To evaluate efficacy and safety of eszopiclone compared with placebo in children and adolescents with insomnia associated with attention-deficit/hyperactivity disorder (ADHD).
A 12-week, randomized, ...double-blind, placebo-controlled trial evaluated efficacy and safety of high- or low-dose eszopiclone (1 or 2 mg in children aged 6-11 years, 2 or 3 mg in children ages 12-17 years), given every evening, in 486 patients with ADHD-related insomnia. The primary efficacy variable was change in latency to persistent sleep from baseline to week 12, based on polysomnography. Key secondary measures were polysomnography-measured wake time after sleep onset, Clinical Global Impression Parent/Caregiver and Child scales, and the Conners' ADHD rating scales. The safety of eszopiclone was further studied over 1 year of open-label treatment in 55 patients who completed the double-blind study, and 249 patients with no previous eszopiclone exposure.
Neither low-dose nor high-dose eszopiclone significantly reduced latency to persistent sleep compared with placebo after 12 weeks of treatment. Secondary outcomes were considered nonsignificant based on the hierarchical statistical analysis plan. The most frequent treatment-emergent adverse events over 12 weeks with eszopiclone were headache, dysgeusia, and dizziness. The study results demonstrated that eszopiclone was well tolerated over 1 year of treatment, with 11.2% of patients discontinuing open-label treatment because of an adverse event.
Eszopiclone (up to 3 mg) failed to reduce latency to persistent sleep on polysomnography after 12 weeks in children aged 6 to 17 years with ADHD-related insomnia. Eszopiclone was well tolerated in the 1-year study.
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The proneural basic‐helix‐loop‐helix (bHLH) transcription factors Ascl1 and Neurog2 direct the differentiation of specific populations of neurons by regulating the transcription of ...specific sets of genes during embryonic development. Here we describe the generation of stable P19 embryonic carcinoma cells expressing comparable levels of Ascl1 and Neurog2 mRNA in a tetracycline inducible system and the resulting neuronal differentiation of these cell lines in response to doxycycline.
Microarray analysis of these cell lines showed that Ascl1 and Neurog2 overlap in their gene regulation but each bHLH protein also regulated distinct genes. We demonstrated that DNA methylation accompanied repression of the Oct4 gene by both Ascl1 and Neurog2, although DNA demethylation was not observed for any genes induced by either Ascl1 or Neurog2. While the ID1 gene showed preferential induction by Ascl1 over Neurog2, the induction of ID1 reporter constructs was dependent on distinct sets of E‐boxes within the ID1 proximal promoter. Finally, the induction of the Ppp1r14a gene was specifically induced by Neurog2 and this induction was at least partially due to preferences of Neurog2 for distinct canonical E‐box sequences within the Ppp1r14a promoter.
Together, these results suggest that further complexities in the mechanisms by which Ascl1 and Neurog2 regulate gene expression during neuronal differentiation.
Abstract
Pharmacologically targeting the HER2 oncoprotein with therapeutics such as the monoclonal antibody (mAb), trastuzumab, provides clinical benefit for patients with HER2-positive (HER2+) ...cancers. However, a significant number of patients eventually progress on these therapies. Efforts to overcome therapeutic resistance through combination therapy with small molecule inhibitors of HER2 have been limited by toxicities associated with off-target activity and/or limited efficacy. In this preclinical study, we explore single-agent and combined activity of tucatinib, a novel HER2-selective small molecule inhibitor. Tucatinib demonstrated potent, selective activity in a panel of 456 human cancer cell lines, with activity restricted to cell lines (breast and non-breast) with HER2-amplification, including models of acquired resistance to trastuzumab. Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT-signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard of care (SOC) trastuzumab/pertuzumab/docetaxel combination, with the exception that the chemotherapy-sparing tucatinib/trastuzumab combination did not require a dosing holiday to achieve the same efficacy. In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER) (HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer. These data support expanded clinical investigations of tucatinib as a combination partner for other novel and approved targeted therapies for HER2-driven malignancies.
Citation Format: Neil A. O'Brien, Holly K. Huang, Martina S. McDermott, Athena Madrid, Tong Luo, Raul Ayala, Shawnt Issakhanian, Ke Wei Gong, Ming Lu, Jun Zhang, Dennis J. Slamon. Tucatinib has selective activity in HER2-positive cancers and significant combined activity with approved and novel breast cancer targeted therapies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB197.
Most examinations of the clinical efficacy of drugs used to treat depression pool subjects across gender and age groups. This investigation compared these patient subpopulations on the basis of ...remission and response rates associated with venlafaxine and selective serotonin reuptake inhibitor (SSRI) treatment.
