Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia.

BACKGROUND: Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver. METHODS: We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24. RESULTS: A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; and for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran. CONCLUSIONS: In patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.).

Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia.

BACKGROUND: Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non-high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)-mediated inhibition of lipoprotein lipase. METHODS: We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24. RESULTS: A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of -49.8 percentage points (95% confidence interval [CI], -59.0 to -40.6) with the 10-mg-quarterly dose, -56.0 percentage points (95% CI, -65.1 to -46.8) with the 25-mg-quarterly dose, -62.4 percentage points (95% CI, -71.5 to -53.2) with the 50-mg-quarterly dose, and -44.2 percentage points (95% CI, -53.4 to -35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose. CONCLUSIONS: In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted. (Funded by Arrowhead Pharmaceuticals; MUIR ClinicalTrials.gov number NCT04998201.).

Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial.

Importance: Severe hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains. Objective: To determine the tolerability, efficacy, and dose of plozasiran, an APOC3-targeted small interfering-RNA (siRNA) drug, for lowering triglyceride and apolipoprotein C3 (APOC3, regulator of triglyceride metabolism) levels and evaluate its effects on other lipid parameters in patients with sHTG. Design, Setting, and Participants: The Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (SHASTA-2) was a placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial enrolling adults with sHTG at 74 centers across the US, Europe, New Zealand, Australia, and Canada from May 31, 2021, to August 31, 2023. Eligible patients had fasting triglyceride levels in the range of 500 to 4000 mg/dL (to convert to millimoles per liter, multiply by 0.0113) while receiving stable lipid-lowering treatment. Interventions: Participants received 2 subcutaneous doses of plozasiran (10, 25, or 50 mg) or matched placebo on day 1 and at week 12 and were followed up through week 48. Main Outcomes and Measures: The primary end point evaluated the placebo-subtracted difference in means of percentage triglyceride change at week 24. Mixed-model repeated measures were used for statistical modeling. Results: Of 229 patients, 226 (mean [SD] age, 55 [11] years; 176 male [78%]) were included in the primary analysis. Baseline mean (SD) triglyceride level was 897 (625) mg/dL and plasma APOC3 level was 32 (16) mg/dL. Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001), driven by placebo-adjusted reductions in APOC3 of -77% (95% CI, -89.1% to -65.8%; P < .001) at week 24 with the highest dose. Among plozasiran-treated patients, 144 of 159 (90.6%) achieved a triglyceride level of less than 500 mg/dL. Plozasiran was associated with dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) level, which was significant in patients receiving the highest dose (placebo-adjusted LS-mean increase 60% (95% CI, 31%-89%; P < .001). However, apolipoprotein B (ApoB) levels did not increase, and non-high-density lipoprotein cholesterol (HDL-C) levels decreased significantly at all doses, with a placebo-adjusted change of -20% at the highest dose. There were also significant durable reductions in remnant cholesterol and ApoB48 as well as increases in HDL-C level through week 48. Adverse event rates were similar in plozasiran-treated patients vs placebo. Serious adverse events were mild to moderate, not considered treatment related, and none led to discontinuation or death. Conclusions and Relevance: In this randomized clinical trial of patients with sHTG, plozasiran decreased triglyceride levels, which fell below the 500 mg/dL threshold of acute pancreatitis risk in most participants. Other triglyceride-related lipoprotein parameters improved. An increase in LDL-C level was observed but with no change in ApoB level and a decrease in non-HDL-C level. The safety profile was generally favorable at all doses. Additional studies will be required to determine whether plozasiran favorably modulates the risk of sHTG-associated complications. Trial Registration: ClinicalTrials.gov Identifier: NCT04720534.

A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients.

