BACKGROUNDSerelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODSIn this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTSA total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONSIn this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.

Single-stranded oligodeoxynucleotides (ODN), containing nonmethylated cytosine–guanine motifs (CpG ODN), are recognized by the innate immune system as “danger signals.” CpG ODN are efficacious immunomodulators but require phosphorothioate (PT) or other backbone modifications for metabolic stability, which cause toxicities in mice and primates. We therefore designed a covalently closed DNA molecule (dSLIM®) where two single-stranded loops containing CG motifs are connected through a double-stranded stem in the absence of any nonnatural DNA component. The most promising immunomodulator, MGN1703, comprises two loops of 30 nucleotides containing three CG motifs each, and a connecting stem stem of 28 base pairs. MGN1703 stimulates cytokine secretion [interferon (IFN)-α, IFN-γ, interleukin (IL)-12, IL-6, and IL-2] and activates immune cells by increased expression of CD80, CD40, human leukocyte antigen (HLA)-DR and ICAM-1. Efficacy of immunomodulation strictly depends on the descriptive dumbbell shape and size of the molecule. Variations in stem length and loop size lead to reduced potency of the respective members of the dSLIM® class. In a representative mouse model, toxicities from injections of high amounts of a CpG ODN-PT and of MGN1703 were evaluated. The CpG ODN-PT group showed severe organ damage, whereas no such or other pathologies were found in the MGN1703 group. Oncological clinical trials of MGN1703 already confirmed our design.

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5001 Panobinostat is a potent class I/II/IV oral pan-deacetylase inhibitor which has shown promising clinical activity in patients with multiple myeloma and myelofibrosis, some with compromised renal and hepatic functions. The metabolism mediated by cytochrome P450 3A4 (CYP3A4) and non-CYP pathways is the major clearance pathway of panobinostat, with drug and metabolites being excreted in nearly similar amounts by liver/bile (54.3) and kidneys (40.6). However, the effects of impaired renal and hepatic function on panobinostat pharmacokinetics (PK) have not been elucidated. This study was designed to assess the impact of renal dysfunction on the PK and safety of panobinostat when compared to that of patients with normal renal function. Patients with advanced cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2, AST/ALT 2.5 ULN, normal bone marrow, and varying degrees of renal function were enrolled. Renal function was categorized as normal (as control), mild, moderate, or severe according to baseline 24-hour urine creatinine clearance (CrCL). Serial blood and urine panobinostat samples collected up to 96 and 24 hours, respectively, following a single PK test dose of 30 mg panobinostat were assessed for plasma and urine concentrations by liquid chromatography tandem mass spectrometry. PK parameters were derived from individual plasma or urine concentrationtime data using non-compartmental analysis. The following week, patients continued to receive panobinostat 30 mg orally 3 times a week. Dose was modified according to tolerability. PK results from 19 patients (15 male, 4 female) in this ongoing study are tabulated below. Median age was 66 years, and 13/19 patients had ECOG PS 1. Safety results were available in 18 patients. The most frequent drug-related adverse events (AEs) were grade (Gr) 34 thrombocytopenia in 7 patients (2 normal, 2 mild, 3 moderate) and Gr 3 fatigue in 5 patients (1 normal, 1 mild, 3 moderate). Other drug-related Gr 3 AEs included nausea, diarrhea, and hyperphosphatemia (1 normal patient each); asthenia and anemia (1 mild patient each); and ventricular bigeminy and dehydration (1 moderate patient). Two deaths on therapy not suspected to be study drugrelated occurred in the normal group. Although efficacy is not the primary study objective, PR was noted in 1 moderate patient with bladder cancer while SD was noted in 5 patients (2 pancreatic, 1 ovarian, 1 bladder and 1 renal cancer) as best overall response in these heavily pre-treated patients. The currently available results unexpectedly showed that patients with renal dysfunction did not have higher panobinostat exposures than the control group and the PK of panobinostat did not seem to have a distinct rank-order relationship with the severity of renal dysfunctionPK parameters median rangeRenal Function ClassificationNormal n7(CrCL 80 mL/min)Mild n6(50 CrCL 80 mL/min)Moderate n6(30 CrCL 50 mL/min)Tmax (hr)1.0 0.5-41.0 0.5-41.0 0.5-2Cmax (ng/mL)36.7 30.0-107.014.4 5.8-33.522.8 9.5-52.3AUC0-inf (nghr/mL)371 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{180}{441}\) \end{document}108 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{76}{234}\) \end{document}202 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{78}{329}\) \end{document}t1/2(hr)32.9 25.2-42.836.0 23.7-55.634.3 31.4-35.4ClR/F (L/hr)1.6 0.4-2.71.4 0.5-2.82.1 0.2-3.8Xu0-24hr ( of dose)1.8 1.2-4.00.6 0.2-1.30.7 0.2-1.9 AUC0-inf, area under the concentration-time curve from zero to infinity; Cmax, maximum concentration; t1/2, half-life; Tmax, time to maximum plasma concentration; Xu0-24h, percentage of drug excreted in urine; ClR/F, apparent renal clearance. Disclosures: Sharma: Novartis: Research Funding. Valera:Novartis Pharmaceuticals: Employment. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Mires:Novartis Pharmaceuticals: Employment. Porro:Novaratis Pharma AG: Employment. Woo:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Hess:Novartis: Equity Ownership.

