OCE-205 in rats and non-human primates: Pharmacokinetic and pharmacodynamic analysis.

Treatment for complications associated with the hemodynamic consequences of decompensated cirrhosis remains suboptimal. Terlipressin, the latest pharmacological management of hepatorenal syndrome-acute kidney injury (HRS-AKI), targets the vasopressin system but has serious side effects. OCE-205 is a novel peptide designed to target the vasopressin receptor system as a mixed V1a agonist/antagonist, resulting in effective partial agonism without V2 agonism. We examined the in vivo pharmacokinetic/pharmacodynamic properties of OCE-205 in healthy rats and cynomolgus monkeys. OCE-205 was administered by IV or SC bolus injection; arginine vasopressin (AVP) or terlipressin were comparators. After IV OCE-205 administration in rats, mean plasma concentration decreased in a mostly linear manner to 2 mg/mL after 120 min, and for SC administration, slowly decreased to ∼50 ng/mL after 300 min. Compared with pre-test values, arterial blood pressure values significantly increased after all OCE-205 doses tested. For monkeys, the concentration after IV OCE-205 administration was mostly linear to 5 ng/mL after 180 min, and for SC administration, ∼3 ng/mL after 480 min. Subcutaneous OCE-205 administration increased mean arterial pressure (MAP) versus baseline, with ΔMAP in OCE-205-treated animals marked and long-lasting while terlipressin induced an increase from baseline in MAP, with negligible ΔMAP, on average, by 150 min after administration in all groups. AVP, but not OCE-205, significantly increased blood lactate concentrations. OCE-205 was well tolerated in adult male rats and cynomolgus monkeys following single-dose bolus administration. The preclinical results of OCE-205, with its demonstrated V1a selective partial agonist activity and potentially tolerable safety profile, suggest its potential utility for treatment of the cardiovascular complications of cirrhosis. Institutional protocol number: Procedures were approved by the Ferring Research Institute (FRI) Institutional Animal Care and Use Committee (IACUC) on November 27, 2006 under protocol FRI 06-011, and by the Sinclair Research Center IACUC under protocol S11177.

OCE-205, A Novel, Selective Vasopressin Receptor Mixed Agonist-Antagonist: Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics from a Phase 1 Study in Healthy Volunteers.

BACKGROUND: OCE-205, a novel, selective vasopressin V1a receptor mixed agonist/antagonist with no V2 receptor activity, may treat the portal hypertension-related complications of end-stage liver disease with an improved therapeutic profile over currently utilized nonselective full-agonist vasopressin analogs. OBJECTIVES: This Phase 1, double-blind, placebo-controlled, within-dose-group randomized trial investigated the safety, tolerability, and pharmacokinetic/pharmacodynamic profiles of OCE-205 in healthy adults. METHODS: Subjects received a single intravenous dose of OCE-205 0.1, 0.3, 0.45, 0.6, or 0.9 mg, or placebo infused over 6 h. Safety and tolerability were assessed, and blood samples were obtained for pharmacokinetic analyses. Sixty-four subjects were randomized and treated. RESULTS: Area under the concentration-time curve (AUC) and maximum plasma concentrations (Cmax) were approximately dose-proportional across doses from 0.1 to 0.9 mg. OCE-205 terminal half-life was ~ 1.5 h. Diastolic, and to a lesser extent systolic, blood pressure increased in all OCE-205 dose groups; pulse rate decreased. Overall changes in mean arterial pressure were similar to changes in diastolic blood pressure. Absolute changes in cardiac output, by echocardiogram, were somewhat dose-dependent, with mean reductions of 3-12% after the 0.9 mg dose, and individual reductions ≤ 20 to 25% across all doses. The most frequent adverse events were abdominal pain, abnormal gastrointestinal sounds, and diarrhea, with no reported cases of mesenteric ischemia. Adverse events were generally mild or moderate in severity. CONCLUSION: OCE-205 was safe and well tolerated, with a pharmacodynamic profile achieving submaximal partial agonism consistent with mixed agonism-antagonism of the V1a receptor. OCE-205 shows promise as a treatment for some complications of end-stage liver disease.

