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Supported by The Leukemia and Lymphoma Foundation Targeting Bcl-2 in CLL Asher Chanan-Khan, MDJennifer R Brown, MD PhD Professor of Medicine Director,

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Presentation on theme: "Supported by The Leukemia and Lymphoma Foundation Targeting Bcl-2 in CLL Asher Chanan-Khan, MDJennifer R Brown, MD PhD Professor of Medicine Director,"— Presentation transcript:

1 Supported by The Leukemia and Lymphoma Foundation Targeting Bcl-2 in CLL Asher Chanan-Khan, MDJennifer R Brown, MD PhD Professor of Medicine Director, CLL Center, DFCI Mayo Clinic FloridaAssociate Professor, Harvard

2 Bcl-2 (B-cell lymphoma 2) First detected in Follicular NHL having t(14;18) Translocation results in overproduction of Bcl-2 anti-apoptotic protein t(14;18) rarely seen in CLL, though Bcl-2 is overexpressed in ~80% of cases Bcl-2 prevents Bax/Bak pro-apoptotic executioner molecules Dysregulated expression counters physiologic apoptosis Bcl-2 protein bound to portion of Bax

3 Bcl-2 family proteins govern the decision to undergo mitochondrial apoptosis 3 J Clin Oncol. 2012, 30: 3127

4 4 Displacement of Bim from Bcl-2 induces rapid, irreversible cell death J Clin Oncol. 2012, 30: 3127

5 Bcl-2 Is Expressed in Most Types of Cancer Solid TumorsHematologic Cancers BreastMelanomaSCLCCLL Myeloma LymphomaAMLProstate (HR)Colorectal 1. Lanzafame S et al. Pathol Res Pract Yang H-B et al. Anticancer Res Jiang S-X et al. J Pathol Cerroni L et al. Am J Dermatopathol Sullivan GF et al. Clin Cancer Res Karakas T et al. Ann Oncol Lazaridou A et al. Leukemia Lymphoma Chen X et al. Chin J Oncol Puthier D et al. Leukemia

6 Bcl-2 expression is increased in and on CLL cells McCarthy et al Mol Med Sep-Oct;14(9-10): mRNA A. B. C.

7 High Bcl-2 Expression in CLL Is Associated with Lower Survival Cumulative Proportion Surviving Months Faderl et al., Leukemia. 16: , Bcl-2 <3.2 >3.2 Pats P= Died 23 36

8 Interaction with stromal cells increases anti-apoptotic Bcl-2 proteins in CLL cells Patel et al Leuk Lymph 2014 Apr;55(4): Bcl-2 Bcl-w Mcl-1 Bcl-x L

9 Therapeutic strategies to disrupt Bcl-2 function 1. Antisense-based (Oblimersen sodium) 2. Small molecule-based (BH3 mimetics) AT-101 (Phase II) Obatoclax – limited efficacy, non-oral availability ABT-263 / Navitoclax – increased thrombocytopenia ABT-199 (Phase III)

10 Adapted from Zeitlin B D et al. JCO 2008;26: Small-molecule inhibitors of Bcl-2 family proteins BH3 mimetics

11 BH3 Mimetics “mimic” BH3-containing pro- apoptotic proteins Navitoclax and ABT-199 mainly disrupt Bim:Bcl-2 complexes, not free Bcl-2, Mcl-1 or Bcl-w Displaced Bim can antagonize Mcl-1 and/or directly activate Bax/Bak Ability to bind Bcl-2 (or other anti-apoptotic Bcl-2 family proteins) with affinities comparable to endogenous ligands likely dictates efficiency to displace Bcl-2  increased Bak/Bax activation  apoptosis Czabotar et al Nat Rev Mol Cell Biol Jan;15(1):49-63.

12 ABT-263 Oral inhibitor of Bcl- xL, Bcl-2 and Bcl-w Binds hydrophobic BH3 binding pocket with high affinity (K i ≤ 1 nM)

13 ABT-737 Induces Apoptosis in Primary CLL Cells Independent of clinical features: FISH, IGVH, ZAP-70

14 ABT-263 Induces Reversible Thrombocytopenia: Dog Toxicology Study Platelet Count

15 Phase 1 ABT-263 in Relapsed CLL: Study M Phase I/2a dose-escalation trial –Modified continuous reassessment method Eligibility: –Relapsed or refractory CLL and requiring treatment –Platelets ≥ 75,000/mm 3 –Exclusions: History of immune thrombocytopenia Prior stem cell transplantation Blood 2009; 114: 883

16 Enrolled Patient Characteristics N=29 Age: 67 (50-79 y) Gender (M:F):19:10 No. of prior therapies: 4.5 (1-11) Fludarabine refractory: 9 (31%) Lymphocyte Count: 15.5 x 10 9 /L (0.8 – 284.3) Bulky nodes (> 5cm): 12 (41%) FISH:17p: 11 / 25 (44%) 11q: 5 / 25 (20%)

17 ABT-263 in Relapsed CLL: Thrombocytopenia is Dose-Limiting Intermittent - 250mgContinuous - 250mg 25 Lead-in dose of 100 mg x 7 days followed by continuous dosing minimizes platelet nadir

