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Diuretic Treatment of Edema – Week 24 Pbo N = 528 Any Mura ≤ 5 mg N = 1743 Any Pio N = 572 Edema Events, n 3522051 Diuretic use (n) % 5 (14.3) 52 (23.6)

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Presentation on theme: "Diuretic Treatment of Edema – Week 24 Pbo N = 528 Any Mura ≤ 5 mg N = 1743 Any Pio N = 572 Edema Events, n 3522051 Diuretic use (n) % 5 (14.3) 52 (23.6)"— Presentation transcript:

1 Diuretic Treatment of Edema – Week 24 Pbo N = 528 Any Mura ≤ 5 mg N = 1743 Any Pio N = 572 Edema Events, n 3522051 Diuretic use (n) % 5 (14.3) 52 (23.6) 12 (23.5) Phase 3 Short-term 3 - 3 - 42

2 Heart Failure vs. Edema Incidence of Heart Failure Patients with Finding n/N (%) Patients without Finding n/N (%) Edema during study 20/615 (3.3%) 10/2354 (0.4%) Edema at baseline 3/198 (1.5%) 27/2771 (1.0%) History of edema † 4/209 (1.9%) 9/1529 (0.6%) † Data available for phase 3 only Phase 2 and 3 Short-term and Long-term 4 - 54

3 Subjects Referred to Urologic Consultation (N = 89) Microscopic Hematuria – Urology Consultations Completed Consultation (N = 85) Did Not Complete Consultation (N = 4):  3 refused consultation  1 discontinued early from study Normal Consults (N = 41) Clinical Findings (N = 44):  Kidney stones (N = 11)  Infections (N = 9)  Prostate disease (N = 5)  Inflammation (N = 5)  Bladder cancer (N = 2) †  More than 1 finding (N = 4)  Miscellaneous (N = 8) †† Phase 2 and 3 Short-term and Long-term † † 2 additional bladder cancers (recurrences) † † † † e.g. Pyuria, suture materials, urethral obstruction, cystic cystitis 3 - 1 - 12

4 Pbo N = 528 Mura 2.5 mg N = 535 Mura 5 mg N = 512 Calcium Oxalate Baseline incidence On-study incidence 18.8% 14.4% 16.9% 15.3% 16.3% 13.1% Triple Phosphate Baseline incidence On-study incidence 0.8% 0.2% 0 0.8% 0.2% 0 Amorphous Phosphate Baseline incidence On-study incidence 0.6% 0 0.4% 1.0% 0.8% 1.0% Urine Crystals: Baseline and On-study Incidence - 24 Weeks % of Subjects 018, 021ST, 022ST pooled Placebo-controlled Studies, Short-term 3 - 1 - 9

5 Any Pbo N = 528 Mura ≤ 5 mg N = 2636 Any Mura N = 3122 Any Pio ≤ 45 mg N = 823 Urolithiasis 21.23 (n = 7) 8.40 (n = 21) 8.10 (n = 28) 9.13 (n = 7) Urolithiasis Incidence Incidence per 1,000 patient-years (n) Phase 2 and 3 Short-term and Long-term 3 - 1 - 14

6 Summary – Bladder Cancer 4 cases (2 on Mura, 2 on Pio) u 2 recurrent cases –Mura 10 mg – onset D58 –Pio 15 / 45 mg – onset D256 u 2 new-onset cases –Mura 10 mg – onset D573 Relevant PMH: microscopic hematuria at baseline, smoking historyRelevant PMH: microscopic hematuria at baseline, smoking history –Pio 30 mg – onset D170 Relevant PMH: foundry, carpet warehouse workerRelevant PMH: foundry, carpet warehouse worker u Males, age range 62-71 years u 2 subjects with history of smoking u 3 cases identified as superficial or non-invasive Phase 2 and 3 Short-term and Long-term 3 - 1 - 17

7 Observed and Expected Incidence Rates for Bladder Cancer a PharMetrics Research Database – Integrated claims from 2000-2003 Incidence per 1000 patient-years (95% CI) Any Muraglitazar Observed Rate PharMetrics Expected Rate PharMetrics a Expected Rate Bladder0.57 (0.16-2.09)0.55 (0.48-0.65) Phase 2 and 3 Short-term and Long-term 3 - 1 - 15

8 Change from Baseline in A1C by Quartiles of Change from Baseline in Weight at Week 24 (LOCF) ≤ 0 1278.47 0 – 2.0 938.69 2.0 – 4.1 1078.66>4.11089.0 -1.24 -1.23 -1.50 -2.11 Monotherapy Studies  B/L in Weight (kg) n = Baseline Mean (%)  A1C (%) With 95% CI Muraglitazar 5 mg 006 ST, 018 ST + OL 3 - 5 - 20

9 In db/db Mice, Muraglitazar Improves Insulin Sensitivity, Increases Insulin Content in the Pancreas u db/db mice (~10 week old) were treated for 2 weeks; Animals were overnight fasted. * p < 0.05 vs vehicle Pancreas – Insulin Insulin (ng/mL) Glucose (mg/dL) Minutes After Glucose Administration oGTT 8 - 27

10 Muraglitazar Prevents Loss of Pancreatic Islet Insulin Content in Pre-Diabetic db/db Mice u ~ 5 week old db/db mice were treated for 12 weeks; Insulin staining after 8 weeks u Animals were fasted overnight. *p <0.05 vs vehicle Vehicle Mura (10 mg/kg) Insulin (pancreas) Insulin (islet) 8 - 30

