Translational Development Strategies for TAK-063, a Phosphodiesterase 10A Inhibitor.

BACKGROUND: TAK-063 is an inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the striatum. PDE10A hydrolyzes both cyclic adenosine monophosphate and cyclic guanosine monophosphate and modulates dopamine signaling downstream of receptor activation in both direct and indirect pathways of the striatum. TAK-063 exhibited antipsychotic-like effects in animal models; however, the translatability of these models to the clinical manifestations of schizophrenia and the meaningfulness for new targets such as PDE10A has not been established. METHODS: The TAK-063 phase 1 program included a comprehensive translational development strategy with the main objective of determining whether the antipsychotic-like pharmacodynamic effects seen in nonclinical models would translate to human subjects. To evaluate this objective, we conducted a single-rising dose study (84 healthy subjects), a positron emission tomography (PET) study (12 healthy subjects), a functional magnetic resonance imaging blood oxygen level-dependent (BOLD) study (27 healthy subjects), and a multiple-rising dose study that included people with schizophrenia (30 healthy Japanese subjects and 47 subjects with stable schizophrenia). In addition, assessments of cognition and electroencephalography (27 healthy subjects and 47 subjects with stable schizophrenia) were included. RESULTS: PDE10A engagement by TAK-063 was verified with a novel PET radiotracer for use in primates and humans. TAK-063 showed favorable pharmacokinetic and safety profiles in humans, and TAK-063 reduced ketamine-induced changes in electroencephalography and BOLD signaling in animal models and healthy human subjects. In addition, analogous effects on cognition were observed in animal models and human subjects. CONCLUSIONS: Overall, the phase 1 results showed some consistent evidence of antipsychotic activity. This translational strategy may be valuable for the future development of novel therapeutic approaches, even when relevant nonclinical models are not available.

A human [(11)C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor.

Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington's disease. In this study, the brain kinetics of [(11)C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [(11)C]T-773. Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [(11)C]T-773: two baseline PETs and one postdose PET (3hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3hours and 23hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (VT), which was calculated as the VT of the putamen minus the VT of the cerebellum. Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean VT was 5.5±0.7 in the putamen and 2.3±0.5 in the cerebellum in the baseline PET. Absolute VT variability between the two baseline scans was less than 7%. Reproducibility of VT was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3hours after a single administration of 3 to 1000mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100mg of TAK-063. In conclusion, [(11)C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.

Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG).

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing. OBJECTIVE: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients. METHODS: Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls. RESULTS: Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P < 0.01). CONCLUSIONS: Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial.

SPR1NT ( NCT03505099 ) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies of SMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26; P < 0.001; 11 within the normal developmental window). All survived without permanent ventilation at 14 months as per protocol; 13 maintained body weight (≥3rd WHO percentile) through 18 months. No child used nutritional or respiratory support. No serious adverse events were considered related to treatment by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for children expected to develop SMA type 1, highlighting the urgency for universal newborn screening.

Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial.

Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.

BACKGROUND: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy. METHODS: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed). FINDINGS: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus). INTERPRETATION: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1. FUNDING: Novartis Gene Therapies.

A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects.

RATIONALE: Phosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest efficacy in schizophrenia treatment. OBJECTIVE: This randomized, double-blind, placebo-controlled, incomplete-crossover study investigated effects of single oral administration of TAK-063 on ketamine-induced changes in blood oxygen level-dependent (BOLD) signal in healthy males. METHODS: Healthy men aged 18 to 45 years with normal magnetic resonance imaging (MRI) scans and electroencephalogram measurements at screening were eligible. Each subject was randomized to one of nine treatment schedules: all subjects received placebo and two of three doses of TAK-063 followed by ketamine. The primary endpoint was ketamine-induced brain activity in select regions of the brain during resting state. Secondary endpoints included pharmacokinetic parameters of TAK-063, proportion of subjects with treatment-emergent adverse events (AEs), and percentage of subjects meeting criteria for abnormal safety laboratory tests and vital sign measurements. RESULTS: The study comprised 27 subjects. Prior to ketamine infusion, TAK-063 exerted region-specific effects on resting state functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced the Cohen's effect size for resting-state fMRI BOLD signal in key brain regions examined, and exerted similar effects on BOLD signal during the working memory task across all doses. TAK-063 was safe and well tolerated. CONCLUSIONS: Our results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required.

Asenapine versus olanzapine in acute mania: a double-blind extension study.

