1 FDA Review of DASATINIB Oncology Drug Advisory Committee (ODAC) June 2, 2006

2 Review teams Clinical - Michael Brave, M.D., Vicki Goodman, M.D., Edvardas Kaminskas, M.D., Ann T. Farrell, M.D., and Robert Justice, M.D. Statistical - Janet Jiang, Ph.D., and Raji Sridhara, Ph.D. Chemistry- William Timmer, Ph. D., Ravi Haranpanalli, Ph.D., and Richard Lostritto, Ph.D. Pharmacology/Toxicology- Haleh Saber-Mahloogi Ph.D., and David Morse, Ph.D. Clinical Pharmacology- Angela Men, Ph.D., Leslie Kenna, Pharm. D., Julia Bullock, Ph.D., and Brian Booth, Ph.D. Project Management- Amy Baird, B.A.

3 Overview Regulatory Background Clinical Studies Dose Finding Populations Studied and Efficacy Results Safety Issues Conclusions Questions for the Committee

4 Proposed Indication for Dasatinib Treatment of adults with chronic, accelerated, or blast phase CML with resistance to or intolerance of prior therapy including imatinib, and with Philadelphia chromosome-positive ALL or lymphoid blast CML with resistance to or intolerance of prior therapy.

5 Gleevec® Approval History Accelerated approval was granted on the basis of 3 single-arm trials of CML patients in blast crisis, accelerated phase, or in chronic phase after failure of interferon-  therapy. Full approval was granted after a longer follow-up of the above Phase 2 studies.

6 Imatinib Resistance or Intolerance in CML Imatinib resistance: Primary: Imatinib treatment is ineffective - no cytogenetic or hematologic response. Acquired: Progression of disease after a cytogenetic or hematologic response. Imatinib intolerance: Discontinuation of imatinib because of toxicity. Intolerance of ≥ 400 mg/day.

7 FDA Issues with the NDA 1)Whether a lower starting dose should be further evaluated. 2)Whether sufficient data (magnitude/ duration) have been provided for the imatinib intolerant population.

8 Clinical Studies Submitted - 1 PhasePopulationNo. of Patients Treated Phase 2, Single- arm Chronic Phase CML (CP CML) 186 Phase 2, Single- arm Accelerated Phase CML (AP CML) 107 Phase 2, Single- arm Myeloid Blast Phase CML (MB CML) 74 Phase 2, Single- arm Lymphoid Blast CML (LB CML) or Ph+ ALL 78

9 Clinical Studies Submitted - 2 PhasePopulationNo. of Patients Treated Phase 1All phases of CML; Ph+ ALL 84 Phase 2, Two- arm, randomized CP CML36

10 Study Design - 1 The 4 multicenter, international, Phase 2 trials to evaluate efficacy and safety were single-arm. Minimum follow-up is 6 months after the start of therapy, but patients will be followed for 24 months. Primary efficacy endpoint in CP CML is major cytogenetic response (MCyR),defined as CCyR (0% Ph+ cells) + PCyR (1-35% Ph+ cells) at 12 weeks.

11 Study Design - 2 Primary efficacy endpoint in advanced phases of CML and in ALL is major hematologic response (MaHR), defined as – Complete Hematologic Response, or –No Evidence of Leukemia. Secondary endpoints include median durations of responses.

12 Dose Finding Sponsor’s recommended dose for Phase 2 studies of 70 mg b.i.d. was determined on the basis of cytogenetic and hematologic responses, not on the basis of maximally tolerated dose (MTD).

13 Dose Response in CP CML - MCyR Total Daily DoseNo. responses/ No. treated % with Responses 15 mg0/3 0% 30 mg1/333% 50 mg1/617% mg3/1030% mg6/6100% 140 mg6/967% 180 mg1/333%

14 Dose Response in Advanced Phases of CML and Ph+ ALL - MaHR Total Daily DoseNo. responses/ No. treated % with Responses 35 mg b.i.d.0/1 0% 50 mg b.i.d.3/838% 70 mg b.i.d.5/1729% 90 mg b.i.d.2/1118% 120 mg b.i.d.1/714%

15 Comment on Recommended Dose These response data suggest that 50 mg b.i.d. may result in similar response rates as 70 mg b.i.d. in both chronic phase and advanced phases patients.

16 Populations Studied in Single-Arm Trials CP CML N = 186 AP CML N = 107 MB CML N = 74 LB CML N = 42 Ph+ ALL N = 36 Median time since Dx 64 months91 months49 months28 months20 months Imatinib >3 yr >1 yr 54% 80% 68% 92% 47% 85% 24% 52% 3% 56% % Bone marrow transplant 9%18%12%33%42%

17 Dasatinib treatment Starting dose: 70 mg b.i.d. Duration of treatment in months, median (range), at the time of data cut-off. –CP CML 5.6 (0.03 – 8.3) –AP CML 5.5 (0.2 – 10.1) –MB CML 3.5 (0.03 – 9.2) –LB CML2.8 (0.1 – 6.4) –Ph+ ALL3.2 (0.2 – 8.1)

18 Response Rates in CP CML EndpointCP CML MCyR rate (95% CI) 45% (37% - 52%) Median duration (months) Not reached* CHR rate (95% CI) 90% (85% - 94%) *100% of responders in response at F/U.

