x. This is the x position of the points on the attractor. (v) In• crement p by a small amount (in this figure, p-+p+ ~),and set the new initial point (x 0 ,y0) to the last point produced in the last step, and return to step (iii). Continue until p reaches the rightmost value Pmar. in the figure (in (a), Pmax =0.10). (vi) If Pmaxis reached, go to step (v), except now decrease p by a small amount every time (here p-+p-~) until Pmin is reached again. Step (vi) enables us to plot the x positions of coexisting attractors. The same steps are used to produce Figs. 3-5. The numbers of iterations in steps (iii) and (iv), and the amount of increment in steps (v) and (vi) are varied for each figure.

Mipomersen significantly reduced LDL cholesterol, apolipoprotein B, and lipoprotein(a) in patients with hypercholesterolemia with, or at risk for, coronary heart disease not controlled by existing therapies. (Safety and Efficacy of Mipomersen [ISIS 301012] as Add-On Therapy in High Risk Hypercholesterolemic Patients; NCT00770146).

Background— Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease. Methods and Results— This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and coronary artery disease on maximally tolerated statin and LDL-C ≥2.6 mmol/L (≥100 mg/dL) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and magnetic resonance imaging assessment of hepatic fat. Of 124 randomized patients (41 placebo, 83 mipomersen), 114 (41 placebo, 73 mipomersen) completed treatment. Mean (95% confidence interval) LDL-C decreased significantly with mipomersen (−28.0% [−34.0% to −22.1%] compared with 5.2% [−0.5% to 10.9%] increase with placebo; P <0.001). Mipomersen significantly reduced apolipoprotein B (−26.3%), total cholesterol (−19.4%), and lipoprotein(a) (−21.1%) compared with placebo (all P <0.001). No significant change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and influenza-like symptoms. Five mipomersen patients (6%) had 2 consecutive alanine aminotransferase values ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo ( P <0.001). Conclusions— Mipomersen is an effective therapy to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00706849.

AimsTo evaluate the efficacy and safety of extended dosing with mipomersen in patients with familial hypercholesterolaemia (HC) taking maximally tolerated lipid-lowering therapy.Methods and resultsA planned interim analysis of an ongoing, open-label extension trial in patients (n = 141) with familial HC receiving a subcutaneous injection of 200 mg mipomersen weekly plus maximally tolerated lipid-lowering therapy for up to 104 weeks. The mean changes in low-density lipoprotein cholesterol (LDL-C) from baseline to weeks 26 (n = 130), 52 (n = 111), 76 (n = 66), and 104 (n = 53) were −28, −27, −27, and −28%; and in apolipoprotein B −29, −28, −30, and −31%, respectively. Reductions in total cholesterol, non-high-density lipoprotein-cholesterol, and lipoprotein(a) were comparable with decreases in LDL-C and apolipoprotein B levels. Mean high-density lipoprotein cholesterol increased from baseline by 7 and 6% at weeks 26 and 52, respectively. The long-term safety profile of mipomersen was similar to that reported in the associated randomized placebo-controlled Phase 3 trials. Adverse events included injection site reactions and flu-like symptoms. There was an incremental increase in the median liver fat during the initial 6–12 months that appeared to diminish with continued mipomersen exposure beyond 1 year and returned towards baseline 24 weeks after last drug dose suggestive of adaptation. The median alanine aminotransferase level showed a similar trend over time.ConclusionLong-term treatment with mipomersen for up to 104 weeks provided sustained reductions in all atherosclerotic lipoproteins measured and a safety profile consistent with prior controlled trials in these high-risk patient populations.Clinicaltrials.govNCT00694109.