Eveline Oestreicher Stock

Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients With cholesteryl ester storage disease

Cholesteryl ester storage disease (CESD), an inherited deficiency of lysosomal acid lipase (LAL), is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. To assess the clinical effects and safety of the recombinant human LAL, sebelipase alfa, nine patients received four once‐weekly infusions (0.35, 1, or 3 mg·kg−1) in LAL‐CL01, which is the first human study of this investigational agent. Patients completing LAL‐CL01 were eligible to enroll in the extension study (LAL‐CL04) in which they again received four once‐weekly infusions of sebelipase alfa (0.35, 1, or 3 mg·kg−1) before transitioning to long‐term every‐other‐week infusions (1 or 3 mg·kg−1). Sebelipase alfa was well tolerated, with mostly mild adverse events unrelated to sebelipase alfa. No antidrug antibodies were detected. Transaminases decreased in patients in LAL‐CL01 and increased between studies. In seven patients receiving ongoing sebelipase alfa treatment in LAL‐CL04, the mean ± standard deviation (SD) decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL‐CL01 were 46 ± 21 U/L (−52%) and 21 ± 14 U/L (−36%), respectively (P ≤ 0.05). Through week 12 of LAL‐CL04, these seven patients also showed mean decreases from baseline in total cholesterol of 44 ± 41 mg/dL (−22%; P = 0.047), low density lipoprotein‐cholesterol of 29 ± 31 mg/dL (−27%; P = 0.078), and triglycerides of 50 ± 38 mg/dL (−28%, P = 0.016) and increases in high density lipoprotein‐cholesterol of 5 mg/dL (15%; P = 0.016). Conclusion: These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with CESD is well tolerated, rapidly decreases serum transaminases, and that these improvements are sustained with long‐term dosing and are accompanied by improvements in serum lipid profile. (HEPATOLOGY 2013;58:950–957)

Cardiovascular disease in women.

Gender-specific data focused on cardiovascular disease (CVD) are becoming increasingly available. This is of great importance, given that CVD has become the number 1 killer of women, and unlike for men, mortality rates do not seem to be declining. Many factors are cited as the causes of sex-based differences, including delays in recognizing symptoms, underutilization of diagnostic tests and treatments, as well as anatomic, physiological, and genetic factors. Evidence of fundamental biological differences in vascular function and the underlying pathologic processes is only beginning to elucidated, motivated by growing evidence of differences in clinical presentations and outcomes between men and women. The good news is that we are starting to see improvements in outcomes for women, such as after coronary revascularization; decrease in complication rates with the advent of new techniques, such as radial access for cardiac catheterizations; as well as increased participation of women in clinical trials. The underlying mechanisms of ischemic heart disease remain to be elucidated, and will help guide therapy and ultimately may explain the higher prevalence of : subendocardial myocardial infarctions, spontaneous arterial dissections, plaque erosion, increased vasospastic disorders, such as coronary microvascular disease, and pulmonary hypertension in women compared with men. We have made great progress in understanding gender-related differences in CVDs, but much remains to be done to optimize the prevention of CVD for both men and women.

Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency.

BACKGROUND & AIMS Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. METHODS Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. RESULTS 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patients event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. CONCLUSIONS Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function.

IMPORTANCE The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE). OBJECTIVES To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism. DESIGN, SETTING, AND PARTICIPANTS Whole-exome sequencing was performed on the patients DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the probands mother, wife, 2 daughters, and normolipidemic control participants. MAIN OUTCOME MEASURES Whole-exome sequencing, lipoprotein analysis, and neurocognitive function. RESULTS The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patients apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally. CONCLUSIONS AND RELEVANCE Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

Advanced Lipid Testing Uncovers Hidden Cardiovascular Disease Risk: A Case Control Analysis

Lead Author’s Financial Disclosures: None Study Funding: This study was funded by Boston Heart Diagnostics on a contract and approved protocol with the Cardiovascular Research Institute, University of California, San Francisco, CA. All analyses were run in a blinded fashion. Background/Synopsis: Recommended standard lipid testing includes total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), and calculated low density lipoprotein cholesterol (LDL-C), which many healthcare providers view as providing insufficient information about cardiovascular disease (CVD) risk. Objective/Purpose: To compare standard lipid profile testing with advanced lipid and inflammatory marker analysis in a CVD case-control study. Methods: In addition to standard methods, we measured serum direct LDL-C, small dense LDL-C (sdLDL-C), very low density lipoprotein cholesterol (VLDL-C), apolipoprotein (apo) B, apoA-I, lipoprotein(a) or Lp(a), HDL particles by gel electrophoresis and apoA-I immunoblotting, high sensitivity C reactive protein (hsCRP), and serum amyloid A (SAA) in 298 documented CVD cases (mean age 68.4 years, 54% male, 46% female) and 609 age and gender matched controls. All subjects were off lipid altering medications. All cases were sampled more than 4 weeks after any CVD event. All subjects had blood drawn after an overnight fast. Results: In male and female cases, median TC levels were 1% and 3% higher, TG levels 19% and 29% higher, direct LDL-C 2% and 17% higher, sdLDL-C 46% and 46% higher, VLDL-C 22% and 4% higher, apoB 6% and 17% higher, and Lp(a) 26% and 70% higher, respectively, than in matched controls. In male and female cases, median HDL-C levels were 25% and 26% lower, apoA-I 9% and 7% lower, while apoA-I values in HDL particles were 30% and 26% lower in very large a-1 HDL, 9% and 11% lower in large a-2 HDL, 4% and 4% lower in medium a-3 HDL, 13% and 6% lower in small a-4 HDL, and 16% and 15% higher in very small preb-1 HDL as compared to matched controls. In male and female cases, median hsCRP levels were 113% and 178% higher, and SAA levels were 41% and 43% higher than in matched controls. Values for sdLDL-C, Lp(a), apoA-I in preb-1 HDL and a-1 HDL, hsCRP, and SAA were all significantly different (p,0.001) in male and female cases versus controls. Conclusions: Our results indicate that advanced lipid and inflammatory marker testing provides significantly more information distinguishing CVD cases from controls than does standard lipid testing. Our data supports the use of advanced testing in CVD prevention, especially in CVD patients being considered for proprotein convertase subtilisin/kexin type 9 inhibitor therapy.

STATIN TREATMENT REDUCES PEBETA-1 HDL LEVELS IN DYSLIPIDEMIC PATIENTS

Prebeta-1 HDL is a small molecular species of high-density lipoprotein (HDL) that is the principal acceptor of cholesterol effluxed from macrophages. High prebeta-1 HDL levels are associated with increased risk of structural coronary artery disease (CAD) and myocardial infarction. Prebeta-1 HDL

Sebelipase Alfa Improves Dyslipidemia in Patients with Cholesteryl Ester Storage Disease

Radhika Tripuraneni, MD, MPH, Reena Sharma, MD, Manisha Balwani, MD, MS, Chris Bourdon, MD, Simeon Boyd, MD, Catherine Breen, MD, Anthony Quinn, MBChB, PhD, Eugene Schneider, MD, John Kane, MD, PhD, Bruce Kessler, MD, Patrick Deegan, MD, Greg Enns, MD, Eveline Stock, MD, Tomas Honzik, MD, PhD, V era Malinov a, MuDr., Chet Whitley, MD, PhD, Vassili Valayannopoulos, MD, PhD, Jennifer Burg, BA, (San Francisco, California)