Search

Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. Methods: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (low density lipoprotein cholesterol). Results: MK-0616 displayed high affinity ( K i = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84–103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple–oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43–85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. Conclusions: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

Novel therapeutics for pulmonary arterial hypertension (PAH) with improved safety/tolerability profiles are needed to address continued high rates of morbidity/mortality.This Phase 1 study evaluated efficacy/safety of inhaled single-dose MK-5475, an investigational, small-molecule stimulator of soluble guanylate cyclase designed for inhaled delivery via a dry-powder inhaler device, in participants with PAH (Clinicaltrials.gov: NCT03744637). Eligible participants were 18-70 years of age; body mass index ≤35 kg/mMK-5475 was generally well tolerated without systemic side effects on blood pressure or heart rate up to 24 h post dose. With respect to the primary pharmacodynamic outcome, mean reductions in pulmonary vascular resistance ranged from 21% to 30% across 120 μg and 360 μg doses.Treatment with inhaled single-dose MK-5475 showed rapid and sustained reductions in pulmonary vascular resistance and increases in pulmonary blood volume. MK-5475 was generally well tolerated versus placebo without vasodilatory systemic side effects. The promising pulmonary selectivity and favorable safety/tolerability profile of MK-5475 seen in this study of adult participants with PAH lays the foundation for further clinical development.

AIMS: To characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of the once‐weekly dipeptidyl peptidase‐4 (DPP‐4) inhibitor omarigliptin in healthy subjects and patients with type 2 diabetes mellitus, and use these models to support the dosing recommendation for patient labelling including patients with renal impairment. METHODS: PK and PD were assessed from a total of 9827 omarigliptin concentrations collected from 1387 healthy subjects and patients participating in Phase 1, 2 and 3 studies examining single‐ or multiple‐dose weekly administration of omarigliptin at doses ranging from 0.25 to 400 mg. Population PK and PD analyses were performed using nonlinear mixed effect modelling. RESULTS: A semi‐mechanistic 2‐compartment model with linear unbound clearance and concentration‐dependent binding of omarigliptin to the DPP‐4 enzyme in both the central and peripheral compartments adequately described omarigliptin PK. Key covariates on omarigliptin PK included reduced unbound clearance with renal impairment. A direct effect sigmoid maximum inhibitory efficacy model adequately described the relationship between omarigliptin plasma concentrations and DPP‐4 inhibition. These models supported the current Japan label instructions that the approved omarigliptin 25‐mg once‐weekly dose be halved in patients with severe renal impairment and in those with end‐stage renal disease. Also, if patients missed a dose, the next dose of omarigliptin should be taken as soon as remembered up to and including the day before the next scheduled dose. No other clinically important covariates were identified. CONCLUSION: The models in the present analysis adequately described PK and PD characteristics of omarigliptin and supported the dosing and administration section of the omarigliptin label.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection and related morbidity and mortality in infants. Passive immunization with an RSV-neutralizing antibody can provide rapid protection to this vulnerable population. Proof-of-concept for this approach has been demonstrated by palivizumab; however, the use of this antibody is generally restricted to the highest-risk infants due to monthly dosing requirements and its cost. To address the large unmet medical need for most infants, we are evaluating MK-1654, a fully human RSV-neutralizing antibody with half-life extending mutations targeting site IV of the fusion protein. In this 2-part, placebo-controlled, double-blind, first-in-human study, 152 healthy adults were randomized 3:1 to receive a single dose of MK-1654 or placebo in 5 cohorts (100 or 300 mg as an intramuscular dose or 300, 1000, or 3000 mg as an intravenous dose). Safety, pharmacokinetics, antidrug antibodies, and RSV serum-neutralizing antibody titers were evaluated through 1 year. MK-1654 serum concentrations increased proportionally with dose and resulted in corresponding elevations in RSV serum-neutralizing antibody titers. The antibody displayed a half-life of 73 to 88 days and an estimated bioavailability of 69% at the 300-mg dose. The overall safety profile of MK-1654 was similar to placebo, and treatment-emergent antidrug antibodies were low (2.6%) with no associated adverse events. These data support the continued development of MK-1654 for the prevention of RSV disease in infants.

To assess the efficacy and safety of once-weekly omarigliptin as monotherapy in people with type 2 diabetes mellitus (T2DM).People with T2DM not on glucose-lowering medications, or who were washed off monotherapy or low-dose dual therapy, were randomized double-blind to omarigliptin 25 mg (n=165) or matching omarigliptin placebo (n=164) for 24 weeks, followed by a 30-week period to assess continuing efficacy and safety longer-term of omarigliptin during which metformin was added to the placebo group and metformin placebo to the omarigliptin group.From a mean baseline HbA1c of 8.0-8.1%, the least squares mean (95% CI) change from baseline in HbA1c at week 24 (primary endpoint) was -0.49% (-0.73, -0.24) in the omarigliptin group and -0.10% (-0.34, 0.14) in the placebo group, for a between-group difference of -0.39% (-0.59, -0.19) (p.001). Protocol deviation in use of metformin by 38 of 252 (15%) people whose samples were available for evaluation probably attenuated glycemic efficacy results, as suggested by the LS mean difference -0.53% (-0.75, -0.32) after censoring of such participants. At 24 and 54 weeks, the incidences of adverse events (AEs) were similar in the omarigliptin and placebo groups. During 54 weeks there were no AEs of symptomatic hypoglycemia in the omarigliptin group and 5 AEs in the placebo group. Over 54 weeks, a majority of the omarigliptin treatment had a persistent reduction in HbA1c, remaining rescue-free.In people with T2DM, omarigliptin monotherapy improved glycemic control over 54 weeks and was generally well tolerated with a low risk of hypoglycemia. ClinicalTrials.gov Identifier: NCT01717313. EudraCT Number: 2012-003626-24.

Background Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary. Methods Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population. Findings The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants. Interpretation An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.

