Cortical bone mineral density is increased by the cathepsin K inhibitor ONO-5334, which leads to a robust increase in bone strength: results from a 16-month study in ovariectomised cynomolgus monkeys.

This study evaluated the long-term effects of the cathepsin K inhibitor ONO-5334 on bone mass and strength in ovariectomised (OVX) cynomolgus monkeys. Animals were assigned to one of the following six groups: Sham (non-OVX), OVX control treated with vehicle, ONO-5334 1.2, 6 or 30 mg/kg/day, p.o., or alendronate (ALN) 0.05 mg/kg/2 weeks, i.v. for 16 months. Peripheral quantitative computed tomography (pQCT) analysis revealed that ONO-5334 increased not only trabecular bone mineral density (BMD) but also cortical BMD in the distal radius and the lumbar vertebra. ONO-5334 and ALN suppressed the deterioration of trabecular architecture by micro-CT analysis in the distal radius. Assessments of bone strength showed that ONO-5334 increased maximum load at the distal and midshaft radius. The linear regression lines between bone mass and strength in the lumbar vertebra were tended to be shifted towards increasing bone strength in the ONO-5334 6 and 30 mg/kg groups compared with the ALN groups. This indicated that bone strength was higher in the ONO-5334 groups than the ALN group, even though bone mineral content (BMC) and BMD were comparable. Subpopulation analysis revealed that, at similar integral BMC or BMD level, cortical bone mass for ONO-5334 was higher than for ALN; the opposite effects were observed for trabecular bone. In conclusion, ONO-5334 preferentially increased cortical bone, which may provide a greater contribution to bone strength. Since these results support a different mode of action for ONO-5334 compared with that of ALN, ONO-5334 may offer new therapeutic options to patients with osteoporosis.

Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis.

BACKGROUND: ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain. METHODS: Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship. sCTX was selected because it has a high signal-to-noise ratio compared to other telopeptides. A negative sigmoidal shape for the PK/PD relationship between plasma ONO-5334 and sCTX levels was obtained in our previous study. RESULTS: The simulated sCTX inhibition reached >99% of the maximal inhibitory effect (Emax) at 0.5 h in all treatment groups, and decreased to <80% Emax at 8 and 12 h at 50 mg BID and 100 mg QD, respectively. However, sCTX inhibition at 300 mg QD was maintained at ≥82% Emax over 24 h. The mean sCTX inhibition rates for 24 h at 100 mg QD, 300 mg QD and 50 mg BID were 63, 95 and 80% Emax, respectively. There was a positive linear relationship by treatment group between mean sCTX inhibition over 24 h and observed BMD gain in the phase II study. CONCLUSION: The dose response for BMD with ONO-5334 at 100 and 300 mg QD and higher BMD gain at 50 mg BID vs. 100 mg QD can be explained by sCTX inhibition over 24 h. The simulation gave the antiresorptive effect of ONO-5334 over 24 h and allowed prediction of BMD gain due to ONO-5334. TRIAL REGISTRATION: The registration number in The European Union Clinical Trials Register is 2007-002417-39 . The date of registration was August 31, 2007.

Effects of 16-month treatment with the cathepsin K inhibitor ONO-5334 on bone markers, mineral density, strength and histomorphometry in ovariectomized cynomolgus monkeys.