A meta-analysis of original data from 8 comparable double-blind, active-controlled, randomized clinical trials (4 also placebo-controlled) was conducted. Antidepressant efficacy was assessed for patients (N = 2,045) aged 18 to 83 years (subgroups: < or = 40, 41-54, 55-64, and > or = 65 years) who met DSM-III-R criteria for major depression or DSM-IV criteria for major depressive disorder and were randomly assigned to receive venlafaxine (immediate release, N = 474; extended release, N = 377), one of several SSRIs (N = 748), or placebo (N = 446) for up to 8 weeks. Symptoms of depression were assessed using the Hamilton Rating Scale for Depression (HAM-D). Remission was defined as a HAM-D-17 score < or = 7, response was defined as > or = 50% decrease in HAM-D-21 score, and absence of depressed mood was defined as a HAM-D depressed mood item score of 0.
We detected no significant age-by-treatment, gender-by-treatment, or age-by-gender-by-treatment interactions; men and women of different ages within a given antidepressant treatment group exhibited similar rates of remission, response, and absence of depressed mood. Regardless of age or gender, remission rates during venlafaxine therapy were significantly higher than during SSRI therapy (remission rates at week 8: venlafaxine, 40%-55% vs. SSRI, 31%-37%; p < .05). Regardless of patient age or gender, onset of remission was more rapid with venlafaxine than with SSRI treatment. By contrast, rates of absence of depressed mood with venlafaxine (34%-42%) and SSRIs (31%-37%) did not differ significantly and tended to be similar for all patient subgroups.
These data suggest that men and women have comparable responses to SSRIs and venlafaxine across various age groups. Moreover, patients exhibited a more rapid onset and a greater likelihood of remission with venlafaxine therapy than with SSRI therapy regardless of age or gender.
Patients with major depressive disorder (MDD) and significant anxiety are less responsive to antidepressants than those without anxiety. In this post hoc analysis of patients with insomnia and ...comorbid anxious depression, eszopiclone cotherapy with a selective serotonin reuptake inhibitor (SSRI) was compared with placebo cotherapy.
Data were pooled from 2 randomized, double-blind, 8-week trials. One trial (conducted from January 2004 to October 2004) included patients with DSM-IV insomnia and comorbid MDD treated with fluoxetine concurrently with eszopiclone 3 mg/d or placebo. The other trial (conducted from July 2005 to April 2006) included patients with DSM-IV-TR insomnia and comorbid generalized anxiety disorder treated with escitalopram concurrently with eszopiclone 3 mg/d or placebo. Anxious depression was defined as a baseline 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 14 (excluding insomnia items) and an anxiety/somatization factor score ≥ 7. Treatment group differences were determined for mean changes in HDRS-17 scores (with and without insomnia items), HDRS anxiety/somatization scores, and response and remission rates. Severity of insomnia was assessed by the Insomnia Severity Index (ISI).
In the combined dataset, 347 of 1,136 patients (30.5%) had insomnia and comorbid anxious depression. Significant improvements in insomnia were observed for eszopiclone cotherapy relative to placebo cotherapy (mean change from baseline on the ISI: -11.0 vs -7.8, respectively; P < .001). There were greater reductions in HDRS-17 scores at week 8 following cotherapy with eszopiclone compared with placebo when the insomnia items were included (mean change: -14.1 vs -11.2, respectively; P < .01) or excluded (-10.6 vs -8.9; P < .01), but not for anxiety/somatization (-4.3 vs -4.1; P = .23). Response rates were greater for eszopiclone cotherapy than for placebo cotherapy (55.6% vs 42.0%, respectively; P = .01; 50.0% vs 44.4% when insomnia items were removed; P = .3). Remission rates were not significantly different (32.6% vs 27.2%, respectively; P = .28).
In this post hoc analysis of patients with insomnia and comorbid anxious depression derived from 2 trials, 8 weeks of eszopiclone therapy coadministered with an SSRI resulted in significantly greater improvements in insomnia, significantly greater reductions in HDRS-17 total score, and significantly greater HDRS-17 response rates compared with placebo coadministration. There were no significant differences in response rates (when insomnia items were excluded) and remission rates, as well as in anxiety/somatization scores. Further research is warranted to determine whether these modest antidepressant effects can be replicated, and anxiolytic effects demonstrated, when evaluated in a prospective manner.
Insomnia marked by sleep maintenance difficulty is extremely prevalent. Yet, problems staying asleep have been relatively neglected as a research focus compared to problems falling asleep. Insomnia ...treatment studies typically have not required participants to have a problem specifically with sleep maintenance. It is possible that exclusion of such subjects limits the detection of treatment effects in the overall trial in general, and of effects on sleep maintenance specifically. In order to address these issues we conducted a post hoc analysis of a 6-month placebo-controlled trial in which there were no inclusion criteria that specified sleep maintenance difficulties to assess the variable effects of baseline wake time after sleep onset (WASO – the primary maintenance measure) on the efficacy of eszopiclone 3mg.