PURPOSE: AMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF). METHODS: Healthy adults (Parts A/B) and HF patients (Part C) aged 18-85 years were randomized 3:1 to single-dose oral/IV AMG 986 or placebo (Part A); multiple-dose oral/IV AMG 986 or placebo (Part B); or escalating-dose oral AMG 986 or placebo (Part C). PRIMARY ENDPOINT: treatment-emergent adverse events, laboratory values/vital signs/ECGs; others included AMG 986 pharmacokinetics, left ventricular (LV) function. RESULTS: Overall, 182 subjects were randomized (AMG 986/healthy: n = 116, placebo, n = 38; AMG 986/HF: n = 20, placebo, n = 8). AMG 986 had acceptable safety profile; no clinically significant dose-related impact on safety parameters up to 650 mg/day was observed. AMG 986 exposures increased nonlinearly with increasing doses; minimal accumulation was observed. In HF with reduced ejection fraction patients, there were numerical increases in percent changes from baseline in LV ejection fraction and stroke volume by volumetric assessment with AMG 986 vs placebo (stroke volume increase not recapitulated by Doppler). CONCLUSIONS: In healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03276728. DATE OF REGISTRATION: September 8, 2017.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Olpasiran in Healthy Japanese and Non-Japanese Participants: Results from a Phase I, Single-dose, Open-label Study.

PURPOSE: Olpasiran, an N-acetyl galactosamine-conjugated, hepatocyte-targeted, small interfering RNA, is being developed to reduce plasma lipoprotein (Lp)-(a) concentration by directly targeting the LPA gene. This study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of a single SC injection of olpasiran in healthy, Japanese and non-Japanese participants. METHODS: In this Phase I, open-label, parallel-design study, Japanese participants were randomized in a 1:1:1:1 ratio to receive a single 3, 9, 75, or 225 mg dose of olpasiran. Non-Japanese participants received a single 75 mg dose of olpasiran. The primary end points were pharmacokinetic parameters, including Cmax, AUCinf, tmax, and t1/2. Tolerability and change in Lp(a) concentration were also assessed. FINDINGS: A total of 27 enrolled participants had a mean (SD) age of 48.0 (12.5) years. Olpasiran Cmax and AUCinf were increased in an approximately dose-proportional manner in the Japanese groups. Mean (SD) Cmax values were 242 (121.0) and 144 (71.3) ng/mL, and mean (SD) AUCinf values were 3550 (592.0) and 2620 (917.0) h·ng/mL, in the Japanese and non-Japanese groups, respectively, given 75 mg of olpasiran. Median tmax ranged from 3.0 to 9.0 hours and mean (SD) t1/2 ranged from 4.0 (0.3) to 6.9 (1.6) hours across all groups. The maximal Lp(a) reduction occurred at day 57, with mean (SD) Lp(a) percentage reductions from baseline ranging from 56.0% (21.0%) to 99.0% (0.2%). A reductions in Lp(a) was observed as early as day 4. All adverse events were mild in severity, with no serious or fatal adverse events. No clinically important changes in tolerability-related laboratory analytes or vital signs were observed. IMPLICATIONS: In this population of healthy Japanese participants, dose-proportional increases in exposure and reduced Lp(a) in a dose-dependent manner were found with single 3, 9, 75, and 225 mg doses of olpasiran. The magnitude and durability of Lp(a) reductions were similar between the Japanese and non-Japanese groups. Olpasiran was well tolerated, with no clinically important adverse events or laboratory or vital sign abnormalities.

Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I, Open-Label, Randomized Study.

BACKGROUND AND OBJECTIVE: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure. The current phase I study was conducted to evaluate the pharmacokinetics and safety of a single-dose 200-mg capsule formulation of AMG 986 relative to the tablet formulation in 12 healthy subjects. METHODS: In a two-period, two-way crossover design, eligible subjects were randomized 1:1 to tablet/capsule or capsule/tablet treatment sequences; each treatment sequence lasted for approximately 6 days and comprised six subjects. RESULTS: Following a single oral dose of AMG 986, the geometric mean maximum observed concentration (Cmax) values were 9670 ng/mL and 6920 ng/mL and the geometric mean area under the curve from time zero to 120 h (AUC0-120h) values were 68,000 ng*h/mL and 59,900 ng*h/mL for the tablet and capsule, respectively. The geometric least squares means (90% confidence interval [90% CI]) for the ratios of capsule/tablet were 0.88 (90% CI 0.81-0.96) and 0.72 (90% CI 0.57-0.91) for AUC0-120h and Cmax, respectively. AMG 986 had an acceptable safety profile; all adverse events were grade 1 or 2 in severity. CONCLUSION: There was a modest 12% decrease in AUC0-120h and a 28% decrease in Cmax with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986.