We examined the effects of ONO-5334, a cathepsin K inhibitor, on bone markers, BMD, strength and histomorphometry in ovariectomized (OVX) cynomolgus monkeys. ONO-5334 (1.2, 6 and 30mg/kg/day, p.o.), alendronate (0.05mg/kg/2weeks, i.v.), or vehicle was administered to OVX monkeys (all groups N=20) for 16months. A concurrent Sham group (N=20) was also treated with vehicle for 16months. OVX significantly increased bone resorption and formation markers and decreased BMD in lumbar vertebra, femoral neck, proximal tibia and distal radius. Alendronate suppressed these parameters to a level similar to that in the Sham-operated monkeys. ONO-5334 at doses 6 and 30mg/kg decreased bone resorption markers to a level roughly half of that in the Sham group, while keeping bone formation markers level above that in the Sham monkeys. Changes in DXA BMD confirmed that ONO-5334 at doses 6 and 30mg/kg increased BMD to a level greater than that in the Sham group in all examined sites. In the proximal tibia, in vivo pQCT analysis showed that ONO-5334 at doses 6 and 30mg/kg suppressed trabecular BMD loss to the sham level. However, ONO-5334 increased cortical BMD, cortical area and cortical thickness to a level greater than that in the Sham group, suggesting that ONO-5334 improves both cortical BMD and cortical geometry. Histomorphometric analysis revealed that ONO-5334 suppressed bone formation rate (BFR) at osteonal site in the midshaft femur but did not influence OVX-induced increase in BFR at either the periosteal or endocortical surfaces. Unlike alendronate, ONO-5334 increased osteoclasts surface (Oc.S/BS) and serum tartrate-resistant acid phosphatise 5b (TRAP5b) activity, highlighting the difference in the mode of action between these two drugs. Our results suggest that ONO-5334 has therapeutic potential not only in vertebral bones, but also in non-vertebral bones.

Bone turnover markers and pharmacokinetics of a new sustained-release formulation of the cathepsin K inhibitor, ONO-5334, in healthy post-menopausal women.

A sustained-release tablet (SRT) of ONO-5334 was compared to the immediate-release tablet (IRT) dose, which demonstrated effects on bone mineral density (BMD) comparable to those of therapy with alendronate. The single-dose phase was a randomized, partial single-blind, crossover study where 50-, 100-, and 300-mg SRTs and 300-mg IRTs were administered to nine post-menopausal women. The multiple-dose phase was a randomized, double-blind, placebo-controlled, parallel-group study where 100- and 300-mg SRTs, or placebo were administered to 24 women. After a single administration of a 300-mg SRT, mean C max was 3.3-fold lower, mean AUCinf was 0.83-fold lower and mean C 24h was 5.4-fold higher compared to the 300-mg IRT. Repeated SRT dosing did not significantly affect PK, although C 24h increased slightly. After a single ONO-5334 dose, serum CTX-I was suppressed by ~50 % within 1 h, reaching maximum suppression 6 h post-dose. Greater suppression was maintained longer by the 300-mg SRT vs. the 300-mg IRT. Second morning void and cumulative urine CTX-I showed clear dose-response effects at/over 24 h for SRT, with maximum suppression occurring at/over 24 h (except 50- and 300-mg cumulative urine). Repeated dosing suggested greater suppression of urine CTX-I. Compared with the IRT, the SRT showed reduced C max, greater C 24h, and slightly reduced AUCinf dose for dose. The SRT showed clear dose-response suppression on bone resorption and greater efficacy dose for dose vs. the IRT.

Modeling and simulation of bone mineral density response from a phase 2 study of ONO-5334, a new cathepsin K inhibitor, to support dose selection in osteoporosis.

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this modeling study were to (1) develop exposure-response (E-R) models to relate ONO-5334 exposure to bone mineral density (BMD), (2) predict BMD responses to various doses of ONO-5334 for both immediate release tablet (IRT) and sustained release tablet (SRT) formulations where only BMD response after administration of IRT had been studied to date, (3) inform selection of appropriate formulation/dose using simulation for future clinical trials. A population pharmacokinetic (PK) model was developed to simultaneously analyze data for both IRT and SRT. The exposure metrics at steady state were estimated by post hoc Bayesian prediction using the final population PK model. E-R models were developed using dose-ranging data with only IRT from postmenopausal females with osteoporosis. Based on the developed model, lumbar spine and total hip BMD after administration of ONO-5334 SRT as well as IRT were simulated. The simulation results showed that ONO-5334 SRT should provide comparable BMD responses at a lower dose relative to IRT (a finding consistent with the results from a previous population PK-PD modeling study with bone resorption markers).

Effects of novel cathepsin K inhibitor ONO-5334 on bone resorption markers: a study of four sustained release formulations with different pharmacokinetic patterns.

