1. Ibrutinib (PCI-32765) First-In-Class BTK Inhibitor IM Los Angeles 18 Jan 2013 1

2. The Discovery of Agammaglobulinemia in 1952 Colonel Ogden C. Bruton ( a† 908, † 2003), Chief of Pediatrics at Walter Reed Army Hospital From: Bruton, OC: Agammaglobulinemia, Pediatrics 1952 1952;9;722-728 2

3. 1993 – Btk gene was cloned and characterized 2005 – First synthesis of Ibrutinib (PCI-32765) 2009 – First human treated with Ibrutinib 2014/2015 – Anticipated first regulatory approval The Scientific Journey of Ibrutinib 1952 – Colonel Bruton described a genetic disorder, agammaglobulinemia 19501960197019801990200020102020 3 3

4. B cell receptor signaling pathway Btk is essential for: BCR activation of NF-kB (apoptosis) 1 BCR activation of integrins (adhesion) 2 Chemokine-controlled migration and homing 3 1 Davis et al, Nature 463, 88-94 2 Spaargaren et al, J. Exp. Med 198, 1539-50 3 de Gorter et al, Immunity 26, 93–104 4 ibrutinib

5. Ibrutinib: First-in Class Inhibitor of BTK Forms a specific and irreversible bond with cysteine-481 in BTK Highly potent BTK inhibition at IC 50 =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 5 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 5

6. Inhibition of Downstream Signaling for Ibrutinib D0HH2 Cell Line 6 PMA/Ionomycin PPP Anti-IgG Y-223 PPP P (1 hour drug exposure followed by washout)

7. Ibrutinib Inhibits BCR-driven Cell Adhesion 7 To edit footers: "insert tab>header and footer" and apply to all

8. Mechanism of Action: Migration and Homing 8 To edit footers: "insert tab>header and footer" and apply to all

9. Efficacy Established in Spontaneous Canine Lymphoma 9 To edit footers: "insert tab>header and footer" and apply to all  10 year old Airedale terrier  Aggressive, surface IgG+ B-cell lymphoma Probe- Labeled BTK Probe assay Day 0, pre-dose 4-hours 24-hours Day 7, pre-dose Day 0, pre-dose Day 7, pre-dose PBMC Lymph Node

10. Probe Assay for BTK Occupancy Complete occupancy in Patient – 1.25 mg/kg once daily 10 Probe Total Btk Actin Day 1, pre-doseDay 1, 4HRDay 2, pre-doseDay 8, pre-doseDay 8, 4HR Day 15, pre-doseDay 29, pre-dose x

11. Plasma concentration profile reflects inhibition profile of reversibly inhibited off targets Occupancy indicates irreversible inhibition of BTK Durable BTK inhibition following an oral dose Plasma Concentration of PCI-32765 vs. BTK Occupancy Patients dosed at 2.5 mg/kg/day 11

12. Phase 1 Study in NHL and CLL CLL/SLL MCL DLBCL FL Other Indolent NHL % Change of Tumor Burden 12

13. Phase 2 study in Mantle Cell Lymphoma- Best Response (Efficacy Population n=110, Median Follow Up 9.2 mo) Wang M et al, ASH 2012 13

14. Best response with longer follow up 14 Wang M et al, ASH 2012

15. Kaplan-Meier Progression-Free Survival and Duration of response 15 All Treated Population 111 Median PFS (CI 95%) months13.9 (6.64, NR) All Responded Population 75 Median DOR (CI 95%) monthsNR (NR, NR) Responder All Treated PFS DOR

16. 16 18 mo PFS at 420 mg dose is estimated at 88% for R/R patients and 96% at 15 mo for TN patients. Phase 2 Study in CLL- PFS with Ibrutinib Monotherapy

17. 17 R/R no del 17p PFS = 81% 95% CI = [64%, 91%] R/R del 17p PFS = 53% 95% CI = [28%, 72%] Historical data: 3-7 ms R/R CLL patients by 17p status treated with ibrutinib (PCYC-1102-CA): Median PFS not reached (median f/u 22 ms)

18. Rapid Nodal Response Accompanied by Egress of CD19/CD5+ B-cells 18 Day 22 Lymphocyte Count CD5 CD19 Day 1 Day 8 Day 15 Lymphocyte Count CD5 CD19 Day 1 Day 8 Lymphocyte Count CD5 CD19 Day 1 Day 8 Day 2 Lymphocyte Count CD5 CD19 Day 1 Day 8 18

19. Treatment Emergent AEs in >10% of Patients Regardless of Relationship to Study Therapy (1014 cycles administered to all pts) Wang M et al, ASH 2012 19

20. Treatment Emergent Infectious AEs ≥ Grade 3 Regardless of Relationship to Study Therapy (1014 cycles administered to all pts) Wang M et al, ASH 2012 20

21. Conclusions Ibrutinib is a first-in-class, selective, covalent, irreversible inhibitor of BTK Orally, daily administered Well tolerated Activity demonstrated in range of B-cell malignancies with high ORR –Mantle Cell Lymphoma –CLL 21