Pharmacodynamics of selective inhibition of γ-secretase by avagacestat.

A hallmark of Alzheimer's disease (AD) pathology is the accumulation of brain amyloid ß-peptide (Aß), generated by γ-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, γ-secretase inhibitors (GSIs) may lower brain Aß and offer a potential new approach to treat AD. As γ-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of Aß and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) Aß levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF Aß40 and Aß42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending-dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF Aß40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF Aß levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.

A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat.

AIM: To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women. METHODS: All subjects received double-blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-ß (Aß)(1-40) concentratios and exploration of Notch biomarkers. RESULTS: Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median t(max) between 1 and 2 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,∞) values than those aged less than 75 years. An exploratory analysis of Aß(1-40) serum concentrations showed a pattern of decreasing concentrations over the first 4-6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly. CONCLUSIONS: The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer's disease.

Pharmacokinetics and Safety of the Tyrosine Kinase 2 Inhibitor Deucravacitinib in Healthy Chinese Subjects.

INTRODUCTION: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, blocks cytokine signaling involved in psoriasis pathogenesis. This ethnic-bridging study evaluated deucravacitinib pharmacokinetics, tolerability, and safety in healthy Chinese subjects. METHODS: This phase I, double-blind, single-/multiple-dose study randomized healthy Chinese subjects 4:1 to a single dose of deucravacitinib 6 mg or placebo (group 1) or deucravacitinib 12 mg or placebo (group 2) on day 1; groups 1 and 2 received deucravacitinib 6 mg and 12 mg once daily, respectively, or placebo on days 5-19. Blood samples were collected on days 1-5 (0 predose-96 h postdose), day 5 (0-24 h postdose), days 9 and 12 (0 h), and day 19 (0-24 h postdose). Deucravacitinib and metabolite (BMT-153261, BMT-158170) concentrations were determined using liquid chromatography/mass spectrometry; pharmacokinetic parameters were calculated using noncompartmental analysis. Urine was collected on days 1-4 (4 h predose-96 h postdose). Safety was monitored throughout. RESULTS: Forty healthy Chinese subjects (groups 1 and 2: deucravacitinib, n = 32; placebo, n = 8) were enrolled. Deucravacitinib was rapidly absorbed after single-/multiple-dose administration, with median time to maximal plasma concentration of 1.5-2.3 h. Systemic exposure after single or multiple doses increased approximately twofold with twofold dose increase. Modest deucravacitinib accumulation was observed after multiple-dose administration (1.3- to 1.4-fold increase in area under the curve [AUC] under one dosing interval). Metabolite-to-parent ratios for maximal plasma concentration and AUC remained consistent in each dose group. Mean urinary percent recovery and renal clearance were similar between dose groups. Most adverse events (AEs) were mild/moderate, with no serious treatment-related AEs, deaths, or discontinuations due to AEs. CONCLUSION: Deucravacitinib was safe and well tolerated in healthy Chinese subjects. Deucravacitinib exhibited rapid absorption, dose-related increases in exposure, comparable half-life, and no evidence of time-dependent pharmacokinetics, suggesting minimal effect of Chinese ethnicity on deucravacitinib pharmacokinetics. CLINICAL TRIAL REGISTRATION: NCT03956953.

Deucravacitinib, a new oral medication, blocks an enzyme called tyrosine kinase 2 (TYK2), which is activated in plaque psoriasis. This reduces thick, scaly patches of skin, itching, and other symptoms. How a drug is absorbed and its effects can vary between patients of different races and ethnicities. We studied the safety of deucravacitinib in healthy Chinese volunteers. We also studied how bigger or smaller doses of deucravacitinib change how much of it is absorbed into the blood. We found that most side effects of deucravacitinib were mild or moderate compared to volunteers taking placebo, a look-alike pill that contains no drug. The most common side effects were skin rashes and headaches. No serious side effects were related to deucravacitinib. Deucravacitinib was quickly absorbed into the blood. The time it took for deucravacitinib to reach its maximum amount in the blood was similar regardless of how large of a dose was initially taken. Increasing the amount of deucravacitinib taken also increased the total amount of deucravacitinib absorbed, both in terms of the total amount absorbed and the maximum amount in blood at one time. These results in healthy Chinese volunteers were similar to the results of other studies in a general population of many races and ethnicities. Deucravacitinib works the same in Chinese patients as in patients of other ethnicities. Chinese patients will not need to adjust their dose when taking deucravacitinib.

