The annual ACC scientific sessions are ongoing in New Orleans April 2-5, 2011. Two abstracts will be presented regarding mipomersen: These scientific presentations provide additional details on the safety and efficayc data from these two phase 3 trials.
Sunday 4/3/2011:
SAFETY AND EFFICACY OF MIPOMERSEN ADMINISTERED AS ADD-ON THERAPY IN PATIENTS WITH HYPERCHOLESTEROLEMIA AND HIGH CARDIOVASCULAR RISK
e-Abstract:1011-304Topic:15. Pharmacology/Hormones/Lipids—Clinical (Click for link)
Authors:William C. Cromwell, Gregory S. Thomas, Ingrid Boltje, Wai Chin, Michael Davidson, Presbyterian Cardiovascular Institute, Charlotte, NC, Univ Chicago Pritzker School of Med, Chicago, IL
Background: Many patients on lipid-lowering therapies (LLT) are unable to achieve target LDL cholesterol (LDL-C) levels. This double-blind phase 3 study examined the safety and efficacy of mipomersen (Mipo), an apolipoprotein (apo) B synthesis inhibitor, in hypercholesterolemic patients at high CHD risk (NCEP-ATP III).
Methods: Adults (≥ 18 years) on maximally tolerated statin ± ezetimibe, bile-acid sequestrants, and/or niacin with LDL-C ≥ 100 mg/dL and TG < 200 mg/dL were randomized (2:1) to Mipo 200 mg or placebo (Pbo) sc weekly for 26 weeks. The primary endpoint was % LDL-C change from baseline (BL) at Week 28 or 2 weeks after last dose if treatment was not completed. Additional endpoints included apo B, total-C, non-HDL-C and lipoprotein (Lp)(a).
Results: One hundred fifty-eight patients were randomized (105 Mipo; 53Pbo), including 88 (56%) patients with type 2 diabetes (55% Mipo, 58% Pbo). At BL all patients were taking a statin (63 on maximal approved dose [41% Mipo; 38% Pbo)]) with 25 patients (18% Mipo, 12% Pbo) on ezetimibe. Mean (95%CI) % change in LDL-C from BL was -37% (-42, -32) with Mipo vs -5% (-11, 2) with Pbo ( p<0.001). Significant reductions also occurred for apo B (38%), total-C (26%), non-HDL-C (36%), and Lp(a) (24% ), all p<0.001 vs Pbo], with no change in HDL-C. LDL-C <70 mg/dL was attained in 50% Mipo patients vs 4% in Pbo. Forty-five (43%) Mipo and 9 (17%) Pbo patients withdrew from the trial (26 Mipo, 2 Pbo for adverse events [AE]). Common on-treatment AEs included injection site reactions (78% Mipo, 31% Pbo) and flu-like symptoms (34% Mipo, 21% Pbo). No Pbo patients had ALT elevations ≥3 × ULN; 15 (14%) Mipo patients had ALT elevations ≥3 × ULN, without concomitant significant bilirubin elevations; 10 patients (10%) occurring on consecutive measurements at least 7 days apart. 1 patient had ALT ≥10 × ULN. There were 13 on-treatment SAEs [7 Mipo (1 possibly related), 6 Pbo (1 death)]. Results were similar in patients with and without diabetes.
Conclusions: Mipo 200 mg s.c. weekly significantly reduced LDL-C and other atherogenic lipids and lipoproteins in patients at high CHD risk with LDL-C > 100 mg/dL despite maximally tolerated statin therapy. Safety findings were consistent with prior studies.
Tuesday April 5th:
APOLIPOPROTEIN B SYNTHESIS INHIBITION BY MIPOMERSEN REDUCES LOW-DENSITY LIPOPROTEIN CHOLESTEROL WHEN ADDED TO MAXIMALLY TOLERATED LIPID-LOWERING MEDICATION IN PATIENTS WITH SEVERE HETEROZYGOUS HYPERCHOLESTEROLEMIA
e-Abstract: 920-3Topic:15. Pharmacology/Hormones/Lipids—Clinical (Click for link)
Authors:Jean Claude Tardif, Mary McGowan, Richard Ceska, Lesley J. Burgess, Handrean Soran, Ioanna Gouni-Berthold, Gilbert Wagener, Scott Chasan-Taber, Montreal Heart Institute, Montreal, Canada
Background: In 2 prior studies, mipomersen (MIPO) 200 mg sc weekly reduced LDL-C in patients with homozygous and heterozygous familial hypercholesterolemia (HeFH) by 25% and 28% respectively when added to lipid-lowering therapies (LLT), including high dose statins. Patients with severe hypercholesterolemia (SH) often fail to normalize LDL-C despite potent LLT. This randomized, double-blind, placebo-controlled, multi-center phase 3 trial examined the safety and efficacy of MIPO in patients with SH, 90% of whom were HeFH.
