Biologics in Ulcerative Colitis. Chris Probert

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1 Biologics in Ulcerative Colitis Chris Probert

2 Why aren t there more trials of biologics in UC? perhaps because of ciclosporin therapy perhaps because of pouch surgery

3 Similarities in treatment Many established treatments are shared between UC and CD: corticosteroids, mesalazines, azathioprine, methotrexate All are considered to work in a broadly similar manner in both conditions.

4 Why not use biologics? Have we been too cleaver?

5 Differences Immune response is the target Is it the same? Th1/Th2 paradigm: murine immunology UC: Th2 disease CD: Th1 disease Perhaps biologics against immune response may not work equally well in both diseases.

6 Similarities TNFα Pro-inflammatory cytokine - increased in the blood and intestinal mucosa of patients with both active ulcerative colitis and Crohn's disease. Surely, antitnf agents should work in both forms of IBD.

7 Anti-TNF agents - CDP571 Humanised chimeric TNFα antibody (n=15) activity quickly improvement not sustained further studies have not been reported APT 1997

8 Anti-TNF agents - infliximab: open studies Open studies: biased and often positive Chey et al n=8 Single infusion of infliximab dramatic response "significant, major effect on active UC" AJG 2001

9 Anti-TNF agents - infliximab: open studies Su et al n= 27 Most severe UC, most steroid failures 12 (44%) achieved remission, 6 (22%) partial response, 9 (33%) - no respond, 5 - colectomy. 11/12 responders had severe UC Benefits were "less in patients with steroid-refractory disease" AJG 2002

10 Anti-TNF agents - infliximab: open studies Actis et al n=8 6 were steroid failures 4/8 responded initially, sustained response = 25% Kohn et al n=13 All steroid refractory 10 (77%) responded quickly Dig Liver Dis 2002

11 Anti-TNF agents - infliximab: open studies Open studies paved the way for RCTs (although some were already underway) Suggested a benefit - perhaps greatest in severe disease, perhaps least in steroid refractory disease Note response = / remission

12 RCT 1: Sands et al Severe UC, steroid failures, n=11 Single infliximab infusions (n=8) vs placebo (n=3) 50% infliximab group responded by week 2 - (CAI improved), of the failures - 1 had CiA and 1 had colectomy IBD 2001

13 RCT 2: Probert et al Moderately severe SR UC, n= 43 Single infusion 5mg/kg vs placebo - open label (10mg/kg) if no response. At 2w remission rate = 3/23 vs 1/19 (inf vs pl) At 6w 9/23 (39%) vs 6/20 (30%) Data did not support the widespread use of infliximab in the management of SR UC Gut 2003

14 RCT 3: Ochsenkuhn et al Acute severe UC (T&W>10, non-sr UC), n= inflix, 7 - prednisolone (1.5mg/kg) Success = >5 reduction to <10 after 3w 5/6 infliximab gp responded 6/7 pred gp responded the benefit continued >13w. EJGH 2004

15 RCT 4: Armuzzi et al Mod-severe steroid dependent UC, n=20 3 doses inflix (0,2,6) vs methylpred. Remission 9/10 with infliximab vs 8/10 with methyl prednisolone Odd result in steroid resistant patients DDW 2004

16 RCT 5: Jarnerot et al Moderate and severe UC, n= 45 Colectomy rate 7/24 vs 14/21 (inf. vs pl.) (Equivalent to 66% (vs 30%) response) The authors concluded that infliximab was a safe and effective rescue therapy UEGW 2004

17 Infliximab (DDW) Act 1 Act 2

18 Anti-CD3 Antibodies Visilizumab: humanized chimeric anti-cd3 Phase 1 study, severe SR UC, n=26 8 pt received 15µg/kg iv days 1 & 2, 18 pt 10µg/kg iv days 1 & of 20 reported had sustained response. Cytokine release syndrome T-cell depletion lasting for up to 8 weeks DDW 2004

19 Anti α4 Antibodies Natalizumab: humanized chimeric anti α4 Efficacious in CD and MS UC study, n=10 Single infusion (3mg/kg) 5/10 good response by w2 6/10 by week 4. Drug withdrawal after problems in MS APT 2002

20 Interferons Potential role via increased in soluble TNF receptor p55 and reduced in IL-5 and IL-13 Open label study, n=32 Interferon-2α prednisolone enema AJG 2001 RCT, n=60 Pegylated interferon-α placebo Gut 2003

21 Interferon-β-1a Interferon-β-1a, RCT, n=17 Moderate UC Clinical response (fall in UCSS >3) 50% with IFN-ß-1a 14% with placebo (p=0.14). Endoscopic remission better with IFN-ß-1a (p=0.02). But dose limiting side effects Gut 2003

22 Epidermal Growth Factor Sinha et al, RCT, n= 24 Left sided/distal UC EGF enemas or placebo, with oral mesalazine. 10/12 EGF - remission at 2 weeks vs 1/12 with placebo but mitogenic potential? NEJM 2003

23 IL-2 Receptor Antibodies Basiliximab chimeric monoclonal Licensed for steroid resistant graft rejection of allogenic renal transplants In vitro steroid sensitiser in UC Effective in UC in pilot study (9/10) APT 2003

24 Basiliximab - IL2 blockade Results 24 weeks 28 Patients 21 (75%) Improved 18 (64%) full remission 3 (11%) improved 7 (25%) No improvement -6 colectomies -1 Ciclosporin DDW 2004

25 IL-2 Receptor Antibodies Daclizumab humanised antibody Effective in pilot 8/10 improved 5/10 in 8W AJG 2003 RCT, n=159, failed to meet the primary end point of significant difference in remission rates Press release

26 IL-2 Receptor Antibodies: difference Daclizumab was not used as a steroid enhancer. Need RCT of basiliximab

27 Conclusion Lessons from Crohn s disease Targeted treatments may work Repeated treatment and scheduling may matter.

28 Conclusion Particular biologics may have a role in specific subgroups of patients Infliximab, Natalizumab, Visilizumab and Interferon-β may each have a role in UC Basiliximab looks promising for SR UC

29 Conclusion A tantalising glimpse into the future The devil will be in the detail - of study design and patient selection.

30 Thank you