The purpose of the study was clarify the effect of the cathepsin K inhibitor ONO-5334 on bone resortion markers using sustained release (SR) formulations with different pharmacokinetic (PK) patterns, and identify the optimal SR formulation. The PK profiles and pharmacodynamic effect on bone resorption markers of 4 SR candidates formulations were evaluated in healthy postmenopausal women within a randomized, 2-part, open-label crossover study. In Part A, subject received a single dose of each formulation orally in the fed state. In Part B, two selected formulations were evaluated in the fasted state. From the results from Part A, C(max) was reduced and plasma concentrations of ONO-5334 were sustained with all SR formulations compared with an immediate release tablet. In pharmacodynamics, the level of C-terminal telopeptide of type I collagen (CTX) in serum and urine were inhibited with SR tablets rather than with granules. C max and area under the concentration-time curve from time 0 to the last measurable time point (AUC(0-t)) of SR tablets were higher than those of granules. From Part B, C max in the fasted condition was lower than that in the fed condition with two SR tablets. In contrast, C(24 h) in the fasted condition was slightly higher than that in the fed condition, but AUC(0-t) was similar. The inhibitory effect on CTX in serum and urine may depend on the PK pattern of ONO-5334. The SR tablets was well tolerated in postmenopausal women and has the optimal SR profiles on pharmacodynamics effect on bone resortion markers and PK profile. These results suggest that SR tablets of ONO-5334 are an excellent drug candidate for osteoporosis.

Population pharmacokinetic and pharmacodynamic modeling of different formulations of ONO-5334, cathepsin K inhibitor, in Caucasian and Japanese postmenopausal females.

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50 ) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.

Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study.

Cathepsin K inhibitors, such as ONO-5334, are being developed for the treatment of postmenopausal osteoporosis. However, their relative effects on bone resorption and formation, and how quickly the effects resolve after treatment cessation, are uncertain. The aim of this study was to examine the efficacy and safety of 24-month treatment with ONO-5334 and to assess the effect of treatment cessation over 2 months. We studied 197 postmenopausal women with osteoporosis or osteopenia with one fragility fracture. Patients were randomized to ONO-5334 50 mg twice daily, 100 mg or 300 mg once daily, alendronate 70 mg once weekly (positive control), or placebo for 24 months. After 24 months, all ONO-5334 doses were associated with increased bone mineral density (BMD) for lumbar spine, total hip, and femoral neck (p < 0.001). ONO-5334 300 mg significantly suppressed the bone-resorption markers urinary (u) NTX and serum and uCTX-I throughout 24 months of treatment and to a similar extent as alendronate; other resorption marker levels remained similar to placebo (fDPD for ONO-5334 300 mg qd) or were increased (ICTP, TRAP5b, all ONO-5334 doses). Levels of B-ALP and PINP were suppressed in all groups (including placebo) for approximately 6 months but then increased for ONO-5334 to close to baseline levels by 12 to 24 months. On treatment cessation, there were increases above baseline in uCTX-I, uNTX, and TRAP5b, and decreases in ICTP and fDPD. There were no clinically relevant safety concerns. Cathepsin K inhibition with ONO-5334 resulted in decreases in most resorption markers over 2 years but did not decrease most bone formation markers. This was associated with an increase in BMD; the effect on biochemical markers was rapidly reversible on treatment cessation.

Serum and urine bone resorption markers and pharmacokinetics of the cathepsin K inhibitor ONO-5334 after ascending single doses in post menopausal women.