18 Navitoclax induces CLL cell apoptosis in vivo and reduces disease burden Roberts A W et al. JCO 2012;30:

19 ABT-263 in Relapsed CLL: Efficacy Best Response (N = 29 evaluable) –9 Partial Responses (PR) (1996 NCI-WG or CT of nodes) –ORR:31% (9/29) –19 of 21 pts with elevated ALC had >50% sustained reduction (90%) 11 of 29 pts with nodal disease had PR by CT (38%) Median time on study = 7 months

20 ABT-263 Phase 1 Study Progression-Free Survival Median PFS = 25 months

21 Response Correlates with Low MCL-1 and High BIM:MCL-1 or BIM:BCL-2 Ratios MCL-1BIM:MCL1 Ratio BIM:BCL2 Ratio

22 ABT-263 Slightly Less Potent than ABT-737: Likely Insignificant S Khaw D Huang AW Roberts

23 Apoptosis In Vitro Is Inhibited in Whole Blood, by Albumin Binding CCR 2010; 16:  M ABT263 1M1M

24 Co-Culture with CD154 + Fibroblasts Leads to ABT-737 Resistance M Davids, J Brown, A Letai, unpublished data

25 ABT-199: Selective Bcl-2 small molecule inhibitor Developed by structure-based NMR- guided design using ABT-263 as a scaffold Potently binds Bcl-2 with a K i of 0.010nM Causes less thrombocytopenia than ABT-263 (due to less selectivity for Bcl- xL) Oral availability (daily dose schedule) Currently being investigated in phase III trials in CLL, Non-Hodgkin's lymphoma and multiple myeloma ABT-199 ABT-263 Bcl-2 Souers AJ et al. Nat. Med. (Vol.19) 2013; Seymour JF et al. ASCO 2013, Abstract #7018

26 ABT-199 Dosing Schema Daily ABT-199 doses increased weekly to the designated cohort dose (DCD) Initial Ramp-Up Schema: Dose Escalation Ramp-Up Schema: Expanded Safety Cohort * 3 patients (1 each in cohorts 2, 3, & 5) received ABT mg as initial dose ** Step-up doses range from 100 to 400 mg # DCD ranges from 150 to 1200 mg

27 Patient Characteristics (n=105) CharacteristicsAll CLL/SLL Age, yMedian66 [36 – 86] Bulky nodes, n (%)≥5 cm58 (55) ≥10 cm17 (16) Number of prior therapies Median4 [1 - 11] IGHV mutation statusUnmutated36/48 (75) 17p StatusDeleted23 (22) Not Deleted49 (47) Missing9/24 (31) Fludarabine, n (%)Prior Treatment 87 (83) Refractory62 (59)

28 Adverse Events All Grades ≥20% of pts N=105 n (%) Diarrhea 42 (40) Neutropenia 38 (36) Nausea 37 (35) Upper respiratory tract infection 35 (33) Fatigue 27 (27) Cough 21 (20) Grades 3/4 ≥ 5% pts n (%) Neutropenia 35 (33) Anemia 10 (10) Febrile neutropenia 7 (7) Thrombocytopenia 7 (7) Hyperglycemia 7 (7) Tumor lysis syndrome (TLS) 7 (7) Hypokalemia 5 (5)

29 Presentation Title | Date xx.xx.xx | Company Confidential © Serious Adverse Events (SAEs) Possibly or Probably Related to ABT-199 SAEs (≥ 2 pts) N=105 n (%) Febrile neutropenia4 (4) Tumor lysis syndrome (TLS)*3 (3) Other SAEs (n=1): sudden death* (in the setting of TLS) As of April 9, 2014, in the 49 patients treated since modifications were made to the dose ramp-up scheme as well as the tumor TLS prophylaxis and monitoring schedule, no additional events of clinical TLS (or SAEs of TLS) have been reported.

30 Best Percent Change from Baseline in Blood Lymphocyte Count and Nodal Mass by CT Scan Nodal Mass by CT Scan (n= 93) The median time to 50% reduction 1.4 months, range [0.65 – 13.7]* 78 (84%) evaluable patients had at least a 50% reduction in sum of the product of diameters (SPD) of nodal masses *coincides with first protocol specified CT scan at 6 weeks. 30 Blood Lymphocytes (n=60) Median Time to 50% reduction: 14 days, range [1 – 49] Data represents patients with lymphocyte count >5 x 10 9 /L at baseline Cohort Dose (mg)

31 Best Percent Change from Baseline in Bone Marrow Infiltrate (n=51) Median time to 50% reduction: 5.5 months, range [1.9 – 17.4]* 46/51 (90%) evaluable patients have had at least a 50% reduction. Anti-tumor activity of ABT-199 was observed in all tumor compartments. # ^ # Patient had 70% infiltrate at baseline and at Week 24 ^Patient did not have CLL infiltrate at baseline.

