The RUTHERFORD-2 trial in heterozygous FH: Results and implications

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1 The RUTHERFORD-2 tril in heterozygous FH: Results nd implictions Slide deck kindly supplied s n eductionl resource by Professor Derick Rl MD PhD Crbohydrte & Lipid Metbolism Reserch Unit University of Witwtersrnd Johnnesburg, South Afric Selected from presenttion given on Mrch 29, 2014, Fetured Clinicl Reserch Session 400, Americn College of Crdiology, Wshington DC,

2 The RUTHERFORD-2 Study! Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Fmilil Hypercholesterolemi Disorder (NCT )! Design: A 12-week, rndomized, double-blind, plcebo-controlled, multicenter phse 3 study! Objective: To evlute the efficcy nd sfety of evolocumb (AMG 145) 140 mg Q2W nd 420 mg QM dministered subcutneously in lrge cohort of HeFH ptients unble to chieve n LDL-C < 100 mg/dl despite sttin therpy with or without ezetimibe 2

3 RUTHERFORD-2 Study Design 140 mg SC Q2W N = 111 Screening Period with Plcebo Injection Rndomiztion 2:2:1:1 420 mg SC QM N = 110 Plcebo SC Q2W N = 55 End of Study Plcebo SC QM N = 55 Mx. 6 weeks Dy 1 Week 2 Week 4 b Week 6 b Week 8 Week 10 Week 12 Week 14 c or plcebo SC Q2W or plcebo SC QM N s re number of ptients rndomized. One ptient in ech of the plcebo Q2W nd evolocumb Q2W groups did not receive ny doses of the study drug nd were not included in the nlyses b Injections t weeks 4 nd 6 were done t home c Week 14 ws follow-up cll for Q2W ptients to cpture dverse events nd concomitnt medictions Q2W, biweekly; QM, monthly; SC, subcutneous 3

4 RUTHERFORD-2: Bseline Chrcteristics Chrcteristic Plcebo Q2W (N = 54) 140 mg Q2W (N = 110) Plcebo QM (N = 55) 420 mg QM (N = 110) Age (yers), men (SD) 51 (14) 53 (12) 47 (12) 52 (12) Femle, % Rce: white, % PCSK9 (ng/ml), men (SD) HeFH clssifiction, % 431 (124) 458 (145) 441 (146) 436 (139) Definite Probble Sttin use, % Ezetimibe use, % Bsed on Simon Broome criteri HeFH, heterozygous fmilil hypercholesterolemi; Q2W, biweekly; QM, monthly; SD, stndrd devition 4

5 RUTHERFORD-2: Bseline Lipids Chrcteristic Plcebo Q2W (N = 54) 140 mg Q2W (N = 110) Plcebo QM (N = 55) 420 mg QM (N = 110) LDL-C (mg/dl), men (SD) ApoB (mg/dl), men (SD) HDL-C (mg/dl), men (SD) ApoA1 (mg/dl), men (SD) Triglycerides (mg/dl), medin (Q1, Q3) Lp() (nmol/l), medin (Q1, Q3) 151 (37) 161 (51) 152 (43) 154 (43) 114 (30) 119 (31) 110 (22) 115 (26) 53 (17) 50 (16) 49 (13) 52 (16) 145 (28) 142 (34) 135 (24) 143 (29) 96 (75, 143) 119 (87, 161) 102 (79, 151) 113 (85, 157) 44 (24, 105) 78 (29, 206) 87 (36, 219) 61 (17, 194) Determined by the Friedewld formul with reflexive testing vi preprtive ultrcentrifugtion when clculted LDL-C ws < 40 mg/dl or triglyceride levels were > 400 mg/dl Apo, polipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(), lipoprotein (); Q2W, biweekly; QM, monthly; SD, stndrd devition 5

6 RUTHERFORD-2: Men % Chnge in LDL-C from Bseline to the Men of Weeks 10 nd 12, nd Week 12 Alone Adjusted Men Percent Chnge ± SE from Bseline % 60% b Weeks 10 nd 12 61% 2% 64% Determined by the Friedewld formul with reflexive testing vi preprtive ultrcentrifugtion when clculted LDL-C ws < 40 mg/dl or triglyceride levels were > 400 mg/dl b P < 0.001; plcebo-djusted tretment difference nlyzed using repeted mesures model which included tretment group, strtifiction fctors (from IVRS), scheduled visit nd the interction of tretment with scheduled visit s covrites LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly; SE, stndrd error % 66% b 60% b 61% b Plcebo Q2W (N = 54) Plcebo QM (N = 55) 140 mg Q2W (N = 110) 420 mg QM (N = 110) 61% Week 12 5% 56% 6