Partial vasopressin 1a receptor agonism reduces portal hypertension and hyperaldosteronism and induces a powerful diuretic and natriuretic effect in rats with cirrhosis and ascites.

The vasopressin system has emerged as a therapeutic focus for lowering portal hypertension and reducing splanchnic vasodilation in patients with refractory ascites. Clinically available vasopressin agonists are limited by preferential selectivity for V1 receptors that also have steep concentration-response curves with potential risks of excess vasoconstriction and/or complete antidiuretic effects. OCE-205 is a novel, selective, partial V1a receptor agonist with mixed agonist/antagonist activity and no V2 receptor activation at therapeutic doses. We carried out two studies assessing the in vivo effects of OCE-205 in different rat models of cirrhosis and ascites. In a carbon tetrachloride rat cirrhosis model, OCE-205 administration produced a marked reduction in portal hypertension and hyperaldosteronism, along with robust diuretic and natriuretic effects. These effects were accompanied by marked decreases in ascites volume, with three of five animals experiencing total mobilization of ascites. There was no evidence of fluid overload or sodium or water retention, confirming OCE-205's lack of V2 receptor activity. In a second, corroborative study using a bile duct ligation rat model of ascites, OCE-205 produced significant decreases in ascites volume and body weight and a significant increase in urine volume versus vehicle. Urine sodium excretion increased significantly after the first administration of OCE-205 relative to vehicle; however, repeat administration over 5 days did not lead to hyponatremia. Thus, in separate in vivo models, the mixed agonist/antagonist OCE-205 demonstrated relevant and expected endpoint findings consistent with its known mechanism of action and in vitro pharmacology without apparent unwanted effects or nonspecific toxicities.

OCE-205, a Selective V1a Partial Agonist, Reduces Portal Pressure in Rat Models of Portal Hypertension.

Purpose: Management of decompensated cirrhosis may include the use of vasoconstrictors that can lead to serious adverse events. OCE-205 was designed as a highly selective V1a receptor partial agonist, intended to have a wider therapeutic window than full vasopressin agonists. Methods: We aimed to characterize the activity of OCE-205 treatment in two rat models of portal hypertension (PHT). For both models, OCE-205 was administered as a subcutaneous bolus injection. Thirty male Wistar rats were fed a methionine/choline-deficient (MCD) diet to model PHT. Animals received OCE-205 (10, 25, 100, or 500 µg/kg) or intra-arterial terlipressin (100 µg/kg). In a more severe model of PHT, 11 male Sprague Dawley rats had the common bile duct surgically ligated (BDL) and received OCE-205. Portal pressure (PP) and mean arterial pressure (MAP) were measured. Results: For PP in the MCD model, MAP increased while PP decreased in rats treated with OCE-205 or terlipressin; the peak changes to MAP were 14.7 and 33.5 mmHg, respectively. Changes in MAP began to plateau after 10 min in the OCE-205 groups, whereas in the terlipressin group, MAP rapidly increased and peaked after 20 min. Across all treatment groups in the BDL model, a dose-related decrease from baseline in PP was observed following OCE-205, plateauing as the dose increased. In all treatment groups, PP change remained negative throughout the 30-min testing period. In both PHT rat models, a reduction in PP was coupled to an increase in MAP, with both plateauing in dose-response curves. Conclusion: Data support OCE-205 as a promising candidate for further development. Institutional Protocol Number: Procedures were approved by the Ferring Research Institute (FRI) Institutional Animal Care and Use Committee on July 13, 2011, under protocol FRI-07-0002.

Pharmacokinetics/pharmacodynamics of L-ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes.

Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48 hours' standard care were randomly assigned to continuous intravenous OP (10, 15, or 20 g/day, based on Child-Turcotte-Pugh score) or matching placebo for 5 days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose-dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented ~50%-60% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3 hours postinfusion was significantly greater versus placebo (p = 0.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (p = 0.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (p = 0.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE.

Efficacy and Safety of Ornithine Phenylacetate for Treating Overt Hepatic Encephalopathy in a Randomized Trial.