Background Type 2 diabetes (T2D) is a progressive disease that often requires a patient to use multiple antihyperglycemic agents to achieve glycemic control with disease progression. Omarigliptin is a once-weekly dipeptidyl peptidase-4 inhibitor. The purpose of this trial was to assess the efficacy and safety of adding omarigliptin to the treatment regimen of patients with T2D inadequately controlled by dual therapy with metformin and glimepiride. Methods Patients with T2D and HbA1c ≥7.5% and ≤10.5% while on metformin (≥1500 mg/day) and glimepiride (≥4 mg/day) were randomized to omarigliptin 25 mg once-weekly (N = 154) or placebo (N = 153) for 24 weeks. The primary objective was to assess whether omarigliptin was superior to placebo in reducing HbA1c at Week 24. Secondary objectives were to assess the effects of omarigliptin vs. placebo on FPG and the proportion of subjects attaining HbA1c goals of

Aims To assess the safety and efficacy of omarigliptin in Japanese patients with type 2 diabetes (T2D). Methods In a 24-week double-blind trial, 414 patients with T2D were randomized to omarigliptin 25 mg once weekly, sitagliptin 50 mg once daily or placebo. The double-blind period was followed by a 28-week open-label extension during which all patients received omarigliptin 25 mg once weekly. Efficacy endpoints were glycated haemoglobin (HbA1c), 2-hour postprandial glucose (PPG) and fasting plasma glucose (FPG) levels. Results After 24 weeks, the least squares (LS) mean change from baseline in HbA1c was −0.66% for omarigliptin, −0.65% for sitagliptin and 0.13% for placebo. The difference in LS mean for omarigliptin vs placebo was −0.80% ( P

Objective: To evaluate the efficacy and safety of adding the once-weekly DPP-4 inhibitor omarigliptin or the sulfonylurea glimepiride to the treatment regimen of patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy. Methods: Patients with T2DM and HbA1c ≥6.5% to ≤9.0% while on a stable dose of metformin (≥1500 mg/day) were randomized to omarigliptin 25 mg once-weekly (N = 376) or glimepiride up to 6 mg once-daily (N = 375) for 54 weeks. The primary hypothesis was that omarigliptin is non-inferior to glimepiride in reducing HbA1c at Week 54. Results: The mean baseline HbA1c was 7.5% in the omarigliptin group and 7.4% in the glimepiride group. After 54 weeks, the least squares (LS) mean change from baseline in HbA1c was -0.30% in the omarigliptin group and -0.48% in the glimepiride group, with a between-group difference (95% CI) of 0.18% (0.06, 0.30), which met the prespecified criterion for declaring non-inferiority. The incidence of symptomatic hypoglycemia was 5.3% in the omarigliptin group and 26.7% in the glimepiride group. With the exception of hypoglycemia, the incidences of adverse events and discontinuations were similar between treatment groups. Relative to baseline, omarigliptin was associated with a mean weight loss (−0.4 kg) and glimepiride a mean weight gain (+1.5 kg). Conclusions: After 54 weeks, as add-on therapy to metformin, once-weekly omarigliptin was generally well tolerated and non-inferior to glimepiride in improving glycemic control, with a lower incidence of hypoglycemia and with weight loss versus weight gain.

To examine the efficacy and safety of the once-weekly (q.w.) dipeptidyl peptidase-4 inhibitor, omarigliptin, in patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.In a randomized, double-blind trial, patients with T2DM on a stable dose of metformin monotherapy (≥1500 mg/day) with glycated hemoglobin (HbA1c) of 7.0-10.5% were randomized to omarigliptin 25 mg q.w. or matching placebo (n = 201 in both) for 24 weeks (primary timepoint) followed by an additional 80-week treatment period.At week 24, from a mean baseline HbA1c of 8.0-8.1%, the least squares (LS) mean (95% CI) change from baseline in HbA1c (primary end-point) was -0.54% (-0.69%, -0.40%) in the omarigliptin group and 0.00% (-0.14%, 0.15%) in the placebo group, for a between-group difference of -0.55% (-0.75%, -0.34%); p .001. Between-group differences (LS mean 95% CI) for the secondary end-points of 2-h post-meal glucose and fasting plasma glucose (omarigliptin vs placebo) were -0.8 mmol/L (-1.4, -0.2) (p = .011) and -0.5 mmol/L (-0.9, -0.1) (p = .010), respectively. At week 24, the incidences of symptomatic hypoglycemia and subjects with one or more adverse event (AE), serious AEs, and discontinuations due to an AE were similar in the omarigliptin and placebo groups. Over 104 weeks, omarigliptin treatment provided a clinically meaningful reduction in HbA1c.In patients with T2DM, adding omarigliptin 25 mg q.w. to metformin monotherapy improved glycemic control over 104 weeks and was generally welltolerated with a low risk of hypoglycemia.

Introduction Daily dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used with other orally administered antihyperglycemic agents (AHA), as combination therapy, to treat Japanese patients with type 2 diabetes. When combination therapy is indicated, use of a once-weekly (q.w.) orally administered DPP-4 inhibitor might be an appropriate therapeutic option for some patients. Methods A 52-week trial was conducted to assess the safety and tolerability (primary objectives) and glycemic efficacy (secondary objectives) of the q.w. DPP-4 inhibitor omarigliptin as add-on therapy to five different classes of orally administered AHA [sulfonylurea (SU), glinide (GL), biguanide (BG), thiazolidinedione (TZD), or α-glucosidase inhibitor (AGI)] commonly used in Japan and having different mechanisms of drug action from DPP-4 inhibitors. The trial consisted of an initial 24-week double-blind, placebo-controlled period during which patients (stratified by background AHA) were randomized to omarigliptin 25 mg q.w. or placebo, followed by a 28-week open-label period during which patients on placebo were switched to omarigliptin. Results After 24 weeks, the percentages of patients with adverse events (AEs), serious AEs, drug-related AEs, AEs of symptomatic hypoglycemia, or who discontinued from trial medication because of an AE were generally similar in the omarigliptin and placebo groups, in all background AHA strata and in the overall population. From a mean baseline HbA1c of approximately 8.0%, the placebo-adjusted least-squares mean changes from baseline ranged from −0.80% (AGI stratum) to −1.16% (TZD stratum); p

