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COZAAR™ (losartan) in Type 2 Diabetes and Nephropathy

COZAAR™ (losartan) in Type 2 Diabetes and Nephropathy. Michael C. Elia, PhD Director, Regulatory Affairs Merck Research Laboratories. RENAAL. R eduction of E ndpoints in N IDDM with the A II A ntagonist L osartan.

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COZAAR™ (losartan) in Type 2 Diabetes and Nephropathy

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  1. COZAAR™ (losartan) inType 2 Diabetes and Nephropathy Michael C. Elia, PhD Director, Regulatory AffairsMerck Research Laboratories

  2. RENAAL Reduction of Endpoints in NIDDM with the AII Antagonist Losartan • A multicenter, international, double-blind, randomized, placebo-controlled study designed to evaluate the long-term renal protective effects of losartan in patients with type 2 diabetes and nephropathy • Prior to initiating RENAAL: • No conclusive, long-term renal outcomes data in patients with type 2 diabetes and nephropathy

  3. RENAAL • Primary endpoint - time to event analysis of the composite of: • Doubling of serum creatinine, • End-stage renal disease (defined as the need for chronic dialysis or transplantation), or • Death • Key results • Losartan delays progression of renal disease • ESRD and death status known for all patients • Safety and tolerability consistent with current labeling • Renal protective benefit of losartan exceeds that attributable to reduction in blood pressure alone

  4. COZAAR™ (losartan): Proposed New Indication Renal Protection in Type 2 Diabetic Patients with Proteinuria COZAAR is indicated to delay the progression of renal disease as measured by a reduction in the combined incidence of doubling of serum creatinine, end-stage renal disease (need for dialysis or renal transplantation) or death.

  5. Evidentiary Standard for ApprovalsBased Primarily on a Single Study • In Jan-02, FDA Cardio-Renal Advisory Committee discussed the evidence needed to support a new claim for renal protection in patients with type 2 diabetes and proteinuria • Useful to review the evidentiary standard needed to support a new claim

  6. Use of a Single Study to Support a New Claim Points to Consider for COZAAR FDA Guidance - Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998) • Large multicenter study • Treatment benefit on multiple endpoints involving different events • Consistency among pre-defined subgroups • Supportive data from separate (smaller) clinical and preclinical studies

  7. COZAAR™ (losartan): Proposed New Indication Renal Protection in Type 2 Diabetic Patients with Proteinuria COZAAR is indicated to delay the progression of renal disease as measured by a reduction in the combined incidence of doubling of serum creatinine, end-stage renal disease (need for dialysis or renal transplantation) or death.

  8. COZAAR™ (losartan) inType 2 Diabetes and Nephropathy Agenda for Merck Presentation • Background and Rationale • RENAAL Demographicsand Efficacy Results • RENAAL Safety Results • Review of the Evidenceand Conclusions Dr. S. Shahinfar,Senior DirectorCV Clinical Research Dr. W. Keane, Vice PresidentClinical Development

  9. Merck Consultants • Clinical Consultants • Barry Brenner, MD - Chair, Steering Committee (P.I.) Professor of Medicine, Harvard Medical SchoolDirector Emeritus, Renal Division, Brigham and Women’s Hospital, Boston • Steven Haffner, MD - Chair, Adjudication Committee Professor of Medicine, University of Texas Health Science Center, San Antonio • Carl Erik Mogensen, MD - Chair, DSMC Professor of Medicine, Aarhus Kommunehospital, Aarhus, Denmark

  10. Merck Consultants • Clinical Consultants (cont’d) • Peter Kowey, MD - Member, DSMC Professor of Medicine, Jefferson Medical CollegeChief, Division of Cardiovascular DiseasesMain Line Hospitals, Philadelphia • Marvin Konstam, MD Professor of Medicine & Radiology, Chief of CardiologyTufts-New England Medical Center, Boston • Statistical Consultant • Scott Zeger, PhD Professor and Chair, Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University

  11. Losartan in Type 2 Diabetes and Nephropathy Shahnaz Shahinfar, MD Senior Director, Cardiovascular Clinical ResearchMerck Research Laboratories