Calculation and mitigation of isotopic interferences in liquid chromatography-mass spectrometry/mass spectrometry assays and its application in supporting microdose absolute bioavailability studies.

A methodology for the accurate calculation and mitigation of isotopic interferences in liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assays and its application in supporting microdose absolute bioavailability studies are reported for the first time. For simplicity, this calculation methodology and the strategy to minimize the isotopic interference are demonstrated using a simple molecule entity, then applied to actual development drugs. The exact isotopic interferences calculated with this methodology were often much less than the traditionally used, overestimated isotopic interferences simply based on the molecular isotope abundance. One application of the methodology is the selection of a stable isotopically labeled internal standard (SIL-IS) for an LC-MS/MS bioanalytical assay. The second application is the selection of an SIL analogue for use in intravenous (i.v.) microdosing for the determination of absolute bioavailability. In the case of microdosing, the traditional approach of calculating isotopic interferences can result in selecting a labeling scheme that overlabels the i.v.-dosed drug or leads to incorrect conclusions on the feasibility of using an SIL drug and analysis by LC-MS/MS. The methodology presented here can guide the synthesis by accurately calculating the isotopic interferences when labeling at different positions, using different selective reaction monitoring (SRM) transitions or adding more labeling positions. This methodology has been successfully applied to the selection of the labeled i.v.-dosed drugs for use in two microdose absolute bioavailability studies, before initiating the chemical synthesis. With this methodology, significant time and cost saving can be achieved in supporting microdose absolute bioavailability studies with stable labeled drugs.

In vitro and in vivo metabolism and pharmacokinetics of BMS-562086, a potent and orally bioavailable corticotropin-releasing factor-1 receptor antagonist.

The absorption, distribution, metabolism, and excretion (ADME) and the pharmacokinetic characteristics of BMS-562086 [pexacerfont; 8-(6-methoxy-2-methyl-3-pyridinyl)-2,7-dimethyl-N-[(1R)-1-methylpropyl]pyrazolo(1,5-a)-1,3,5-triazin-4-amine (DPC-A69448)] were investigated in vitro and in animals to support its clinical development. BMS-562086 was orally bioavailable in rats, dogs, and chimpanzees, with an absolute oral bioavailability of 40.1, 58.8, and 58.5%, respectively. BMS-562086 was extensively metabolized in hepatocytes from all species and completely metabolized in rats. The primary biotransformation pathways found for BMS-562086 in both liver microsomal and hepatocyte preparations and in rats were similar. These included O-demethylation, hydroxylation at the N-alkyl side chain and N-dealkylation. Multiple cytochromes P450 including CYP3A4/5 were involved in the metabolic clearance of BMS-562086. Both renal and biliary excretion played a significant role in elimination of the metabolites of BMS-562086. The involvement of other metabolic enzymes in addition to CYP3A4/5 in elimination of BMS-562086 suggests a reduced potential for drug-drug interaction through modulation of CYP3A4/5. Chimpanzees proved to be a good animal model in predicting BMS-562086 human clearance. Virtual clinical trials performed with a population-based ADME simulator suggested that a minimal dose of 100 mg daily would provide sufficient drug exposure to achieve plasma concentrations above the projected human efficacious plasma concentration of BMS-562086 (> 500 nM). In summary, BMS-562086 exhibited favorable ADME and pharmacokinetic properties for further development.

Development of oral extended release formulations of 6-hydroxybuspirone.

