Emma A. Meagher

Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study

BACKGROUND Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. METHODS We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. FINDINGS 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0·0001) at week 56 and 38% (-52 to -24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. INTERPRETATION Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. FUNDING FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

Indices of lipid peroxidation in vivo: strengths and limitations

Oxidant stress has been widely implicated as a mechanism of disease, yet clinical trials of antioxidants have not included a biochemical basis for dose selection or patient inclusion. Many of the indices traditionally employed to assess lipid peroxidation have relied on measurements performed in ex vivo systems of questionable relevance to events in vivo. Commonly employed in vivo indices of lipid peroxidation are constrained by such issues as the nonspecificity or instability of the target anylate, contamination of the anylate by events ex vivo, and nonspecificity of analytical methodology. More recently, specific methodology based on mass spectrometry has been applied to both 4-hydroxynonenal and a variety of isoprostanes in human biological fluids. Measurement of these compounds in urine reflects lipid peroxidation in vivo and offers a noninvasive approach that may be readily applied to clinical trials.

Alcohol-induced generation of lipid peroxidation products in humans

To address the hypothesis that elevated blood alcohol increases systemic oxidant stress, we measured urinary excretion of isoprostanes (iPs), free radical-catalyzed products of arachidonic acid. Ten healthy volunteers received acute doses of alcohol (Everclear-R) or placebo under randomized, controlled, double-blind conditions. Urinary iPF2a-III increased in a time- and dosage-dependent manner after dosing with alcohol, with the peak urinary iPF2a-III excretion correlating with the rise in blood alcohol. To determine whether oxidant stress was associated with alcohol-induced liver disease (ALD), we then studied the excretion of iP in individuals with a documented history of alcohol-induced hepatitis or alcohol-induced chronic liver disease (AC). Both urinary iPF2a-III and urinary iPF2a-VI were markedly increased in patients with acute alcoholic hepatitis. In general, urinary iPF2a-III was significantly elevated in cirrhotic patients, relative to controls, but excretion was more pronounced when cirrhosis was induced by alcohol than by hepatitis C. Excretion of iPF2a-VI, as well as 4-hydroxynonenal and the iPF2a-III metabolite, 2,3-dinor-5, 6-dihydro-iPF2a-III, was also increased in AC. Vitamin C, but not aspirin, reduced urinary iPs in AC. Thus, vasoactive iPs, which serve as indices of oxidant stress, are elevated in the urine in both acute and chronic ALD. Increased generation of iPs by alcohol in healthy volunteers is consistent with the hypothesis that oxidant stress precedes and contributes to the evolution of ALD.

Safety and Effectiveness of Niaspan When Added Sequentially to a Statin for Treatment of Dyslipidemia

Niaspan, when added to a stable dose of a statin in 66 subjects, was found to be safe and highly effective in improving lipid parameters. Subgroup analyses demonstrated its effectiveness in lowering low-density lipoprotein cholesterol in persons not at the National Cholesterol and Education Program low-density lipoprotein cholesterol target and in raising high-density lipoprotein cholesterol in persons with levels < 40 mg/dl.

Antioxidant Therapy and Atherosclerosis: Animal and Human Studies

Oxidation of LDL cholesterol appears to play a central role in the pathogenesis of atherosclerosis. Animal models of atherosclerosis have elucidated this process and have demonstrated an antioxidant effect of vitamin administration that has been correlated with delayed progression or regression of atherosclerosis. However, clinical trials of antioxidants present a confused picture. Explanations proposed for the discrepancy in results include differences in patient characteristics, the antioxidant content of their diets and dose selection. However, a striking feature of these trials is the absence of a biochemical basis for patient inclusion or dose selection. Reliable, quantitative indices of free radical induced modification of lipids, such as F2-isoprostanes have emerged. Future trials of anti-oxidant therapy in cardiovascular disease should be targeted toward patients with high levels of oxidant stress or patients with depletion of endogenous antioxidants. The dose of anti-oxidant should be chosen based on a surrogate readout, such as F2 isoprostanes, that is a reliable, reproducible and easily obtainable in vivo measure of oxidant stress.