  12. Losartan in Type 2 Diabetes and NephropathyAgenda • Background and Rationale • RENAAL Demographics and Efficacy Results • RENAAL Safety Results • Review of Evidence and Conclusions

  13. End-Stage Renal Disease: An Unmet Medical Need • Type 2 diabetes is the most common type of diabetes • Up to 40% of Type 2 diabetic patients develop nephropathy • Incidence of end-stage renal disease (ESRD) is increasing worldwide • Diabetic nephropathy is the leading cause of ESRD in the US • ESRD is an irreversible condition requiring dialysis as life support • Up to 40% of patients die within 2 years after initiating dialysis

  14. Diabetic Nephropathy • Diabetic nephropathy is primarily a glomerular disease • Progression of renal disease is multifactorial • Hemodynamic • Non-hemodynamic • Angiotensin II is hypothesized to play an important role in the progression of nephropathy

  15. Theoretical Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury Increased Albuminuria Afferent Arteriolar Dilatation IncreasedGlomerularPressure Blood Flow Glomerulus Angiotensin II Efferent ArterioleConstriction Blood Flow

  16. Angiotensin II Increased filtering membrane permeability Inflammation and fibrosis Glomerulosclerosis Theoretical Non-Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury

  17. Preclinical Renal Data: Blockade of Angiotensin II System • In experimental diabetic models, blockade of angiotensin II reduced glomerulosclerosis and proteinuria • In experimental models of non-diabetic renal disease, blockade of angiotensin II, but not other antihypertensive therapy, reduced glomerulosclerosis and proteinuria

  18. Clinical Renal Outcomes Data: Renin-Angiotensin System Blockade in Diabetic Nephropathy • Type 1 Diabetes - Captopril Collaborative Study (1993), N=409 • ESRD/death reduced (RR: 50%; 95% CI:18,70) • Type 2 Diabetes - No conclusive evidence of a benefit on ESRD

  19. Factors that Differentiate Type 2 from Type 1 Diabetic Patients • Age • Obesity • Insulin resistance • Advanced atherosclerosis • Long standing hypertension

  20. Current Clinical Approaches to Delay Progression to ESRD in Type 2 Diabetes • Metabolic control • Blood pressure control

  21. In patients with type 2 diabetes and nephropathy, does angiotensin II blockade with losartan offer renal protection? Primary Study Question in RENAAL

  22. RENAAL Reduction of Endpoints in NIDDM with the AII Antagonist Losartan A multicenter, multinational, double-blind, randomized, placebo-controlled study to evaluate the renal protective effects of losartan in patients with type 2 diabetes and nephropathy

  23. RENAAL: Study Organization Steering Committee (Blinded) Chairman: Barry M. Brenner, MD Professor of Medicine,Harvard Medical School Director Emeritus, Renal DivisionBrigham & Women’s Hospital, Boston Data and Safety Monitoring Committee (Unblinded) Chairman:Carl Erik Mogensen, MD Professor of Medicine,Aarhus Kommunehospital,Denmark Endpoint AdjudicationCommittee (Blinded) Chairman: Steven M. Haffner, MD Professor of MedicineUniversity of Texas Health Science Center Merck Coordinating and Data Management Center 250 centers from 28 countries worldwide

  24. RENAAL: Primary Hypothesis • In type 2 diabetic patients with nephropathy, losartan compared to placebo will increase the time to the first event of the composite endpoint of: • Doubling of serum creatinine (sCr) • ESRD (need for chronic dialysis or transplantation) • Death (all cause mortality)

  25. Doublingof sCr ~50% Loss ofRenal Function Progression of Renal Diseasein Type 2 Diabetes ESRD or Death 100% Loss ofRenal Function NormalRenal Function Time Death from any cause may occur at any time

  26. RENAAL: Secondary Hypotheses • In type 2 diabetic patients with nephropathy, losartan compared to placebo will: • Renal • Reduce the rate of progression of renal disease, as measured by the slope of 1/sCr • Reduce proteinuria during the course of the study • Cardiovascular • Increase the time to the first event of the composite endpoint of cardiovascular morbidity/mortality (cardiovascular death, MI, stroke, first hospitalization for heart failure, first hospitalization for unstable angina, peripheral and coronary revascularization)

