevator; recto-vaginal; anal strictures

Infliximab - Accent II

Sands et al . NEJM 2004;350:876-885  Maintenance trial  282 patients  3 infusions of infliximab  Then IFX or placebo for 54 wks

Charm Maintenance of Healing of Draining Fistulas: Weeks 26 and 56 PBO 40 mg EOW 40 mg weekly both ADA groups

50 40

p= 0.043

p= 0.043

30 33 28 30 33 28 30 20 13 13 10 6/47 10/30 11/40 21/70 6/47 10/30 11/40 0 Week 26 Week 26 and 56

Healing = no draining fistulas Patients with fistulas: draining fistulas at both screening and baseline

21/70

Colombel JF et al. Gastroenterology 2007

Long-Term Maintenance of Fistula Response

All Ada + Placebo 100 90 80 70 60 50 40 30 20 10 0

CHARM 6 mo 12 mo 18 mo 2 years 3 years from baseline CHARM baseline

88 94 90 92 30/34 29/31 28/31 22/24

24 wk OLE 48 wk OLE 60 wk OLE 108 wk OLE

97 97 94 96 33/34 30/31 29/31 23/24

24 wk OLE 48 wk OLE 60 wk OLE 108 wk OLE Healed Fistulas ≥50% Reduction in Fistulas *Includes all pts with healed fistulas at end of CHARM (placebo, eow, weekly; n=40). Two placebo-treated pts with healed fistulas did not enter the OLE. At week 24 in the OLE, data on fistula outcomes were missing for 4 patients; at 60 weeks in the OLE, data missing for 7 patients; at week 108, data missing for 14 patients. As-observed analysis.

Perianal Disease Therapy

Statement 5D

Complex fistulas

Cone-like fistulectomy of each fistula tract should be firstly performed with sparing of sphincteric structures.

Seton placement should be recommended

[EL 4, RG D]

, the timing of removal depending on subsequent therapy Anti-TNFs should be used as the first choice of medical therapy for complex perianal Crohn’s disease [Infliximab

EL1b, RG A

; Adalimumab

EL1b, RG B].

Combination with surgical therapy is recommended despite a lack of clinical trials

[EL4, RG D]

Antibiotics and/or azathioprine/6-mercaptopurine should be used as a second line medical treatment, despite a lack of clinical trials

[EL4 RG D]

Orlando A et al Dig Liver Dis 2010

TREATMENT OF COMPLEX FISTULAS

Sanitizing the Perineum

“cone-like” technique

Surgical Sanitization • Surgical evaluation under anesthesia before treatment and at week 8 • Surgical evaluation every 8 weeks or in case of lost of response or complications •

Obtain a healthy surgical wound.

•

Complicated procedures or aggressive medical therapy can be attempted with a reasonable chance of healing

Treatment of perianal Crohn’s disease with combined surgical and biological therapy

Aim: Evaluate the efficacy of IFX after surgical drainage and loose seton placement Methods: - 95 patients with complex fistula or simple fistula with rectal involvement were treated with IFX (0,2,6 and every 8 weeks until fistula closure) after EUA and seton placement.

- Definitions

Healing

: complete closure of fistulas tract (confirmed by EUA and MRI)

Improvement

: reduction of drainage Results: Complete closure was observed in in 61 pts (64%) and improvement in 18 pts (19%); median time to close was 28 weeks (range 14-54).

Gionchetti et al. ECCO 2008

Adalimumab in Perianal Fistula

Bologna Experience Patients and Methods • 64 pts (from january 2008 to september 2009) • 28f/36m, mean age 32y (range 16-52), 8 smokers • Inclusion criteria: – Perianal fistulizing CD including AZA/6MP/MTX intolerant or failure anf IFX secondary failure • Treatment: – Surgical sanitization – Induction= ADA 160/80mg – Maintenance= 40mg eow or weekly in case of lost of response – AZA/6MP stopped at the beginning of ADA treatment and steroid tapered (2,5mg/wk) after induction