A Phase 1, Open-Label Study to Evaluate the Effect of Food and Concomitant Itraconazole Administration on the Pharmacokinetics of AMG 986 in Healthy Subjects.

This phase 1, open-label study evaluated the effect of food and administration of the cytochrome P450 3A4 and P-glycoprotein inhibitor itraconazole (ITZ) on the pharmacokinetics of AMG 986. In cohort 1, 12 healthy subjects received a single oral dose of AMG 986 200 mg ± food on days 1 and 10. In cohort 2, 15 healthy subjects received oral ITZ 200 mg once daily on days 8 to 15 and a single oral dose of AMG 986 10 mg on days 1 and 11. The geometric least squares mean ratios of fed/fasted for AMG 986 maximum observed concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity (AUCinf ) were 0.76 (90%CI, 0.61-0.95) and 1.07 (90%CI, 0.94-1.22), respectively. The geometric least squares mean ratios of AMG 986 10 mg plus ITZ 200 mg/AMG 986 10 mg alone for AMG 986 Cmax and AUCinf were 1.36 (90%CI, 1.25-1.48) and 5.13 (90%CI, 4.71-5.59), respectively. Overall, 3 subjects experienced mild treatment-related adverse events; there were no serious or fatal adverse events. In conclusion, food had no apparent effect on the exposure of AMG 986 200 mg; therefore, food restrictions are not required. Potent cytochrome P450 3A4 and/or P-glycoprotein inhibitors may warrant AMG 986 dose reduction and should be coadministered with caution in patients with heart failure treated with AMG 986.

A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVE: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects. METHODS: This was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg. RESULTS: Following oral administration, median time to maximum observed plasma concentration (tmax) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (Cmax) and AUC∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity. CONCLUSION: AMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.

Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a).

Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5-8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662 ), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71-97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.

Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986.

INTRODUCTION: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure (HF). The safety and pharmacokinetics (PK) of AMG 986 in participants with renal impairment (RI) remains unknown. METHODS: This phase 1 study compared the safety and PK of AMG 986 200 mg in six participants with severe RI (estimated glomerular filtration rate [eGFR] 15-29 mL/min/1.73 m2) versus six participants with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). RESULTS: Following a single oral dose of AMG 986 200 mg on day 1, the maximum observed concentration increased 1.41-fold (90% confidence interval [CI] 0.88-2.27) and the area under the curve from time zero to infinity increased 1.23-fold (90% CI 0.73-2.06) in participants with severe RI versus normal renal function. AMG 986 had an acceptable safety profile; all adverse events were mild in severity. CONCLUSIONS: The results of this study support the enrollment of HF patients with RI to clinical trials of AMG 986 without the need for dose adjustments. TRIAL REGISTRATION NUMBER: NCT03318809 (registered: October 24, 2017).

A Phase I, Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Pharmacokinetics, Safety, and Tolerability of Etelcalcetide Administered Intravenously to Chinese Patients With Chronic Kidney Disease Undergoing Hemodialysis.

PURPOSE: This study reports data from the first evaluation of etelcalcetide treatment in Chinese adults with chronic kidney disease and secondary hyperparathyroidism. METHODS: This phase I, randomized study compared thrice-weekly etelcalcetide (5 mg per dose intravenously) and placebo in 33 Chinese adults (aged 18-70 years) receiving hemodialysis. Patients in both treatment groups received standard-of-care treatment with a total of 12 doses of the investigational product during a 4-week treatment period, followed by 4 weeks of washout and follow-up. Pharmacokinetic (PK) parameters (primary endpoint), tolerability (secondary endpoint), and changes in intact parathyroid hormone (iPTH) and corrected calcium (cCa) concentrations (exploratory endpoints) were assessed. PK parameters, ie, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-last), assessed over the interdialytic interval following the first and last doses were evaluated. The incidence of treatment-emergent adverse events (AEs) and anti-etelcalcetide antibodies was assessed. FINDINGS: Etelcalcetide administered to 25 patients was compared with placebo administered to 8 patients. Etelcalcetide exposure, assessed by Cmax and AUC0-last, increased after multiple-dose administration of etelcalcetide through day 27, with a mean (SD) accumulation ratio of 3.02 (0.61) based on AUC. At least one AE was reported for all patients in the etelcalcetide group and for 87.5% of patients in the placebo group. Serious AEs were reported in 12% of patients in the etelcalcetide group only. No deaths occurred, and a single discontinuation because of patient withdrawal of consent was reported in the etelcalcetide group. Preexisting anti-etelcalcetide antibodies were detected in one patient. The mean serum cCa level for all patients was maintained at >1.75 mmol/L. The iPTH and cCa concentrations decreased as expected, and a maximum mean decrease from baseline of 35.13% in iPTH levels was detected on day 27. IMPLICATIONS: Multiple doses of 5 mg etelcalcetide were well tolerated, and observed etelcalcetide PK and safety profiles were similar to those in reports in adults of ethnicities other than Chinese. Changes in serum iPTH and serum calcium levels were consistent with expected responses to etelcalcetide. ClinicalTrials.gov identifier: NCT03283098.