OBJECTIVE: To assess the efficacy and tolerability of asenapine versus olanzapine in the extended treatment of bipolar mania. METHODS: Patients with bipolar I disorder experiencing acute manic or mixed episodes who completed either of two 3-week, double-blind trials with asenapine 5 or 10 mg twice daily, olanzapine 5 to 20 mg once daily, or placebo were eligible for this 9-week, double-blind extension study. Patients receiving active medication in the 3-week trials continued the same regimen; those who had received placebo were blindly switched to asenapine but were assessed for safety outcomes only. The primary efficacy measure was the change from baseline to day 84 on the Young Mania Rating Scale (YMRS) total score in the per-protocol population. Results on the primary efficacy outcome were used to determine the noninferiority of asenapine versus olanzapine. RESULTS: A total of 504 patients (placebo/asenapine, n = 94; asenapine, n = 181; olanzapine, n = 229) were enrolled in the extension study. At day 84, the mean (SD) change from baseline in YMRS total score was -24.4 (8.7) for asenapine and -23.9 (7.9) for olanzapine. Prespecified statistical analysis for noninferiority indicated no significant difference between asenapine and olanzapine. The overall incidence of treatment-emergent adverse events was similar across treatment groups (77% placebo/asenapine, 77% asenapine, 78% olanzapine). Clinically significant weight gain occurred in 10%, 19%, and 31% of the placebo/asenapine, asenapine, and olanzapine groups, respectively. CONCLUSIONS: Asenapine was efficacious, showed noninferiority to olanzapine, and was well tolerated in the extended treatment of patients experiencing manic symptoms associated with bipolar I disorder.

A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states.

OBJECTIVE: Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania. METHODS: After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5-20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values. RESULTS: Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean +/- SE changes in YMRS scores were observed on day 2 with asenapine (-3.0 +/- 0.4) and olanzapine (-3.4 +/- 0.4) versus placebo (-1.5 +/- 0.5, both p < 0.01) and were maintained until day 21 (-10.8 +/- 0.8 with asenapine, -12.6 +/- 0.8 with olanzapine; both p < or = 0.0001 versus placebo, -5.5 +/- 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures. CONCLUSIONS: These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode.

A phase 2, randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute exacerbation of schizophrenia.

INTRODUCTION: TAK-063 is a potent, selective inhibitor of phosphodiesterase 10A, an enzyme selectively expressed in medium spiny neurons of the striatum. This randomized, parallel-group study evaluated the efficacy and safety of 20-mg daily TAK-063 versus placebo in subjects with acutely exacerbated symptoms of schizophrenia (NCT02477020). METHODS: Adults aged 18 to 65 with diagnosed schizophrenia and psychotic symptoms that exacerbated within 60 days before screening were included. Subjects who discontinued psychotropic medications before screening were randomized 1:1 to 6 weeks of placebo (n = 81) or 20-mg TAK-063 (n = 83). Weekly efficacy visits were conducted during the treatment period, and dose de-escalation was allowed (blinded) to 10-mg TAK-063 for intolerability. RESULTS: The primary endpoint, change from baseline in the Positive and Negative Syndrome Scale total score at week 6, was not achieved (least-squares mean difference vs placebo [standard error] = -5.46 [3.44]; p = 0.115). Secondary endpoints were generally supportive of antipsychotic efficacy. Consistent with previous phase 1 studies, TAK-063 was safe and well tolerated, and most adverse events were mild or moderate in severity and did not result in discontinuation. No deaths occurred, and the incidence of akathisia and dystonia, categories of extrapyramidal syndromes, was more frequent in the TAK-063 group than placebo. CONCLUSIONS: Although the study did not meet the primary endpoint (effect size = 0.308), the effects of TAK-063 on the primary and secondary endpoints may be suggestive of antipsychotic activity. Interpretation of these results is confounded by a relatively high placebo effect and a lack of dose-ranging or active reference.

A Randomized Multiple Dose Pharmacokinetic Study of a Novel PDE10A Inhibitor TAK-063 in Subjects with Stable Schizophrenia and Japanese Subjects and Modeling of Exposure Relationships to Adverse Events.