  27. RENAAL: Key Inclusion/Exclusion Criteria Inclusion Criteria Exclusion Criteria • Type 2 diabetes • Age 31-70 years • Proteinuria defined as:urine albumin/creatinine (UA/Cr) >300 mg/g or >500 mg protein/24hours • Serum creatinine:1.3-3.01 mg/dL • Known non-diabetic renal disease, e.g., renal artery stenosis • HbA1C >12% • History of: • MI or CABG (within 1 month) • Stroke or PTCA (within 6 months) • TIA (within 1 year) • Heart failure2 1 Lower limit 1.5 mg/dL in male patients >60 kg. 2 Protocol amendment.

  28. RENAAL: Study Design (I) • Double-blind • Randomized • Placebo-controlled • Multicenter (250 sites in 28 countries) • Stratified for baseline proteinuria (UA/Cr <2000, 2000 mg/g) • Clinic visits every 3 months • Planned one year enrollment, 5 year maximum follow-up

  29. RENAAL: Study Design (II) Losartan 100 mg + Titrate other antihypertensives Losartan 100 mg Losartan 50 mg Urine Protein Dipstick Goal: Titrate to achieve trough BP <140/90 mmHg Placebo Maintain other antihypertensives; Discontinue ACEI or AIIA Placebo Placebo + Titrate other antihypertensives 6 Week Run-in 4 Wks 4 Wks Planned 5 year maximum follow-up Baseline Stratificationand Randomization

  30. RENAAL: Study Design (III) Patient Follow-up • Patients were to remain on study therapy, with clinic visits every three months, regardless of a non-fatal event, until study completion • For patients who discontinued study therapy: • Clinic visits for renal and CV endpoints were to be conducted every three months • Telephone contact for ESRD and death information was conducted if clinic visits were not feasible, therefore doubling of serum creatinine and CV morbidity were not collected • ESRD and death information was collected on all patients

  31. RENAAL: Early Study Termination • On February 10, 2001, the Steering Committee, while blinded to the study results, voted unanimously to end RENAAL prior to its planned termination date of March 2002 because of concerns of continuing the placebo group without blockade of the renin-angiotensin system • This decision was based on increasing evidence that ACE inhibitors may be effective in reducing cardiovascular events in patients with cardiovascular risk factors1,2 1Heart Outcomes Prevention Evaluation Study, NEJM 2000;342:145-53. 2Mann et al, Annals of Int Med, 2001;134:629-36.

  32. Agenda • Background and Rationale • RENAAL Demographics and Efficacy Results • Renal (Primary and Secondary) • Cardiovascular (Secondary) • RENAAL Safety Results • Review of Evidence and Conclusions

  33. RENAAL: Patient Disposition 3893 Screened 2380 Ineligible 1513 Randomized 751 Losartan 762 Placebo 407 Completed onstudy drug 142 D/C study drug after aprimary event 202 D/C study drug prior toa primary event 359 Completed onstudy drug 162 D/C study drug after aprimary event 241 D/C study drug prior toa primary event

  34. RENAAL: Baseline Demographics (I) Placebo Losartan N Age (yrs) Male (%) SBP/DBP (mmHg) BMI (kg/m2) 751 60 62 152/82 30 762 60 65 153/82 29

  35. Losartan(n=751)% Placebo(n=762)% 16174819 17201845 18145018 17191846 RENAAL: Baseline Demographics (II) Race Asian Black Caucasian Hispanic Region Asia Europe Latin America North America

  36. Losartan(n=751)% Placebo(n=762)% 92 9 12 0 21 9 50 66 7 20 95 10 14 0.1 22 9 49 62 7 17 RENAAL: Medical History at Baseline Treatment for hypertension Angina pectoris Myocardial infarction Stroke Anemia Amputation Neuropathy Retinopathy Laser therapy/photocoagulation Smoking (current)

  37. RENAAL: Selected Mean Baseline Laboratory Values Losartan(n=751) Placebo(n=762) Urine albumin/creatinine (mg/g)1 Serum creatinine (mg/dL) Serum potassium (mEq/L) Hemoglobin (g/dL) Hemoglobin A1c (%) 1873 1.9 4.6 12.5 8.5 1743 1.9 4.6 12.5 8.4 1UA/Cr 1873 mg/g = approximately 3.4 grams per 24 hours (calculated). 1743 mg/g = approximately 3.2 grams per 24 hours (calculated).