First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers.

AG10 is a novel, potent, and selective oral transthyretin (TTR) stabilizer being developed to treat TTR amyloidosis (ATTR). This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics (ex vivo stabilization) of orally administered AG10 in healthy adult volunteers. Both mutant and wild-type ATTR are underdiagnosed diseases with limited therapeutic options. As TTR amyloidogenesis is initiated by dissociation of TTR tetramers destabilized due to inherited mutations or aging, AG10 is designed to treat the disease at its source. Four single and three multiple ascending dose levels of AG10 or matching placebo were orally administered. Safety and tolerability were assessed by vital signs, electrocardiogram, adverse events, and clinical laboratory tests. Pharmacokinetics were measured using a validated bioanalytical assay. Pharmacodynamics were assessed via three pharmacodynamic assays of TTR stabilization. AG10 was uniformly well tolerated, and no safety signals of clinical concern were observed. Pharmacokinetic observations included time to maximum concentration <1 hour, dose-dependent maximum concentration and area under the plasma concentration-time curve, low intersubject variability, and half-life ∼25 hr. Complete (>90%) stabilization of TTR was observed across the entire dosing interval at steady state on the highest dose tested. Serum TTR levels, an in vivo reflection of TTR stabilization by AG10, increased from baseline following 12 days of dosing. AG10 appears to be safe and well tolerated in healthy adult volunteers and can completely stabilize TTR across the dosing interval, establishing clinical proof of concept. Based on these data, AG10 has the potential to be a safe and effective treatment for patients with either mutant or wild-type ATTR.

Stabilization of Cardiac Function With Diflunisal in Transthyretin (ATTR) Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an underappreciated cause of heart failure that results from misfolded TTR (prealbumin) protein. Diflunisal is an approved non-steroidal anti-inflammatory drug that stabilizes TTR, with limited data available regarding effects on cardiac structure and function. METHODS AND RESULTS: ATTR-CM patients (n=81, 41% treated with 250 mg twice-daily diflunisal by clinical practice) were retrospectively identified with baseline and follow-up (median interval 1 year) serum biomarker and echocardiographic data compared, including global longitudinal strain (GLS). Chi-squared and Wilcoxon tests assessed differences between subjects, divided by treatment group, and univariable and multivariable linear regression was performed. At baseline, patients treated with diflunisal were younger (68 vs 77 years, P = .0001), with lower B-type natriuretic peptide (BNP; 249 vs 545 pg/mL, P = .009) and serum creatinine (1.1 vs 1.2 mg/dL, P = .04), but similar TTR concentration (P = .31), cardiac troponin I (P = .06), and GLS (P = .67). At follow-up, diflunisal untreated versus treated patients showed differences in TTR concentration (19 vs 33 mg/dL, P = .01) and favorable differences in left atrial volume index (+4.6 vs -1.4 mL/m2, P = .002) and cardiac troponin I (+0.03 vs -0.01 ng/mL, P = .01) for the entire cohort. Among the subset with wild-type ATTR (n=53), diflunisal treatment was associated with differences in GLS (+1.2% untreated vs +0.1% treated, P = .03). Changes in wall thickness (P = .2), left ventricular ejection fraction (P = .71), and BNP (P = .42) were similar between groups. CONCLUSIONS: In ATTR-CM, diflunisal treatment resulted in measurable differences in some parameters of cardiac structure and function after only 1 year of administration. Further longer-term analysis is warranted.

Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations.

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.

Occurrence of Clinically Diagnosed Hypertrophic Cardiomyopathy in the United States.

Hypertrophic cardiomyopathy (HC) is the most common genetic heart disease and an important cause of sudden death and heart failure symptoms. The current prevalence for HC (1:500) is based on echocardiographic population studies in which a substantial proportion of affected subjects have not come to clinical recognition. Therefore, we sought to define the subset of patients with HC who are diagnosed in the US. A proprietary integrated claims database including medical condition International Classification of Diseases, Ninth Revision diagnostic codes for over 160 million individual patients in the US was interrogated for 2013 to identify the prevalence of clinically recognized HC. Patients with ≥1 claim for any of the HC International Classification of Diseases, Ninth Revision diagnosis codes from January to December 2013 were identified. The combined occurrence rate of HC was stratified by age and gender and multiplied by the 2013 United States population in the same age/gender categories to produce the final projected prevalence. The analysis was performed on 169,089,614 patients, of whom 59,009 unique patients were identified with ≥1 claim for HC. The projected estimated occurrence of diagnosed HC in the US in 2013 was 1:3,195 for a total of 98,958 subjects. Average age at HC diagnosis was in the fifth decade of life, with 43% of the cohort composed of women. In conclusion, leveraging a claims-based data analytic technique, about 100,000 patients are diagnosed clinically with HC in the US, an occurrence which is less than the prevalence reported in systematic population studies based on echocardiographic diagnosis. This observation supports the view that many patients with HC are undiagnosed throughout life and enhances our understanding of the burden of this genetic heart disease on the health care system.

Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial.

UNLABELLED: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with an overall prevalence of at least 1:500 in the adult population although only a fraction of affected patients come to clinical recognition. It is also the most common cause of sudden cardiac death in young adults and a major cause of morbidity caused by chronic heart failure symptoms. However, more than half a century since the original description of the disease, there is no currently approved therapy for the treatment of patients with HCM, and to date there have been only 5 randomized studies of medical therapies in HCM. As such, unmet medical need in HCM has been highlighted by the National Heart, Lung, and Blood Institute (NHLBI) as a research priority. Encouragingly, the infrastructure needed to conduct rigorous clinical trials in HCM has recently emerged because of the heightened awareness and understanding of the disease, development of clinical centers of excellence, and advances in diagnostic imaging. In this article, we will discuss the complex pathophysiology of HCM, review the current therapeutic landscape, describe new mechanistic insights into the central role of the late sodium current in HCM, and introduce the scientific rationale and execution of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial, the largest randomized, double-blind, placebo controlled clinical trial, now underway, designed to evaluate the effect of a novel pharmacological approach in patients with symptomatic HCM. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02291237.

Pharmacokinetic evaluation of treprostinil (oral) for the treatment of pulmonary arterial hypertension.

INTRODUCTION: This review summarizes current information on the first oral prostanoid approved for treatment of pulmonary arterial hypertension, treprostinil diolamine , which, similar to other prostacyclin analogs, vasodilates, impacts remodeling (antiproliferative), reduces endothelial cell dysfunction, inhibits platelet aggregation (antithrombotic) and increases right heart inotropy. AREAS COVERED: From a pharmacological point of view, it appears that with sustained blood concentrations for 8 - 10 h after a single dose, twice or thrice daily dosing is possible. This review discusses three randomized trials of oral treprostinil that have been completed (FREEDOM-M, FREEDOM-C, FREEDOM-C2). FREEDOM-C and -C2 evaluated oral treprostinil in patients on stable background therapy; FREEDOM-M evaluated oral treprostinil as monotherapy. In FREEDOM-M, the primary end point (6-minute walk distance; 6MWD) was attained, but was not reached in either FREEDOM-C trial. As such, the FDA did not grant approval. Thus, another clinical trial (FREEDOM-EV) is underway: oral treprostinil in patients on background therapy evaluating co-primary end points: i) change in 6MWD; and ii) occurrence of predetermined events. In the interim, oral treprostinil was approved in December 2013. EXPERT OPINION: The use and future of oral treprostinil is not clear. This will depend on the ability to titrate the drug to high levels with acceptable tolerance, on the results of FREEDOM-EV trial and on the impact of selexipag and other oral prostanoids being developed.