BACKGROUND: Phosphodiesterase 10A (PDE10A) is selectively expressed in medium spiny neurons of the striatum. TAK-063 is a selective inhibitor of PDE10A in clinical development for the treatment of schizophrenia. OBJECTIVES: Safety, tolerability, and pharmacokinetics (PK) of TAK-063 were evaluated following multiple rising oral doses, and PK/adverse event (AE) models were developed to characterize the relationship between TAK-063 exposure and incidence of specific AEs. METHODS: Healthy Japanese subjects (HJS) aged 20-55 years and subjects with stable schizophrenia (SSS) aged 18-55 years were enrolled and randomized to either TAK-063 or placebo. Study medication was administered as a tablet once daily (at night) with food over a 7-day period. RESULTS: TAK-063 and placebo groups consisted of 62 and 15 subjects, respectively. A majority of subjects (71 of 77) completed the study. AEs were mostly of mild or moderate severity, and no deaths were reported. The most common AE was somnolence. For equivalent doses, the rate of extrapyramidal syndromes (EPS) was higher in SSS than in HJS. PK parameters were comparable between HJS and SSS at equivalent doses. The incidence of somnolence and EPS symptoms increased with exposure, and this was described with the PK/AE model. A maximum tolerated dose was not determined. CONCLUSIONS: Multiple doses of TAK-063 were safe and well tolerated. PK/AE models characterized the incidence of somnolence and EPS with increasing TAK-063 exposure, and simulations suggested that a once-daily dose range of up to 30 mg would be suitable for future studies. CLINICALTRIALS. GOV IDENTIFIER: NCT01879722.

Efficacy and safety of sublingual ramelteon as an adjunctive therapy in the maintenance treatment of bipolar I disorder in adults: A phase 3, randomized controlled trial.

BACKGROUND: The optimal long-term management strategy for bipolar I disorder patients is not yet established. Evidence supports the rationale for circadian rhythm regulation to prevent mood episode relapse in bipolar patients. This study evaluated the efficacy and safety of a new sublingual formulation of the melatonin receptor agonist ramelteon (ramelteon SL) as adjunctive therapy in the maintenance treatment of bipolar I patients. METHODS: In a double-blinded trial in the United States and Latin America, adult bipolar I disorder patients stable for ≥ 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1mg (n = 164), 0.4mg (n = 160), or 0.8mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power ≥ 30% compared with placebo. RESULTS: No significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon. LIMITATIONS: A low rate of relapse events precluded detection of any statistically significant difference between groups. CONCLUSIONS: The study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions.

A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor.

RATIONALE: Schizophrenia is a complex neuropsychiatric disorder characterized, in part, by impaired dopamine signaling. TAK-063 is a selective inhibitor of phosphodiesterase 10A, a key regulator of intracellular signaling pathways that is highly expressed in the striatum. OBJECTIVE: Safety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study. METHODS: Healthy Japanese and non-Japanese volunteers were randomized into dose cohorts of 3, 10, 30, 100, 300, and 1000 mg. Each fasting volunteer randomly received a single dose of TAK-063 or placebo. Individuals from the 100-mg cohort also received a post-washout, 100-mg dose under fed conditions. A total of 84 volunteers enrolled (14 per cohort). RESULTS: The most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). The three severe AEs recorded occurred at the highest doses: orthostatic hypotension (n = 1; 300 mg) and somnolence (n = 2; 1000 mg). There were no deaths, serious AEs, or discontinuations due to AEs. TAK-063 exposure increased in a dose-dependent manner. Median T max was reached 3 to 4 h postdose. Fed conditions slowed absorption (T max = 6 h) and increased oral bioavailability. Renal elimination was negligible. Safety and pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Impairments in cognitive function consistent with the effects of other sedative or hypnotic agents were detected using a validated, computerized cognition battery, CNS Vital Signs. CONCLUSIONS: TAK-063 was safe and well tolerated at doses up to 1000 mg and demonstrated a pharmacokinetic profile supporting once-daily dosing. Further evaluation of the clinical safety and efficacy of TAK-063 is warranted.

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group.

Disturbed sleep is one of the most common complaints following traumatic brain injury (TBI) and worsens morbidity and long-term sequelae. Further, sleep and TBI share neurophysiologic underpinnings with direct relevance to recovery from TBI. As such, disturbed sleep and clinical sleep disorders represent modifiable treatment targets to improve outcomes in TBI. This paper presents key findings from a national working group on sleep and TBI, with a specific focus on the testing and development of sleep-related therapeutic interventions for mild TBI (mTBI). First, mTBI and sleep physiology are briefly reviewed. Next, essential empirical and clinical questions and knowledge gaps are addressed. Finally, actionable recommendations are offered to guide active and efficient collaboration between academic, industry, and governmental stakeholders.

Asenapine for long-term treatment of bipolar disorder: a double-blind 40-week extension study.