Reducing the maximum plasma concentration whilst maintaining the exposure was shown to ameliorate adverse events following the oral administration of 6-hydroxybuspirone. This observation, along with a desire to provide for once daily dosing of this compound, provided the basis for the development of an extended release formulation. Hydrophilic matrix tablets based on hydroxypropyl methylcellulose and containing citric acid to provide for an acid microenvironment were prepared and evaluated by in vitro drug release studies and in vivo pharmacokinetic and scintigraphic studies using samarium oxide (¹5³Sm) labelled dosage forms. The dosage forms were found to release the contained drug by a predominantly diffusion mechanism and the release rate was relatively independent of environmental pH. Following administration of the extended release formulations to volunteers, comparative pharmacokinetic data indicated that the extended release formulations provided for a reduction in the maximum plasma concentration of 64-70% relative to that provided by the same dose given as an oral solution, whilst maintaining exposure relative to the oral solution. By examination of absorption curves derived by Wagner-Nelson analysis of pharmacokinetic data it was noted that drug release in vivo correlated well with drug release observed in vitro and no marked change in rate of absorption was noted when dosage forms were located in and releasing drug in the colon. The robust control of drug release seen in vitro translated to a good in vivo performance.

Lack of Electrocardiographic Effects of Deucravacitinib in Healthy Subjects.

Deucravacitinib is a novel, oral, selective inhibitor of the intracellular signaling kinase tyrosine kinase 2. This phase 1, randomized, partially double-blind, 4-period crossover study in healthy adults was conducted to determine whether deucravacitinib 12 mg (therapeutic dose) or 36 mg (supratherapeutic dose) had a clinically relevant effect on the corrected QT interval and other electrocardiographic (ECG) parameters. Subjects received 1 of 4 sequences of placebo, deucravacitinib 12 mg, deucravacitinib 36 mg, and moxifloxacin 400 mg (positive control) in a randomized crossover fashion. The placebo-corrected change from baseline for the QT interval corrected for heart rate using the Fridericia method (QTcF), ECG parameters, and safety measures were evaluated. A clinically meaningful QTcF prolongation of >10 milliseconds was not found for deucravacitinib at tested doses. Assay sensitivity was demonstrated by the observation of known QT effects of moxifloxacin in the study. Deucravacitinib had no clinically relevant effect on other parameters and was generally well tolerated. The majority of adverse events (AEs) were mild, and all AEs resolved by study's end. Three treatment-related serious AEs of pharyngitis, cellulitis, and lymphadenopathy occurred in 1 subject following administration of deucravacitinib 12 mg, but resolved by end of study. This study demonstrated that a single oral dose of deucravacitinib 12 or 36 mg did not produce a clinically relevant effect on the corrected QT interval or other measured ECG parameters in healthy adults.

Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder.

BACKGROUND: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). METHOD: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. RESULTS: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015). CONCLUSIONS: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment.

Disposition and metabolism of [14C]brasofensine in rats, monkeys, and humans.

Brasofensine is an inhibitor of the synaptic dopamine transporter. These studies were conducted to characterize the pharmacokinetics, absolute bioavailability, disposition, and metabolism of brasofensine after i.v. and/or p.o. administrations of [(14)C]brasofensine in rats (1.5 mg/kg i.v., 4 mg/kg p.o.) and monkeys (4 mg i.v., 12 mg p.o.) and humans (50 mg p.o.). Brasofensine was rapidly absorbed after p.o. administration in rats and monkeys, with peak plasma concentrations occurring 0.5 to 1 h but 3 to 8 h for brasofensine in humans. Plasma terminal elimination half-lives were approximately 2 h in rats, approximately 4 h in monkeys, and approximately 24 h in humans. Total body clearance and steady-state volume of distribution values were 199 ml/min/kg and 24 l/kg, respectively, in the rat and 32 ml/min/kg and 46 l/kg, respectively, in the monkey. Absolute bioavailability was 7% in rats and 0.8% in monkeys. After a single p.o. dose, urinary excretion of radioactivity accounted for 20% of the administered dose in rats, 70% in monkeys, and 86% in humans, with the remainder excreted into the feces. Brasofensine had extensive first-pass metabolism following p.o. administration in humans, monkeys, and rats. It primarily underwent O- and N-demethylation and isomerization. Some of the desmethyl metabolites were further converted to glucuronides. These primary metabolites and glucuronides of demethyl brasofensine (M1 and M2) were major circulating metabolites in humans and were also observed in rat and monkey plasma.