Gionchetti et al. ECCO 2010

100 80 60 40 20 0 31 12,5

8/64

week 8

20/64

Results

Remission Response 22 47

14/64 30/64

week 24 62 73

32/52 38/52

week 52

Perianal Crohn’s Disease INFLIXIMAB FOR PERIANAL FISTULAS

LOCAL INFUSION

General Surgery Department; Policlinico S. Orsola; University of Bologna, Italy * Internal Medicine Department; Policlinico S. Orsola; University of Bologna, Italy

April, 2005 •Mantoux test before first infusion •EUA (Spinal or General anesthesia) •15-21mg / patient •6 initial infusions at 0, 4 and 8 , 12, 16, 20 weeks and eventually subsequent infusions every 4 weeks

Local Infusion of Infliximab (81 pts)

65 5 2 7 1 1

Perianal Crohn’s Disease Contraindications to I.V. infusion Associated colo - proctitis Not responders to I.V. infusion Surgical complications of IPAA Pouch-vaginal fistula Cuffitis Pouch-anal fistula

Local Infusion of Infliximab

Healed patients (“Grade 4”) BEFORE AFTER

Overall success

64.1 %

53,2 %

Local Infusion of Infliximab Results

Remaining

35.9 %

Mean f.u. 48 months

84 % 4% 6% 4% 2% 11,1 % 13,6 % 6,1 % 9,9 % 6,1 %

Local Injection of adalimumab for perianal Crohn’s Disease: Better than infliximab?

Poggioli G, Laureti S, Pierangeli F, Bazzi P, Coscia M, Gentilini L, Rizzello F, Gionchetti P

Inflamm Bowel Dis, 2010 29 pts treated



8 rescue therapy after local injection of Infliximab



21 naïve therapy

• Injection of 40 mg every 15 days • Outpatient treatment • Consistence more convenient for local injection • Same technique as Infliximab local injection

Local Injection of adalimumab for perianal Crohn’s Disease: Better than infliximab ? Poggioli G, Laureti S, Pierangeli F, Bazzi P, Coscia M, Gentilini L, Rizzello F, Gionchetti P Inflamm Bowel Dis, 2010

29 pts treated



8 rescue therapy after local injection of Infliximab



21 naïve therapy

•

Well tolerated procedure

•

8 pts closed fistulas ( score 4 ) 59 %

(after a median of 10 injections )

•

17 pts still in treatment (f.u. 60-120 days)

•

4 pts ruled out of treatment *

•

Dose finding ? (40 mg 20 mg?) 27 % 14 %

* 1 adverse event – 1 pts with ileal stenosis- 2 pts lack of compliance for pain

Risk of infection as a consequence of anti TNF therapy

The London Position Statement of the WCG on biological therapy for IBD with the ECCO (2009)

• Anti-TNF therapy is associated with an increased relative risk of

opportunistic infection

immunomodulators.

and this risk is further increased by combination therapy with other •

Education, screening, monitoring

prophylaxis can reduce the incidence procedures and

Risk of malignancies as a consequence of anti-TNFs

The London Position Statement of the WCG on biological therapy for IBD with the ECCO (2009)

• No consistent evidence of an increased overall risk of malignancy in patients with IBD treated with anti-TNF therapy • In a meta-analysis of 26 clinical trials, cohort studies, or case series including 8905 patients receiving anti-TNF therapy for Crohn’s disease (21,178 patient years), the observed rate of non-Hodgkin’s lymphomas was 3-fold higher than expected from cancer-registry data (SIR 3.2, 95%CI 1.5–6.9). However, the majority of patients were receiving combination therapy with anti-TNF therapy and thiopurines. (Siegel et al, CGH 2009) • Hepatosplenic T-cell lymphoma in patients with IBD is very rare, but young patients treated with a combination IFX and thiopurines appear to be predisposed

Conclusions • • • • • Biologics offer a chance of therapy for patients with Steroids/AZA “Incomplete control” In selected cases “early therapy” may determine a better outcome The anti-TNF therapies have shown similar efficacy. Combination therapy with biologics and immunosuppressive is associated with increased toxicity, which is concerning to both physician and patients Absolute risks of serious opportunistic infections and lymphoma/cancer are low but must be taken into account.