751LB After 52 Weeks, Pitavastatin is Superior to Pravastatin for LDL-C Lowering in Patients with HIV Craig A. Sponseller1, Vladimir A. Kryzhanovski2 , Roger E. Morgan3, Stuart E. Campbell3, Melanie A. Thompson4, Judith A. Aberg5 1Kowa Pharmaceuticals America, Inc., Montgomery, AL; 2Eli Lilly and Company, Indianapolis, IN; 3Kowa Research Institute, Inc., Morrisville, NC; 4AIDS Research Consortium of Atlanta, GA; 5ICAHN School of Medicine at Mount Sinai, New York, NY Figure 1. Mean Percent Change from Baseline to Week 52 in LDL-C Figure 4. Mean Percent Change from Baseline to Week 52 in Total Table 3. Change from Baseline to Week 52 in LDL-C According to Viral Table 6. Selected Safety Parameters (52-week data) INTRODUCTION OBJECTIVE RESULTS Cholesterol Hepatitis B or C Status at Randomization • The prevalence of cardiovascular (CV) disease is increasing among • To evaluate the long-term (52-week) safety and efficacy of pitavastatin 0.0 0.0 Pitavastatin Pravastatin Table 1. Subject Disposition and Analysis Populations 4 mg 40 mg the population of adults with human immunodeficiency virus (HIV) 4 mg vs. pravastatin 40 mg in HIV-infected adults with dyslipidemia l Pitavastatin 4 mg Pravastatin 40 mg (n=126) (n=126) infection.1 Since the HIV infection itself may be considered an inde- following completion of the 40-week safety extension of INTREPID. Pitavastatin 4 mg Pravastatin 40 mg pendent risk factor for CV disease, more aggressive management of Hepatitis Hepatitis Hepatitis Hepatitis Number of Subjects (%) Number of Subjects B/C B/C Total B/C B/C Total dyslipidemia due to HIV, antiretroviral (ARV) therapy, and other host -10.0 -10.0 Treatment-Emergent Adverse Event (TEAE) 2 Randomized 126 126 Present Absent Present Absent factors is warranted. -13.7 (11.5) Any TEAE 85 (67.5) 88 (69.8) Completed 12 weeks 111 113 • Some statins depend on the cytochrome P450 (CYP) enzyme system for LDL-C, mean (SD), mg/dL Treatment-related TEAE 16 (12.7) 12 (9.5) their metabolism, particularly the CYP3A pathway. Likewise, ARV drugs, Completed 52 weeks 99 91 in Total Cholestero -19.1 (12.2) Treatment-emergent serious adverse -20.5 (15.4) 7 (5.6) 3 (2.4) particularly protease inhibitors, inhibit CYP3A4, and inhibition of this -20.0 -20.0 n=11 n=110 n=121 n=13 n=113 n=126 event (SAE) enzyme may lead to CYP-mediated drug-drug interactions (DDIs) when METHODS Safety population 126 126 (SD) 145.8 156.0 155.1 143.2 155.9 154.6 Deaths 0 0 statins and ARV drugs are concomitantly administered.3,4 Difference in Baseline mITT population 121 126 LS Mean %=Δ -4.5 (23.9) (26.0) (25.9) (24.8) (23.6) (23.9) Discontinuations due to TEAEs 6 (4.8) 5 (4.0) Study Design P=0.009 • Recently, the FDA released a public safety announcement regarding The study period was February 2011–March 2013. -29.7 (17.4) the use of statins in combination with HIV/HCV protease inhibitors • INTREPID was a Phase 4, multicenter, 12-week, randomized, -30.0 Change -30.0 n=7 n=89 n=96 n=11 n=79 n=90 Most Common (occurring in >5% in either treatment group) TEAEs Difference in % and the risk of muscle-related injury. Caution should be used when double-blind, double-dummy superiority study followed by a 40-week Mean % Change (SD) in LDL-C Table 2. Baseline Demographics and Characteristics LS Mean %=Δ -8.4 120.4 107.9 108.9 116.2 123.0 122.2 Diarrhea 12 (9.5) 4 (3.2) prescribing statins with protease inhibitors due to risk for serious safety extension study (NCT01301066). P<0.001 Week 52 (12.2) (27.7) (27.0) (31.7) (25.8) (26.5) Bronchitis 8 (6.3) 3 (2.4) drug interactions. Only pitavastatin and pravastatin have no dose limi- Mean • There was a minimum 4-week washout/dietary stabilization period Pitavastatin Pravastatin Nasopharyngitis 7 (5.6) 6 (4.8) tations, restrictions, or contraindications when coadministered with -40.0 -40.0 Change from -29.3 -49.3 -47.8 -30.6 -32.8 -32.6 prior to randomization. 