AIMS: To investigate the safety, pharmacokinetics and pharmacodynamics of the new cathepsin K inhibitor, ONO-5334. METHODS: A double-blind, placebo-controlled, randomized study was carried out in 52 healthy post menopausal females. Single ascending doses of ONO-5334 (3-600 mg) were evaluated in six cohorts. The effect of food was studied at ONO-5334 100 mg. RESULTS: Across the doses tested, mean ONO-5334 C(max) occurred 0.5-1.0 h after dosing and the the t(1/2) ranged from 9.1 to 22 h. Linear increases in C(max) and AUC(0,∞) were observed in the 3-300 mg and 3-600 mg dose range, respectively. After food, the geometric mean ratio (95% CI) C(max) and AUC(0,∞) for ONO-5334 were 0.78 (0.31, 1.94) and 0.95 (0.67, 1.35)-fold greater than fasted, respectively. ONO-5334 significantly reduced serum bone resorption markers within 4 h vs. placebo. Statistical significance was achieved for ONO-5334 doses ≥30 mg for C-terminal telopeptide of type 1 collagen (CTX) and ≥300 mg for N-terminal telopeptide of type 1 collagen (NTX). Statistical significance was still evident at 24 h for ONO-5334 100 mg with serum CTX and 600 mg with serum NTX. The maximum suppression in serum CTX occurred at 4 h post dose with difference compared with placebo of -32%, -59%, -60% and -66% for 30, 100, 300 and 600 mg ONO-5334, respectively. Second morning urine void 24 h post dose showed statistically significant suppression of urinary CTX and NTX at 100 mg and above vs. placebo. ONO-5334 600 mg showed statistically significant suppression up to 72 h for serum CTX, urinary CTX and urinary NTX and 48 h for serum NTX vs. placebo. Adverse events were transient with no evidence of dose relationship. CONCLUSIONS: ONO-5334 displayed linear plasma pharmacokinetics over the (predicted therapeutic) dose range, 3-300 mg, with clear suppression of urinary bone resorption markers at doses ≥100 mg for serum markers at 24 h. ONO-5334 was well tolerated up to 600 mg day(-1) when administered to healthy post menopausal women.

EEG spectral power density profiles during NREM sleep for gaboxadol and zolpidem in patients with primary insomnia.

There is significant interest in the functional significance and the therapeutic value of slow-wave sleep (SWS)-enhancing drugs. A prerequisite for studies of the functional differences is characterization of the electroencephalography (EEG) spectra following treatment in relevant patients. We evaluate for the first time gaboxadol and zolpidem treatments in insomniac patients using power spectra analysis. We carried out two randomized, double-blind, crossover studies. Study 1, 38 patients received gaboxadol 10 mg and 20 mg and zolpidem 10 mg; study 2, 23 patients received gaboxadol 5 mg and 15 mg. Treatments were administered during two nights and compared with placebo. Gaboxadol 10, 15 and 20 mg enhanced slow-wave activity (SWA) and theta power. In 1 Hz bins gaboxadol 10 and 20 mg enhanced power up to 9 Hz. In study 2, 15 mg gaboxadol showed a similar effect pattern. Zolpidem suppressed theta and alpha power, and increased sigma power, with no effect on SWA. In the 1 Hz bins zolpidem suppressed power between 5-10 Hz. Gaboxadol dose-dependently increased SWA and theta power in insomniac patients. In contrast, zolpidem did not affect SWA, reduced theta and alpha activity and enhanced sigma power. EEG spectral power differences may be consequences of the different mechanisms of action for zolpidem and the SWS-enhancing agent, gaboxadol.

Pharmacodynamic effects on biochemical markers of bone turnover and pharmacokinetics of the cathepsin K inhibitor, ONO-5334, in an ascending multiple-dose, phase 1 study.

Selective inhibitors of cathepsin K, which has a major role in the degradation of bone collagen, are potential new treatments for osteoporosis. The pharmacokinetics and the pharmacodynamic effects on biochemical markers of bone turnover of the new cathepsin K inhibitor, ONO-5334, were investigated in a multiple ascending dose, phase 1 study. A total of 120 healthy postmenopausal women were enrolled, and doses of 10 to 600 mg once daily and 50 and 300 mg twice daily were evaluated in 15- and 28-day multiple-dosing cohorts. Plasma ONO-5334 concentration reached steady state within 2 days. Twenty-four hours after the last dose in the 15-day multiple-dose cohort, 100, 300, and 600 mg once daily reduced urinary C-terminal telopeptide of type I collagen by a mean (± standard deviation) 44.9% ± 13.6%, 84.5% ± 4.4%, and 92.5% ± 1.3%, respectively. The 28-day cohort showed similar effects. There were far smaller effects on bone-specific alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase 5b (TRAP5b), or osteocalcin (OC) (measured after 28 days). ONO-5334 was well tolerated up to 600 mg/d and for up to 28 days of multiple dosing. Multiple dosing with ONO-5334 100 mg resulted in considerable suppression of bone resorption markers with no appreciable effects on bone formation markers (B-ALP, OC) or osteoclast number (TRAP5b).

