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

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 ;9;

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

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, Spaargaren et al, J. Exp. Med 198, de Gorter et al, Immunity 26, 93–104 4 ibrutinib

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: , 2011 Ponader, et al., ASH Meeting Abstracts 116:45,

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)

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

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

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

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

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 vs. BTK Occupancy Patients dosed at 2.5 mg/kg/day 11

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

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

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

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 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 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)

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

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

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

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