Aim To compare the efficacy and safety of the once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin or once-daily DPP-4 inhibitor sitagliptin in patients with type 2 diabetes (T2DM) and inadequate glycaemic control on metformin. Materials and methods Patients with T2DM with a glycated haemoglobin (HbA1c) concentration ≥6.5% to ≤9.0% while on a stable dose of metformin (≥1500 mg/d) were randomized in a double-blind manner to receive omarigliptin 25 mg once weekly (n = 322) or sitagliptin 100 mg once daily (n = 320). The primary analysis assessed whether omarigliptin was non-inferior to sitagliptin in reducing HbA1c at week 24, based on the criterion of having an upper bound of the 95% confidence interval (CI) about the difference less than the non-inferiority bound of 0.3%. Results The mean baseline HbA1c was 7.5% in both groups. After 24 weeks, the least squares (LS) mean change in HbA1c from baseline was −0.47% in the omarigliptin group and −0.43% in the sitagliptin group, with a between-group difference of −0.03% (95% CI −0.15, 0.08). This result met the prespecified criterion for declaring non-inferiority. The LS mean change from baseline in fasting plasma glucose and the percentage of patients with HbA1c

The use of multiple lipid-modifying agents with different mechanisms of action is often required to regulate lipid levels in patients with dyslipidemia. During combination therapy, alterations in the pharmacokinetics of any of the drugs used and their metabolites may occur. Three separate open-label, randomized, crossover studies evaluated the potential for pharmacokinetic interaction between extended-release niacin (with and without concomitant laropiprant) and simvastatin in healthy subjects. Study 1 used single doses of extended-release niacin and simvastatin; study 2 used multiple-dose coadministration of extended-release niacin/laropiprant and simvastatin in healthy subjects; and study 3 used single doses of both extended-release niacin and the coadministration of extended-release niacin/laropiprant and simvastatin in healthy Chinese subjects. During each treatment period, plasma samples were collected predose and at prespecified postdose time points for pharmacokinetic analyses. The safety and tolerability of simvastatin with and without coadministered extended-release niacin (or extended-release niacin/laropiprant) were assessed by clinical evaluation of adverse experiences. In 2 studies in healthy subjects, modest increases in exposure to simvastatin acid (by ∼60%) by extended-release niacin and extended-release niacin/laropiprant were observed. Based on the clinical experience with simvastatin, these effects are not believed to be clinically meaningful. In the third study on healthy Chinese subjects, no statistically meaningful increases in exposure to simvastatin by extended-release niacin and extended-release niacin/laropiprant were observed. In all populations examined in these studies, the coadministration of extended-release niacin and simvastatin was generally well tolerated.

Background Omarigliptin is a once-weekly (q.w.) oral DPP-4 inhibitor that is approved for the treatment of patients with type 2 diabetes mellitus (T2DM) in Japan. To support approval of omarigliptin in the United States, the clinical development program included a cardiovascular (CV) safety study. Subsequently, a business decision was made not to submit a marketing application for omarigliptin in the United States, and the CV safety study was terminated. Herein we report an analysis of data from that early-terminated study. Methods In this randomized, double-blind study, 4202 patients with T2DM and established CV disease were assigned to either omarigliptin 25 mg q.w. or matching placebo in addition to their existing diabetes therapy. A Cox proportional hazards model was used to summarize the primary endpoint of time to first major adverse CV event (MACE, the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke) and the analysis of first event of hospitalization for heart failure (hHF). Results The median follow-up was approximately 96 weeks (range 1.1–178.6 weeks). The primary MACE outcome occurred in 114/2092 patients in the omarigliptin group (5.45%; 2.96/100 patient-years) and 114/2100 patients in the placebo group (5.43%; 2.97/100 patient-years), with a hazard ratio (HR) of 1.00 (95% confidence interval [CI] 0.77, 1.29). The hHF outcome occurred in 20/2092 patients in the omarigliptin group (0.96%; 0.51/100 patient-years) and 33/2100 patients in the placebo group (1.57%; 0.85/100 patient-years), with an HR of 0.60 (95% CI 0.35, 1.05). After 142 weeks, the least-squares mean difference (omarigliptin vs. placebo) in glycated hemoglobin levels was −0.3% (95% CI −0.46, −0.14). The numbers of patients with adverse events, serious adverse events or discontinued from study medication due to adverse events were similar in the omarigliptin and placebo groups. Conclusions In this CV safety study of patients with T2DM and established CV disease, omarigliptin did not increase the risk of MACE or hHF and was generally well tolerated. Trial registration ClinicalTrials.gov: NCT01703208. Registered 05 October 2012

Purpose The objective of this clinical trial was to assess the efficacy and safety of omarigliptin monotherapy in young adult patients with type 2 diabetes mellitus (T2DM). Unexpected efficacy results in this trial led to a series of investigations that identified the use of prohibited medication by a substantial number of trial patients. Methods Patients with T2DM who were ≥18 to Findings The mean age of trial participants was 39.2 years, approximately 60% were male, mean body mass index was 32.5 kg/m2, and mean duration of diabetes was 3.1 years. The mean baseline HbA1c value was 7.9% in the omarigliptin group and 8.1% in the placebo group. After 24 weeks, the least squares mean change (95% CI) in HbA1c value from baseline was –0.33% (–0.60 to –0.06) in the omarigliptin group and –0.45% (–0.72 to –0.18) in the placebo group, with a between-group difference of 0.12% (–0.26 to 0.49; P = 0.535). Similarly, no between-group difference was observed for the other glycemic parameters (2-hour postmeal glucose and fasting plasma glucose levels). No issues were identified in drug allocation, dispensing or supply, patient compliance with trial medication, sample handling or analysis, or site trial conduct that explained the observed results. Measurement of drug levels from future biomedical research samples uncovered the use, with no investigator knowledge, of an antihyperglycemic agent that was prohibited by the protocol (ie, metformin) by 42.4% (39 of 92) of patients. Metformin was used by more patients in the placebo group (57% [25 of 44]) than in the omarigliptin group (29% [14 of 48]). Implications The use of prohibited metformin in a trial of a dipeptidyl peptidase–4 inhibitor, omarigliptin, introduced a confounding factor that invalidated the results of the trial. This behavior may have been encouraged in the trial by protocol-specified self-monitoring of blood glucose levels. Use of prohibited medication may be an underappreciated confounder in clinical trial research. Trial registrations: MK-3102-028 (US); ClinicalTrials.gov identifier, NCT01814748; EudraCT number, 2012-004303-12 (EU).