EEG power spectra response to a 4-h phase advance and gaboxadol treatment in 822 men and women.

STUDY OBJECTIVE: To explore the effect of gaboxadol on NREM EEG in transient insomnia using power spectral analysis and evaluate the response between men and women. METHODS: This was a randomized, double-blind, 3-way, parallel-group transient insomnia study in 22 sleep laboratories. After a baseline night (N1), subjects underwent a 4-h phase-advance of their habitual sleep time the following night (N2). Healthy subjects aged 18-64 y were given single-blind placebo on N1 followed by double-blind treatment on N2 (gaboxadol 10 mg [n = 271], 15 mg [n = 274], or placebo [n = 277]) RESULTS: At baseline, women showed significantly greater values in low frequency activity (< 10 Hz) and in high spindle/low beta frequency activity (14-18 Hz) compared to men. During the phase advance (placebo N2-baseline N1), there was a significant increase in power within the high spindle/low beta frequency range (15-17 Hz) and a significant reduction in beta activity (20-32 Hz), which was greater in women than men. Gaboxadol induced a significant (dose-related) increase in low frequencies (< 8 Hz) and a significant (dose-related) decrease within the alpha/spindle range (11-12 Hz). The effect was dependent upon sex, with a greater magnitude of effect observed in women than men. CONCLUSION: Gaboxadol shows a characteristic NREM EEG spectral profile in a model of transient insomnia. Men and women show clear differences in NREM EEG activity at baseline, to gaboxadol treatment and to phase-shifts in habitual sleep/wake times. The exact mechanisms underlying the sex differences remain unclear, but sex is an important variable in studies evaluating sleep and gaboxadol. TRIAL REGISTRY INFORMATION: TRIAL REGISTRY: www.clinicaltrials.gov, study identifier: NCT00102167.

Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study.

Osteoporosis occurs when there is an imbalance between resorption and formation of bone, with resorption predominating. Inhibitors of cathepsin K may rebalance this condition. This is the first efficacy study of a new cathepsin K inhibitor, ONO-5334. The objective of the study was to investigate the efficacy and safety of ONO-5334 in postmenopausal osteoporosis. This was a 12-month, randomized, double-blind, placebo- and active-controlled parallel-group study conducted in 13 centers in 6 European countries. Subjects included 285 postmenopausal women aged 55 to 75 years with osteoporosis. Subjects were randomized into one of five treatment arms: placebo; 50 mg twice daily, 100 mg once daily, or 300 mg once daily of ONO-5334; or alendronate 70 mg once weekly. Lumbar spine, total hip, and femoral neck BMD values were obtained along with biochemical markers of bone turnover and standard safety assessments. All ONO-5334 doses and alendronate showed a significant increase in BMD for lumbar spine, total hip (except 100 mg once daily), and femoral neck BMD. There was little or no suppression of ONO-5334 on bone-formation markers compared with alendronate, although the suppressive effects on bone-resorption markers were similar. There were no clinically relevant safety concerns. With a significant increase in BMD, ONO-5334 also demonstrated a new mode of action as a potential agent for treating osteoporosis. Further clinical studies are warranted to investigate long-term efficacy as well as safety of ONO-5334.

Alterations in cyclic alternating pattern associated with phase advanced sleep are differentially modulated by gaboxadol and zolpidem.

OBJECTIVE: to evaluate cyclic alternating pattern (CAP) in a phase advance model of transient insomnia and the effects of gaboxadol and zolpidem. DESIGN: a randomized, double-blind, cross-over study in which habitual sleep time was advanced by 4 h. SETTING: 6 sleep research laboratories in US PARTICIPANTS: 55 healthy subjects (18-57 y) INTERVENTIONS: Gaboxadol 15 mg (GBX), zolpidem 10 mg (ZOL), and placebo (PBO). MEASUREMENTS: routine polysomnographic (PSG) measures, CAP, spectral power density, and self-reported sleep measures RESULTS: The phase advance model of transient insomnia produced significant changes in CAP parameters. Both GBX and ZOL significantly and differentially modified CAP parameters in the direction of more stable sleep. GBX brought the CAP rate in stage 1 sleep and slow wave sleep (SWS) closer to baseline levels but did not significantly change the CAP rate in stage 2. ZOL reduced the CAP rate in stage 2 to near baseline levels, whereas the CAP rate in stage 1 and SWS was reduced substantially below baseline levels. The CAP parameter A1 index (associated with SWS and sleep continuity) showed the highest correlation with self-reported sleep quality, higher than any traditional PSG, spectral, or other self-reported measures. CONCLUSION: disruptions in CAP produced by phase advanced sleep were significantly and differentially modulated by gaboxadol and zolpidem. The relative independence of CAP parameters from other electrophysiological measures of sleep, their high sensitivity to sleep disruption, and their strong association with subjective sleep quality suggest that CAP variables may serve as valuable endpoints in future insomnia research.

