Proprotein convertase subtilisin/kexin type 9 (PCSK9) has gained attention as a key regulator of serum low density lipoprotein cholesterol (LDL-C) levels. This novel protease causes the degradation of hepatic low density lipoprotein receptors. In humans, gain-of-function mutations in PCSK9 cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDL-C levels and cardiovascular risk. Previous studies have demonstrated that statins upregulate PCSK9 mRNA expression in cultured cells and animal models. In light of these observations, we studied the effect of atorvastatin on circulating PCSK9 protein levels in humans using a sandwich ELISA to quantitate serum PCSK9 levels in patients treated with atorvastatin or placebo for 16 weeks. We observed that atorvastatin (40 mg/day) significantly increased circulating PCSK9 levels by 34% compared with baseline and placebo and decreased LDL-C levels by 42%. These results suggest that the addition of a PCSK9 inhibitor to statin therapy may result in even further LDL-C decreases. The serum protease proprotein convertase subtilisin/ kexin type 9 (PCSK9) has gained tremendous attention as a potential key regulator of serum low density lipoprotein cholesterol (LDL-C) levels (1-3). PCSK9 is a protease made by the liver that acts to degrade hepatic low density lipoprotein receptors (LDLRs) (4-10). The mechanism by which PCSK9 degrades LDLRs is extremely complex and is only beginning to be understood. It was recently suggested that the protease itself does not have to be proteolytically active to cause degradation of the LDLR but rather binds to the LDLR and subsequently targets it for intracellular destruction within the hepatocyte (11-13). Regardless of the exact mechanism, the result of LDLR levels being decreased is that the liver has a decreased ability to bind LDL from the circulation and serum LDL-C levels increase. Therefore, mutations in PCSK9 can have dramatic effects on serum LDL-C levels in humans.Patients with gain-of-function mutations of PCSK9 manifest severe familial hypercholesterolemia and accompanying increased cardiovascular risk (14-17). These mutations in PCSK9 account for ?10-25% of familial dominant hypercholesterolemia cases that could not be explained by mutations in either the LDLR or apolipoprotein B (apoB) (14-17). In contrast, heterozygous subjects with loss-of-function mutations in PCSK9, including mutations that prevent the self-cleavage and secretion of the protein itself, have significantly decreased levels of serum LDL-C and dramatically decreased cardiovascular risk (18)(19)(20). Approximately 2% of African-Americans carry such mutations, with an accompanying 80-90% decreased risk of serious cardiovascular events (18). Recently, the first compound heterozygote for PCSK9 loss-of-function mutations was described. This subject, a healthy 32 year old female, had an extremely low serum LDL-C level of 14 mg/dl (20).Interestingly, statins have been shown to increase the activity/nuclear t...

CSL112 is apoA-I purified from human plasma and reconstituted with phosphatidylcholine (PC) to form high-density lipoprotein (HDL)-particles suitable for infusion. CSL112 is in development for the potential treatment of acute coronary syndromes (ACS) by optimizing cholesterol efflux. This study assesses the pharmacokinetics (PK), safety and tolerability of CSL112. Repeat doses of CSL112 or placebo were administered intravenously once- (3.4 g or 6.8 g) or twice-weekly (3.4 g) to healthy subjects in a placebo-controlled, randomized (3 CSL112: 1 placebo), ascending-dose study (NCT01281774). Twenty-seven subjects received CSL112 and nine received placebo. Study endpoints included plasma apoA-I and PC concentrations and specific PK parameters. CSL112 infusions immediately produced robust increases in apoA-I concentration in a dose-proportional manner, reaching levels higher than observed with currently available or investigational HDL products. After infusion of CSL112, apoA-I levels remained above baseline for approximately 3 days. Multiple infusions of CSL112 were safe and well tolerated with no evidence of major organ toxicity or immunogenicity. CSL112 may provide a novel option to rapidly transport cholesterol from atherosclerotic plaque to the liver and reduce early recurrent events following ACS. The data presented here support continued clinical development of CSL112 in patient populations.