7 RUTHERFORD-2: LDL-C Gol Achievement < 70 mg/dl Proportion of Ptients (%) % Weeks 10 nd 12 Week 12 65% b 79%b 67% 80% % 2% 0 Plcebo Q2W (N = 54) Plcebo QM (N = 55) 140 mg Q2W (N = 110) 420 mg QM (N = 110) 66% b Determined by the Friedewld formul with reflexive testing vi preprtive ultrcentrifugtion when clculted LDL-C ws < 40 mg/dl or triglyceride levels were > 400 mg/dl b P < 0.001; nlyzed using CMH test, strtified by the strtifiction fctors LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly 7 68% 2% 61% b 63%

8 RUTHERFORD-2: Sfety nd Tolerbility Adverse events (AEs), n (%) Plcebo (N = 109) (N = 220) Tretment-emergent AEs 53 (48.6) 124 (56.4) Most common AEs in Ptients Nsophryngitis 5 (4.6) 19 (8.6) Hedche 4 (3.7) 9 (4.1) Contusion 1 (0.9) 9 (4.1) Bck pin 1 (0.9) 8 (3.6) Nuse 1 (0.9) 8 (3.6) Arthrlgi 2 (1.8) 8 (3.6) Serious AEs 5 (4.6) 7 (3.2) AEs leding to discontinution of study drug 0 (0.0) 0 (0.0) Deths 0 (0.0) 0 (0.0) Potentil injection-site rections b 4 (3.7) 13 (5.9) Neurocognitive AEs c 0 (0.0) 0 (0.0) Muscle-relted SMQ d 1 (0.9) 10 (4.5) Anti-evolocumb ntibodies, e % NA 0.0 Occurring in 3.5% of evolocumb-treted ptients b Reported using high-level term grouping, which includes injection site (IS) rsh, IS inflmmtion, IS pruritus, IS rection, nd IS urticri c Serched HLGT terms: Deliri (incl confusion); cognitive nd ttention disorders nd disturbnces; dementi nd mnestic conditions; disturbnces in thinking nd perception; mentl impirment disorders.na = not pplicble d Stndrd Medicl Dictionry for Regultory Activities (MedDRA) Queries. e Binding or neutrlizing 8

9 RUTHERFORD-2: Key Lbortory Results Lbortory Results Plcebo (N = 109) (N = 220) ALT or AST > 3 ULN t ny post-bseline visit, % CK > 5 ULN t ny post-bseline visit, % CK > 10 ULN t ny post-bseline visit, % ALT, lnine minotrnsferse; AST, sprtte minotrnsferse; CK, cretine kinse; ULN, upper limit of norml 9

10 RUTHERFORD-2: Conclusions! dministered either biweekly or monthly yielded significnt reductions in LDL-C in HeFH ptients on sttins with or without ezetimibe. " The men reduction of LDL-C t Week 12 ws 61% in the 140 mg Q2W nd 56% in the 420 mg QM evolocumb dose groups, respectively. " The men reduction of LDL-C t the men of Weeks 10 nd 12 ws 61% in the 140 mg Q2W nd 63% in the 420 mg QM evolocumb dose groups, respectively.! 140 mg biweekly nd 420 mg monthly dosing regimens were cliniclly equivlent.! The mjority of ptients chieved LDL-C trgets.! tretment resulted in fvorble chnges in other lipoproteins. 10

11 RUTHERFORD-2: Conclusions! ws well tolerted, with no notble difference in the AE profile compred with plcebo. " The rte of nsophryngitis nd muscle-relted dverse events (AEs) ws higher in the evolocumb group. The imblnce in the overll set of muscle-relted AEs ws not due to significnt imblnces in ny individul muscle-relted event (i.e., cretine kinse).! my offer new nd effective tretment option to further reduce LDL-C in HeFH ptients. 11