Effect of gaboxadol on sleep in adult and elderly patients with primary insomnia: results from two randomized, placebo-controlled, 30-night polysomnography studies.

STUDY OBJECTIVES: To evaluate the efficacy and tolerability of gaboxadol in the treatment of adult and elderly patients with primary insomnia. DESIGN: Randomized, double-blind, placebo-controlled, multicenter, 30-night, polysomnography studies. SETTING: Sleep laboratory. PATIENTS: Primary insomnia, 18-64 y (adult study), or > or =65 y (elderly study). INTERVENTIONS: Adult study: gaboxadol 15 mg (GBX15; N = 148), 10 mg (GBX10; N = 154), or placebo (N = 156); elderly study: GBX10 (N = 157), gaboxadol 5 mg (GBX5; N = 153), or placebo (N=176). MEASUREMENTS AND RESULTS: Primary endpoints were wake after sleep onset (WASO) and latency to persistent sleep (LPS). Slow wave sleep (SWS) was a secondary endpoint. Analyses were based on the change from baseline for the average of nights 1/2, and nights 29/30, and compared gaboxadol versus placebo. Exploratory endpoints included patient's subjective assessment of total sleep time (sTST), WASO (sWASO), time to sleep onset (sTSO), and number of awakenings (sNAW); these analyses were based on weekly means. 1) Adult study. GBX15 significantly (P < or = 0.05) improved WASO through nights 29/30 but had no significant effects on LPS. No significant differences were seen for GBX10 versus placebo on WASO or LPS. GBX15 and GBX10 enhanced SWS. GBX15 significantly improved sTST, sWASO, sTSO, and sNAW at weeks 1 and 4. 2) Elderly study. GBX10 significantly improved WASO through nights 29/30; a significant improvement was also seen for GBX5 at nights 1/2 but this was not maintained through nights 29/30. GBX10 significantly improved LPS at nights 1/2 but the improvement was not maintained through nights 29/30; no significant differences were seen for GBX5 versus placebo on LPS. GBX10 and GBX5 enhanced SWS. GBX10 significantly improved sTST at week 1, and sTST, sWASO, and sNAW at week 4. Gaboxadol was generally well tolerated in both studies. CONCLUSIONS: The maximum studied doses of gaboxadol (GBX15 in adult patients and GBX10 in elderly patients) were effective at enhancing objective polysomnography measures of sleep maintenance and SWS, and also some subjective sleep measures, over 30 nights but had little or no effects on sleep onset. The clinical relevance of the enhancement of SWS by gaboxadol is unclear.

Efficacy of the selective extrasynaptic GABA A agonist, gaboxadol, in a model of transient insomnia: a randomized, controlled clinical trial.

OBJECTIVE: The hypnotic efficacy of gaboxadol, a selective extrasynaptic GABA A agonist (SEGA), was evaluated in a phase-advance model of transient insomnia. METHODS: Healthy subjects (18-64 years) completed a randomized, double-blind, parallel group study in which the sleep period was advanced 4h from habitual sleep time. Polysomnographic (PSG) and self-reported sleep measures were used to compare gaboxadol 10mg (N =271) and 15 mg (N =274) versus placebo (N =277). RESULTS: In the placebo group, the phase-advance procedure disrupted sleep maintenance as measured by PSG wakefulness after sleep onset (WASO) and self-reported WASO (sWASO), and also, to a lesser extent, disrupted sleep onset as measured by PSG latency to persistent sleep (LPS) and self-reported time to sleep onset (sTSO). Both doses of gaboxadol decreased WASO and sWASO versus placebo (p

Evaluation of automated and semi-automated scoring of polysomnographic recordings from a clinical trial using zolpidem in the treatment of insomnia.

