CS-1 CRESTOR ® Safety Howard G. Hutchinson, MD Vice President, Clinical Research. - презентация

1 CS-1 CRESTOR ® Safety Howard G. Hutchinson, MD Vice President, Clinical Research

2 CS-2 Provide an overall benefit-risk profile demonstrating –Greater beneficial effects on key lipid parameters at both the start dose and across the dose-range compared with marketed statins –A similar safety profile compared with approved drugs in the statin class –A low potential for significant drug-drug interactions Objectives of the Rosuvastatin Clinical Development Program

3 CS-3 Safety Overview Safety data come from 27 clinical trials conducted worldwide ~ 50% of patients were from the United States 12,569 patients treated with rosuvastatin at doses up to 80 mg –> 14,000 patient-yr of exposure 9

4 CS-4 Safety Presentation Agenda Demographics Exposure Adverse events Liver effects Skeletal muscle effects Renal effects Drug-drug interactions

5 CS-5 Demographic Characteristics of Patients (1) Combined All Controlled/Uncontrolled and RTLD Pool Demographic characteristic Rosuvastatin N = 12,569 Age, yr Mean (SD)58.1 (11.8) Age distribution, n (%) < 65 yr8633 (68.7) 65 yr3936 (31.3) 75 yr915 (7.3) Sex, n (%) Male6626 (52.7) Female5943 (47.3) Postmenopausal4019 (67.6) 9 PTT C1.4.1 andC1.4.2

6 CS-6 Demographic Characteristics of Patients (2) Combined All Controlled/Uncontrolled and RTLD Pool Demographic characteristic Rosuvastatin N = 12,569 Ethnic origin, n (%) Caucasian11,081 (88.2) Hispanic297 (2.4) Black820 (6.5) Asian234 (1.9) Other137 (1.1) 9 PTT C1.4.1 andC1.4.2

7 CS-7 Baseline Medical Conditions of Interest Combined All Controlled/Uncontrolled and RTLD Pool Medical condition Rosuvastatin, n (%) N = 12,569 Renal impairment 6603 (52.5) Mild (CrCl 50 to 80 mL/min) 5579 (44.4) Moderate (CrCl 30 to < 50 mL/min) 983 (7.8) Severe (CrCl < 30 mL/min) 41 (0.3) Hypertension 6529 (51.9) Cardiovascular disease 4530 (36.0) Diabetes 2080 (16.5) 9 PTT C1.4.4 andC1.4.6 Creatinine clearance (CrCI) derived using Cockcroft-Gault formula.

8 CS-8 Maximum Continuous Duration of Treatment Combined All Controlled/Uncontrolled and RTLD Pool Cumulative duration of treatment Rosuvastatin daily dose 5 mg N = mg N = mg N = mg N = mg N = mg N = wk wk wk wk wk Patient-yr of treatment PTT C2.4.3 and C2.4.4 Total patients – 12,569 Total patient-yr – 14,231

9 CS-9 Summary of Patient-Reported Adverse Events The frequency and types of AEs reported were similar to comparator statins The frequency and types of AEs were similar at the 5-mg, 10-mg, 20-mg, and 40-mg doses At the 80-mg dose, increased frequencies of nausea, myalgia, asthenia, and constipation were observed Well tolerated regardless of age, sex, ethnicity, presence of comorbidities, or concomitant medications

10 CS-10 Safety Presentation Agenda Demographics Exposure Adverse events Liver effects Skeletal muscle effects Renal effects Drug-drug interactions

11 CS-11 Evaluation of Rosuvastatin Effects on the Liver Liver function tests were evaluated at each visit In this section, the percentage of patients with ALT > 3 × ULN on 2 occasions (persistent elevations) is presented –AST changes mirrored ALT changes –ALT increases associated with bilirubin increases were rarely observed

12 CS-12 Persistent ALT Elevations by Dose Combined All Controlled/Uncontrolled and RTLD Pool Rosuvastatin doseN > 3 × ULN on 2 occasions, % 5 mg mg mg mg mg Total12,4580.4

13 CS-13 Persistent ALT > 3 × ULN Frequency by % LDL-C Reduction Ref: Prescribing Information and Summary Basis of Approval documents. Fluvastatin ( mg) Rosuvastatin ( mg) Lovastatin ( mg) Atorvastatin ( mg) Simvastatin ( mg)