32 Objective Responses of ABT-199 Treated Patients Responses All n (%), n = 78 del (17p) n (%), n = 19 F-Refractory n (%), n =41 IGHV Unmutated n (%), n =24 Overall response60 (77)15 (79)31 (76)18 (75) Complete response (CR/CRi) # 18 (23)5 (26)9 (22)7 (29) Stable disease10 (13)2 (11)7 (17)2 (8) Disease progression2 (3)1 (5)1 (3)2 (8) The median duration of response has not yet been reached based on current patient enrollment numbers.

33 Current Status of Enrolled Patients (n=105; April 9, 2014) Median Time on Study Dose Escalation Patients (all dose levels): 17.1 months, range [0.06 – 29.7] Safety Expansion Patients: 4.7 months, range [0.52 – 9.3] Discontinuations As of April 9, 2014, 105 patients are enrolled and 37 have discontinued for the following reasons: 22 Progressive Disease (of which 15 were from Richter’s) 12 Adverse Events 3 other (1 need for Coumadin, 2 proceeded to alloSCT) Based on the preliminary safety and efficacy profile of ABT-199, 400 mg is currently being explored as the safety expansion dose.

34 Progression Free Survival (PFS) at 400 mg or Higher Median PFS for patients treated at or above 400 mg has not yet been reached (median follow-up of 5.3 months, range [0.03 – 22]) As of April 9, 2014, the median PFS for all patients is approximately 18 months

35 BH3 Profiling provides functional confirmation of on target Bcl-2 antagonism and may predict depth of clinical response to ABT-199 Davids, Deng, Letai (unpublished data) p= % cyto C release ABT uM %cyto C release BAD 80 uM BAD vs. ABT-199 Mitochondrial Depolarization R square=0.7465

36 Dosing Schedule of ABT-199 and Rituximab – Cohorts OR: if one or more electrolytes meet Cairo-Bishop criteria and/or if there is ≥ 30% decrease in ALC with first dose 400mg, 500mg, 600mg and safety expansion cohorts dosed with this schedule

37 37 Current Status of Evaluable Patients (April 16, 2014 cut-off) Median time on study = 7.5 months, range [ ] Original Dosing Regimen = 13.3 months, range (1.5 – 19.6) Amended Dosing Regimen = 5.1 months, range (0.03 – 9.2) Active patients, SE = Safety Expansion Discontinuations 7 out of 45 patients Progressive Disease (n = 5)  Richter’s transformation (4)  Progressive CLL (1) Adverse Event (n = 1)  Fatal tumor lysis Withdrew Consent (n = 1)

38 Responses of Patients treated with ABT- 199 and Rituximab Response Evaluable Patients n=25 (%) Overall Response21 (84) CR (n=4)/ CRi (n=5)*9 (36) Disease progression1 (4) Discontinued prior to M7 assessment # 2 (8 ) Of the 20 patients on study < 7 months (still receiving combination): 5 have a PR, 6 have a PR at first CT; 9 have not yet been evaluated

39 Presentation Title | Date xx.xx.xx | Company Confidential © Minimal Residual Disease (MRD) MRD was assessed by local lab using 4 color flow cytometry in 8/9 CR/CRi patients and 6 patients with a PR (based on available data) PatientResponseSourceSensitivityMRD 1CRBone Marrow10 -4 Negative 2CRPeripheral Blood10 -3 Negative 3CRBone Marrow % 4CRBone Marrow10 -3 Negative Peripheral Blood10 -3 Negative 5CRBone Marrow10 -4 Negative 6CRBone Marrow10 -4 Negative 7CRBone Marrow % 8CRBone Marrow10 -4 Negative 9 PRBone Marrow10 -4 Negative 10 PRBone Marrow10 -4 < 1% 11 PRBone Marrow10 -4 Negative 12 PRPeripheral Blood10 -4 Negative 13 PRBone Marrow10 -4 Negative 14 PRBone Marrow10 -4 Negative

40 Complete Remission: Discontinuation of ABT patients have discontinued ABT-199 after achieving CR/CRi (2 with MRD negativity) Patients had 1, 3, and 4 prior therapies; one had fludarabine refractory disease –Patients are continuing follow-up on study –Patients remain in CR at the time of this analysis (8.6, 8.8, and 11.6 months after cessation)

41 Ongoing Clinical Trial 1. Phase III, randomized study in relapsed/refractory CLL to evaluate the benefit of ABT rituximab vs. BR. 2. Phase 2 study of ABT-199 in patients with relapsed or refractory CLL harboring 17p deletion.

42 Not just Bcl-2… Zeitlin B D et al. JCO 2008;26:

43 Potential mechanisms of resistance to ABT-199 Mcl-1 upregulation Stromal mediated resistance Mutations in BCL2 or BAX ABT199 alone (Low BCL2/MCL1 ratio) Touzeau et al Leukemia (2014) 28, 210–212; Soderquist et al J. Biol. Chem. 2014, 289: ; Fresquet et al Blood 2014 Jun 26;123(26):

44 Summary BCL-2 is a critical survival pathway in CLL BCL-2 family interactions are complex – influenced by multiple family members and the microenvironment –Targeting BCL-XL is problematic in CLL patients ABT199 has profound clinical activity, including in bone marrow clearance –Clinical care required due to TLS Resistance likely to emerge –? Early signal of excess Richter’s transformation

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