Additional file 1. Adjudication guidelines for cardiac events.

Two open-label, parallel-group studies evaluated the influence of renal and hepatic insufficiency on the pharmacokinetics of a single-dose anacetrapib 100 mg. Eligible participants included adult men and women with moderate hepatic impairment (assessed by Child-Pugh criteria) or severe renal impairment (CrCl

Anacetrapib is a cholesteryl ester transfer protein inhibitor in Phase III development. This double-blind, double-dummy, randomized, placebo- and active-comparator-controlled, 4-period, balanced crossover study evaluated the effects of anacetrapib (100 mg and 800 mg) on QTcF interval in healthy subjects. QTcF measurements were made up to 24 h following administration of single doses of anacetrapib 100 or 800 mg, moxifloxacin 400 mg, or placebo in the fed state. The primary hypothesis was supported if the 90% CI for the least squares (LS) mean differences between anacetrapib 800 mg and placebo in QTcF interval change from baseline were entirely

Aims To characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916. Methods Data are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4–100 mg MK-0916 (n = 16). In the second study, subjects received 0.2–225 mg MK-0916 followed by daily doses of 0.2–100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [13C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [13C4]cortisone. Results Doses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1–1.8 h). Exposure (measured as the area under the concentration–time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses 6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11β-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nm. Exposure to MK-0916 was generally well tolerated. Conclusions These findings indicate that 11β-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated.

Background Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection and hospitalization in infants. Prophylaxis for RSV infection is only recommended for the highest risk infants, leaving the majority of infants unprotected. MK-1654 is a fully human monoclonal antibody targeting the RSV fusion (F) protein with Fc domain mutations to extend half-life that is being developed to provide passive immunity against RSV in infants. The safety profile, development of anti-drug antibodies (ADAs), serum neutralizing antibody (SNA) titers, and pharmacokinetics (PK) in healthy adult volunteers receiving single-ascending doses of MK-1654 was evaluated. Methods In this double-blinded ongoing Phase 1 study, healthy adults of non-childbearing potential (19 to 59 years) were randomized in a 3:1 ratio to receive a single dose of MK-1654 or placebo (0.9% sodium chloride injection, USP) as a bolus intramuscular injection (IM) or in an intravenous infusion (IV) for at least 2.5 hours. Dose levels included 100 and 300 mg IM, and 300, 1,000, and 3,000 mg IV. Standard methods were used to assess safety and tolerability. Serum was tested for ADAs and RSV A SNA titers at time points up to day 120 and up to day 90, respectively. MK-1654 adult PK and estimated PK for infants will be reported separately. Results A total of 152 subjects (male = 117, female = 35) have been enrolled (mean age = 41 years). No deaths, serious adverse events, discontinuations due to AEs, clinically significant laboratory AEs, or dose-dependent pattern of drug-related AEs were reported. Sixty-six subjects reported 181 clinical AEs (97.8% mild and 2.2% moderate in intensity). The most common AEs (≥5%) were headache, nasal congestion, vessel puncture site hemorrhage, oropharyngeal pain, rhinorrhea and nausea. No treatment emergent ADAs have been identified through time points tested. Administration of MK-1654 resulted in a dose-dependent increase in RSV A SNA titers through Day 90 (figure). Updated safety, SNA titers and ADAs will be provided. Conclusion MK-1654 was generally well tolerated at doses up to 300 mg IM and up to 3,000 mg IV and resulted in a dose-dependent increase in SNA titers, reflecting biologically active MK-1654 in the serum. No treatment emergent ADAs have been observed. Disclosures A. Aliprantis, Merck: Employee and Shareholder, Salary and stock options. D. Wolford, Merck: Employee and Shareholder, Salary and stock options. L. Caro, Merck: Employee and Shareholder, Salary and stock options. B. Maas, Merck: Employee and Shareholder, Salary and stock options. H. Ma, Merck: Employee and Shareholder, Salary and stock options. K. Vora, Merck: Employee, Salary. D. Geng, Merck: Employee and Shareholder, Salary and stock options. R. Railkar, Merck: Employee and Shareholder, Salary and stock options. A. Lee, Merck: Employee and Shareholder, Salary and stock options. L. Sterling, Merck: Investigator, Research grant. E. Lai, Merck: Employee and Shareholder, Salary and stock options.

G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.

Laropiprant (LRPT) is being developed in combination with Merck's extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD2 receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A2 receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time at 24 h post-dose (trough) was pre-specified as the primary pharmacodynamic endpoint in both studies. Two separate, double-blind, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose LRPT on the pharmacodynamics of multiple-dose clopidogrel or aspirin. Healthy subjects were...

Laropiprant is a selective antagonist of the prostaglandin D2 receptor subtype 1, and is primarily eliminated via glucuronidation with a minor contribution from oxidative metabolism via CYP3A. The effects of multiple oral doses of clarithromycin on the pharmacokinetics of laropiprant were investigated in an open-labeled, randomized, 2-period cross-over study. A single oral dose of 40 mg laropiprant was administered alone or coadministered with 500 mg clarithromycin b.i.d. on Day 5 of a 7-day clarithromycin regimen. Geometric mean ratios (90% confidence intervals) for AUC0-∞ and Cmax of laropiprant in the presence versus absence of clarithromycin were 1.39 (1.19, 1.62) and 1.46 (1.17, 1.80), respectively. No statistically significant differences were observed in Tmax (P= 0.543) or apparent terminal half-life (P= 0.502) of laropiprant, which implies that the effect of clarithromycin on laropiprant is largely a first-pass rather than a systemic effect. The results of this study suggest that laropiprant is not a sensitive CYP3A substrate, and strong CYP3A inhibitors like clarithromycin are not expected to have a clinically meaningful impact on the pharmacokinetics of laropiprant.

