Diuretic Treatment of Edema – Week 24Diuretic Treatment of Edema – Week 24
PboPboN = 528N = 528
Any MuraAny Mura ≤ 5 mg≤ 5 mg
N = 1743N = 1743Any PioAny PioN = 572N = 572
Edema Events, nEdema Events, n 3535 220220 5151
Diuretic useDiuretic use(n) %(n) % 5 (14.3)5 (14.3) 52 (23.6)52 (23.6) 12 (23.5)12 (23.5)
Phase 3 Short-termPhase 3 Short-term
3 - 3 - 42
Heart Failure vs. EdemaHeart Failure vs. Edema
Incidence of Heart FailureIncidence of Heart Failure
PatientsPatientswith Findingwith Finding
n/N (%)n/N (%)
PatientsPatientswithout Findingwithout Finding
n/N (%)n/N (%)
Edema during studyEdema during study 20/615 (3.3%)20/615 (3.3%) 10/2354 (0.4%)10/2354 (0.4%)
Edema at baselineEdema at baseline 3/198 (1.5%)3/198 (1.5%) 27/2771 (1.0%)27/2771 (1.0%)
History of edemaHistory of edema†† 4/209 (1.9%)4/209 (1.9%) 9/1529 (0.6%)9/1529 (0.6%)
††Data available for phase 3 onlyData available for phase 3 only
Phase 2 and 3 Short-term and Long-termPhase 2 and 3 Short-term and Long-term
4 - 54
Subjects Referred to Urologic Subjects Referred to Urologic Consultation (N = 89)Consultation (N = 89)
Microscopic Hematuria – Urology ConsultationsMicroscopic Hematuria – Urology Consultations
Completed Consultation (N = 85)Completed Consultation (N = 85)Did Not Complete Consultation (N = 4):Did Not Complete Consultation (N = 4): 3 refused consultation3 refused consultation 1 discontinued early from study1 discontinued early from studyNormal Consults Normal Consults
(N = 41)(N = 41)
Clinical Findings (N = 44):Clinical Findings (N = 44): Kidney stones (N = 11)Kidney stones (N = 11) Infections (N = 9)Infections (N = 9) Prostate disease (N = 5)Prostate disease (N = 5) Inflammation (N = 5)Inflammation (N = 5) Bladder cancer (N = 2)Bladder cancer (N = 2)††
More than 1 finding (N = 4)More than 1 finding (N = 4) Miscellaneous (N = 8)Miscellaneous (N = 8)††††
Phase 2 and 3 Short-term and Long-termPhase 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
PboPboN = 528N = 528
Mura 2.5 mgMura 2.5 mgN = 535N = 535
Mura 5 mgMura 5 mgN = 512N = 512
Calcium OxalateCalcium OxalateBaseline incidenceBaseline incidenceOn-study incidenceOn-study incidence
18.8% 18.8% 14.4%14.4%
16.9%16.9%15.3%15.3%
16.3% 16.3% 13.1%13.1%
Triple PhosphateTriple Phosphate Baseline incidenceBaseline incidence
On-study incidenceOn-study incidence0.8% 0.8% 0.2%0.2%
000.8%0.8%
0.2% 0.2% 00
Amorphous PhosphateAmorphous PhosphateBaseline incidenceBaseline incidenceOn-study incidenceOn-study incidence
0.6% 0.6% 00
0.4% 0.4% 1.0%1.0%
0.8% 0.8% 1.0%1.0%
Urine Crystals: Baseline and On-study Incidence -Urine Crystals: Baseline and On-study Incidence -24 Weeks 24 Weeks
% of Subjects% of Subjects
018, 021ST, 022ST pooled018, 021ST, 022ST pooled
Placebo-controlled Studies, Short-termPlacebo-controlled Studies, Short-term
3 - 1 - 9
Any PboAny PboN = 528N = 528
Mura Mura ≤ 5 mg ≤ 5 mg N = N =
26362636Any MuraAny MuraN = 3122N = 3122
Any Pio Any Pio ≤ 45 mg≤ 45 mgN = 823N = 823
UrolithiasisUrolithiasis 21.2321.23(n = 7)(n = 7)
8.40 8.40 (n = 21)(n = 21)
8.10 8.10 (n = 28)(n = 28)
9.13 9.13 (n = 7)(n = 7)
Urolithiasis IncidenceUrolithiasis Incidence
