After 52 Weeks, Pitavastatin Is Superior to Pravastatin for LDL-C Lowering in Patients with HIV

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 (31.1% vs. 20.9%, respectively) and significantly greater reductions in b Difference in Virologic Failureb 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. Esser S, et al. Clin Res Cardiol. 2013;102(3):203-13. Pitavastatin Pravastatin Pitavastatin Pravastatin 2. Aberg JA, et al. Clin Infect Dis. 2014;58(1):1-10. Pitavastatin 4 mg: subjects received 1 tablet of pitavastatin 4 mg + Hepatitis B or C (present), n (%) 12 (9.5) 13 (10.3) n=98 n=90 n=98 n=90 non-HDL-C:HDL-C a -30.1 (20.5) -22.7 (18.4) -5.7 (-11.5, 0.1) 0.001 1 placebo capsule. 3. Chauvin B, et al. Clin Pharmacokinet. 2013;52(10):815-31. CD4 count, mean (SD), cells/mm3 648.5 (246.8) 563.7 (211.3) a 4. FDA Drug Safety Communication. Interactions between certain HIV or Pravastatin 40 mg: subjects received 1 capsule of pravastatin 40 mg TC:HDL-C -24.1 (16.3) -18.1 (14.6) -4.8 (-9.4, -0.2) 0.001 HIV-1 RNA viral load, mean (SD), log copies 1.2 (0.3) 1.1 (0.2) Figure 3. Mean Percent Change from Baseline to Week 52 in Figure 6. Mean Percent Change from Baseline to Week 52 in HDL-C hepatitis C drugs and cholesterol-lowering statin drugs can increase the (2 tablets of pravastatin 20 mg overencapsulated) + 1 placebo tablet. risk of muscle injury, March 1, 2012. Available at http://www.fda.gov/Drugs/ non-HDL-C Oxidized LDL-Cb -23.1 (18.9) -18.0 (21.4) -5.1 (-11.4, 1.2) 0.113 conclusIons DrugSafety/ucm293877.htm. c 0.0 40.0 Lipid and Other Measurements a 5. LIVALO [package insert]. Montgomery, AL: Kowa Pharmaceuticals America, n=97 for pitavastatin b Following the 40-week safety extension period, adverse Statistical Analysis LDL-C, mean (SD), mg/dL 155.1 (25.9) 154.6 (23.9) n=93 for pitavastatin and n=88 for pravastatin Inc. / Indianapolis, IN: Eli Lilly and Company; October 2013. event profiles and overall safety were maintained 6. PRAVACHOL [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Efficacy data were analyzed using the modified intention-to-treat Apo B, mean (SD), mg/dL 123.9 (18.2) 127.6 (19.4) August 2013. (mITT) population, defined as all randomized subjects who received 30.0 Table 5. Change from Baseline to Week 52 in HIV-1 RNA Viral Load, and remained similar for both pitavastatin 4 mg and Total cholesterol, mean (SD), mg/dL 238.4 (32.4) 238.1 (31.0) -10.0 7. Stender S, et al. Eur J Prev Cardiol. 2013;20(1):40-53. at least 1 dose of study drug and had at least 1 on-treatment lipid CD4 Cell Count, and hsCRP pravastatin 40 mg consistent with 12-week data.

8. Morgan RE, et al. J Clin Lipidol. 2012;6(3):280-2. assessment. Triglycerides, mean (SD), mg/dL 174.2 (93.8) 172.4 (73.2) in HDL-C 9. Sponseller CA, et al. Pitavastatin 4 mg provides greater LDL-C reduction Lipid parameters were analyzed using last observation carried forward HDL-C, mean (SD), mg/dL 49.6 (15.0) 49.1 (11.8) in Non-HDL-C Pitavastatin Pravastatin The lipid-modifying effects of pitavastatin 4 mg

compared to pravastatin 40 mg over 12 weeks of treatment in HIV-infected -19.0 (14.5) (SD) (LOCF) data and an ANCOVA model, with percent change in lipid 20.0 b adults with dyslipidemia. Poster presented at CROI 2013. 4 mg 40 mg P-value observed after 12 weeks of therapy in HIV-infected non-HDL-C, mean (SD), mg/dL 188.8 (29.6) 189.0 (29.3) (SD) -20.0 parameter from Baseline to Week 52 as the dependent variable Difference in Parameter (n=98) (n=90) LS Mean %=Δ 1.5 adults with dyslipidemia were maintained at 52 weeks and treatment as the independent variable, adjusting for site and Apo A-1, mean (SD), mg/dL 142.1 (29.6) 142.2 (24.4) P=0.70 -26.1 (15.9) Mean Change from Baseline (SD) of therapy: superior LDL-C reduction and significantly viral hepatitis B or C infection status at randomization. In cases Oxidized LDL-C, mean (SD), mg/dL 64.7 (17.2) 70.2 (20.0) where data failed a test of normality, treatments were also compared 10.0 HIV-1 RNA viral load, greater decreases in Apo B, non-HDL-C and total hsCRP, mean (SD), mg/L 4.0 (8.4) 5.5 (14.3) -30.0 8.9 (17.5) 0.03 (0.4) 0.07 (0.4) 0.81 Disclosures: C. Sponseller is an employee of Kowa Pharmaceuticals using a nonparametric, van Elteren test to confirm ANCOVA analysis Difference in a 7.2 (15.4) log copies cholesterol. Changes in HDL-C and triglycerides were America, Inc. V. Kryzhanovski is an employee of Eli Lilly and Company, conclusions; p-values were 2-sided and significance was tested. CHD=coronary heart disease; NCEP ATP III=National Cholesterol Education Program Adult LS Mean %=Δ -5.7 Mean % Change P<0.001

Mean % Change not significantly different. Indianapolis, IN. R. Morgan and S. Campbell are employees of Kowa Research Treatment Panel III. CD4 count, cells/mm3 -8.3 (124.0) 36.5 (157.5) 0.18 All safety analyses were performed on the safety population, defined a Institute, Inc., Morrisville, NC. M. Thompson and J. Aberg were study investi- Safety population. 0.0 as all randomized subjects who received at least 1 dose of study drug. bThis study population falls outside of the 4 major Statin Benefit groups according to the There were no significant differences between gators and are consultants to Kowa Pharmaceuticals America, Inc. -40.0 hsCRP, mg/L -1.2 (6.5) -1.1 (14.4) 0.08 2013 ACC/AHA cholesterol guidelines. a pitavastatin 4 mg and pravastatin 40 mg in CD4 cell c Pitavastatin Pravastatin Pitavastatin Pravastatin Acknowledgments: Lorraine R. Baer, PharmD (Baer PharMed Consulting, Modified intent-to-treat population (n=121 for pitavastatin and n=126 for pravastatin, n= 97 for pitavastatin n=97 n=90 n=97 n=90 bp-values from ANCOVA model of LS mean percent change from baseline. Ltd.) for content development support. except LDL-C where n=120 for pitavastatin and n=125 for pravastatin). counts or HIV-1 RNA viral loads after 52 weeks of therapy.

Poster presented at the CROI 2014 Conference on Retroviruses and Opportunistic Infections, March 3–6, 2014, Boston, MA, USA. Research sponsored by Kowa Pharmaceuticals America, Inc. and Eli Lilly and Company.