4 mg 40 mg protease inhibitors.4 Pitavastatin Pravastatin Pitavastatin Pravastatin baseline (36.8) (28.8) (29.7) (30.7) (23.8) (24.6) Headache 7 (5.6) 3 (2.4) • Eligible subjects were randomized in a 1:1 ratio, stratified by the n=96 n=90 n=98 n=90 Upper respiratory tract infection 5 (4.0) 14 (11.1) • Pitavastatin has a reduced potential for CYP-mediated DDIs. The presence or absence of viral hepatitis B or C, to either pitavastatin 4 mg Demographics/Characteristicsa n=126 n=126 Percent principal route of pitavastatin metabolism is glucuronidation via or pravastatin 40 mg. Dosing was once daily in the morning. -17.1 -30.7 -29.7 -20.3 -20.5 -20.5 Sinusitis 4 (3.2) 10 (7.9) Age, mean (SD), years 50.1 (7.5) 49.2 (8.7) change from liver uridine 5'-diphosphate glucuronosyltransferases (UGT), namely Figure 2. Mean Percent Change from Baseline to Week 52 in Apo B Figure 5. Mean Percent Change from Baseline to Week 52 in a (16.7) (17.2) (17.4) (20.5) (14.7) (15.4) Nausea 4 (3.2) 7 (5.6) • Blood samples for determination of lipid parameters were drawn baseline UGT1A3 and UGT2B7, with subsequent formation of pitavastatin Males, n (%) 106 (84.1) 111 (88.1) Triglycerides following an overnight fast. lactone. Pitavastatin is only minimally metabolized by CYP; marginally 0.0 0.0 Musculoskeletal and Connective Tissue Disorders Race, n (%) -2.0 (41.5) P-value N/A N/A <0.05 N/A N/A <0.05 by CYP2C9 and to a lesser extent by CYP2C8.5 • Study outcomes included lipid parameters (e.g., LDL-C, Apo B, total Back pain 4 (3.2) 4 (3.2) cholesterol, etc.) as well as safety assessments (e.g., CD4 cell count, Caucasian 107 (84.9) 96 (76.2) aOnly subjects with both baseline and Week 52 endpoint values were included in • Similarly, pravastatin is not dependent on the CYP system for its African-American 16 (12.7) 23 (18.3) summaries of Week 52 percent change from baseline. Arthralgia 3 (2.4) 4 (3.2) 6 HIV-1 viral load, adverse events, etc.). metabolism. Other 3 (2.4) 7 (5.6) -8.3 (29.5) Pain in extremity 2 (1.6) 4 (3.2) • In adults without HIV infection, pitavastatin 4 mg has demonstrated Ethnicity, n (%) -10.0 -10.0 Difference in Table 4. Change from Baseline to Week 52 in Secondary Lipid Myalgia 2 (1.6) 3 (2.4) significantly greater reductions in LDL-C vs. pravastatin 40 mg in LS Mean %=Δ 9.4 Study Population Not Hispanic/Latino 95 (75.4) 92 (73.0) P=0.09 Parameters 12-week studies.7,8 Laboratory Enzyme Parametersa 2 • Adults (18- to 70-years-old) with documented HIV infection and Body mass index, mean (SD), kg/m 27.2 (4.5) 28.2 (4.9) in Triglycerides • In HIV-infected adults with dyslipidemia, the 12-week data from the documented dyslipidemia. in Apolipoprotein B -19.6 (13.4) Pitavastatin Pravastatin ALT >2 x ULN 4 (3.4) 4 (3.6) INTREPID (HIV-infected patieNts and TREatment with PItavastatin Framingham 10-year risk CHD -20.0 -20.0 • Subjects were on stable ARV therapy for ≥6 months prior to (SD) 4 mg 40 mg Least Squares AST >2 x ULN 1 (0.9) 0 (0.0) vs. pravastatin for Dyslipidemia) trial demonstrated superior LDL-C assessment score (%) 6.6 (5.1) 6.4 (4.8) (SD) randomization, with HIV-1 RNA viral load <200 copies/mL and CD4 -25.4 (13.8) (n=98) (n=90) Mean Percent CK >5 x ULN 2 (1.7) 0 (0.0) reduction with pitavastatin 4 mg compared with pravastatin 40 mg Parameter P-value count >200 cells/mm3 for ≥3 months prior to randomization. NCEP ATP III-calculated 10-year risk CHD Difference Difference in b (31.1% vs. 20.9%, respectively) and significantly greater reductions in b Virologic Failure 4 (3.2) 6 (4.8) assessment score categories , n (%) LS Mean %=Δ -4.9 Mean Percent Change from (95% CI) 9 • Subjects had fasting serum LDL-C of 130–220 mg/dL (inclusive) and apolipoprotein (Apo B), non-HDL-C and total cholesterol. >20%/CHD history/risk equivalents 7 (5.6) 9 (7.1) -30.0 P<0.001 -30.0 Baseline (SD) triglycerides ≤400 mg/dL after the minimum 4-week washout/dietary ALT=alanine transaminase; AST=aspartate transaminase; CK=creatine kinase; ULN=upper • The long-term (52-week) safety and efficacy data from INTREPID are 10–20% 30 (23.8) 29 (23.0) limit of normal. stabilization period. an=117 for pitavastatin and n=112 for pravastatin. presented here. <10% and ≥2 risk factors 74 (58.7) 78 (61.9) Mean % Change Apo A-1 4.5 (11.6) 2.1 (11.6) 1.72 (-1.8, 5.3) 0.342 b <10% and 0–1 risk factor 15 (11.9) 10 (7.9) Mean % Change Virologic failure was defined as an HIV-1 RNA viral load value >200 copies/mL and a >0.3 References Apo B:Apo A-1 -27.7 (15.0) -21.0 (14.9) -5.3 (-9.7, -0.9) 0.018 log increase from baseline. Treatment Groups Duration of HIV, mean (SD), years 12.7 (7.7) 12.5 (7.2) -40.0 -40.0 1.