Incidence per 1,000 patient-years Incidence per 1,000 patient-years (n)(n)
Phase 2 and 3 Short-term and Long-termPhase 2 and 3 Short-term and Long-term
3 - 1 - 14
Summary – Bladder CancerSummary – Bladder Cancer
4 cases (2 on Mura, 2 on Pio)4 cases (2 on Mura, 2 on Pio) 2 recurrent cases 2 recurrent cases
– Mura 10 mg – onset D58Mura 10 mg – onset D58
– Pio 15 / 45 mg – onset D256Pio 15 / 45 mg – onset D256
2 new-onset cases2 new-onset cases
– Mura 10 mg – onset D573Mura 10 mg – onset D573
• Relevant PMH: microscopic hematuria at baseline, Relevant PMH: microscopic hematuria at baseline, smoking historysmoking history
– Pio 30 mg – onset D170Pio 30 mg – onset D170
• Relevant PMH: foundry, carpet warehouse workerRelevant PMH: foundry, carpet warehouse worker
Males, age range 62-71 yearsMales, age range 62-71 years
2 subjects with history of smoking2 subjects with history of smoking
3 cases identified as superficial or non-invasive3 cases identified as superficial or non-invasive
Phase 2 and 3 Short-term and Long-termPhase 2 and 3 Short-term and Long-term
3 - 1 - 17
Observed and Expected Incidence Rates for Bladder CancerObserved and Expected Incidence Rates for Bladder Cancer
aPharMetrics Research Database – Integrated claims from 2000-2003
Incidence per 1000 Incidence per 1000 patient-years (95% CI)patient-years (95% CI)
Any Muraglitazar Any Muraglitazar Observed RateObserved Rate
PharMetricsPharMetricsa
Expected RateExpected Rate
Bladder 0.57 (0.16-2.09) 0.55 (0.48-0.65)
Phase 2 and 3 Short-term and Long-termPhase 2 and 3 Short-term and Long-term
3 - 1 - 15
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
Change from Baseline in A1C by Quartiles of Change Change from Baseline in A1C by Quartiles of Change from Baseline in Weight at Week 24 (LOCF)from Baseline in Weight at Week 24 (LOCF)
≤ ≤ 001271278.478.47
0 – 2.00 – 2.09393
8.698.69
2.0 – 4.12.0 – 4.11071078.668.66
>4.1>4.11081089.09.0
-1.24 -1.23
-1.50
-2.11
Monotherapy StudiesMonotherapy Studies
B/L in Weight (kg)B/L in Weight (kg)n =n =
Baseline Mean (%)Baseline Mean (%)
A1C (%)A1C (%)WithWith
95% CI95% CI
Muraglitazar 5 mgMuraglitazar 5 mg
006 ST, 018 ST + OL006 ST, 018 ST + OL 3 - 5 - 20
0
30
60
90
120
150
Vehicle Mura 10mg/kg
U/g
ram
*
0
5
10
15
20
25
0 15 30 60 90
**
Vehicle
MURA
0
200
400
600
800
1000
1200
1400
0 15 30 60 90
**
*
**
Vehicle
MURA
In In db/dbdb/db Mice, Muraglitazar Improves Insulin Mice, Muraglitazar Improves Insulin Sensitivity, Increases Insulin Content in the PancreasSensitivity, Increases Insulin Content in the Pancreas
db/dbdb/db mice (~10 week old) were treated for mice (~10 week old) were treated for2 weeks2 weeks; Animals were overnight fasted.; Animals were overnight fasted.* p < 0.05 vs vehicle* p < 0.05 vs vehicle
Pancreas – Insulin
Insu
lin(n
g/m
L)
Glu
cose
(mg
/dL
)
Minutes After Glucose Minutes After Glucose AdministrationAdministration
oGTToGTT
8 - 27
0
5
10
15
20
25
30
35
40
Vehicle 1 3 10
MURA (mg/kg)
U/g
pan
crea
s
Week 4
Week 8
Week 12
*
*
*
*
**
Muraglitazar Prevents Loss of Pancreatic Islet Muraglitazar Prevents Loss of Pancreatic Islet Insulin Content in Pre-Diabetic Insulin Content in Pre-Diabetic db/dbdb/db Mice Mice
