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

Bruton’s Agammaglobulinemia, Bruton Tyrosine Kinase, 1993 Development Person Disease Enzyme Drug ibrutinib N H 2 O Ogden Bruton (1908-2003) Bruton’s Agammaglobulinemia, 1952 Bruton Tyrosine Kinase, 1993 Synthesized 2005 First in human 2009 1st approval 2013

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 117:6287-6296, 2011 Ponader, et al., ASH Meeting Abstracts 116:45, 2010

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: 416-425. 2. Treon et al, NEJM 2012; 367: 826-33. 3. Shinners et al, J Immunol 2007; 179: 3872-80. 4. Murphy et al, Janeway’s Immuno Biol 7th Ed 2008; 240. 5. Buggy and Elias, Int Rev Immunol 2012; 31: 119-132. 6. Wiestner, Blood; 120: 4686-4691. 7. de Gorter et al, Immunity 2007; 26: 93-104.

Ibrutinib – Key Milestones “breakthrough” for MCL, WM and CLL 2013 2014 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

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 420 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.

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

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

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

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

High Expectations in Onco-Hematology

GRAZIE