Methods: Adults (≥ 18 yrs) with LDL-C ≥300 mg/dL or LDL-C ≥200 mg/dL with coronary heart disease or other forms of clinical atherosclerotic disease on a maximally tolerated statin and at least one other class of LLT were enrolled. Patients continued prescribed LLT regimen and were randomized (2:1) to MIPO 200 mg s.c. weekly or placebo (PBO) for a 26-week period. The primary end point was percent reduction in LDL-C from baseline to week 28 or 2 weeks after the last dose for those not completing dosing.
Results: Fifty-eight patients were randomized (39 MIPO, 19 PBO) at 26 clinical centers in 6 countries. Forty-five (78%) patients completed the treatment period. Eight (21%) Mipo and 1 (5%) PBO patient(s) withdrew due to an adverse event (AE). LDL-C was reduced by 36% from a mean baseline level of 276 mg/dL in the MIPO group vs. an increase of 13% from a BL of 249 mg/dL in the PBO group (p<0.001). This represents a >100 mg/dL mean reduction of LDL-C in the MIPO group. Similarly, MIPO produced highly significant (p<0.001) reductions in other atherogenic lipoproteins [e.g., apo B and Lp(a)]; there was no change in HDL-C. The most common on-treatment AEs were injection site reactions (90% MIPO, 32% PBO) and flu-like symptoms (46% MIPO, 21% PBO). Six (15%) MIPO patients and no PBO patients had ALT ≥3 × ULN on consecutive measure at least 7 days apart. One MIPO patient had ALT ≥10 × ULN. ALT elevations were not associated with clinically significant increases in bilirubin.
Conclusions: MIPO treatment reduced LDL-C and apoB significantly. The present data support the potential utility of MIPO as a pharmacologic option for additional LDL-C lowering in these patients not adequately controlled under existing LLTs.
Sunday 4/3/2011:
SAFETY AND EFFICACY OF MIPOMERSEN ADMINISTERED AS ADD-ON THERAPY IN PATIENTS WITH HYPERCHOLESTEROLEMIA AND HIGH CARDIOVASCULAR RISK
e-Abstract:1011-304Topic:15. Pharmacology/Hormones/Lipids—Clinical (Click for link)
Authors:William C. Cromwell, Gregory S. Thomas, Ingrid Boltje, Wai Chin, Michael Davidson, Presbyterian Cardiovascular Institute, Charlotte, NC, Univ Chicago Pritzker School of Med, Chicago, IL
Background: Many patients on lipid-lowering therapies (LLT) are unable to achieve target LDL cholesterol (LDL-C) levels. This double-blind phase 3 study examined the safety and efficacy of mipomersen (Mipo), an apolipoprotein (apo) B synthesis inhibitor, in hypercholesterolemic patients at high CHD risk (NCEP-ATP III).
Methods: Adults (≥ 18 years) on maximally tolerated statin ± ezetimibe, bile-acid sequestrants, and/or niacin with LDL-C ≥ 100 mg/dL and TG < 200 mg/dL were randomized (2:1) to Mipo 200 mg or placebo (Pbo) sc weekly for 26 weeks. The primary endpoint was % LDL-C change from baseline (BL) at Week 28 or 2 weeks after last dose if treatment was not completed. Additional endpoints included apo B, total-C, non-HDL-C and lipoprotein (Lp)(a).