Myocardial reverse remodeling.

Despite an extensive literature defining the mechanisms and significance of pathological myocardial remodeling, there has been no comprehensive review of the inverse process, often labeled reverse remodeling. Accordingly, the goal of this review is to overview the varied settings in which clinically significant reverse remodeling has been well documented. When available, we reviewed relevant randomized, controlled clinical trials, and meta-analyses with sufficient cardiac imaging data to permit conclusions about reverse remodeling. When these types of studies were not available, relevant case-control studies and case series that employed appropriate methodology were reviewed. Regression of pathological myocardial hypertrophy, chamber shape distortions, and dysfunction occurs in a wide variety of settings. Although reverse remodeling occurs spontaneously in some etiologies of myocardial dysfunction and failure, remodeling is more commonly observed in response to medical, device-based, or surgical therapies, including ß-blockers, revascularization, cardiac resynchronization therapy, and valve surgery. Indeed, reverse remodeling following pathophysiologically targeted interventions helps validate that the targeted mechanisms are propelling and/or sustaining pathological remodeling. The diverse clinical settings in which reverse remodeling has been observed demonstrates that myocardial remodeling is bidirectional and occurs across the full spectrum of myocardial disease severity, duration, and etiology. Observations in several settings suggest that recovered hearts are not truly normal despite parallel improvements at organ, tissue, and cellular level. Nevertheless, the link between reverse remodeling and improved outcomes should inspire further research to better understand the mechanisms responsible for both reverse remodeling and persistent deviations from normalcy.

Temporal associations between thoracic volume overload and malignant ventricular arrhythmias: a study of intrathoracic impedance.

BACKGROUND: Acute exacerbations of heart failure (HF) are believed to trigger malignant ventricular arrhythmias, but the temporal association between fluid accumulation and ventricular arrhythmias has not been evaluated in an objective manner. We hypothesized that increased intrathoracic fluid accumulation in patients with HF, as measured by an index of intrathoracic impedance, is associated with an increased risk of ventricular arrhythmias. METHODS AND RESULTS: We analyzed interrogations in a cohort of 96 patients with left ventricular dysfunction (EF ≤ 35%) with devices that monitor intrathoracic impedance (OptiVol fluid index). Treated episodes of ventricular tachycardia or fibrillation (VT/VF) were adjudicated and stratified according to predetermined fluid index thresholds (OptiVol indices of 15, 30, 45, 60 Ω-days). VT/VF episodes occurred in 16 patients (17%). VT/VF was more common on days when the fluid index was elevated using threshold values of 15, 30, and 45 Ω-days (P = 0.006, 0.04, 0.02, respectively). There were no differences in the percent of time above any threshold between patients with and without VT/VF. CONCLUSIONS: In patients with HF who develop VT/VF, volume overload, as detected by an index incorporating changes in intrathoracic impedance, was temporally associated with malignant ventricular tachyarrhythmias.

Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells.

We have recently identified a new class of compounds that selectively kill cells that express P-glycoprotein (P-gp, MDR1), the ATPase efflux pump that confers multidrug resistance on cancer cells. Several isatin-beta-thiosemicarbazones from our initial study have been validated and a range of analogues synthesized and tested. A number demonstrated improved MDR1-selective activity over the lead, NSC73306 (1). Pharmacophores for cytotoxicity and MDR1 selectivity were generated to delineate the structural features required for activity. The MDR1-selective pharmacophore highlights the importance of aromatic/hydrophobic features at the N4 position of the thiosemicarbazone and the reliance on the isatin moiety as key bioisosteric contributors. Additionally, a quantitative structure-activity relationship (QSAR) model that yielded a cross-validated correlation coefficient of 0.85 effectively predicts the cytotoxicity of untested thiosemicarbazones. Together, the models serve as effective approaches for predicting structures with MDR1-selective activity and aid in directing the search for the mechanism of action of 1.