11 Plot of Mean Change from Baseline in A1C at Week 24 (LOCF) by Race 1g - 1

12 Plot of Mean Change from Baseline in A1C at Week 24 (LOCF) by Ethnicity Study CV168006 CV168018 CV168021 CV168022 CV168025 Dose Mura 5 Mura 2.5 Mura 5 Mura 2.5 + Gly Mura 5 + Gly Mura 2.5 + Met Mura 5 + Met Hispanic/ Latino Non- Hispanic/ Latino Change from Baseline A1C (%) -2.0-1.5-0.50.00.5 1h - 1

13 Number (%) of Subjects Reporting Edema AEs by Subgroup Subgroup Any Pbo N = 528 Any Mura ≤ 5 mg N = 2374 Any Pio ≤ 45 mg N = 823 Age, n (%) < 65 years < 65 years  65 years  65 years30/4611/67(6.5) (1.5) (1.5)200/201140/363 (9.9) (11.0) (9.9) (11.0)72/7115/112 (10.1) (10.1) (4.5) (4.5) Gender, n (%) MaleFemale11/27320/255 (4.0) (4.0) (7.8) (7.8)111/1272129/1102 (8.7) (8.7) (11.7) (11.7)29/42548/398 (6.8) (6.8) (12.1) (12.1) Race, n (%) White Black BlackOther25/4503/343/44 (5.6) (5.6) (8.8) (8.8) (6.8) (6.8)202/201225/17213/190 (10.0) (10.0) (14.5) (14.5) (6.8) (6.8)67/7188/592/46 (9.3) (9.3) (13.6) (13.6) (4.3) (4.3) Phase 2 and 3, Short-term 1g - 3

14 Mean Hemoglobin Levels Over Time – Week 24 Dose-Ranging Study Study 006 ST Week Hemoglobin (g/dL) Mura 0.5 mgMura 1.5 mgMura 5 mg Pio 15 mgMura 10 mgMura 20 mg 3 - 7 - 25

15 AEs of Anemia – 24 Weeks u 1 SAE of anemia on muraglitazar 5 mg (GI bleeding) u 1 SAE of anemia on pioglitazone 30 mg (gastric bleeding) u 2 subjects on muraglitazar were discontinued due to anemia Any Pbo N = 528 Mura ≤ 5 mg N = 2374 Any Pio N = 823 Anemia AEs, n (%) 2 (0.4)15 (0.6)5 (0.6) Phase 2 and 3, Short-term 3 - 7 - 32

16 Change from Baseline in ANC at Week 24 Study 006 ST Neutrophils (Absolute) (x 10*3 c/μL) 0.5 mg N = 104 1.5 mg N = 136 5 mg N = 152 10 mg N = 174 20 mg N = 157 Pio 15 mg N = 125 Baseline3.834.013.983.884.003.91 Change from Baseline Mean (SD) Mean (SD) -0.18 (1.08) -0.13 (1.19) -0.40 (1.09) -0.81 (1.06) -1.10 (1.22) -0.11 (0.86) Dose-Ranging Study Muraglitazar 3 - 7 - 5

17 Any Pbo Any Mura  5 mg Mura 10 mg Any Pio  45 mg Number of Subjects with Data 5192333245811 ANC < 1000 on at Least 2 Consecutive Visits 1 (0.2%) 1 (0.2%) 3 (0.1%) 3 (0.1%) 1 (0.4%) 1 (0.4%) 0 Number (%) of Subjects with ANC < 1000 on 2 Consecutive Visits u No cases were associated with clinical sequelae u 2 subjects on muraglitazar discontinued Phase 2 and 3 ST + 006 LT 3 - 7 - 2

18 CV Mortality in Combination Therapy Studies Muraglitazar Cox Model Trend Test Study Pbo / Pio 2.5 mg 5 mg 021 8.1 (1) 0 4.8 (1) – 0220 3.8 (1) 4.2 (1) – 021 + 022 3.5 (1) 2.1 (1) 4.3 (2) P = 0.739 HR–0.611.32 0250– 10.7 (5) 021 + 022 + 025 1.4 (1) 2.1 (1) 7.65 (7) P = 0.074 HR–2.05.87 Events / 1000 PY Exposure (n) HR = hazard ratio relative to Pbo / Pio. SA - 39

19 Cardiovascular Risk Factors in Subjects with and without a CV Event With CV EventWithout CV Event N = 123N = 4197 % Hypertension6955 Previous MI164 Coronary Artery Disease (CAD)165 Stable Angina124 Percutaneous Coronary Intervention112 Unstable Angina (Hospitalization)81 Carotid Artery Disease71 Coronary Artery Bypass Graft (CABG)62 Peripheral Vascular Disease52 Congestive Heart Failure41 Peripheral Vascular Surgery21 Transient Ischemic Attack (TIA)21 Carotid Endarterectomy or Stenting2<1 Cerebrovascular Accident (CVA)22 3 - 11 - 54

20 Cardiovascular Risk Factors at Baseline in Subjects with and without a CV Event With CV EventWithout CV Event N = 123N = 4197 % Gender: Male7153 Gender: Female2947 Race: Caucasian85 Race: Black57 Race: Other118 Smoking: Current2819 Family History CHD3624 SBP  130 6150 DBP  80 5056 BMI  30 kg/m 2 5458 Waist circ > 40 inches male & > 35 inches female6370 A1C  7.0% 90 Total Cholesterol  200 mg/dL 3948 HDL Chol  40 mg/dL male &  50 mg/dL female 6257 LDL Cholesterol  100 mg/dL 6369 Triglycerides  150 mg/dL 6358 hs-CRP  3 mg/L 3538 3 - 11 - 55


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