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Background: Most patients with acute myeloid leukemia (AML) die from relapsed disease, including those who attain complete remission (CR). Post-remission treatment designed to kill chemoresistant leukemia stem cells (LSC) and eradicate minimal residual disease (MRD) could delay or prevent relapse. The Interleukin-3 Receptor alpha chain (IL3Rα/CD123) is overexpressed on LSC and AML blasts compared to normal hematopoietic cells. CSL362 is a fully humanized anti-CD123 monoclonal antibody, engineered for greater antibody-dependent cell-mediated cytotoxicity (ADCC) by high affinity for NK cell CD16. CSL362 has potent activity against AML cells in vitro and in mouse xenograft models. In this Phase 1 study we evaluated the safety, PK and immunogenicity of repeat doses of CSL362 as post-remission treatment for AML patients. Exploratory endpoints include effects on CD123+ normal blood cells (basophils and pDC), NK cells, levels of serum cytokines, CSL362 binding to CD123 on monocytes, and MRD. Methods: Eligibility criteria include CD123+ AML in 1st or 2nd CR /CRp, adverse risk factors (disease history, cytogenetics, molecular mutations or MRD), and no plan for allogeneic stem cell transplantation. Intravenous CSL362 is given over 3 hours every 14 days x 6 doses. Final evaluation for safety is at week 16 and for remission status is at week 24. Sequential cohorts of 3 - 6 pts have been treated at 5 dose levels, from 0.3 to 9.0 mg/kg. Serum is assayed centrally for cytokines, PK and immunogenicity. Standardized whole blood biomarker assays are performed at each site by flow cytometry, and analyzed centrally. Bone marrow is sampled at baseline, weeks 5 and 12. Results: To date, 25 pts (16M, 9F) median age 66 yr (range 32-83 yr) have received 118 infusions of CSL362; 15 pts received all 6 doses, 6 pts relapsed on study, 1 pt was withdrawn for an SAE (infusion reaction); 3 pts are ongoing. Adverse events related to CSL362 in ≥ 10% of pts (CTCAE V4 grades) were infusion reactions (12 pts; 15 grade 1-2, 2 grade 3 events), increased C-reactive protein (3 pts; 4 grade 2 events), hypertension (3 pts; 6 grade 1-2, 2 grade 3 events), and hypotension (3 pts; 2 grade 2, 1 grade 3 events). There have been 3 dose limiting toxicities (1 hypertension, 2 infusion reactions), and 3 related SAEs (2 infusion reactions, 1 transient delirium). Infusion reactions have been manageable with supportive care. A protocol amendment to allow hydrocortisone premedication has been effective to prevent or reduce the severity of reactions. At follow-up ≥ 6 months from first dose, 10 of 20 evaluable pts maintained CR. Median duration of CR from start of CR and ongoing at last follow-up was 34+ weeks [range 26 – 52+ weeks]. Of 6 evaluable pts who were MRD positive at baseline, 3 converted to negative on study. Biomarker assays show rapid, complete in vivo depletion of basophils and pDC (cells that have high expression of CD123) at all dose levels, ≤ 6 hours post-dose. Depletion is sustained for ≥ 15 days at doses ≥ 3.0 mg/kg. NK cells (which do not express CD123) in blood fall transiently then recover from day 3 post-dose to ≥ baseline by day 8. CSL362 saturation of CD123 on monocytes (cells that have low CD123 expression) in vivo occurs rapidly post-dose at all dose levels and is sustained ≥ 15 days at dose levels ≥ 3.0 mg/kg. Serum CSL362 concentration demonstrated a nonlinear PK profile with slower clearance and longer half-lives at higher doses. PK profiles at doses above 3 mg/kg seem to be dose proportional. The half-life for the two higher dose levels is 4-5 days. Cytokine assays showed increased levels of GM-CSF, IFN-γ, IL-1β, IL-6, IL-8, TNF-α, IL-15 and IL-1RA after the 1st dose, returning to baseline by day 8. Levels after dose 6 were lower than after the dose 1. Low level anti-CSL362 antibody titers were detected coincident with trough concentrations of CSL362 in 6 of 18 pts tested thus far, with no effects on PK or association with adverse events. Conclusion: CSL362 is safe and well tolerated in AML pts with CR/CRp and high risk of relapse. Potent, targeted ADCC of normal cells (basophils and pDC) that highly express CD123 is evident at all dose levels tested, with durable depletion at ≥ 3.0 mg/kg. At dose levels ≥ 3.0 mg/kg, saturation of CD123 on marker monocytes is durable for the inter-dose interval. These data indicate it is likely that dose levels ≥ 3.0 mg/kg are required to maximize ADCC against residual AML. A phase 2 study of CSL362 is planned. Figure 1 Figure 1. Disclosures Roboz: Glaxo SmithKline: Consultancy; Celgene: Consultancy; Agios: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Busfield:CSL Limited: Employment. Barnden:CSL Limited: Employment. Sedgmen:CSL Limited: Employment. Ghosh:CSL Limited: Employment. Hosback:CSL Limited: Employment. Davis:CSL Limited: Employment. Dyson:CSL Limited: Employment. Dasen:CSL Behring: Employment. DeWitte:CSL Behring: Employment, Equity Ownership. Bensen-Kennedy:CSL Behring: Employment.