~ 5 week old ~ 5 week old db/dbdb/db mice were treated for mice were treated for 12 weeks12 weeks; ; Insulin staining after 8 weeks Insulin staining after 8 weeks
Animals were fasted overnight. *Animals were fasted overnight. *pp <0.05 vs vehicle <0.05 vs vehicle
Vehicle
Mura (10 mg/kg)
Insulin (pancreas) Insulin (islet)
8 - 30
Plot of Mean Change from Baseline in A1C Plot of Mean Change from Baseline in A1C at Week 24 (LOCF) by Raceat Week 24 (LOCF) by Race
-2.0 -1.5 -1.0 -0.5 0.0 0.5
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
Mura 5 + Met
White
Black
Other
Change from Baseline A1C (%)Change from Baseline A1C (%) 1g - 1
Plot of Mean Change from Baseline in A1C Plot of Mean Change from Baseline in A1C at Week 24 (LOCF) by Ethnicityat 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
Mura 5 + Met
Hispanic/Latino
Non-Hispanic/Latino
Change from Baseline A1C (%)Change from Baseline A1C (%)
-2.0 -1.5 -1.0 -0.5 0.0 0.5
1h - 1
Number (%) of Subjects Reporting Edema AEs by SubgroupNumber (%) of Subjects Reporting Edema AEs by Subgroup
SubgroupSubgroupAny PboAny PboN = 528N = 528
Any MuraAny Mura≤ ≤ 5 mg5 mg
N = 2374N = 2374
Any PioAny Pio≤ ≤ 45 mg45 mgN = 823N = 823
Age, n (%)Age, n (%)
< 65 years< 65 years
65 years65 years
30/46130/461
1/671/67
(6.5)(6.5)
(1.5)(1.5)
200/2011200/2011
40/36340/363 (9.9) (9.9) (11.0)(11.0)
72/71172/711
5/1125/112
(10.1)(10.1)
(4.5)(4.5)
Gender, n (%)Gender, n (%)
MaleMale
FemaleFemale
11/27311/273
20/25520/255
(4.0)(4.0)
(7.8)(7.8)
111/1272111/1272
129/1102129/1102
(8.7)(8.7)
(11.7)(11.7)
29/42529/425
48/39848/398
(6.8)(6.8)
(12.1)(12.1)
Race, n (%)Race, n (%)
WhiteWhite
BlackBlack
OtherOther
25/45025/450
3/343/34
3/443/44
(5.6)(5.6)
(8.8)(8.8)
(6.8)(6.8)
202/2012202/2012
25/17225/172
13/19013/190
(10.0)(10.0)
(14.5)(14.5)
(6.8)(6.8)
67/71867/718
8/598/59
2/462/46
(9.3)(9.3)
(13.6)(13.6)
(4.3)(4.3)
Phase 2 and 3, Short-termPhase 2 and 3, Short-term
1g - 3
Mean Hemoglobin Levels Over Time – Week 24Mean Hemoglobin Levels Over Time – Week 24PROTOCOL: CV168 FDA AD COM
Draft XXX:Mean Hemoglobin Levels Over Time
CV168006 ST Phase
PROGRAM SOURCE: /WWBDM/CLIN/PROJ/CV/168/FDA_ADV/DEV/STATS/PLOT_ADCOM_LAB_006ST.SAS 10-JUN-2005 09:30Dataset: Treated Subjects
Treatment MUR 0.5 MUR 1.5 MUR 5 MUR 10 MUR 20 PIO 15
Hem
oglo
bin
(g/d
L)
13.0
13.2
13.4
13.6
13.8
14.0
14.2
14.4
14.6
14.8
15.0
Week0 4 8 12 16 20 24
Dose-Ranging StudyDose-Ranging Study
Study 006 STStudy 006 ST
WeekWeek
Hem
og
lob
in (
g/d
L)
Hem
og
lob
in (
g/d
L)
Mura 0.5 mg Mura 1.5 mg Mura 5 mg
Pio 15 mgMura 10 mg Mura 20 mg
3 - 7 - 25
AEs of Anemia – 24 WeeksAEs of Anemia – 24 Weeks
1 SAE of anemia on muraglitazar 5 mg (GI bleeding)1 SAE of anemia on muraglitazar 5 mg (GI bleeding)
1 SAE of anemia on pioglitazone 30 mg (gastric bleeding)1 SAE of anemia on pioglitazone 30 mg (gastric bleeding)
2 subjects on muraglitazar were discontinued due to anemia2 subjects on muraglitazar were discontinued due to anemia
Any PboAny PboN = 528N = 528
Mura Mura ≤ 5 mg≤ 5 mgN = 2374N = 2374
Any PioAny PioN = 823N = 823
Anemia AEs, n (%)Anemia AEs, n (%) 2 (0.4) 15 (0.6) 5 (0.6)
