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THE BRUTON'S TYROSINE KINASE INHIBITOR, PCI32765, IS WELL TOLERATED AND DEMONSTRATES PROMISING CLINICAL ACTIVITY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND SMALL LYMPHOCYTIC LYMPHOMA (SLL): AN UPDATE ON ONGOING PHASE 1 STUDIES

JAN A. BURGER, MD, PHD1, SUSAN O'BRIEN, MD1, NATHAN FOWLER, MD2, RANJANA ADVANI, MD3, JEFF PORTE SHARMAN, MD4, RICHARD R. FURMAN, MD5, RAQUEL IZUMI, PHD6, JOSEPH BUGGY, PHD6, DAVID LOURY, PHD6, AHMED HAMDY, MD6, JOHN C. BYRD, MD7 AND KRISTIE A. BLUM, MD7

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 2Lymphoma/Myeloma, UT MD Anderson Cancer Center, Houston, TX 3Dept. of Medicine/Oncology, Stanford University, Stanford, CA 4Willamette Valley Center Institute, Springfield, OR 5Weill Medical College of Cornell University, New York, NY 6Pharmacyclics, Inc, Sunnyvale, CA 7The Ohio State University, Columbus, OH

Disclosures

Jan Burger, MD

· · · · · RESEARCH FUNDING/PI: Pharmacyclics EMPLOYEE: N/A STOCKHOLDER: N/A CONSULTANT: Pharmacyclics SCIENTIFIC ADVISORY BOARD: Pharmacyclics

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PCI32765

Novel Small Molecule Btk Inhibitor

·

O

Forms a specific and irreversible bond with cysteine481 in Btk Potent Btk inhibition

· IC50 = 0.5 nM

·

NH 2 N N N N

·

N O

Orally available Once daily dosing results in 24hr sustained target inhibition

·

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Btk Regulates Multiple Cellular Processes in CLL

· B cell receptor (BCR) signaling

­ PCI32765 blocks BCR signals and induces apoptosis

·

Btk Btk

Chemokinemediated CLL migration and adhesion

­ PCI32765 reduces lymphadenopathy

·

Cytokine secretion

­ PCI32765 blocks CCL3/4, TNF

Burger JA and Gandhi V, Blood 2009;114(12):25601

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Patients Included in Pooled Analysis (N=54)

Phase 1a (N=16)

1 Cycle = 28 days with 7 days rest Cohort 1 2 3 4 5 Cohort CD1 CD2 Dose (mg/kg/day) 1.25 2.5 5.0 8.3 12.5 1 Cycle = 35 days with no rest Dose 8.3 mg/kg/day 560 mg/day (fixed) N 6 1 N 0 3 3 1 2 Cohort R/R Naive

Phase 1b/2 (N=38)

1 Cycle = 28 days Dose (mg/day) 420 420 N 27 11

Median follow up 1.8 months

Median follow up 8.3 months

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Baseline Characteristics (N=54)

Median age, years (range) CLL/ SLL, n (%) Rai stage (N=44) 0, n (%) I/II, n (%) III/IV, n (%) Median prior therapies, number (range) Nucleoside analogue, n (%) AntiCD20 agents, n (%) Bendamustine, n (%) Alemtuzumab, n (%)

*Relapsed or refractory only

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68 (4084) 47 (87)/7 (13) 5 (11) 25 (57) 14 (32) 3 (110)* 41/43 (95) 41/43 (95) 9/43 (21) 4/43 (9)

Objectives of Pooled Analysis

· Describe the characteristics of the antitumor effect of PCI32765 in pts with CLL/SLL:

- Reduction in lymphadenopathy/splenomegaly - Kinetics of change in absolute lymphocyte count (ALC)

· Summarize the objective response and time on treatment to date · Summarize the safety profile of PCI32765

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Maximum % Change in LN Disease

0 10

% Change in LN Dimensions

20 30 40 50 60 70 80 90

SLL (n=7) CLL (n=32)

34 out of 39 evaluable pt had a nodal response = 87%

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100

ALC versus LN Response in Phase 1a Pts (N=16)

