Ustekinumab Induction and Maintenance Therapy in Refractory Crohn’s Disease William J. Sandborn, M.D., Christopher Gasink, M.D., Long-Long Gao, Ph.D., Marion A. Blank, Ph.D., Jewel Johanns, Ph.D., Cynthia Guzzo, M.D., Bruce E. Sands, M.D., Stephen B. Hanauer, M.D., Stephan Targan, M.D., Paul Rutgeerts, M.D., Ph.D., Subrata Ghosh, M.D., Willem J.S. de Villiers, M.D., Ph.D., Remo Panaccione, M.D., Gordon Greenberg, M.D., Stefan Schreiber, M.D., Simon Lichtiger, M.D.,and Brian G. Feagan, M.D., N Engl J Med 2012;367:1519-28 R2 Kyunghan Yoon / Prof. Changkyun Lee 

Background

BACKGROUND Refractory Crohn’s disease -> TNF antagonist 1/3 -> Do not have response to initial treatment (primary nonresponse) 1/3 -> Transient response or a switch to another therapy (secondary nonresponse). Interleukin- 12 and interleukin-23 Overexpression, polymorphism-> Pathogenesis of Crohn’s disease Ustekinumab : human IgG1κ monoclonal antibody, blocks the biologic activity of IL-12 & 23 Patients with moderate- to-severe Crohn’s disease that was resistant to TNF antagonists -> Effect of Ustekinumab ?? Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care (ADDITION-Europe)

Method

Methods Randomized, double-blind, placebo-controlled phase 2b trial of ustekinumab (Oct 2008 ~ Dec 2010) Primary end point Clinical response (≥100-p↓ from the baseline CDAI score) at week 6 Secondary end points Clinical remission (CDAI score, <150 points) at week 6 Clinical response at week 4, and clinical remission at week 22 among patients with a response to ustekinumab at week 6. Crohn’s Disease Activity Index (CDAI, 0~600) - Higher scores indicating worse disease - 50-point change indicating the minimal clinically important difference

1st randomization 2nd randomization

Methods Inclusion criteria 18 years old ↑ 3-month↑ history of Crohn’s disease with a score of 220 to 450 points on the CDAI Primary nonresponse, a secondary nonresponse, or unacceptable side effects after receiving a TNF antagonist No previous therapies specifically targeting interleukin-12 or interleukin-23 Exclusion criteria Bowel resection within 6 months before enrollment and those with the short-bowel syndrome Abscess, active tuberculosis, current infection, or other previous or current opportunistic infection or cancer.

Result

No significant difference Results Table 1. Baseline Characteristics of the Patients in the Induction Phase No significant difference

Ustekinumab > Placebo No significant difference Results Figure 1. Efficacy of Ustekinumab in the Induction Phase Response Ustekinumab > Placebo Remission No significant difference

Response & Remission (maintenance phase) Ustekinumab > Placebo Results Figure 2. Efficacy of Ustekinumab in the Maintenance Phase Response & Remission (maintenance phase) Ustekinumab > Placebo 69.4 41.7 42.5 27.4 P<0.001 P= 0.03

Results Serious infections Table 2. Adverse Events during the Induction Phase (Week 0 to Week 8) Serious infections Five patients receiving 6 mg/kg Ustekinumab(C. difficile infection, viral gastroenteritis, UTI, anal abscess, and vaginal abscess) One patient receiving 1 mg/kg of ustekinumab (staphylococcal infection in a central catheter) One patient receiving placebo (anal abscess) Serious adverse events & Infusion reactions were uncommon

Results Table 3. Adverse Events during the Maintenance Phase (Week 8 to Week 36) There were no deaths, major adverse cardiovascular events, tuberculosis, or other serious opportunistic infections One basal-cell carcinoma was reported in a patient who received 1 mg/kg of ustekinumab

Conclusion

Conclusions Induction therapy Maintenance therapy Remission?? Response & Remission↑ Response↑ Ustekunumab CD patients When compared with routine care, an intervention to promote target-driven, intensive management of patients with type 2 diabetes detected by screening was associated with small increases in the prescription of drugs and improvements in cardiovascular risk factors, but was not associated with signifi cant reductions in the incidence of cardiovascular events or death over 5 years. Placebo