14 CS-14 Safety Presentation Agenda Demographics Exposure Adverse events Liver effects Skeletal muscle effects Renal effects Drug-drug interactions

15 CS-15 Evaluation of Rosuvastatin Effects on Skeletal Muscle Creatine kinase (CK) was evaluated at each visit In this section, the following data are presented –CK > 10 × ULN –Myopathy: CK > 10 × ULN + muscle symptoms –Rhabdomyolysis: myopathy + hospitalization + intravenous fluids

16 CS-16 CK > 10 × ULN by Dose Combined All Controlled/Uncontrolled and RTLD Pool Rosuvastatin doseN> 10 × ULN, % 5 mg mg mg mg mg Total12,

17 CS-17 Cases of Myopathy Combined All Controlled/Uncontrolled and RTLD Pool Patients with myopathy Rosuva doseN All cases, n (%) Possibly treatment related, n (%) 5 mg (0.2)0 10 mg (0.1)0 20 mg (0.1)1 (0.03) 40 mg (0.1)1 (0.03) 80 mg (1.0)11 (0.7) Total12,45737 (0.3)13 (0.1) CK elevations > 10 × ULN plus muscle symptoms. 9

18 CS-18 Risk Factors for Myopathy (80-mg Dose) Age –< 65 yr 0.2% (2/1200) – 65 yr 2.3% (9/383) Renal insufficiency –CrCl 80 mL/min 1.2% (9/760) –CrCl > 80 mL/min 0.2% (2/823) Hypothyroidism –2 patients with myopathy at 80-mg dose had an elevated TSH 9

19 CS-19 CK > 10 × ULN Frequency by % LDL-C Reduction Prescribing Information and Summary Basis of Approval documents. Heart Protection Study. Lancet. 2002;360:7-22. % Cerivastatin ( mg) Rosuvastatin ( mg) Pravastatin ( mg) Atorvastatin ( mg) Simvastatin ( mg)

20 CS-20 Summary of Effects of Rosuvastatin on Skeletal Muscle At rosuvastatin doses up to and including 40 mg, safety profile similar to marketed statins –Greater lipid modification achieved with rosuvastatin Increased frequency of adverse effects at the 80-mg dose –2% to 4% additional LDL-C lowering achieved compared with 40 mg –Well tolerated in patients < 65 yr old –All patients recovered

21 CS-21 Safety Presentation Agenda Demographics Exposure Adverse events Liver effects Skeletal muscle effects Renal effects Drug-drug interactions

22 CS-22 Background (1) Observed increased frequency of proteinuria at the 80-mg dose Important questions addressed in this section –Frequency –Magnitude –Nature –Short-term and long-term consequences

23 CS-23 Background (2) Background prevalence of proteinuria is up to 10% on routine dipstick urinalysis Proteinuria can have a functional or organic cause Proteinuria can have a glomerular or tubular etiology –Glomerular proteinuria caused by leakage of albumin and other larger-molecular-weight proteins –Tubular proteinuria caused by reduced reabsorption of normally filtered proteins

24 CS-24 Frequency of Proteinuria, Hematuria, and Proteinuria/Hematuria (FDA Table 15) TreatmentDoseN Urine protein 2+, % Urine blood 1+, % Proteinuria 2+ and hematuria 1+, % Placebo Rosuvastatin 5 mg 10 mg 20 mg 40 mg 80 mg Atorvastatin10 mg 20 mg 40 mg 80 mg Simvastatin20 mg 40 mg 80 mg Pravastatin20 mg 40 mg

25 CS-25 Magnitude of Proteinuria NMean (SD)Median 10th - 90th percentile Protein/creatinine (mg/mg) (0.55) Albumin/creatinine (mg/mg) (0.22) Proteinuria: none or trace to 2+ or greater. Ratios × 1000 approximate excretion in mg/day. 32

26 CS-26 Nature of Proteinuria and Hematuria Proteinuria primarily tubular in origin –Gel electrophoresis shows a tubular pattern –Quantitation of proteins shows increased levels of low-molecular-weight proteins (α-1 microglobulin, β-2 microglobulin, RBP) –Back-titration of patients shows greatest reductions in low-molecular-weight proteins Hematuria –Red blood cells present on microscopic evaluation –Not myoglobin –Resolves on back-titration