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ALC versus LN Response: Continuous Dosing

Absolute Lymphocyte Count

70 60 50

ALC x 109/L

40 30 20 10 0 0 2 4 6 8 10 12 14 16 18

pretreatment

Weeks

2 months on treatment

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Response in Evaluable Patients

80

32 evaluable patients 13 evaluable patients

Response Rate (%)

62% 60 40 25% 20 8% 0 0%

CR PR (n=8) Nodal Response w Lymphocytosis (n=17) CR (n=1) Nodal Response PR (n=8) w Lymphocytosis (n=2)

53%

15%

2 months F/U (Phase 1b/2)

8 months F/U (Phase 1a)

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Time on Study (N=54)

Phase 1b/2 Pts

On Study (n=43) NonPD D/C (n=7) PD (n=4)

Phase 1a Pts 0

2

4

Months

6

8

10

12

12

All Adverse Events ( 10% Incidence)

100 80 % Grade 3 % Grade 4

% of Patients

60 40 20 0

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All Adverse Events ( 10% Incidence)

100 80 % Grade 1 % Grade 2 % Grade 3 % Grade 4

% of Patients

60 40 20 0

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Overview of Grade 3 Laboratory AEs

· No renal or hepatic AEs reported · No evidence of cumulative toxicity in pts with 6 months follow up

100

% of Patients

80 60 40 20 0

% Grade 3 % Grade 4

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Conclusions

· PCI32765, an oral Btk inhibitor, is active and well tolerated in patients with CLL/SLL · Rapid lymph node responses are associated with a transient lymphocytosis, indicating a unique phenomena of BCRtargeted therapy · The lack of drugrelated myelosuppression or cumulative toxicity supports further investigation in various CLL treatment settings

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ACKNOWLEDGEMENTS

CLINICAL & LABORATORY SITE PERSONNEL

· MD Anderson Cancer Center, Houston, TX Justin Cummings, Clayton Dreyer, Talia LaPushin, Manolo Pasia Diana Rodriguez , Shana White · Dept. of Medicine/Oncology, Stanford University, Stanford, CA Nini Estevez ,Sipra Choudhury , Dina Chinichian , Cheryl Langford , Michelle Takahashi · Willamette Valley Center Institute, Springfield, OR Jeanne Schaffer, Anita Brown · Weill Medical College of Cornell University, New York, NY Nathalie Avignon · The Ohio State University, Columbus, OH Amy Johnson PhD, Asha Ramanummi, Mona Stefanos, Tammi McMath · Hematology/Oncology, University of Chicago Hospitals, Chicago, IL Shyrell Robinson · North Star Lodge Cancer Center, Yakima, WA Mark Lapsley , Beth Parker · Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT Karen Lepuschenko · Northwest Cancer Specialists, Vancouver, WA Denise Hill , Judy Welch

PHARMACYCLICS PERSONNEL · CHANDRA MANNEM, TASHEDA NAVARRO, SARA RODRIGUEZ, CLARA PLASCENCIA

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Frequency of Adverse Events (N=54)

n (%)

Any AE

Grade 3 AE

50 (93) 20 (37) 42 (78) 9 (17) 14 (26) 6 (11) 2 (4)

Any Related AE

Related Grade 3 AE

Any SAEs

Related SAEs**

Deaths*

*All deaths occurred in the setting of documented disease progression and determined not study related by investigator. **Hospitalizations for viral adenitis, subdural hematoma, viral infection, FTT, sepsis, HA& dizziness 19

Response (N=54)

Phase 1a

(n=16) RR 420 Median Followup (range) CLL SLL Best response CR PR LN/spleen PR w/ lymphocytosis SD PD Nonevaluable/TETE 8.3 mos (0.511.7) 11 5 1 8 2 2 0 3 1.8 mos (0.73.7) 26 1 0 5 16 2 1 3

Phase Ib/2

(n=38) Naive 1.8 mos (1.21.9) 10 1 0 3 1 4 0 3

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