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is associated with increased morbidity, mortality, and health care resource use. In this phase 2b study, we evaluated the efficacy and safety of ornithine phenylacetate (OP), an ammonia scavenger, in hospitalized patients with cirrhosis, increased levels of ammonia at screening, and acute or overt HE. METHODS: We conducted a double-blind study of 231 patients with cirrhosis and HE at multiple sites in North America, Europe, Israel, and Australia from January 7, 2014, through December 29, 2016. Patients were assigned randomly to groups that received placebo or OP (10, 15, or 20 g/d, based on the severity of liver disease), plus each institution's standard of care (eg, lactulose to achieve 2-3 bowel movements with or without rifaximin, in accordance with guidelines). The primary end point was time to confirmed clinical response, defined as reduction to HE staging tool (HEST) stage 2 from baseline HEST stages 3/4 or improvement to HEST stages 0/1 from baseline stage 2, in the intent-to-treat population (all patients with increased levels of ammonia at screening, determined by a local laboratory). RESULTS: Median times to clinical improvement, based on ammonia measurements at local laboratories, did not differ significantly between the groups given OP vs the placebo group (P = .129). Analyses of central laboratory-confirmed increases in levels of ammonia at baseline (n = 201) showed clinical improvement in HE at a median of 21 hours sooner in groups given OP vs placebo. The percentages of patients with any specific adverse event did not differ significantly between groups. Serious adverse events occurred in 25% of patients in the OP group and in 29% in the placebo group (P = .552). CONCLUSIONS: In a randomized controlled trial of patients with cirrhosis and HE, we found no significant difference in time to clinical improvement between patients given OP vs placebo. However, OP appears to be safe and should undergo further testing for treatment of hyperammonemia in hospitalized patients receiving treatment for the underlying precipitant of acute or overt HE. ClinicalTrials.gov no: NCT01966419.

Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia.

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. l-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60 µM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 µg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] µg/mL), and increased to target levels in all but one who received 20 g every 24 hours (150 [100] µg/mL). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r = 0.831, P < 0.0001). Mean ammonia concentrations based on the area under the curve decreased to a greater extent in patients who received 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting. CONCLUSION: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013).

Effect of caffeine on SPECT myocardial perfusion imaging during regadenoson pharmacologic stress: a prospective, randomized, multicenter study.

A multicenter, double-blind, randomized study was conducted to assess the effect of caffeine on regadenoson stress myocardial perfusion imaging (MPI). Subjects with a high likelihood of coronary artery disease underwent a rest single-photon emission computed tomography MPI on day 1 (MPI-1) and a stress MPI with regadenoson on day 3 (MPI-2). Individuals with ≥1 segment with a reversible defect received double-blind caffeine tablets (200 or 400 mg) or placebo 90 min before a repeat regadenoson stress MPI (MPI-3) on day 5. Overall, 207 subjects completed the study (caffeine 200 mg, n = 70; caffeine 400 mg, n = 71; placebo, n = 66). The mean number of segments with reversible defects decreased from MPI-2 to MPI-3 in the caffeine 200 and 400 mg groups versus no significant change in the placebo group [mean ± standard deviation: -0.61 ± 1.097, -0.62 ± 1.367, and 0.12 ± 0.981, respectively (overall treatment effect, P < 0.001)]. The majority of subjects who received caffeine shifted to a lower ischemia size category from MPI-2 to MPI-3, with no clear pattern observed in subjects who received placebo. For caffeine exposed patients with ≥3 segments with reversible defects at MPI-2, 21/23 had fewer detected at MPI-3. Both the 200 and 400 mg doses of caffeine significantly reduced the number of segments with reversible defects detected by regadenoson stress MPI.

Finding unrecognized information in overactive bladder clinical trial data: a new approach to understanding placebo and treatment effects.