BACKGROUND: Asenapine is approved in the United States for acute treatment of manic or mixed episodes of bipolar I disorder with or without psychotic features. We report the results of long-term treatment with asenapine in patients with bipolar I disorder. METHODS: Patients completing either of two 3-week efficacy trials and a subsequent 9-week double-blind extension were eligible for this 40-week double-blind extension. Patients in the 3-week trials were randomized to flexible-dose asenapine (5 or 10mg BID), placebo, or olanzapine (5-20mg QD; included for assay sensitivity only). Patients entering the extension phase maintained their preestablished treatment; those originally randomized to placebo received flexible-dose asenapine (placebo/asenapine). Safety and tolerability endpoints included adverse events (AEs), extrapyramidal symptoms, laboratory values, and anthropometric measures. Efficacy, a secondary assessment, was measured as change in Young Mania Rating Scale (YMRS) total score from 3-week trial baseline to week 52 with asenapine or olanzapine; the placebo/asenapine group was assessed for safety only. RESULTS: Incidence of treatment-emergent AEs was 71.9%, 86.1%, and 79.4% with placebo/asenapine, asenapine, and olanzapine, respectively. The most frequent treatment-emergent AEs were headache and somnolence with placebo/asenapine; insomnia, sedation, and depression with asenapine; and weight gain, somnolence, and sedation with olanzapine. Among observed cases, mean ± SD changes in YMRS total score at week 52 were -28.6 ± 8.1 and -28.2 ± 6.8 for asenapine and olanzapine, respectively. LIMITATIONS: The study did not have a long-term placebo group. CONCLUSIONS: In this 52-week extension in patients with bipolar mania, asenapine was well tolerated and long-term maintenance of efficacy was supported.

Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Asenapine is indicated in adults for acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. This randomized, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of asenapine in bipolar I disorder. METHODS: Adults experiencing manic or mixed episodes were randomized to 3 weeks of flexible-dose treatment with sublingual asenapine (day 1: 10mg BID, 5 or 10mg BID thereafter; n=185), placebo (n=98), or oral olanzapine (day 1: 15 mg QD, 5-20mg QD thereafter; n=205). Primary efficacy, YMRS total score change from baseline to day 21, was assessed using ANCOVA with last observation carried forward. RESULTS: Mean daily doses were 18.4 mg asenapine and 15.9mg olanzapine. Least squares mean changes in YMRS total score on day 21 were significantly greater with asenapine than placebo (-11.5 vs -7.8; P<0.007), with advantage seen as early as day 2 (-3.2 vs -1.7; P=0.022). Changes with olanzapine on days 2 and 21 also exceeded placebo (both P<0.0001). YMRS response and remission rates with olanzapine, but not asenapine, exceeded those of placebo. Incidence of EPS-related adverse events was 10.3%, 3.1%, and 6.8% with asenapine, placebo, and olanzapine, respectively; incidence of clinically significant weight gain (7.2%; 1.2%; 19.0%). Mean weight change (baseline to endpoint) was 0.9, 0.1, and 2.6 kg with asenapine, placebo, and olanzapine, respectively. LIMITATIONS: As this short-term study was designed for comparisons with placebo, any comparisons between asenapine and olanzapine should be interpreted cautiously. CONCLUSIONS: Asenapine was superior to placebo in reducing YMRS total score and was well tolerated.

Dissociation of protein kinase-mediated regulation of metabotropic glutamate receptor 7 (mGluR7) interactions with calmodulin and regulation of mGluR7 function.

Presynaptic metabotropic glutamate receptors (mGluRs) often act as feedback inhibitors of synaptic transmission and serve important roles in defining the activity of glutamatergic synapses. Recent investigations have begun to identify novel interactions of presynaptic mGluRs, especially mGluR7, with multiple protein kinases and putative regulatory proteins that probably serve to further shape the overall activity of glutamatergic synapses. In the present study, we report that in addition to protein kinase C (PKC), cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) can inhibit calmodulin (CaM) interactions with the carboxyl-terminal tail of mGluR7. These actions are mediated by PKC-, PKA-, or PKG-dependent phosphorylation of mGluR7 at a single serine residue, Ser(862), in the carboxyl terminus of the receptor. Mutation of this residue inhibits kinase-mediated phosphorylation of the mGluR7 carboxyl terminus and reverses kinase-mediated inhibition of CaM binding to mGluR7. However, PKC-mediated inhibition of the functional coupling of mGluR7 to G protein-coupled inward rectifier potassium (GIRK) currents in a heterologous expression system is not affected by mutating Ser(862). Furthermore, mutation of Ser(862) to glutamate to mimic receptor phosphorylation and inhibit CaM interactions with mGluR7 does not affect receptor function. These studies demonstrate that the ability of these second messenger-dependent kinases to inhibit mGluR7-mediated activation of GIRK current is not dependent on the phosphorylation of Ser(862) or the regulation of CaM binding to mGluR7. Furthermore, our studies suggest that CaM binding is not required for mGluR7-mediated activation of GIRK current.