Laropiprant, a prostaglandin D(2) receptor-1 antagonist shown to reduce flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, randomized, 2-period crossover study assessed the effects of laropiprant on the pharmacokinetics of digoxin, with 13 healthy subjects randomized to 2 treatments administered in random order with a 10-day or longer washout period: (A) single-dose digoxin 0.5 mg on day 1 and once-daily oral doses of laropiprant 40 mg for 10 days beginning 5 days prior to digoxin dosing (day -5 to day 5); (B) single-dose digoxin 0.5 mg on day 1. Blood was collected over the course of 120 hours post digoxin dose to assess pharmacokinetics of immunoreactive digoxin. Comparability was declared if the 90% confidence interval for the geometric mean ratio of laropiprant+digoxin to digoxin alone of the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) for immunoreactive digoxin fell within 0.80 to 1.25. The AUC(0-infinity) and maximum observed plasma concentration (C(max)) geometric mean ratios of immunoreactive digoxin were 0.91 (90% confidence interval, 0.76-1.10) and 1.04 (90% confidence interval, 0.91-1.21), respectively. Median time of occurrence of C(max) and mean half-life of immunoreactive digoxin were comparable in the presence and absence of laropiprant. Coadministration of digoxin and laropiprant was generally well tolerated. The small decrease in exposure to immunoreactive digoxin (approximately 10%) following coadministration of laropiprant and digoxin is not considered to be clinically meaningful.

The vestibular portion of the inner ear, the three semicircular canals and their sensory cristae, is responsible for detecting angular head movements. It was proposed that sensory cristae induce formation of their non-sensory components, the semicircular canals. Here, we analyzed the inner ears of Foxg1−/− mouse mutants, which display vestibular defects that are in conflict with the above model. In Foxg1−/− ears, the lateral canal is present without the lateral ampulla, which houses the lateral crista. Our gene expression analyses indicate that at the time when canal specification is thought to occur, the prospective lateral crista is present, which could have induced lateral canal formation prior to its demise. Our genetic fate-mapping analyses indicate an improper separation between anterior and lateral cristae in Foxg1−/− mutants. Our data further suggest that a function of Foxg1 in the inner ear is to restrict sensory fate. Developmental Dynamics 238:2725–2734, 2009. © 2009 Wiley-Liss, Inc.

Flushing symptoms limit the use of niacin as an effective treatment for dyslipidemia; laropiprant, a prostaglandin D2 receptor subtype 1 antagonist, reduces niacin-induced flushing and is being developed in combination with niacin. The aims of this study were to both determine the effect of renal insufficiency on plasma pharmacokinetics of laropiprant and to assess safety and tolerability in patients with severe renal insufficiency. This open-label study compared the pharmacokinetics of a single laropiprant 40-mg dose in 8 nondialyzed, severe renal insufficiency patients (RIs) with healthy matched subjects (HSs) (24-hour creatinine clearance30 mL/min/1.73 m(2) and80 mL/min/1.73 m(2) for RIs and HSs, respectively). In RIs, laropiprant was well tolerated and the area under the concentration time curve (AUC(0-infinity)) was modestly higher (ratio of geometric least-squares means [GMR] for RIs to HSs was 1.58; 90% confidence interval [CI], 1.06-2.35); neither the maximum laropiprant plasma concentration (C(max)) nor the time to C(max) (T(max)) was significantly affected. The apparent terminal half-life (t(1/2)) was 26.0 and 14.8 hours for RIs and HSs, respectively (P = 0.007). Similarly, for the inactive laropiprant glucuronide metabolite, the GMR for AUC(0-infinity) was 2.17 (90% CI, 1.44-3.27), and the apparent t(1/2) values were 25.3 to 14.5 hours (P = 0.037) in RIs and HSs, respectively. Renal insufficiency had no clinically significant effect on laropiprant pharmacokinetics. Because niacin and its metabolites are excreted through the kidneys, the combination of niacin with laropiprant should be used with caution in patients with renal impairment.

Laropiprant (LRPT), a prostaglandin D2 receptor 1 antagonist shown to reduce niacin-induced flushing symptoms, is being developed in combination with niacin for the treatment of dyslipidemia. This study assessed the pharmacokinetics/pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose LRPT. Thirteen subjects received 2 treatments in random order separated by > or =10-day washout: (1) multiple-dose LRPT 40 mg/d for 12 days (days -5 to 7) with coadministered single-dose warfarin 30 mg (day 6) and (2) single-dose warfarin 30 mg (day 1). R+- and S(-)-warfarin and international normalized ratio (INR) were assayed predose and up to 168 hours postdose. Comparability was declared if the 90% confidence intervals (CIs) for the geometric mean ratio (GMR; warfarin + LRPT/warfarin alone) of area under the plasma concentration curve from zero to infinity (AUC0-infinity) for R+- and S(-)-warfarin were contained within (0.80, 1.25). The estimated GMRs of AUC0-infinity (90% CIs) were 1.02 (0.96, 1.09) and 1.04 (0.98, 1.09) for R+- and S(-)-warfarin, respectively. The estimated GMRs of maximum plasma concentration (Cmax) (90% CIs) were 1.13 (1.02, 1.26) and 1.11 (0.99, 1.24) for R+- and S(-)-warfarin, respectively. The estimated GMRs of area under the prothrombin time INR curve from 0 to 168 hours on day 21 (INR AUC0-168 h) and average maximum observed prothrombin time INR (INRmax) were 1.02 (0.99, 1.05) and 1.04 (0.98, 1.10), respectively. There was no evidence of clinically meaningful alterations in the pharmacokinetics and pharmacodynamics (ie, INR) of R(+)- or S(-)-warfarin after coadministration of multiple-dose LRPT and single-dose warfarin.

