Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2010 年３月 25 日 8:30-8:55 ８階 医局 Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I, Baxter JD, Angelin B. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med Mar 11;362(10): Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, Lachmann RH, Gaudet D, Tan JL, Chasan-Taber S, Tribble DL, Flaim JD, Crooke ST. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet Mar 20;375(9719):

From the Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (P.W.L.); Karo Bio, Huddinge ( J.D.K., B.C.), the Faculty of Health Sciences, Linkoping University and Stockholm Heart Center, Stockholm (A.G.O.), and the Department of Endocrinology, Metabolism, and Diabetes, and Center for Biosciences, Department of Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm (B.A.) — all in Sweden; the Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, Aurora (E.C.R.); the Department of Medicine, North Shore University Hospital and the Feinstein Institute for Medical Research, Manhasset, NY (I.K.); and the Center for Diabetes Research, Methodist Hospital Research Institute, Houston (J.D.B.). N Engl J Med 2010;362:

Background Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided.

Method We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either eprotirome (at a dose of 25, 50, or 100 μg per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects on the heart, bone, and pituitary.

Mechanism of Action The reduction of LDL (in humans) ● 1) increased expression of the hepatic LDL- receptor gene. Accelerate clearance of cholesterol by the liver (in rodents) by ● 1) increasing the high-density lipoprotein (HDL) receptor called scavenger receptor B1 (SR-B1) ● 2) increasing the activity of cholesterol 7α- hydroxylase ● 3) increasing fecal excretion of cholesterol and bile acids

Study Design

Percentage changes in serum Lp(a) lipoprotein concentration as a function of the baseline Lp(a) level for individual patients. Individuals with baseline values above 70 mg/dL represented 34% of the study patients.

Study Patients’ Vital Signs

Female Study Patients

Male Study Patients

Results The addition of placebo or eprotirome at a dose of 25, 50, or 100 μg daily to statin treatment for 12 weeks reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively, (mean reduction from baseline, 7%, 22%, 28%, and 32%). Similar reductions were seen in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Eprotirome therapy was not associated with adverse effects on the heart or bone. No change in levels of serum thyrotropin or triiodothyronine was detected, although the thyroxine level decreased in patients receiving eprotirome.

Conclusion In this 12-week trial, the thyroid hormone analogue eprotirome was associated with decreases in levels of atherogenic lipoproteins in patients receiving treatment with statins. (ClinicalTrials.gov number, NCT )

Message 甲状腺ホルモンでコレステロールが低下する。 甲状腺ホルモン類似物質で甲状腺機能に影響させず にコレステロールのみを低下させることが可能とい うことが分かった。 甲状腺機能異常でのコレステロール値変化は代謝状 態の変化による２次的変化というのではなさそう。 これまで ezetimibe や torcetrapib (CETP 阻害剤 ) では スタチンに上乗せで LDL-C が低下したり HDL-C が上 昇しても心血管障害減少には結びつかなかったが， 新しい候補ができた！ それにしても，骨代謝マーカーを測定したというの だが記載がない？

Lancet 2010; 375: 998–1006

Aim Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL- receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease.

Mipomersen (ISIS ) is a 20-mer antisense oligonucleotide that specifically binds apolipoprotein B mRNA and leads to inhibition of protein translation, reducing the synthesis and secretion of lipoproteins LDL and VLDL that contain apolipoprotein B. Mipomersen binding to the mRNA sequence encoding apolipoprotein B results in degradation of the apolipoprotein B mRNA by ribonuclease H, an endoribonuclease that specifically hydrolyses the phosphodiester bonds of RNA when hybridised to DNA, thereby inhibiting translation of the apolipoprotein B protein, and effectively reducing concentrations of apolipoprotein B100. Mipomersen’s half life is about 30 days. (~3 to 6 months to steady state)

Method This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confi rmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs ≥50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT

Trial profile

The most frequent allele was D206E (familial hyper- cholesterolaemia Afrikaner-1), which was present in 24 patients, 14 of whom were true homozygotes, which is consistent with the fact that many of the study population were from South Africa. All patients apart from one were being treated with lipid-lowering drugs (50/51, 98%), 12 (24%) of whom were taking a statin alone (six mipomersen, six placebo) and 38 (76%) of whom were taking a statin in combination with at least one other lipid-lowering agent (27 mipomersen, 11 placebo), most commonly ezetimibe (37/50, 74%). Most patients taking a statin (44/50, 88%) were receiving the maximum dose.

LDL-C10 mmol/L = 386 mg/dl 11.4 = 440mg/dl 8.4 ⇒ 325mg/dl Triglyceride 1 mmol/L = 88.5 mg/dl

Figure 2: Mean percentage change from baseline (week 0) to primary efficacy time point for LDL cholesterol (A), apolipoprotein B (B), and lipoprotein(a) (C) Error bars indicate 95% CI.

Figure 3: Percentage change in LDL cholesterol from baseline for individual patients Response is shown graphically for individual patients in the mipomersen and placebo treatment groups. Each vertical bar represents one patient, arranged in order of response.

No patients developed antibodies to mipomersen.

Hy’s Law cases have the following three components 1.The drug causes hepatocellular injury, generally shown by more frequent 3-fold or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control agent or placebo. 2.Among subjects showing such AT elevations, often with ATs much greater than 3xULN, some subjects also show elevation of serum TBL to >2xULN, without initial findings of cholestasis (serum alkaline phosphatase (ALP) activity >2xULN). 3.No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C, preexisting or acute liver disease, or another drug capable of causing the observed injury. No cases of ALT more than eight times ULN were noted and no patient met Hy’s law.

Results 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11 ・ 4 mmol/L (SD 3 ・ 6) in the mipomersen group and 10 ・ 4 mmol/L (3 ・ 7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (–24 ・ 7%, 95% CI –31 ・ 6 to –17 ・ 7) than with placebo (–3 ・ 3%, –12 ・ 1 to 5 ・ 5; p=0 ・ 0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal.

Conclusion Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hyper cholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins. Funding ISIS Pharmaceuticals and Genzyme Corporation.

In a small, open-label, dose-escalation pilot study in patients with homozygous familial hypercholesterolaemia receiving maximum tolerated lipid-lowering treatment, 300 mg mipomersen administered once per week for 11 weeks after a 2-week loading period produced a 45–51% reduction in LDL cholesterol concentrations in three patients not undergoing apheresis. discussion

Message アンチセンス治療は抗癌剤とか AIDS など特殊 な感染症の治療かと思っていたら脂質異常症の 治療にも使える！ 副作用はさすがにちょっと問題かもしれないが， 血漿交換が必要なくらいの高コレステロール血 症では評価されてくる可能性がある。