Results: One hundred fifty-eight patients were randomized (105 Mipo; 53Pbo), including 88 (56%) patients with type 2 diabetes (55% Mipo, 58% Pbo). At BL all patients were taking a statin (63 on maximal approved dose [41% Mipo; 38% Pbo)]) with 25 patients (18% Mipo, 12% Pbo) on ezetimibe. Mean (95%CI) % change in LDL-C from BL was -37% (-42, -32) with Mipo vs -5% (-11, 2) with Pbo ( p<0.001). Significant reductions also occurred for apo B (38%), total-C (26%), non-HDL-C (36%), and Lp(a) (24% ), all p<0.001 vs Pbo], with no change in HDL-C. LDL-C <70 mg/dL was attained in 50% Mipo patients vs 4% in Pbo. Forty-five (43%) Mipo and 9 (17%) Pbo patients withdrew from the trial (26 Mipo, 2 Pbo for adverse events [AE]). Common on-treatment AEs included injection site reactions (78% Mipo, 31% Pbo) and flu-like symptoms (34% Mipo, 21% Pbo). No Pbo patients had ALT elevations ≥3 × ULN; 15 (14%) Mipo patients had ALT elevations ≥3 × ULN, without concomitant significant bilirubin elevations; 10 patients (10%) occurring on consecutive measurements at least 7 days apart. 1 patient had ALT ≥10 × ULN. There were 13 on-treatment SAEs [7 Mipo (1 possibly related), 6 Pbo (1 death)]. Results were similar in patients with and without diabetes.
Conclusions: Mipo 200 mg s.c. weekly significantly reduced LDL-C and other atherogenic lipids and lipoproteins in patients at high CHD risk with LDL-C > 100 mg/dL despite maximally tolerated statin therapy. Safety findings were consistent with prior studies.
Tuesday April 5th:
APOLIPOPROTEIN B SYNTHESIS INHIBITION BY MIPOMERSEN REDUCES LOW-DENSITY LIPOPROTEIN CHOLESTEROL WHEN ADDED TO MAXIMALLY TOLERATED LIPID-LOWERING MEDICATION IN PATIENTS WITH SEVERE HETEROZYGOUS HYPERCHOLESTEROLEMIA
e-Abstract: 920-3Topic:15. Pharmacology/Hormones/Lipids—Clinical (Click for link)
Authors:Jean Claude Tardif, Mary McGowan, Richard Ceska, Lesley J. Burgess, Handrean Soran, Ioanna Gouni-Berthold, Gilbert Wagener, Scott Chasan-Taber, Montreal Heart Institute, Montreal, Canada
Background: In 2 prior studies, mipomersen (MIPO) 200 mg sc weekly reduced LDL-C in patients with homozygous and heterozygous familial hypercholesterolemia (HeFH) by 25% and 28% respectively when added to lipid-lowering therapies (LLT), including high dose statins. Patients with severe hypercholesterolemia (SH) often fail to normalize LDL-C despite potent LLT. This randomized, double-blind, placebo-controlled, multi-center phase 3 trial examined the safety and efficacy of MIPO in patients with SH, 90% of whom were HeFH.
Methods: Adults (≥ 18 yrs) with LDL-C ≥300 mg/dL or LDL-C ≥200 mg/dL with coronary heart disease or other forms of clinical atherosclerotic disease on a maximally tolerated statin and at least one other class of LLT were enrolled. Patients continued prescribed LLT regimen and were randomized (2:1) to MIPO 200 mg s.c. weekly or placebo (PBO) for a 26-week period. The primary end point was percent reduction in LDL-C from baseline to week 28 or 2 weeks after the last dose for those not completing dosing.
Results: Fifty-eight patients were randomized (39 MIPO, 19 PBO) at 26 clinical centers in 6 countries. Forty-five (78%) patients completed the treatment period. Eight (21%) Mipo and 1 (5%) PBO patient(s) withdrew due to an adverse event (AE). LDL-C was reduced by 36% from a mean baseline level of 276 mg/dL in the MIPO group vs. an increase of 13% from a BL of 249 mg/dL in the PBO group (p<0.001). This represents a >100 mg/dL mean reduction of LDL-C in the MIPO group. Similarly, MIPO produced highly significant (p<0.001) reductions in other atherogenic lipoproteins [e.g., apo B and Lp(a)]; there was no change in HDL-C. The most common on-treatment AEs were injection site reactions (90% MIPO, 32% PBO) and flu-like symptoms (46% MIPO, 21% PBO). Six (15%) MIPO patients and no PBO patients had ALT ≥3 × ULN on consecutive measure at least 7 days apart. One MIPO patient had ALT ≥10 × ULN. ALT elevations were not associated with clinically significant increases in bilirubin.
Conclusions: MIPO treatment reduced LDL-C and apoB significantly. The present data support the potential utility of MIPO as a pharmacologic option for additional LDL-C lowering in these patients not adequately controlled under existing LLTs.
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