Niacin is an effective lipid-modifying therapy whose use has been limited by suboptimal tolerability. The adverse effect of flushing is due to prostaglandin D2 (PGD2)-mediated cutaneous vasodilation. Adjunctive treatment with the PGD2 receptor antagonist laropiprant significantly reduces the incidence and severity of niacin-induced flushing. The objective of this study was to assess the effect of aspirin pretreatment on flushing symptoms with extended-release (ER) niacin/laropiprant in healthy volunteers. A randomized, double-blind, placebo-controlled crossover study compared patient-rated flushing following pretreatment with aspirin 325 mg versus placebo administered 30 minutes before ER niacin 2 g/laropiprant 40 mg. Flushing responses were assessed using participant-reported overall symptom severity score (OSSS), including individual characteristics of redness, warmth, tingling, or itching. The overall incidence and severity of flushing were comparable for participants receiving aspirin or placebo before ER niacin 2 g/laropiprant 40 mg. The difference in 3-day average OSSS between treatments was 0.2 (P=.180). Profiles of flushing severity, frequency, and bothersomeness were comparable for the aspirin/ER niacin/laropiprant and ER niacin/laropiprant regimens. All treatments were safe and well tolerated. Coadministration of aspirin 325 mg daily with ER niacin 2 g/laropiprant 40 mg does not further reduce residual flushing symptoms associated with ER niacin 2 g/laropiprant 40 mg alone.

Background Development of niacin-like agents that favorably affect lipids with an improved flushing profile would be beneficial. Objective To evaluate a niacin receptor partial agonist, MK-0354, in Phase I and II studies. Methods The pharmacokinetic/pharmacodynamic effects of single and multiple doses (7 days) of MK-0354 (300–4000 mg) were evaluated in two Phase I studies conducted in healthy men. A Phase II study assessed the effects of MK-0354 2.5 g once daily on lipids during 4 weeks in 66 dyslipidemic patients. Results MK-0354 single doses up to 4000 mg and multiple doses (7 days) up to 3600 mg produced robust dose-related reductions in free fatty acid (FFA) over 5 hours. Single doses of MK-0354 300 mg and extended release-niacin (Niaspan) 1 g produced comparable reductions in FFA. Suppression of FFA following 7 daily doses of MK-0354 was similar to that after a single dose. In the Phase II study, MK-0354 2.5 g produced little flushing but no clinically meaningful effects on lipids (placebo-adjusted percent change: high-density lipoprotein cholesterol, 0.4%, 95% confidence interval −5.2 to 6.0; low-density lipoprotein cholesterol, −9.8%, 95% confidence interval −16.8 to −2.7; triglyceride, −5.8%, 95% confidence interval −22.6 to 11.9). Conclusion Treatment with MK-0354 for 7 days resulted in plasma FFA suppression with minimal cutaneous flushing. However, 4 weeks of treatment with MK-0354 failed to produce changes in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or triglycerides.

Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D 2 , which leads to poor patient compliance and suboptimal dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin D 2 receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)–induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n = 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n = 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients.

[(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopentaindol-3-yl]acetic acid (MK-0524) is a potent orally active human prostaglandin D(2) receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The metabolism and excretion of [(14)C]MK-0524 in humans were investigated in six healthy human volunteers following a single p.o. dose of 40 mg (202 microCi). [(14)C]MK-0524 was absorbed rapidly, with plasma C(max) achieved 1 to 1.5 h postdose. The major route of excretion of radioactivity was via the feces, with 68% of the administered dose recovered in feces. Urinary excretion averaged 22% of the administered dose, for a total excretion recovery of approximately 90%. The majority of the dose was excreted within 96 h following dosing. Parent compound was the primary radioactive component circulating in plasma, comprising 42 to 72% of the total radioactivity in plasma for up to 12 h. The only other radioactive component detected in plasma was M2, the acyl glucuronic acid conjugate of the parent compound. The major radioactive component in urine was M2, representing 64% of the total radioactivity. Minor metabolites included hydroxylated epimers (M1/M4) and their glucuronic acid conjugates, which occurred in the urine as urea adducts, formed presumably during storage of samples. Fecal radioactivity profiles mainly comprised the parent compound, originating from unabsorbed parent and/or hydrolyzed glucuronic acid conjugate of the parent compound. Therefore, in humans, MK-0524 was eliminated primarily via metabolism to the acyl glucuronic acid conjugate, followed by excretion of the conjugate into bile and eventually into feces.

Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with niacin-induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1), which may mediate niacin-induced vasodilation. The aim of this proof-of-concept study was to evaluate the effects of laropiprant (vs placebo) on niacin-induced cutaneous vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended-release (ER) niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging. Laropiprant was effective after multiple doses in reducing symptoms of flushing and attenuating the increased malar skin blood flow induced by ER niacin. In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of niacin-induced vasodilation.

Nasal congestion in allergic rhinitis results from tissue edema and vasodilatation in the nasal mucosa. Of the mediators released by mast cells in response to allergens, prostaglandin (PG) D(2) is regarded as the most potent inducer of nasal congestion. Intranasal administration of PGD(2) reproduces the nasal blockade experienced by patients with seasonal allergic rhinitis (SAR) via its action on the PGD(2) (DP) receptor to induce nasal vasodilatation. Intranasal challenge with PGD(2) can be a useful tool for evaluating DP-receptor antagonists.The main purpose of this study was to examine the ability of MK-0524, a DP receptor antagonist in development for the treatment of SAR, to block PGD(2) induced nasal congestion in healthy volunteers.To this end, a double-blind, placebo-controlled, randomized, 3-period study was performed in 15 healthy subjects. During each period, subjects received MK-0524 25 mg, MK-0524 100 mg or placebo qd for 3 days. Twenty-four hours following the last dose, nasal provocations with PGD(2) were performed to determine the PD(75), which is the intranasal dose of PGD(2) that provokes a 75% increase in baseline total nasal airway resistance as performed by active anterior rhinomanometry.Following treatment with MK-0524, the PD(75) (mean+/-SD) was significantly shifted from 15.8 +/- 18.3 mug/nostril during the placebo period to more than 512 mug/nostril both following the 25- and 100-mg (maximum challenge dose tested) dose regimen.Whether this45 fold increase in PD(75) will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.

Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D 2 in plasma and could be blocked by pretreatment with aspirin. Two PGD 2 receptors have been identified: PGD 2 receptor 1 (DP1, also called DP) and PGD 2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD 2 (13,14-dihydro-15-keto-PGD 2 ) did not induce cutaneous vasodilation, and DP2 −/− mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD 2 - and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1 +/+ , DP1 +/− , and DP1 −/− mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP −/− mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans.

In animals with binocular vision, retinal ganglion cell (RGC) axons from each eye sort in the developing ventral diencephalon to project to ipsi- or contralateral targets, thereby forming the optic chiasm. Ipsilaterally projecting axons arise from the ventrotemporal (VT) retina and contralaterally projecting axons primarily from the other retinal quadrants. The winged helix transcription factor Foxd1 (previously known as BF-2, Brain Factor 2) is expressed in VT retina, as well as in the ventral diencephalon during the formation of the optic chiasm. We report here that in embryos lacking Foxd1,both retinal development and chiasm morphogenesis are disrupted. In the Foxd1 deficient retina, proteins designating the ipsilateral projection, such as Zic2 and EphB1, are missing, and the domain of Foxg1 (BF-1) expands from nasal retina into the VT crescent. In retina-chiasm co-cultures, VT RGCs from Foxd1 deficient retina are not repulsed by chiasm cells, and in vivo many VT RGCs aberrantly project contralaterally. However, even though the ipsilateral program is lost in the retina, a larger than normal uncrossed component develops in Foxd1 deficient embryos. Chiasm defects include axon stalling in the chiasm and a reduction in the total number of RGCs projecting to the optic tract. In addition, in the Foxd1 deficient ventral diencephalon, Foxg1 invades the Foxd1 domain, Zic2 and Islet1 expression are minimized, and Slit2 prematurely expands, changes that could contribute to axon projection errors. Thus, Foxd1 plays a dual role in the establishment of the binocular visual pathways: first, in specification of the VT retina, acting upstream of proteins directing the ipsilateral pathway; and second, in the patterning of the developing ventral diencephalon where the optic chiasm forms.

During mammalian cerebral corticogenesis, progenitor cells become progressively restricted in the types of neurons they can produce. The molecular mechanism that determines earlier versus later born neuron fate is unknown. We demonstrate here that the generation of the earliest born neurons, the Cajal-Retzius cells, is suppressed by the telencephalic transcription factor Foxg1. In Foxg1 null mutants, we observed an excess of Cajal-Retzius neuron production in the cortex. By conditionally inactivating Foxg1 in cortical progenitors that normally produce deep-layer cortical neurons, we demonstrate that Foxg1 is constitutively required to suppress Cajal-Retzius cell fate. Hence, the competence to generate the earliest born neurons during later cortical development is actively suppressed but not lost.

The patterning of the telencephalon is regulated by the concerted action of distinct mechanisms operating in different portions of this structure. Although much progress has been made in understanding the mechanisms underlying the specification of dorsal and ventral structures, little is known about the specification of the paleocortex, the olfactory cortex located at the interface of the dorsal and ventral telencephalon. The paleocortex is thought to be a dorsal, cortical structure, derived from the lateral extreme of the dorsal telencephalon. We examined mutant mice in which dorsal telencephalic patterning is severely disrupted, to ask how these perturbations affect the paleocortex. In the Lhx2-/- telencephalon, where the cortex is greatly shrunken such that medial and dorsal cortical tissue is undetectable, normal expression of several paleocortical markers is observed. The Gli3-/- telencephalon, where the dorsal telencephalon is ventralized, also displays paleocortical markers. In contrast, when the ventral telencephalon is almost completely deleted, such as in the BF1-/- brain, paleocortical markers are undetectable. These results indicate that the specification of the paleocortex can occur in spite of drastic perturbations of dorsal patterning. Furthermore, in the Lhx2 mutant, the paleocortex is juxtaposed to an expanded and mislocated source of Wnt and Bmp signaling, the cortical hem, whereas, in the Gli3 mutant, paleocortical markers arise even though the cortical hem is missing. This indicates that an increase or decrease in cues from this dorsal signaling center does not disrupt the specification of the paleocortex. Finally, by using an in vitro assay, we found that isolated explants of lateral telencephalon up-regulate normal expression of paleocortical markers when maintained in vitro, from as early as embryonic day (E) 10.5. Together, the results reveal that, although the paleocortex is considered to be a cortical structure, it is specified even when dorsal telencephalic patterning is grossly perturbed. Furthermore, our in vitro data reveal that, if mechanisms outside the lateral telencephalon are involved in the specification of the paleocortex, they must act extremely early, prior to E10.5.

The winged helix gene Brain factor-1 (BF1) has a pleiotropic role in the development of the cerebral hemispheres of the brain. Mice lacking BF1 have defects in the morphogenesis of the structures of the dorsal telencephalon (e.g., neocortex) and the ventral telencephalon (e.g., the basal ganglia). This study focuses on the functions of BF1 in the dorsal telencephalon. We showed previously that telencephalic progenitor cells lacking BF1 differentiate into neurons prematurely. Here, we demonstrate that the loss of BF1 also results in an early lengthening of the cell cycle in neocortical progenitors. To investigate the mechanisms by which BF1 regulates progenitor cell proliferation and differentiation in the developing brain, we have replaced the endogenous BF1 protein with a DNA binding defective form of BF1 in mice, BF1(NHAA). The BF1(NHAA) protein restores the growth of the dorsal telencephalon, by improving the proliferation of progenitor cells. However, the BF1(NHAA) protein does not correct the early neuronal differentiation associated with the loss of BF1. In contrast, replacement of endogenous BF1 with wild-type BF1 corrects the defects in both the proliferation and differentiation of neocortical progenitors. These results demonstrate that BF1 controls progenitor cell proliferation and differentiation in the neocortex through distinct DNA binding-independent and binding-dependent mechanisms.