27 CS-27 Preclinical Effects of Statins on Renal Tubules Drug SpeciesMain effects RosuvastatinRat, dog, rabbit, cynomolgus monkey Tubular degeneration, tubular epithelial cell changes LovastatinRabbitTubular necrosis PravastatinRat, rabbit, cynomolgus monkey Nephropathy, proximal tubule cell necrosis SimvastatinMouse, dog, rabbitTubular epithelial vacuolation, tubular distention FluvastatinRat, dog, rabbitTubular degeneration, epithelial hyperplasia CerivastatinRat, mini-pigsDilated tubules, tubular degeneration AtorvastatinRat, dogDilatation of tubules

28 CS-28 Effect of Statins on Albumin Uptake by OK Cells Combined result of 2 to 4 experiments, mean ± SE 24-hr exposure to statins Concentration, µM % inhibition Rosuva Atorva Simva Prava Fluva

29 CS-29 Inhibition of Albumin Uptake and Inhibition of Cholesterol Synthesis % inhibition of cholesterol synthesis % inhibition of albumin uptake Simva Fluva Prava Atorva Rosuva

30 CS-30 Mevalonate 100 µM Combined results of 2 experiments, mean ± SE Inhibition of Statin Effects on Albumin Uptake by Mevalonate – % of control ControlSimva 10 µM Simva 100 µM Rosuva 10 µM Rosuva 100 µM – +

31 CS-31 Why is Tubular Proteinuria Observed With High-Dose Rosuvastatin Therapy Rosuvastatin is a highly effective inhibitor of HMG-CoA reductase Approximately 28% of rosuvastatin systemic clearance is renal; predominantly by tubular secretion For other statins, the degree of renal excretion or the overall effectiveness inhibiting HMG- CoA reductase is less than that observed with rosuvastatin

32 CS-32 Patients With Investigator-Designated Acute Renal Failure Rosuva dose Number of casesCause 5 mg1Cardiogenic shock 10 mg1Volume depletion 20 mg1Post-CABG 40 mg21 motor vehicle accident (sepsis) 1 recurrent kidney stones 80 mg64 myopathy 2 uncertain 3

33 CS-33 Frequency of > 30% Creatinine Elevations in Patients With Proteinuria at Last Visit Combined All Controlled/Uncontrolled and RTLD Pool Last visit Rosuva doseN Proteinuria, n (%) Creatinine increase > 30%, n 5 mg (0.2)0 10 mg (0.5)0 20 mg (0.9)2 40 mg (1.1)0 80 mg (8.8)11 Proteinuria: none or trace to 2+ or greater.

34 CS-34 Proteinuria 2+, Hematuria 1+, and > 30% Increase in Creatinine at Last Visit Combined All Controlled/Uncontrolled and RTLD Pool C Rosuva doseN Urine protein 2+, urine blood 1+, n (%) Creatinine increase > 30%, n 5 mg mg17071 (0.1)0 20 mg11941 (0.1)1 40 mg26796 (0.2)0 80 mg21512 (5.6)8

35 CS-35 Proportion of Patients With Proteinuria, 96 Wk of Rosuvastatin Treatment Combined All Controlled/Uncontrolled and RTLD Pool Rosuva doseN Any time, n (%) Last visit, n (%) Creatinine increase > 30%, n 5 mg2613 (1.1)00 10 mg83817 (2.0)4 (0.5)0 20 mg1125 (4.5)1 (0.9)0 40 mg1004 (4.0)2 (2.0)0 80 mg59099 (16.8)37 (6.3)7 40 mg (16.9)10 (1.2)0 Proteinuria: none or trace to 2+ or greater. Includes patients who back-titrated from the 80-mg dose. 32

36 CS-36 Proteinuria 2+, Hematuria 1+, and > 30% Increase in Creatinine at Last Visit, 96 Wk of Rosuvastatin Treatment Combined All Controlled/Uncontrolled and RTLD Pool C , C Last visit Rosuva doseN Urine protein 2+, urine blood 1+, n (%) Creatinine increase > 30%, n 5 mg mg7811 (0.1)0 20 mg mg981 (1.0)0 80 mg56213 (2.3)5 40 mg 7612 (0.3)0 Includes patients who back-titrated from the 80-mg dose.