Phase 2 and 3, Short-termPhase 2 and 3, Short-term
3 - 7 - 32
Change from Baseline in ANC at Week 24Change from Baseline in ANC at Week 24
Study 006 STStudy 006 ST
NeutrophilsNeutrophils(Absolute)(Absolute)(x 10*3 c/(x 10*3 c/μμL)L)
0.5 mg0.5 mgN = 104N = 104
1.5 mg1.5 mgN = 136N = 136
5 mg5 mgN = 152N = 152
10 mg10 mgN = 174N = 174
20 mg20 mgN = 157N = 157
PioPio15 mg15 mg
N = 125N = 125
BaselineBaseline 3.83 4.01 3.98 3.88 4.00 3.91
Change from BaselineChange from Baseline
MeanMean (SD) (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 StudyDose-Ranging Study
MuraglitazarMuraglitazar
3 - 7 - 5
Any PboAny Pbo
Any MuraAny Mura 5 mg 5 mg
MuraMura10 mg10 mg
Any PioAny Pio 45 45 mgmg
Number of SubjectsNumber of Subjectswith Datawith Data 519519 23332333 245245 811811
ANC < 1000 on at Least ANC < 1000 on at Least 2 Consecutive Visits2 Consecutive Visits 1 (0.2%)1 (0.2%) 3 (0.1%)3 (0.1%) 1 (0.4%)1 (0.4%) 00
Number (%) of Subjects with ANC < 1000Number (%) of Subjects with ANC < 1000on 2 Consecutive Visitson 2 Consecutive Visits
No cases were associated with clinical sequelaeNo cases were associated with clinical sequelae
2 subjects on muraglitazar discontinued2 subjects on muraglitazar discontinued
Phase 2 and 3 ST + 006 LTPhase 2 and 3 ST + 006 LT 3 - 7 - 2
CV Mortality in Combination Therapy StudiesCV Mortality in Combination Therapy Studies
MuraglitazarCox ModelCox ModelTrend TestTrend TestStudyStudy Pbo / PioPbo / Pio 2.5 mg2.5 mg 5 mg5 mg
021021 8.1 (1)8.1 (1) 00 4.8 (1)4.8 (1) ––
022022 00 3.8 (1)3.8 (1) 4.2 (1)4.2 (1) ––
021 + 022021 + 022 3.5 (1)3.5 (1) 2.1 (1)2.1 (1) 4.3 (2)4.3 (2) P = 0.739P = 0.739
HRHR –– 0.610.61 1.321.32
025025 00 –– 10.7 (5)10.7 (5)
021 + 022 + 025021 + 022 + 025 1.4 (1)1.4 (1) 2.1 (1)2.1 (1) 7.65 (7)7.65 (7) P = 0.074P = 0.074
HRHR –– 2.02.0 5.875.87
Events / 1000 PY Exposure (n)
HR = hazard ratio relative to Pbo / Pio. SA - 39
Cardiovascular Cardiovascular Risk Factors in Subjects with and Risk Factors in Subjects with and without a CV Event without a CV Event
With CV Event Without CV Event
N = 123 N = 4197
% %Hypertension 69 55
Previous MI 16 4
Coronary Artery Disease (CAD) 16 5
Stable Angina 12 4
Percutaneous Coronary Intervention 11 2
Unstable Angina (Hospitalization) 8 1
Carotid Artery Disease 7 1
Coronary Artery Bypass Graft (CABG) 6 2
Peripheral Vascular Disease 5 2
Congestive Heart Failure 4 1
Peripheral Vascular Surgery 2 1
Transient Ischemic Attack (TIA) 2 1
Carotid Endarterectomy or Stenting 2 <1
Cerebrovascular Accident (CVA) 2 2
3 - 11 - 54
Cardiovascular Risk Factors at Baseline in Subjects Cardiovascular Risk Factors at Baseline in Subjects with and without a CV Eventwith and without a CV Event
With CV Event Without CV Event
N = 123 N = 4197% %
Gender: Male 71 53Gender: Female 29 47Race: Caucasian 85 85Race: Black 5 7Race: Other 11 8Smoking: Current 28 19Family History CHD 36 24SBP 130 61 50DBP 80 50 56BMI 30 kg/m2 54 58Waist circ > 40 inches male & > 35 inches female 63 70A1C 7.0% 90 90Total Cholesterol 200 mg/dL 39 48
HDL Chol 40 mg/dL male & 50 mg/dL female 62 57LDL Cholesterol 100 mg/dL 63 69Triglycerides 150 mg/dL 63 58hs-CRP 3 mg/L 35 38
3 - 11 - 55
