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Primer on Kinase Inhibitors Richard R. Furman Directory, CLL Research Center Weill Cornell Medical College / New York Presbyterian Hospital

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BCR-associated Kinases: Proven Effective Therapeutic Targets Nat Rev Immunol 2:945 Syk (spleen tyrosine kinase): R406, PRT062070 Btk (Brutons tyrosine kinase): ibrutinib, CC-292, ACP-196 PI3K (phosphatidyl 3-kinase: idelalisib(GS-1101), IPI-145

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Targeting the BCR++ Antigen Pathway:

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Novel BCR Acting Agents BTK: ibrutinib (PCI-32765) CC-292 (AVL-292) ACP-196 PI 3 Kinase: idelalisib (GS-1101, CAL-101) IPI-145 SYK: fostamatinib (R935778) PRT062070

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Issues with Novel Agents Need to revise Response Criteria Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide therapeutic window Differences

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Issues with Novel Agents Need to revise Response Criteria Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide therapeutic window Differences

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Lymphocytosis + Nodal Reduction with BCR Antagonists

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Redefining Clinical End Points Cheson 2012 Standard response criteria: measure of treatment efficacy For novel agents, response criteria dont measure effect: Thalidomide / lenalidomide: tumor flare BCR Antagonists: lymphocytosis (Not tumor flare) Need to provide means for determining need for treatment discontinuation LRF sponsored committee: May 2011 Cheson BD. JCO 2012.

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Cheson 2012: Recommendations 1.For IMID compounds: Assessment of PD should use repeat observations and incorporate indicators of PD not associated with tumor flares. 2.For BCR-targeted agents: lymphocytosis alone should not be considered an indicator of PD. Need to demonstrate other CLL-related signs or symptoms of PD. 3.Lymphocytosis is distinct from tumor flare

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Issues with Novel Agents Need to revise Response Criteria Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide therapeutic window Differences

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Idelalisib Doses >150 mg BID Associated with Longer PFS PFS -- By Idelalisib Dosing Regimen 50-100 mg BID: 5 cycles (16) 150-350 mg BID: 18 cycles (39) Cycles (28 days) % Progression-Free

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Issues with Novel Agents Need to revise Response Criteria Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide therapeutic window Differences

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Kinase PCI-32765 IC 50 (nM) Kinase PCI-32765 IC 50 (nM) Btk0.46FGR2.31 Ikt10.70Fyn95.55 Bmx/Etk0.76HCK3.67 TEC77.76Lyn200.45 EGFR5.55ABL86.12 JAK316.13Brk3.34 BLK0.52JAK2>10,000 LCK33.24SYK>10,000 IC50 Values of PCI-32765 and Related Kinases

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Brutons Tyrosine Kinase (Btk) B-cell antigen receptor (BCR) signaling required for B cell survival Brutons Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway Inhibitors of Btk block BCR signaling and induces apoptosis

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Ibrutinib: Inhibitor of Brutons Tyrosine Kinase Forms an irreversible bond with cysteine-481 in Btk Potent Btk inhibition IC 50 =0.5 nM Orally bioavailable Daily dosing resulting in 24-hr target inhibition No impact on T-cells or NK cells Possible impact upon bmx, blk, and platlets N N N N NH 2 O N O

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Ibrutinib in CLL: PCYC-1102 Furman RR. iWCLL 2013

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PCYC-1102: Patient Demographics Furman RR. iWCLL 2013 Characteristic TN 65 Years n = 31 R/R n = 85 Median age, years (range) 70 years, n (%) 71 (65, 84) 23 (74) 66 (37, 82) 30 (35) Male, n (%) Female, n (%) 19 (61) 12 (39) 65 (76) 20 (24) Prior Therapies, n (%) < 3 > 3 NA Median = 4 (1-12) 24 (28) 61 (72) 2 M > 3.0 mg/L, n (%)8 (26)39 (46) Rai stage III/IV, n (%) 17 (55) 52 (61) Prognostic markers, n (%) IgV H unmutated del(17p)+ del(11q)+ 15 (48) 2 (6) 1 (3) 65 (76) 29 (34)