Evaluating Research Mentors Working in the Area of Clinical Translational Science: A Review of the Literature

The goal of this paper is to review the evaluation of mentors with a focus on training new investigators in clinical translational science. These scholars include physicians and Ph.D. scientists who are generally assistant professors in clinical departments. This white paper is one of a series of articles focused on the programmatic elements of effective mentoring practices and the “current state of the art.” Evaluating mentor performance and providing formative feedback can lead to stronger mentoring and ultimately lead to increased success of new clinical and translational investigators. While there is general agreement that mentor evaluation can be helpful, the process is difficult. Trainees are reluctant to share negative experiences and to rate their mentors. Mentors are not sure they want to be evaluated. Program leaders are not sure how to effectively use the information. This white paper provides mentees, mentors, and program leaders with new perspectives on mentor evaluation and ideas for future research. Clin Trans Sci 2011; Volume 4: 353–358

Balancing gastroprotection and cardioprotection with selective cyclo-oxygenase-2 inhibitors: clinical implications.

NSAIDs have been the mainstay of treatment in the management of pain and inflammation associated with chronic inflammatory disorders. They are effective. However, complications arising from chronic NSAID use are common and are primarily due to gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulceration and GI bleeds. GI toxicity has been attributed to the blockade of the cyclo-oxygenase (COX)-1-mediated generation of the cytoprotective prostanoids, such as prostaglandin (PG) E2 and PGI2 (prostacyclin). More recently, selective COX-2 inhibitors (‘coxibs’) were designed to inhibit the production of COX-2-dependent inflammatory prostanoids and to leave intact the cytoprotective COX-1 products.The coxibs, while exhibiting similar efficacy to traditional NSAIDs in controlled clinical trials of their efficacy in chronic inflammatory conditions, such as osteoarthritis and rheumatoid arthritis, have been associated with a reduced incidence of surrogate or actual indices of GI toxicity.However, concerns regarding cardiovascular safety in high-risk patients have evolved. These concerns were driven initially by the concept that inhibition of COX-2-derived endothelial PGI2 without concomitant inhibition of platelet thromboxane A2 would result in increased cardiovascular risk. This was borne out in the Vioxx Gastrointestinal Outcomes Research study of rofecoxib, but not demonstrated in the Celecoxib Long Term Arthritis Safety Study trial.Further elucidation of the relative roles of COX-1- and COX-2-generated prostanoids has enabled a greater understanding of the biology of these pathways. However, it is still not completely clear how this understanding may be appropriately translated into clinical medicine.

Long-Term Efficacy and Safety of the Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide in Patients With Homozygous Familial Hypercholesterolemia

Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression.1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins. In a pivotal 78-week open-label trial, lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia.2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat. Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306). Patients continued on lomitapide at the maximally tolerated dose until transition to commercial or compassionate lomitapide. Lipid-lowering therapies, including apheresis, could be modified at the investigator’s discretion if LDL-C was <100 mg/dL. Both studies received institutional review board and regulatory approval, and all participants provided informed consent. Significance of the percent changes from baseline was assessed using a mixed linear model; correlations were assessed with Pearson correlation. Nineteen (mean age, 30.4 years; 10 male/9 female) of the 23 patients who completed the pivotal trial enrolled in the extension trial, and 17 completed week 126 (78 weeks pivotal + 48 weeks extension) assessments (primary efficacy end point). Three patients discontinued prematurely (relocation, elevated transaminases and excess alcohol, sudden cardiac death). The median lomitapide dose remained mostly consistent at 40 mg (range, 20–60 mg) from week 36 in the pivotal study to week 282 in the extension trial. Overall, the median treatment duration with lomitapide across both trials was 5.1 years (range, 2.1–5.7 years). Among the 17 patients who completed week 126, LDL-C decreased from 356±127 mg/dL at baseline to …

Long-term clinical results of microsomal triglyceride transfer protein inhibitor use in a patient with homozygous familial hypercholesterolemia

We report the case of a 49-year-old woman with homozygous familial hypercholesterolemia and a complicated cardiovascular history, treated for 5 years with a microsomal triglyceride transfer protein inhibitor in addition to her other lipid-lowering therapy.

Core informatics competencies for clinical and translational scientists: what do our customers and collaborators need to know?

Since the inception of the Clinical and Translational Science Award (CTSA) program in 2006, leaders in education across CTSA sites have been developing and updating core competencies for Clinical and Translational Science (CTS) trainees. By 2009, 14 competency domains, including biomedical informatics, had been identified and published. Since that time, the evolution of the CTSA program, changes in the practice of CTS, the rapid adoption of electronic health records (EHRs), the growth of biomedical informatics, the explosion of big data, and the realization that some of the competencies had proven to be difficult to apply in practice have made it clear that the competencies should be updated. This paper describes the process undertaken and puts forth a new set of competencies that has been recently endorsed by the Clinical Research Informatics Workgroup of AMIA. In addition to providing context and background for the current version of the competencies, we hope this will serve as a model for revision of competencies over time.