Pharmacokinetics of a newly identified active metabolite of buspirone after administration of buspirone over its therapeutic dose range.

The objective of this study was to assess the pharmacokinetics of a newly identified active metabolite of buspirone, 6-hydroxybuspirone (6OHB), over the therapeutic dose range of buspirone. A 26-day, open-label, nonrandomized, single-sequence, dose-escalation study in normal healthy volunteers was conducted (N = 13). Subjects received escalating doses of buspirone with each dose administered for 5 days starting at a dose of 5 mg twice daily and increasing up to 30 mg twice daily. Plasma concentrations of 6OHB were approximately 40-fold greater than those of buspirone. 6OHB was rapidly formed following buspirone administration, and exposure increased proportionally with buspirone dose. Further research regarding the safety and efficacy of 6OHB itself is warranted.

Pre-absorption physicochemical compatibility assessment of 8-drug metabolic cocktail.

A comprehensive 8-drug metabolic cocktail was designed to simultaneously target 6 Cytochrome P450 enzymes and 2 membrane transporters. This study aimed to assess the pre-absorption risk of this new metabolic cocktail which contained metoprolol, caffeine, midazolam, pravastatin, flurbiprofen, omeprazole, digoxin and montelukast. This paper describes a systematic approach to understand whether the co-administration of the 8 selected drug products, i.e., the physical mixing of these products in the human gastro-intestinal environment, will create any issue that may interfere with the individual drug dissolution which in turns modify the total amount or timing of their availability for absorption. The evaluation consisted of two steps. An initial evaluation was based on theoretical understanding of the physicochemical properties of the drugs and the gastro intestinal environment, followed by in vitro dissolution tests. The results indicated that the designer 8-drug cocktail has acceptable pre-absorption compatibility when dosed simultaneously, and recommended the progression of the cocktail into clinical validation study.

Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial.

IMPORTANCE: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms. OBJECTIVES: To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity. INTERVENTIONS: Oral avagacestat or placebo daily. MAIN OUTCOMES AND MEASURE: Safety and tolerability of avagacestat. RESULTS: Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures. CONCLUSIONS AND RELEVANCE: Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00890890.

Comparison of pharmacokinetics of lanoteplase and alteplase during acute myocardial infarction.

OBJECTIVE: Lanoteplase is a rationally designed variant of tissue plasminogen activator. The aim of this study was to examine the pharmacokinetics and functional activity of a single intravenous bolus dose of lanoteplase with those of a bolus plus two-step infusion of alteplase. DESIGN: Seven-centre substudy of the InTIME-I angiographic trial in patients presenting within 6 hours of onset of suspected acute myocardial infarction. PATIENTS AND PARTICIPANTS: A total of 31 patients (28 males, 3 females) enrolled in this substudy [mean age 59 (range 26 to 76) years]. METHODS: Twenty-three patients randomised to lanoteplase received single bolus doses of 15 kU/kg (n = 5), 30 kU/kg (n = 3), 60 kU/kg (n = 9), or 120 kU/kg (n = 6). Eight patients received alteplase

Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers.