5007 Panobinostat, an orally active hydroxamic acid derivative, is a potent class I/II/IV pan-deacetylase inhibitor that has shown promising clinical activity in hematologic and nonhematologic malignancies. Patients with cancer frequently have impaired renal or hepatic function. The major clearance pathway of panobinostat is metabolism mediated by cytochrome P450 3A4 (CYP3A4) and non-CYP pathways. Panobinostat and its metabolites are excreted in similar amounts in liver (54.3) and kidneys (40.6); however, the effects of impaired renal and hepatic function on panobinostat pharmacokinetics (PK) have not yet been elucidated. This study was designed to assess whether hepatic dysfunction has an impact on the PK of panobinostat and its safety when compared with that of patients with normal hepatic function. Patients with advanced cancer, Eastern Cooperative Oncology Group performance status (PS) 0 to 2, normal bone marrow function, and serum creatinine 1.5 upper limit of normal were enrolled. Hepatic function was categorized as normal (control), mild, moderate, or severe according to the baseline aspartate aminotransferase and total bilirubin levels per National Cancer InstituteCancer Treatment Evaluation Program criteria. Serial plasma samples were collected up to 96 hours following a single PK test dose of panobinostat 30 mg and its concentrations assessed by liquid chromatography tandem mass spectrometry. PK parameters were derived from individual plasma concentrationtime data using non-compartmental analysis. One week after the PK test dose, patients started continuous panobinostat 30 mg 3 times per week every week. Dose was modified according to tolerability. Ten patients with normal, 6 mildly, and 3 moderately impaired hepatic function were enrolled. The median age was 58 years (10 male; 9 female), and 95 of the patients had PS 0 to 1. Thirteen patients (7 normal (70), 4 mild (67), and 2 moderate (67)) experienced grade 3 toxicity suspected to be drug related. Grade 3 or 4 thrombocytopenia occurred in 3 patients in the normal group (30). Grade 3 nonhematologic adverse events included fatigue (4 normal (40), 1 mild (17), 1 moderate (33)), diarrhea (2 normal (20), 1 mild (17)), nausea (3 normal (30), 1 mild (17)), and vomiting (1 normal (10), 1 mild (17)). One patient in the moderate group was discontinued from the study because of grade 3 vasculitis (purpuric rash, proteinuria, anemia, and renal dysfunction). In these heavily pretreated patients, disease stabilization was noted in 3 patients, one with endometrial cancer, one with adenocarcinoma of the lung, and one with prostate cancer. The PK results from 19 patients of this ongoing study are summarized in the table below. The currently available results suggest that the PK and safety of panobinostat are comparable between patients with normal hepatic function and those with mild or moderate liver dysfunction PK parameters, median range Normal hepatic function (n 10) Mild hepatic dysfunction (n 5TUF1-1) Moderate hepatic dysfunction (n 3) Tmax (hr) 2 0.5-7 2 0.5-2 2 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{1}{4}\) \end{document} Cmax (ng/mL) 19.0 6.9-61.8 27.0 17.4-56.3 31.2 15.1-37.3 AUC0-inf (nghr/mL) 184 42.7-347 285 75.8-342 276 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{161}{425}\) \end{document} t1/2 (hr) 28.9 14.2-36.6 25.0 17.5-39.3 23.6 16.3-40.6 One patient was excluded from the PK analysis because of emesis. AUC0-inf, area under the concentration-time curve from zero to infinity; Cmax, maximum concentration; t1/2, half-life; Tmax, time to maximum plasma concentration. Disclosures: Hess: Novartis: Equity Ownership. Porro:Novaratis Pharma AG: Employment. Hengelage:Novartis Pharma AG: Employment, Equity Ownership. St-Pierre:Novartis Pharma AG: Employment. Gazi:Novartis Pharma AG: Employment. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Woo:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Sharma:Novartis: Research Funding.