Kidney epithelia develop from the metanephric mesenchyme after receiving inductive signals from the ureteric bud and from the renal stroma. However, it is not clear how these signals induce the different types of epithelia that make up the nephron. To investigate inductive signaling, we have isolated clusters of epithelial progenitors from the metanephric mesenchyme, thereby separating them from the renal stroma. When the isolated progenitors were treated with the ureteric bud factor LIF, they expressed epithelial proteins (ZO-1, E-cadherin, laminin α5) and produced nephrons (36 glomeruli with 58 tubules), indicating that they are the target of inductive signaling from the ureteric bud, and that renal stroma is not absolutely required for epithelial development in vitro. In fact, stroma-depleted epithelial progenitors produced sevenfold more glomeruli than did intact metanephric mesenchyme (5 glomeruli, 127 tubules). Conversely, when epithelial progenitors were treated with both LIF and proteins secreted from a renal stromal cell line, glomerulogenesis was abolished but tubular epithelia were expanded (0 glomeruli, 47 tubules). Hence, by isolating epithelial progenitors from the metanephric mesenchyme, we show that they are targeted by factors from the ureteric bud and from the renal stroma, and that epithelial diversification is stimulated by the ureteric bud and limited by renal stroma.

SummaryAims To assess the safety and efficacy of omarigliptin in subjects with type 2 diabetes mellitus (T2DM) and chronic renal impairment (RI). Methods Patients with T2DM with moderate RI (estimated glomerular filtration rate [eGFR] ≥30 to

Two open-label, parallel-group studies evaluated the influence of renal and hepatic insufficiency on the pharmacokinetics of a single-dose anacetrapib 100 mg. Eligible participants included adult men and women with moderate hepatic impairment (assessed by Child-Pugh criteria) or severe renal impairment (CrCl30 mL/min/1.73 m(2)). In both studies, patients were matched (race, age, sex, BMI) with healthy control subjects. Twenty-four subjects were randomized in each study (12 with either moderate hepatic or severe renal impairment and 12 matched healthy controls). In the hepatic insufficiency study, the geometric mean ratio (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% CIs for the area under the concentration-time curve from time zero to infinity (AUC(0-∞)) and the maximum concentration of drug in plasma (C(max)) were 1.16 (0.84, 1.60) and 1.02 (0.71, 1.49), respectively. In the renal insufficiency study, the GMRs (mean value for the group with severe renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC(0-∞) and Cmax were 1.14 (0.80, 1.63) and 1.31 (0.93, 1.83), respectively. Anacetrapib was generally well tolerated and there was no clinically meaningful effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of anacetrapib.

Brain factor 1 (BF-1) is a winged-helix transcriptional repressor that plays important roles in both progenitor cell differentiation and regional patterning in the mammalian telencephalon. The aim of this study was to elucidate the molecular mechanisms underlying BF-1 functions. It is shown here that BF-1 interacts in vivo with global transcriptional corepressors of the Groucho family and also associates with the histone deacetylase 1 protein. The ability of BF-1 to mediate transcriptional repression is promoted by Groucho and inhibited by the histone deacetylase inhibitor trichostatin A, suggesting that BF-1 recruits Groucho and histone deacetylase activities to repress transcription. Our studies also provide the first demonstration that Groucho mediates a specific interaction between BF-1 and the basic helix-loop-helix protein Hes1 and that BF-1 potentiates transcriptional repression by Hes1 in a Groucho-dependent manner. These findings suggest that Groucho participates in the transcriptional functions of BF-1 by acting as both a corepressor and an adapter between BF-1 and Hes1. Taken together with the demonstration that these proteins are coexpressed in telencephalic neural progenitor cells, these results also suggest that complexes of BF-1, Groucho, and Hes factors may be involved in the regulation of progenitor cell differentiation in the telencephalon.

Laropiprant is an antagonist of the prostaglandin PGD2 receptor DP1. Laropiprant has a weak affinity for the thromboxane A2 receptor TP. Two double-blinded, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose laropiprant at steady state on the antiplatelet effects of multiple-dose aspirin and clopidogrel. Study 1 had two treatment periods, in which each healthy subject received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 80 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 80 mg (Treatment B) once daily for 7 days. Study 2 consisted of three treatment periods. In the first two, each patient with hypercholesterolemia or mixed dyslipidemia received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 81 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 81 mg (Treatment B) once daily for 7 days. In period 3, patients received a single dose of two tablets of extended release nicotinic acid 1 g/laropiprant 20 mg (Treatment C). In both studies, pharmacodynamic endpoints included bleeding time at 24 (primary) and 4 hours (secondary) post-dose following 7 days of once-daily laropiprant in combination with clopidogrel and aspirin, and platelet aggregation in platelet-rich plasma at 4 and 24 hours post-dose on day 7 (secondary). After 7 days, increased bleeding time of 27% (Study 1) and 23% (Study 2) at 24 hours post-dose was observed with laropiprant compared to placebo (both combined with clopidogrel and aspirin), with corresponding upper bounds of the 90% CI marginally exceeding the prespecified upper comparability bound of 1.50 in both studies. The GMR and 90% CI for bleeding time of laropiprant compared to placebo (both combined with clopidogrel and aspirin) at 4 hours post-dose on day 7 was 0.92 (0.70, 1.21) in Study 1, and 1.46 (1.20, 1.78) in Study 2. Compared with placebo, laropiprant (both combined with clopidogrel and aspirin) increased the inhibition of collagen- and ADP-induced platelet aggregation, respectively, by ∼2.4% and ∼8.1% in Study 1 and by ∼4% and ∼5.4% in Study 2, at 24 hours post-dose on day 7. The inhibition of collagen- and ADP-induced platelet aggregation, respectively, was increased by ∼0.1% and ∼5.0% in Study 1, and by ∼5% and ∼12% in Study 2, at 4 hours post-dose on day 7. In conclusion, co-administration of multiple doses of laropiprant with aspirin and clopidogrel induced a prolongation of bleeding time and an inhibitory effect on platelet aggregation ex vivo in healthy subjects and patients with dyslipidemia.