AvandiaŽ (rosiglitazone maleate)

10/13/99


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Table of Contents

AvandiaŽ (rosiglitazone maleate)

AvandiaŽ SmithKline Beecham Pharmaceuticals

AvandiaŽ - Key Messages

AvandiaŽ Preclinical Findings - Highlights

PPAR? is a Key Molecular Target for Thiazolidinediones

Rosiglitazone - Preclinical Efficacy

Preclinical Findings Common to Thiazolidinediones

Preclinical Findings Common to Thiazolidinediones

Differences in Pharmacological Potency

Differences in Hepatic Safety Profile

PPT Slide

Efficacy and Safety Predictions from Preclinical Studies

AvandiaŽ SmithKline Beecham Pharmaceuticals

AvandiaŽ (rosiglitazone maleate)

AvandiaŽ Data Presentation

AvandiaŽ Phase 2/3 Clinical Program

Dose-response of AvandiaŽ in Monotherapy

Change from Baseline in FPG at Week 8 (Pooled Monotherapy Data)

AvandiaŽ – Monotherapy

Monotherapy Study Design

011: Baseline Demographic Characteristics

011: Baseline Metabolic Characteristics

011: FPG at Week 26

011: HbA1c at Week 26

024: FPG at Week 26

024: FPG Responders

024: HbA1c at Week 26

024: HbA1c by Prior Therapy

Monotherapy Summary

Monotherapy Summary

AvandiaŽ – Durability of Effect

020: Study Design Double-blind, double-dummy

020: FPG Over Time

020: HbA1c Over Time

020: Hypoglycemia

020: Endogenous Insulin Parameters - Change from Baseline at Week 52 Expressed as a Percentage of Baseline

Monotherapy Summary

Monotherapy Summary

AvandiaŽ - Lipid Effects

020: LDL-C Over Time

020: HDL-C Over Time

020: LDL-C/HDL-C Over Time

020: Triglycerides Over Time

020: Free Fatty Acids Over Time

Monotherapy Summary

Monotherapy Summary

Monotherapy Summary

Monotherapy Summary

AvandiaŽ – Combination with Metformin

094 and 093: Eligible Patients

094: Study Design

094: Baseline Metabolic Characteristics

094: FPG at Week 26

094: FPG Responders

094: HbA1c at Week 26

093: Study Design The “Synergy” Study

093: FPG at Week 26 Compared to Baseline

093: FPG Responders

093: HbA1c at Week 26 Compared to Baseline

HbA1c - Treatment Effect (95% CI) Monotherapy

HbA1c - Treatment Effect (95% CI) - AvandiaŽ + Metformin

Conclusions

Conclusions

Conclusions

Conclusions

Conclusions

Conclusions

Conclusions

AvandiaŽ SmithKline Beecham Pharmaceuticals

AvandiaŽ (rosiglitazone maleate)

AvandiaŽ Clinical Program Safety Profile

AvandiaŽ Studies

AvandiaŽ Safety Database Phase 2/3 Clinical Program

AvandiaŽ Safety Database- Patient Years of Treatment

Characteristics of the Safety Populations

Clinical Characteristics of the Safety Population

Frequency of Concomitant Medication Use in the Study Population

Percent of Patients with One or More Adverse Event Report

Most Frequent Adverse Events in Double-blind Trials - AvandiaŽ Monotherapy

Most Frequent Adverse Events in Double-blind Trials - AvandiaŽ in Combination with Sulfonylureas

Most Frequent Adverse Events in Double-blind Trials - AvandiaŽ in Combination with Metformin

Analysis of AEs in Patient Sub-Groups

Adverse Events Leading to Withdrawal

Summary of Serious Non-fatal Adverse Experiences

Reported Deaths

Adverse Event Summary

Areas of Interest Based on Preclinical Findings

Areas of Interest Based on Preclinical Findings

Hemodynamic/Cardiovascular Effects

Echocardiography Study- 080

Echocardiography Study- 080

Mean LVMI at Baseline, Week 28 and Week 52

Echocardiography Results

Mean Ejection Fraction at Baseline, Week 28 and Week 52

Change in Mean 24 Hour Ambulatory Blood Pressure- 080 (Baseline to Week 52 - All Randomized [OC] Population )

Cardiovascular Serious Adverse Experiences -

Deaths Attributed to Cardiac Events

Cardiac Mortality Comparison to Other Clinical Trials and Observational Studies

Frequency of Edema in Double-blind Studies

Hemodynamic / Cardiovascular Conclusions

Areas of Interest Based on Preclinical Findings

Hematology

020: Mean Hematocrit Over Time

Anemia Adverse Events

Criteria for Hemoglobin and Hematocrit Assessment

Percentage of Patients Below Threshold Values for Hemoglobin or Hematocrit

PPT Slide

PPT Slide

Summary: Hematology

Areas of Interest Based on Preclinical Findings

Weight

Weight Mean Change (kg) from Baseline to Week 52

Weight Conclusions

Area of Special Interest

Liver Safety

Study Entry Criteria & Monitoring

ALT Levels > 3x ULRR in the AvandiaŽ Clinical Program

PPT Slide

006.003.00359 AvandiaŽ 1mg bd

024.030.02644 - 105.022.60241 Placebo / AvandiaŽ 8mg od

Two Patients with Jaundice

Liver - Summary

AvandiaŽ Conclusions: Safety Profile

AvandiaŽ SmithKline Beecham Pharmaceuticals

AvandiaŽ (rosiglitazone maleate)

AvandiaŽ: 5 Main Points

AvandiaŽ: 5 Main Points

Type 2 Diabetes: Lessons from UKPDS*

Type 2 Diabetes: Lessons from UKPDS

AvandiaŽ: 5 Main Points

AvandiaŽ: Insulin Sensitizer in Preclinical Studies

AvandiaŽ: 5 Main Points

HbA1c - Treatment Effect (95% CI) Monotherapy

Hypoglycemic Effect is Durable and Clinically Significant

AvandiaŽ: Insulin Sensitizer in Man

AvandiaŽ: Insulin Sensitizer in Man

AvandiaŽ: 5 Main Points

No Evidence of Hepatotoxicity

AvandiaŽ: 5 Main Points

Cardiovascular Lipid Profile

Hemodynamic Effects

Avandia: Conclusion

Positive Risk / Benefit Assessment

AvandiaŽ SmithKline Beecham Pharmaceuticals

AvandiaŽ (rosiglitazone maleate)

AvandiaŽ - Profile

AvandiaŽ - Efficacy

AvandiaŽ - Efficacy

AvandiaŽ - Safety

AvandiaŽ - Safety

AvandiaŽ Proposed Indications

AvandiaŽ (rosiglitazone maleate)

Author: Amy L Werner