# Presentation: 737901

## Diuretic Treatment of Edema – Week 24

|  | Pbo
N = 528 | Any Mura ≤ 5 mgN = 1743 | Any Pio
N = 572 |
| --- | --- | --- | --- |
| Edema Events, n | 35 | 220 | 51 |
| Diuretic use(n) % | 5 (14.3) | 52 (23.6) | 12 (23.5) |

- Phase 3 Short-term

- 3 - 3 - 42

## 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

## Microscopic Hematuria – Urology Consultations

**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

## Urine Crystals: Baseline and On-study Incidence -24 Weeks 

|  |  | 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

## Urolithiasis Incidence

|  | 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

## Summary – Bladder Cancer

**4 cases (2 on Mura, 2 on Pio)**
**2 recurrent cases **
**Mura 10 mg – onset D58**
**Pio 15 / 45 mg – onset D256**
**2 new-onset cases**
**Mura 10 mg – onset D573**
**Relevant PMH: microscopic hematuria at baseline, smoking history**
**Pio 30 mg – onset D170**
**Relevant PMH: foundry, carpet warehouse worker**
**Males, age range 62-71 years**
**2 subjects with history of smoking**
**3 cases identified as superficial or non-invasive**

- Phase 2 and 3 Short-term and Long-term

- 3 - 1 - 17

## Observed and Expected Incidence Rates for Bladder Cancer

- aPharMetrics Research Database – Integrated claims from 2000-2003

| Incidence per 1000 patient-years (95% CI) | Any Muraglitazar Observed Rate |  | PharMetricsaExpected Rate  |
| --- | --- | --- | --- |
| Bladder | 0.57 (0.16-2.09) |  | 0.55 (0.48-0.65) |

- Phase 2 and 3 Short-term and Long-term

- 3 - 1 - 15

## Change from Baseline in A1C by Quartiles of Change from Baseline in Weight at Week 24 (LOCF)

**Change from Baseline in A1C by Quartiles of Change from Baseline in Weight at Week 24 (LOCF)**

**≤ ****0**
**127**
**8.47**

**0 – 2.0**
**93**
**8.69**

**2.0 – 4.1**
**107**
**8.66**

**>4.1**
**108**
**9.0**

**-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

## In db/db Mice, Muraglitazar Improves Insulin   Sensitivity, Increases Insulin Content in the Pancreas

**In *****db/db***** Mice, Muraglitazar Improves Insulin   Sensitivity, Increases Insulin Content in the Pancreas**

* **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

## Muraglitazar Prevents Loss of Pancreatic Islet Insulin Content in Pre-Diabetic db/db Mice

**Muraglitazar Prevents Loss of Pancreatic Islet Insulin Content in Pre-Diabetic *****db/db***** Mice**

- ~ 5 week old *db/db* mice were treated for _12 weeks_;   Insulin staining after 8 weeks
- Animals were fasted overnight. **p* <0.05 vs vehicle

**Vehicle **

**Mura **
- (10 mg/kg)

**Insulin **(pancreas)

**Insulin **(islet)

- 8 - 30

## Plot of Mean Change from Baseline in A1C at Week 24 (LOCF) by Race

- 1g - 1

## Plot of Mean Change from Baseline in A1C at Week 24 (LOCF) by Ethnicity

- 1h - 1

## Number (%) of Subjects Reporting Edema AEs by Subgroup

**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 | 30/461
1/67 | (6.5)
 (1.5) | 200/2011
40/363 |  |  (9.9) (11.0) | 72/711
5/112 |  |  (10.1)
 (4.5) |
| Gender, n (%)
	Male
	Female | 11/273
20/255 |  (4.0)
 (7.8) | 111/1272
129/1102 |  |  (8.7)
 (11.7) | 29/425
48/398 |  |  (6.8)
 (12.1) |
| Race, n (%)
	White
   Black
	Other | 25/450
3/34
3/44 |  (5.6)
 (8.8)
 (6.8) | 202/2012
25/172
13/190 |  |  (10.0)
 (14.5)
 (6.8) | 67/718
8/59
2/46 |  |  (9.3)
 (13.6)
 (4.3) |

- Phase 2 and 3, Short-term

- 1g - 3

## Mean Hemoglobin Levels Over Time – Week 24

- Dose-Ranging Study

**Study 006 ST**

**Week**

**Hemoglobin (g/dL)**

- 3 - 7 - 25

## AEs of Anemia – 24 Weeks

**AEs of Anemia – 24 Weeks**

**1 SAE of anemia on muraglitazar 5 mg (GI bleeding)**
**1 SAE of anemia on pioglitazone 30 mg (gastric bleeding)**
**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

## 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 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Baseline | 3.83 |  | 4.01 | 3.98 | 3.88 | 4.00 | 3.91 |
| Change from Baseline |  |  |  |  |  |  |  |
|   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

## Number (%) of Subjects with ANC < 1000on 2 Consecutive Visits

|  

  | Any Pbo | Any Mura 5 mg | Mura10 mg | Any Pio 45 mg |
| --- | --- | --- | --- | --- |
| Number of Subjectswith Data | 519 | 2333 | 245 | 811 |
| 	ANC < 1000 on at Least 2 Consecutive Visits |     1 (0.2%) |       3 (0.1%) |     1 (0.4%) |     0 |

**Number (%) of Subjects with ANC < 1000****on 2 Consecutive Visits**

**No cases were associated with clinical sequelae**
**2 subjects on muraglitazar discontinued**

**Phase 2 and 3 ST + 006 LT**

- 3 - 7 - 2

## 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) | – |
| 022 | 0 | 3.8 (1) | 4.2 (1) | – |
| 021 + 022 | 3.5 (1) | 2.1 (1) | 4.3 (2) | P = 0.739 |
| HR | – | 0.61 | 1.32 |  |
| 025 | 0 | – | 10.7 (5) |  |
| 021 + 022 + 025 | 1.4 (1) | 2.1 (1) | 7.65 (7) | P = 0.074 |
| HR | – | 2.0 | 5.87 |  |

**Events / 1000 PY Exposure (n)**

- HR = hazard ratio relative to Pbo / Pio.

- SA - 39

## Cardiovascular 	Risk Factors in Subjects with and 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 with and without a CV Event

|  | With CV Event | Without CV Event |
| --- | --- | --- |
|  | N  = 123 | N = 4197 |
|  | % | % |
| Gender: Male | 71 | 53 |
| Gender: Female | 29 | 47 |
| Race: Caucasian | 85 | 85 |
| Race: Black | 5 | 7 |
| Race: Other | 11 | 8 |
| Smoking: Current | 28 | 19 |
| Family History CHD | 36 | 24 |
| SBP  130 | 61 | 50 |
| DBP  80 | 50 | 56 |
| BMI  30 kg/m2 | 54 | 58 |
| Waist circ > 40 inches male & > 35 inches female | 63 | 70 |
| A1C  7.0% | 90 | 90 |
| Total Cholesterol  200 mg/dL | 39 | 48 |
| HDL Chol  40 mg/dL male &  50 mg/dL female | 62 | 57 |
| LDL Cholesterol  100 mg/dL | 63 | 69 |
| Triglycerides  150 mg/dL | 63 | 58 |
| hs-CRP  3 mg/L | 35 | 38 |

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