OBJECTIVE: To evaluate the performance of 2 automated systems, Morpheus and Somnolyzer24X7, with various levels of human review/editing, in scoring polysomnographic (PSG) recordings from a clinical trial using zolpidem in a model of transient insomnia. METHODS: 164 all-night PSG recordings from 82 subjects collected during 2 nights of sleep, one under placebo and one under zolpidem (10 mg) treatment were used. For each recording, 6 different methods were used to provide sleep stage scores based on Rechtschaffen & Kales criteria: 1) full manual scoring, 2) automated scoring by Morpheus 3) automated scoring by Somnolyzer24X7, 4) automated scoring by Morpheus with full manual review, 5) automated scoring by Morpheus with partial manual review, 6) automated scoring by Somnolyzer24X7 with partial manual review. Ten traditional clinical efficacy measures of sleep initiation, maintenance, and architecture were calculated. RESULTS: Pair-wise epoch-by-epoch agreements between fully automated and manual scores were in the range of intersite manual scoring agreements reported in the literature (70%-72%). Pair-wise epoch-by-epoch agreements between automated scores manually reviewed were higher (73%-76%). The direction and statistical significance of treatment effect sizes using traditional efficacy endpoints were essentially the same whichever method was used. As the degree of manual review increased, the magnitude of the effect size approached those estimated with fully manual scoring. CONCLUSION: Automated or semi-automated sleep PSG scoring offers valuable alternatives to costly, time consuming, and intrasite and intersite variable manual scoring, especially in large multicenter clinical trials. Reduction in scoring variability may also reduce the sample size of a clinical trial.

Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia.

STUDY OBJECTIVE: To perform an early evaluation of the efficacy and safety of gaboxadol in the treatment of primary insomnia. METHODS: 26 adults (18-65 years) with DSM-IV criteria for primary insomnia were randomly assigned gaboxadol (5 mg, 15 mg) or placebo in a double-blind, crossover study. After a 3-night polysomnographic (PSG) screen, treatment was administered 30 min before bedtime on 2 consecutive nights during 3 separate sessions including PSG. Efficacy analyses (n = 23) were based on the average of Nights 1 and 2, and compared gaboxadol versus placebo. Baseline was the average of Nights 2 and 3 of the screening session. Both gaboxadol doses significantly (P < 0.05) improved mean total sleep time (mean +/- SD: baseline = 368.0 +/- 51.1 min, 15 mg = 420.3 +/- 24.5 min, 5 mg = 419.8 +/- 20.4 min, placebo = 408.7 +/- 30.4 min). Both gaboxadol doses reduced mean wake after sleep onset, although statistical significance was only achieved with 5 mg (baseline = 61.6 +/- 35.4 min, 15 mg = 38.0 +/- 21.1 min, 5 mg = 34.6 +/- 14.3 min, placebo = 43.4 +/- 22.9 min). Gaboxadol 15 mg also significantly reduced mean latency to persistent sleep (baseline = 55.6 +/- 27.0 min, 15 mg = 23.6 +/- 15.1 min, placebo = 30.0 +/- 19.1 min) and enhanced slow wave duration (baseline = 72.4 +/- 20.8 min, 15 mg = 114.0 +/- 37.5 min, placebo = 93.9 +/- 31.3 min) with no significant effects on REM sleep duration. Patient reports (Leeds Sleep Evaluation Questionnaire) of reduced time to sleep and increased sleep quality showed significant improvement with gaboxadol 15 mg. No next-day residual effects were observed with either dose of gaboxadol (assessed 2 h and 9 h after lights on). All adverse events were mild or moderate. CONCLUSION: Gaboxadol 15 mg was effective and generally well tolerated in the short-term treatment of patients with primary insomnia. Gaboxadol also enhanced slow wave sleep duration and had no significant effects on REM sleep duration. These findings suggest that gaboxadol may be a useful treatment for insomnia.