  38. RENAAL: Primary Hypothesis • Losartan compared to placebo will increase the time to the first event of the composite endpoint of: • Doubling of serum creatinine (DsCr) • ESRD (need for chronic dialysis or transplantation) • Death (all cause mortality)

  39. RENAAL: Analysis of Primary Composite Endpoint Endpoint Captured Patient DsCr ESRD Death A B C D E  –  –    – – –     –

  40. RENAAL: Analysis of Primary Composite Endpoint Endpoint Captured Patient DsCr ESRD Death A B C D E  –  –    – – –     –

  41. 60 40 20 Placebo Losartan 0 RENAAL: Primary Composite Endpoint Doubling of Serum Creatinine/ESRD/Death Risk Reduction: 16.1% (2.3, 27.9) p=0.022 % Patients with an Event 0 12 24 36 48 Months n at Risk Pbo 762 689 554 296 37 751 692 583 330 51 Los

  42. RENAAL: Analysis of Irreversible Clinical Endpoints (Pre-specified) • Irreversible clinical endpoints • ESRD, death, composite of ESRD or death • Key principles: • Patient counted as having endpoint in all relevant analyses • Patient counted only once in any analysis

  43. RENAAL: Analysis of Irreversible Clinical Endpoints (Pre-specified) • ESRD: Time to ESRD, regardless of whether doubling of serum creatinine occurred first • Death: Time to death regardless of whether doubling of serum creatinine or ESRD occurred first • ESRD or death: Time to first event of ESRD or death, regardless of whether doubling of serum creatinine occurred first

  44. RENAAL: Analysis of IrreversibleClinical Endpoints (Pre-specified) Endpoint Captured Patient DsCr ESRD Death A B C D E  –  –    – – –     –

  45. ClinicalEndpoint Analysis ESRD/Death ESRD Death X X – – – X X X X – X X X X – RENAAL: Analysis of IrreversibleClinical Endpoints (Pre-specified) Endpoint Captured Patient DsCr ESRD Death A B C D E  –  –    – – –     –

  46. Placebo Losartan RENAAL: Irreversible Clinical Endpoints (I) ESRD 60 Risk Reduction: 28.6% (11.5, 42.4) p=0.002 40 % Patients with an Event 20 0 0 12 24 36 48 Months n at Risk Pbo 762 715 610 348 43 43 43 43 43 43 751 714 625 375 68 68 68 68 68 68 Los

  47. Placebo Losartan 0 12 24 36 48 RENAAL: Irreversible Clinical Endpoints (II) All Cause Mortality 60 Risk Reduction: -1.7% (-26.9, 18.6) p=0.884 40 % Patients with an Event 20 0 Months n at Risk Pbo 762 732 690 439 65 Los 751 730 680 430 84

  48. Placebo Losartan RENAAL: Irreversible Clinical Endpoints (III) ESRD or Death 60 Risk Reduction: 19.9% (5.3, 32.3) p=0.009 40 % Patients with an Event 20 0 0 12 24 36 48 Months n at Risk 762 715 610 348 43 43 43 43 43 43 Pbo 751 714 625 375 68 68 68 68 68 68 Los

  49. RENAAL: Summary of Primary Compositeand Clinical Endpoints Percent Risk Reduction (95% CI) DsCr/ESRD/Death ESRD Death ESRD or death -50 +50 0 Favors Losartan Favors Placebo

  50. RENAAL: Imbalance in Baseline Risk • Patients were stratified for baseline level of proteinuria, <2000 and 2000 mg/g UA/Cr • Equal numbers of patients were randomized to losartan and placebo within the low and high strata • However, within the high stratum of 2000 mg/g, an imbalance in the distribution of patients was observed • There were more losartan patients in the highest level of proteinuria that led to the imbalance in risk

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