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PCYC-1102: Patient Disposition Furman RR. iWCLL 2013 TN 65 Years n = 31 R/R n = 85 Median time on treatment, months (range) 21.3 (0.3, 26.6)16.3 (0.3, 28.7) Median time on study, months (range)22.1 (2.5, 28.9)22.1 (0.7, 29) Patients still on treatment, n (%)26 (84)53 (62) Patients discontinuing treatment, n (%)5 (16)32 (38) Reasons for treatment discontinuation, n (%) AE Treatment-related AE Death due to AE 2 (6) 1 (3) 0 10 (12) 1 (1) 1 (1) a Disease progression b 1 (3)10 (12) SCT (while in response) Investigator decision (not SCT) Patient decision Lost to Follow-up 0 2 (6) 0 4 (5) 3 (4) 1 (1) a Cryptococcal pneumonia b 7 patients (1 TN and 6 R/R) had disease progression with Richters transformation

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PCYC-1102: Overall Response Among those patients whose initial response was PR-L, the majority achieved classic response by iwCLL criteria: TN: 9/13 (69%) R/R: 38/49 (78%) Combined ORR + (PR-L) in TN (84%) and R/R (88%)

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Ibrutinib Pivotal Study Schema: PCYC-1112 Patients will be randomized 1:1 to either arm A or B Treatment Arm A: Ofatumumab IV 12 IV doses over 24 weeks or until PD Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks) Treatment Arm B: Ibrutinib PO 420 mg (3 x 140mg) orally daily until PD

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PI 3 Kinase Signaling in B Cells Lannutti, B. Blood, 2011 BCR PI3K Delta CD40 STAT T308S473 AKT JAK TRAF6 NF-k pathway JAK mTOR BTK PLC 2 PKC GSK-3 LYN SYK LYN/SYK T-cell Signalingstimulus gp130 STAT BTK PLC 2 p70s6k elf4E B-cell membrane CXCR4/5 BAFFR Stromal cell IL-6R CXCL12/13 BAFF IL-6

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Idelalisib: Specific Inhibitor of p110 Tyrosine Phosphorylation PI3K Isoforms ExpressionBroad Leukocytes Gene KO effectLethal Benign Physiological role Insulin signaling Angiogenesis unknown B-cell signaling, development & survival Neutrophil, T-cell development IC50 (nM)21544278182

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Phase I Study of Idelalisib in Patients with Hematologic Malignancies Idelalisib 50 mg to 350 mg BID Continuous oral dosing (28-day cycles) 48 weeks Endpoints: Phase 2 dose Safety Pharmacodynamics Pharmacokinetics Antitumor activity Previously treated hematologic malignancies: CLL (N=54) iNHL (N=30) MCL (N=21) DLBCL (N=9) myeloma (N=12) AML (N=12)

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CLL Patients Treated with Idelalisib 150 mg BID Brown J. ASCO 2013 Response Rate Nodal Response 39% 33% 81% 72% Overall Response Decrease by 50% of nodal SPD PR with lymphocytosis (Cheson 2012) PR by IWCLL criteria (Hallek 2008)

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CLL Patients Treated with Idelalisib 150 mg BID Brown J. ASCO 2013 ALC SPD

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Single Agent Idelalisib in CLL Brown J. ASCO 2013

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Improvement in Baseline Cytopenias Brown J. ASCO 2013

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Idelalisib in CLL Brown J. ASCO 2013 Median PFS = 17.1 monthsMedian OS not reached Progression Free SurvivalOverall Survival

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Adverse Events (> 15%) and Selected Lab Abnormalities (N=54) Brown J. ASCO 2013 AE, n (%)Any Grade (%) Grade 3 (%) Fatigue17 (32)1 (2) Diarrhea16 (30)3 (6) Pyrexia16 (30)2 (4) Cough13 (24)2 (4) Back pain12 (22)0 Rash12 (22)0 URI12 (22)0 Pneumonia11 (20)10 (19) Night sweats10 (19)0 Chills 9 (17)0 Laboratory abnormality, n (%) AST, increased*13 (24)1 (2) ALT, increased*10 (19)1 (2) *15 subjects total with transaminase elevations

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Idelalisib + Coutre S. ASH 2012, Abs 191 LNR = Nodal Response OR = Response by IWCLL criteria (Hallek 2008) Response Rate 95% CI LNRORLNROR +R +B +BR LNROR

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Idelalisib Pivotal Study Schema: GS-US-312-0116

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IPI-145 IPI-145: Potent Inhibitor of PI3K- and Potent oral inhibitor of both PI3K- and PI3K- Selective for PI3Ks over other protein and lipid kinases Inhibits malignant B and Tcell survival Affects tumor cells directly Disrupts tumor cell interactions within the microenvironment Patel et al ASCO 2013

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Complete Inhibition of PI3K- and >50% Inhibition of at Doses > 25 mg BID Patel. ASCO 2013.

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IPI-145: Clinical Response Patel, et al. ASCO 2013