37 CS-37 Abnormal Urinalysis With Renal Biopsy After Long-term Treatment Rosuvastatin 80 mg 69-y/o South African male History of unspecified renal disease in childhood, stasis ulcers, back pain, and heterozygous FH Medications: aspirin, paracetamol, topical steroids, intramuscular PCN 2 abnormal baseline urinalyses: 1 showed active sediment; other 1+ proteinuria, no active sediment After 18 months, creatinine increased from 1.1 to a maximum of 1.6 mg/dL, urinalysis showed 3+ protein and moderate blood (last on-treatment creatinine 1.4 mg/dL) Renal biopsy showed tubulointerstitial disease Urinalysis abnormalities recurred after rechallenges with rosuvastatin and atorvastatin

38 CS-38 % Change in Creatinine at Last Value in Patients Given at Least 40 mg of Rosuvastatin by Baseline Renal Function Combined All Controlled/Uncontrolled and RTLD Pool 96 wk Renal functionN Mean (SD) % change > 30% increase, % Normal456–5.9 (12.5)0.4 Impaired415–5.3 (10.7)0.2 Mild366–5.3 (10.7)0.3 Moderate 46–4.9 (10.9)0 Severe 3–13.7 (8.1)0 31

39 CS-39 Summary of Effects of Rosuvastatin on the Kidney Findings of proteinuria and proteinuria/hematuria associated with rosuvastatin were thoroughly evaluated Findings observed predominately in patients dosed above 40 mg Rosuvastatin at doses up to and including 40 mg was well tolerated from the renal standpoint Urinalysis or creatinine monitoring not necessary –No evidence for long-term detrimental effects on renal function 9

40 CS-40 Safety Presentation Agenda Demographics Exposure Adverse events Liver effects Skeletal muscle effects Renal effects Drug-drug interactions

41 CS-41 Rosuvastatin Drug Interaction StudiesCYP450 and PgP DrugCharacteristicEffect on AUC Ketoconazole3A4 and PgP inhibitorNot significant Erythromycin3A4 and PgP inhibitor0.2-fold decrease Fluconazole2C9 and 2C19 inhibitorNot significant DigoxinPgP substrateNot significant

42 CS-42 Effect of Cyclosporine on Statin Exposure Ratio of AUC in cyclosporine-treated patients to AUC in historical control patients

43 CS-43 Effect of Gemfibrozil on Statin Plasma Concentrations Ratio of AUC in gemfibrozil-treated patients to AUC in placebo patients

44 CS-44 Effect of Gemfibrozil and Fenofibrate on Rosuvastatin Plasma Concentrations Ratio of rosuvastatin AUC in fibrate-treated patients to AUC in placebo-treated patients

45 CS-45 Other Pharmacokinetic Data Relevant to the Overall Safety of Rosuvastatin Systemic (plasma) exposure unaffected by –Age –Sex –Mild / moderate renal impairment Systemic exposure increases because of –Severe renal impairment –Severe hepatic impairment Ethnicity –Exposure increased in Japanese patients in Japan –No differences in exposure among Caucasian, Black, or Hispanic patients

46 CS-46 Safety Summary Doses up to 80 mg thoroughly explored in a large dyslipidemic patient population (> 12,500) –Large number of elderly patients –Large number of patients with comorbidities 5-mg to 40-mg dose range has a safety profile similar to other marketed statins Increased frequency of some AEs at the 80-mg dose Few drug-drug interactions For at-risk patients, specific labeling information

47 CS-47 Benefits of Rosuvastatin (10 mg to 40 mg) Excellent lipid-modifying effects –At the starting dose –Across the dose-range High percentage of patients achieve goal –At the starting dose –Across the dose-range Provides additional lipid modification compared with existing statin therapies –eg, further LDL-C, non-HDL-C reduction

48 CS-48 Rosuvastatin 10 mg Is an Appropriate Starting Dose for Most Patients With Dyslipidemia Overall favorable benefit-risk profile Additional efficacy compared with 5-mg dose –Better lipid-modifying effects –More patients brought to NCEP goal No difference in safety compared with 5-mg dose For patients on cyclosporine, a 5-mg dose is available

49 CS-49 Rosuvastatin 40 mg Is an Appropriate Top Dose for Patients With Dyslipidemia Provides additional lipid-modifying benefits compared with 20-mg dose Dose studied in > 4000 patients –> 2000 initiated therapy at this dose Important dose for those patients who do not achieve necessary lipid modification at lower doses Dose well tolerated