BACKGROUND: γ-Secretase inhibitors (GSIs) are being investigated for their potential to modify the progression of Alzheimer disease based on their ability to regulate amyloid-ß (Aß) accumulation. BMS-708163 (avagacestat) is an oral GSI designed for selective inhibition of Aß synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Aß synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class. Avagacestat produced up to 190-fold greater selectivity for Aß synthesis than Notch processing in preclinical studies and may therefore produce less toxic adverse events than other less selective compounds. Presented here are the results of the first in-human study for this new GSI compound. OBJECTIVE: The goal of this study was to assess the tolerability profile, pharmacokinetic properties, and effects on pharmacodynamic markers (Aß, trefoil factor family 3 protein, dual specificity phosphatase 6, and hairy and enhancer of split-1) of single, oral doses of avagacestat in healthy, young, male volunteers. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study in 8 healthy young men (age, 18-45 years) per dosing panel. Each study participant was randomized to receive a single dose of placebo (n = 2) or avagacestat (n = 6 for each dose) as an oral solution in 1 of 9 sequential dose panels (0.3, 1.5, 5, 15, 50, 100, 200, 400, and 800 mg). For determination of avagacestat, blood samples were obtained before dosing and for up to 144 hours after dosing. For participants in the 800-mg avagacestat dose panel, additional samples were obtained at 216, 312, and 648 hours. For 40-amino acid isoform of Aß (Aß(1-40)) assessment, plasma samples were collected before avagacestat administration and up to 72 hours after dosing. RESULTS: Avagacestat concentrations peaked quickly after oral administration and then had a biphasic decrease in concentrations with a prolonged terminal phase. Exposures were proportional with doses up to 200 mg. Avagacestat was well tolerated at single oral doses up to 800 mg, with a biphasic effect on plasma Aß(1-40). Adverse events were predominately mild to moderate in severity with no evidence of dose dependence up to 200 mg. CONCLUSIONS: Results from this single-ascending dose study suggest that avagacestat was tolerated at a single-dose range of 0.3 to 800 mg and suitable for further clinical development.

A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects.

BACKGROUND AND OBJECTIVES: Avagacestat is an orally active γ-secretase inhibitor that selectively inhibits amyloid ß (Aß) synthesis in cell culture and animal models. The objective of the current study was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple doses of avagacestat over 28 days in healthy young men and elderly men and women in a placebo-controlled, sequential-panel, ascending multiple-dose study. METHODS: Thirty-three young men were assigned to four serial dose groups of avagacestat 15, 50, 100 or 150 mg (n = 6-7 per dose), or placebo (n = 2 per dose panel; 8 subjects total) once daily for 28 days. Elderly men and women were assigned to serial dose groups of avagacestat 50 mg and then 100 mg (n = 7 men, 6 women) or placebo (n = 2 men, 2 women) once daily for 14 days per dose level. RESULTS: Avagacestat was rapidly absorbed, had a terminal elimination half-life of 38-65 h, and reached a steady-state concentration by day 10 of daily dosing. Exposure in young subjects increased in proportion to dose. There were no apparent differences in steady-state area under the plasma concentration-time curve between young and elderly subjects; however, elderly subjects demonstrated a higher maximum plasma concentration for avagacestat. Doses of avagacestat >50 mg/day reduced steady-state trough concentrations of CSF Aß(1-38), Aß(1-40) and Aß(1-42) in a dose-dependent fashion over 28 days of daily dosing. There were no signs of potential Notch-related dose-limiting toxicities. CONCLUSION: The results support continued evaluation of avagacestat in an elderly target population with predementia and mild to moderate Alzheimer's disease.

Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aß levels in healthy young men.

BACKGROUND: The concentration of amyloid ß (Aß) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of γ-secretase inhibition. Avagacestat is a selective γ-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF Aß concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability. METHODS: This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses. RESULTS: 34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Aß(1-38), Aß(1-40) and Aß(1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups. CONCLUSION: Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Aß concentrations, suggestive of γ-secretase inhibition. The results warrant further clinical study in patients with AD.

Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

OBJECTIVE: To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD). DESIGN: Randomized, double-blind, placebo-controlled,24-week phase 2 study. SETTING: Global, multicenter trial. PATIENTS: A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years,58.9% were APOE ε4 carriers, and baseline measures of disease severity were similar among groups. INTERVENTION: Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily. MAIN OUTCOME MEASURES: Safety and tolerability of avagacestat. RESULTS: Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients. CONCLUSIONS: Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for -secretase target engagement,but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses.This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00810147

Do corticotropin releasing factor-1 receptors influence colonic transit and bowel function in women with irritable bowel syndrome?