19 Response Rates in Advanced Phases of CML and in Ph+ ALL EndpointAP CMLMB CMLLB CMLPh+ ALL MaHR rate (95% CI) 59% (49% - 68%) 32% (22% - 44%) 31% (18% - 47%) 42% (26% - 59%) Median duration (95% CI) Not reached * Not reached* 3.7 months (2.8, not reached) 4.8 months (2.9, not reached) MCyR rate (95% CI) 31% (22% - 41%) 30% (20% - 42%) 50% (34% - 66%) 58% (41% - 75%) * % of responders in response at F/U

20 Responses in Imatinib Resistant and Imatinib Intolerant Populations Disease Phase (endpoint) ResistantIntolerant Chronic (MCyR)62/181 (34%)49/67 (73%) Accelerated (MaHR)62/106 (58%) 7/12 (58%) Myeloid Blast CML (MaHR) 30/90 (33%) 1/7 (14%) Lymphoid Blast CML (MaHR) 14/41 (34%) 2/6 (33%) Ph+ ALL (MaHR) 14/39 (36%) 2/2 (100%) Total (all phases)182/457 (40%)61/94 (65%)

21 Efficacy Conclusions - 1 Dasatinib treatment results in major hematologic and cytogenetic responses in patients with all phases of CML and with Ph+ ALL who are imatinib resistant or intolerant. Responses occur within the first 3 months and appear to be durable. Median durations of responses are 4-5 months in LB CML and Ph+ ALL. Median durations are longer in CP, AP, and MB CML, but the F/U is too short for estimates.

22 Efficacy Conclusions mg b.i.d. is an effective dose, but lower doses also result in responses. Among CP CML patients, imatinib intolerant patients have higher response rates than imatinib resistant patients. Too few imatinib intolerant patients with other phases of CML and with ALL were enrolled to make a comparison.

23 Safety Population Patients who received a starting dose of 70 mg b.i.d. All patients treated on the four single-arm phase 2 studies All patients initially treated with dasatinib on the randomized phase 2 study All patients who received a starting dose of 70 mg bid on the phase 1 study

24 Safety Population 214 chronic phase (CP) patients 110 accelerated phase (AP) patients 84 myeloid blast phase (MB) patients 81 lymphoid blast phase (LB) and Ph + ALL patients

25 Duration of Exposure < 3 months: 32% 3 months to 6 months: 57% > 6 months: 11%

26 Dose Adjustments Disease PhaseDose ReductionInterruption CP50%82% AP45%73% MB35%74% LB11%57% Ph + ALL30%68%

27 Common Treatment-Emergent Adverse Events Adverse EventAll Grades (%)Grade 3/4 (%) Diarrhea475 Pyrexia397 Headache383 Fatigue343 Nausea312 Dyspnea296 Rash/Exanthem291 Peripheral Edema260.2 Abdominal Pain252 NCI CTCAE v. 3.0

28 Common Treatment-Emergent Adverse Events Adverse EventAll Grades (%)Grade 3/4 (%) Cough241 Asthenia224 Vomiting221 Thrombocytopenia1817 Pleural Effusion174 Anorexia151 Weight Decreased141 Bone Pain132 Pain in Extremity120.4 Constipation120.2

29 Common Treatment-Emergent Adverse Events Adverse EventAll Grades (%)Grade 3/4 (%) Epistaxis111 Arthralgia111 Anemia117 Dizziness110.2 Myalgia111 Neutropenia1110 Neutropenic Fever10 Petechiae100.2 Weight Increased100 Chills100.2

30 Hypocalcemia –Baseline 8-30%; Grade 3/4 ≤ 1% –On treatment 46-80%; Grade 3/4 4-22% No muscle spasms attributable to hypocalcemia One seizure in a patient w/ grade 3 hypocalcemia, documented CNS disease

31 Grade 3/4 Hematologic Laboratory Abnormalities Disease PhaseNeutropeniaThrombocytopeniaAnemia Chronic --At Baseline --On Treatment 2% 45% 2% 46% 2% 18% Accelerated --At Baseline --On Treatment 7% 76% 23% 79% 5% 66% Myeloid Blast --At Baseline --On Treatment 24% 79% 45% 82% 15% 66% LB/ Ph + ALL --At Baseline --On Treatment 33% 76% 58% 78% 3% 49%

32 Bleeding Events Any GradeGrade 3/4Grade 5 Any34%10%1% Epistaxis11%1%0% Gastrointestinal10%6%0% CNS1%0.2%1%

33 CNS Hemorrhage 5/6 in blast phase/ALL 1/6 in CP Platelet counts ranged from 1,000-56,000 One event associated with a head injury One subdural hematoma resolved following surgical intervention

34 QTc prolongation QTc prolongation reported as an AE in 9 patients An additional 7 had treatment-emergent QTcB ≥ 500 msec Two patients were reported to have non- sustained ventricular tachycardia There were no reports of torsades de pointes

35 Cardiac Failure 20 patients (4%) had an event 12/20 (60%) had a prior cardiac history One death was attributed to cardiac failure Action: –Dose interruption (9) –Drug discontinuation (4) –Dose reduction (1) –None (6)

36 Fluid Retention Other Than CHF EventAll Grades (%)Grade 3/4 (%) Peripheral Edema260.2 Pleural Effusion175 Periorbital Edema70 Face Edema40 Pericardial Effusion 40.4 Pulmonary Edema30.4

37 Safety Summary GI toxicity was common across all phases of disease Fluid retention events including edema and effusions were common Grade 3/4 myelosuppression increased with dasatinib use 4% experienced cardiac failure 3% had treatment-emergent QTc prolongation as an AE or on ECG Approximately one-third had bleeding events of any type; 5 of 6 fatal events were intracranial

38 FDA Summary of Dasatinib NDA 31-59% achieved responses in CML/ Ph + ALL Responses also seen at lower doses in a limited number of phase 1 patients Median response duration has not been reached for most studies due to limited follow-up Common adverse events include GI, fluid retention, bleeding; myelosuppression was also common Most patients required dose interruptions and/or reductions Due to clear evidence of activity, on February 6, 2006, an expanded access program was initiated