1. IMBRUVICA® (ibrutinib)
Danilo Arienti
Therapeutic Area Medical Manager
Milano, 25 Novembre 2015

2. Bruton’s Agammaglobulinemia, Bruton Tyrosine Kinase, 1993
Development
Person
Disease
Enzyme
Drug
ibrutinib N H 2 O
Ogden Bruton ( )
Bruton’s Agammaglobulinemia,
1952
Bruton Tyrosine Kinase, 1993
Synthesized 2005
First in human 2009
1st approval 2013

3. Ibrutinib: First-in-Class Inhibitor of Bruton’s Tyrosine Kinase (BTK)
Co-development by Janssen and Pharmacyclics
Oral, small-molecule inhibitor of BTK with once daily dosing; previously PCYC 32765
Forms a specific and covalent bond that causes highly potent BTK inhibition
Highly potent BTK inhibition at IC50=0.5nM
Orally administered with once daily dosing resulting in 24-hr target inhibition
Induces growth inhibition and apoptosis in B- cell tumor cells
No cytotoxic effect on T-cells or NK-cells
Honigberg LA et al, Proc Natl Acad Sci USA.107:13075, 2010
Herman SEM et al: Blood 117: , 2011
Ponader, et al., ASH Meeting Abstracts 116:45, 2010

4. BTK: An essential effector of multiple B-cell processes
TLR1,2
BAFF-R3
BCR4-6
CXCR4/57
1. Liu et al, Nat Immunol 2011; 12: Treon et al, NEJM 2012; 367: Shinners et al, J Immunol 2007; 179: Murphy et al, Janeway’s Immuno Biol 7th Ed 2008; 240.
5. Buggy and Elias, Int Rev Immunol 2012; 31: Wiestner, Blood; 120: de Gorter et al, Immunity 2007; 26:

5. Ibrutinib – Key Milestones
“breakthrough” for MCL, WM and CLL
Advani et al
Jan 2013
Byrd et al; Wang et al
Jun 2013
FDA approval: MCL
Nov 2013
FDA approval: CLL
Feb 2014
RESONATE
Jul 2014
EMA approval
CLL, MCL
Oct 2014
ASH 2011
ASH 2012
Jan. 2015
FDA approval WM
May 2015

6. Phase III study in RR/CLL: RESONATE (PCYC-1112)
Phase 3, open-label, randomized, multicenter study
Patients with previously treated CLL or SLL; not appropriate for purine analogue treatment
N=391
Enrolled June 2012  April 2013
RANDOMIZE
Oral ibrutinib mg once daily* n = 195
*until PD or unacceptable toxicity
IV ofatumumab 12 doses over 24 wks* n = 196
*initial dose of 300 mg followed by 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks
Crossover to ibrutinib 420 mg with IRC confirmed PD after end of study E N D O F S T U Y
1:1
IRC, independent review committee; IV, intravenous; PD, progressive disease.
Endpoints: PFS, OS, ORR, and safety assessed by IRC
Byrd JC, et al. N Engl J Med. 2014; ePub 31May2014.

7. RESONATE: ibrutinib vs ofatumumab 90% reduction in the risk of progression or death 53%reduction in the risk of death
Progression Free Survival
Overall Survival
Median follow-up 19 months
Median follow-up 19 months
Pagel, et al. Poster no. 146 iwCLL. 2015

8. Results: Most Common Cumulative AEs for Ibrutinib by Preferred Term (≥ 15%)
Brown JR et al. ASH 2014; Poster/Abstract 3331

9. Ibrutinib offers an important clinical benefit with RR MCL and WD
Phae II

10. Ibrutinib has 'unprecedented' impact on MCL
Response After 2 Cycles of Ibrutinib
“I believe we are witnessing a breakthrough in MCL.
This is great news for patients," said Michael Wang, M.D
Wang M et al, Oral/abstract 904- ASH2012

11. High Expectations in Onco-Hematology

12. GRAZIE