Corticotropin releasing factor (CRF), a mediator of stress response, alters gastrointestinal (GI) functions. Stress-related changes in colonic motility are blocked by selective CRF(1) receptor antagonists. Our aim was to assess whether modulation of central and peripheral CRF(1) receptors affects colonic transit and bowel function in female patients with diarrhea-predominant irritable bowel syndrome (D-IBS). This randomized, double-blind, placebo-controlled, 2-wk study evaluated the effects of oral pexacerfont (BMS-562086), a selective CRF(1) receptor antagonist, 25 and 100 mg qd, on GI and colonic transit of solids [by validated scintigraphy with primary end point colonic geometric center (GC) at 24 h] and bowel function (by validated daily diaries) in 39 women with D-IBS. The 100-mg dose was comparable to a dose that inhibited colonic motility in stressed rats. Treatment effects were compared by analysis of covariance with baseline colonic transit as covariate. The study had 80% power (alpha = 0.05) to detect clinically meaningful (26%) differences in colonic transit. Thirty-nine of 55 patients fulfilled eligibility criteria (9 screen failures, 5 baseline GC24 outside prespecified range). At baseline, three treatment groups had comparable age, body mass index, and GC 24 h. Significant effects of pexacerfont relative to placebo were not detected on colonic GC24 (P = 0.53), gastric emptying, orocecal transit, ascending colon emptying half-time, and stool frequency, consistency, and ease of passage. No safety issues were identified. We conclude that in women with D-IBS, pexacerfont, 25 or 100 mg qd, does not significantly alter colonic or other regional transit or bowel function. The role of central and peripheral CRF(1) receptors in bowel function in D-IBS requires further study.

Pharmacokinetics of 6-hydroxybuspirone and its enantiomers administered individually or following buspirone administration in humans.

The objective of this study was to assess the pharmacokinetics of 6-hydroxybuspirone (6OHB) when given orally via three forms: racemate (BMS-528215), S-enantiomer (BMS-442606) and R-enantiomer (BMS-442608), versus following the administration of buspirone. A double-blind, randomized, four-period, four-treatment, crossover study balanced for residual effects in healthy subjects was conducted (n=20). Subjects received single 10 mg doses of each compound in a randomized fashion with pharmacokinetics determined over a 24 h period. There was a 4-day washout between each dosing period. All three forms of 6OHB (racemate, S-enantiomer and R-enantiomer) were well tolerated. There was nterconversion between enantiomers. The dominant enantiomer was the S-enantiomer no matter which form of 6OHB was administered. All three forms of 6OHB produced approximately 2- to 3-fold greater exposure to total 6OHB than did buspirone. All three forms produced equal exposure to 1-(2-pyrimidinyl)-piperazine (1-PP) which was approximately 30% less than the 1-PP exposure derived from buspirone administration. All three forms of 6OHB produced approximately 3-fold higher 6OHB:1-PP ratios and approximately 2.5-fold higher total 6OHB exposures than did buspirone administration. All compounds were well tolerated. There seemed to be no advantage of one of the enantiomers of 6OHB over the racemate. Therefore, the racemate was chosen for further clinical development.

6-Hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats.

The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 +/- 3.5 ml/min/kg), volume of distribution (2.6 +/- 0.3 l/kg), and half-life (1.2 +/- 0.2 h) of 6-OH-buspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT)(1A) receptor occupancy in a concentration-dependent manner with EC(50) values of 1.0 +/- 0.3 and 0.38 +/- 0.06 microM in the dorsal raphe and 4.0 +/- 0.6 and 1.5 +/- 0.3 microM in the hippocampus, respectively. Both compounds appeared to be approximately 4-fold more potent in occupying presynaptic 5-HT(1A) receptors in the dorsal raphe than the postsynaptic receptors in the hippocampus. Oral dosing of buspirone in rats resulted in exposures (area under the concentration-time profile) of 6-OH-buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP), another major metabolite of buspirone, that were approximately 12 (6-OH-buspirone)- and 49 (1-PP)-fold higher than the exposure of the parent compound. As a whole, these preclinical data suggest that 6-OH-buspirone probably contributes to the clinical efficacy of buspirone as an anxiolytic agent.