AIMS: To identify combinations of variables among overactive bladder (OAB) clinical trial subjects that allow prediction of those who are more--or less--likely to respond strongly to placebo, or to medication. METHODS: Data from two Phase IIIb clinical trials of solifenacin in OAB were combined. Predictive models for placebo and treatment responses were constructed using baseline variables including individual items from the OAB questionnaire. These models were reduced to an essential subset of predictor variables. Two outcome measures are reported: urgency and incontinence. RESULTS: In placebo subjects, 14 selected variables permitted distinction between those who responded with significant reductions in urgency and those who did not. A subset of nine variables in treated subjects permitted distinction between those more--or less--likely to respond to medication. Data for urgency were combined from both placebo and actively treated subjects to identify those who had one of the previously identified clusters of variables. It was possible to predict, among all subjects, who would be likely to experience a strong placebo or active treatment response and who would not. This process was also applied to incontinence data. CONCLUSIONS: We have developed a new process to help understand placebo and treatment responses and their relationships to baseline conditions. The effectiveness of these methods was indicated using data from two solifenacin clinical trials and would benefit from future validation using other data sets. Methods used here are suitable for predicting the placebo effect in other clinical trials.

A randomized, double-blind, placebo-controlled study assessing the safety and tolerability of regadenoson in subjects with asthma or chronic obstructive pulmonary disease.

BACKGROUND: Adenosine receptor stress agents for myocardial perfusion imaging (MPI) may cause A(2B) and/or A(3) receptor-mediated bronchoconstriction, of particular concern to physicians testing patients with asthma or chronic obstructive pulmonary disease (COPD). METHODS: A Phase 4, randomized, double-blind study (NCT00862641) assessed the safety of the selective A(2A) receptor agonist, regadenoson, compared with placebo in subjects with asthma or COPD who represented likely candidates for MPI. RESULTS: Overall, 356 and 176 subjects with asthma and 316 and 151 subjects with COPD received regadenoson and placebo, respectively. The percentage of subjects experiencing a >15% decrease in FEV(1) from baseline to any assessment up to 24 hours post-baseline was not statistically significantly different between the regadenoson and the placebo groups in the asthma or COPD stratum. Dyspnea, the most frequent respiratory adverse event, occurred with higher incidence (P < .0001) in the regadenoson group than the placebo group in the asthma (10.7% vs 1.1%) and COPD (18.0% vs 2.6%) strata. No subjects experienced severe bronchoconstriction, although the occurrence of such reactions with adenosine receptor agonists cannot be ruled out, such that caution is advised. CONCLUSIONS: This information may be helpful to physicians selecting a pharmacologic stress agent for MPI in patients with asthma or COPD.

A randomized, double-blind, placebo-controlled study of the safety and tolerance of regadenoson in subjects with stage 3 or 4 chronic kidney disease.

BACKGROUND: The safety and tolerability of regadenoson, a pharmacologic stress agent that is excreted primarily by the kidneys, were examined in subjects with chronic kidney disease (CKD). METHODS: This multicenter, double-blind, randomized, placebo-controlled study involved men and women, ≥18 years of age, with stage 3 or 4 [estimated glomerular filtration rate (eGFR) 30-59 mL/minute/1.73 m(2) and 15-29 mL/minute/1.73 m(2), respectively] CKD and known or suspected coronary artery disease. Subjects were randomized 2:1 to receive one 10-second intravenous injection of regadenoson 0.4 mg or placebo. The primary outcome measure was the frequency of serious adverse events over 24-h post-dose. RESULTS: The study included 432 subjects with stage 3 (regadenoson n = 287; placebo n = 145) and 72 with stage 4 (regadenoson n = 47; placebo n = 25) CKD. No serious adverse events or deaths were reported over 24-h post-dose. The overall adverse event incidence was higher with regadenoson than placebo (62.6% vs 21.2%; P < .0001). Of the most common adverse events (≥5%) reported by subjects receiving regadenoson, headache (24.9% vs 7.1%), dyspnea (19.2% vs 0.6%), chest discomfort (14.7% vs 0.6%), nausea (14.7% vs 1.2%), flushing (12.0% vs 1.8%), and dizziness (9.6% vs 0.6%) occurred significantly more often (P < .0001) with regadenoson than placebo. There were no trends for clinically meaningful changes in eGFR from baseline to 24-h post-dose in subjects with stage 3 or 4 CKD. CONCLUSIONS: Regadenoson was not associated with any serious or unexpected adverse events in subjects with stage 3 or 4 CKD.