Patients diagnosed with chronic primary insomnia were randomized to eszopiclone 3mg (n=593) or placebo (n=195) nightly for sixmonths. The present analyses of this study consisted of: (1) determination of the distribution of baseline WASO; (2) continuous analysis of the relationship between baseline WASO severity and drug-placebo difference at month 1 and 6; and (3) categorical efficacy analyses of subgroups delimited by the following WASO thresholds: 0, 30, 45, 60, and 90min.
The baseline WASO distribution was: ⩽30=32.2%; >0 to ⩽45=41.5%; >30 to ⩽90=33.0%; >45 to ⩽90=23.7%; >90=22.6%. A relationship between greater baseline WASO severity and a significantly greater drug-placebo difference in efficacy for WASO was evident in both continuous and categorical analyses. Eszopiclone was found to have significant sleep maintenance efficacy at each time point across the entire range of WASO severity studied.
As illustrated in this analysis, a significant proportion of chronic insomnia patients in efficacy trials that select on the basis of sleep onset latency and total sleep time criteria may have normative-range WASO. However, even in the subgroup with minimal WASO there was a significant sleep maintenance effect. The absence of any sleep maintenance effect in a drug trial may reflect the inclusion of relatively many insomnia patients with no baseline WASO abnormality. However, treatments with therapeutic effects on sleep maintenance, can still demonstrate improvement in sleep maintenance, even in a population not selected for this type of sleep problem, if adequately powered. Future clinical trials intending to examine sleep maintenance should employ WASO selection criteria that would ensure sufficient power to detect a sleep maintenance effect. Drug-placebo difference increased as a function of baseline WASO severity, suggesting that eszopiclone’s clinical effectiveness for insomnia may be enhanced in patients with more severe sleep maintenance symptoms.
The basic helix-loop-helix transcription factor Ascl1 plays a critical role in the intrinsic genetic program responsible for neuronal differentiation. Here, we describe a novel model system of P19 ...embryonic carcinoma cells with doxycycline-inducible expression of Ascl1. Microarray hybridization and real-time PCR showed that these cells demonstrated increased expression of many neuronal proteins in a time- and concentration-dependent manner. Interestingly, the gene encoding the cell cycle regulator Gadd45γ was increased earliest and to the greatest extent following Ascl1 induction. Here, we provide the first evidence identifying Gadd45γ as a direct transcriptional target of Ascl1. Transactivation and chromatin immunoprecipitation assays identified two E-box consensus sites within the Gadd45γ promoter necessary for Ascl1 regulation, and demonstrated that Ascl1 is bound to this region within the Gadd45γ promoter. Furthermore, we found that overexpression of Gadd45γ itself is sufficient to initiate some aspects of neuronal differentiation independent of Ascl1.
cAMP-dependent protein kinase (PKA) plays a critical role in nervous system development by modulating sonic hedgehog and bone morphogenetic protein signaling. In the current studies, P19 embryonic ...carcinoma cells were neuronally differentiated by expression of the proneural basic helix-loop-helix transcription factor Ascl1. After expression of Ascl1, but prior to expression of neuronal markers such as microtubule associated protein 2 and neuronal β-tubulin, P19 cells demonstrated a large, transient increase in both mRNA and protein for the endogenous protein kinase inhibitor (PKI)β. PKIβ-targeted shRNA constructs both reduced the levels of PKIβ expression and blocked the neuronal differentiation of P19 cells. This inhibition of differentiation was rescued by transfection of a shRNA-resistant expression vector for the PKIβ protein, and this rescue required the PKA-specific inhibitory sequence of the PKIβprotein. PKIβ played a very specific role in the Ascl1-mediated differentiation process since other PKI isoforms were unable to rescue the deficit conferred by shRNA-mediated knockdown of PKIβ. Our results define a novel requirement for PKIβ and its inhibition of PKA during neuronal differentiation of P19 cells.
Abstract Background Insomnia marked by sleep maintenance difficulty is extremely prevalent. Yet, problems staying asleep have been relatively neglected as a research focus compared to problems ...falling asleep. Insomnia treatment studies typically have not required participants to have a problem specifically with sleep maintenance. It is possible that exclusion of such subjects limits the detection of treatment effects in the overall trial in general, and of effects on sleep maintenance specifically. In order to address these issues we conducted a post hoc analysis of a 6-month placebo-controlled trial in which there were no inclusion criteria that specified sleep maintenance difficulties to assess the variable effects of baseline wake time after sleep onset (WASO – the primary maintenance measure) on the efficacy of eszopiclone 3 mg. Methods Patients diagnosed with chronic primary insomnia were randomized to eszopiclone 3 mg ( n = 593) or placebo ( n = 195) nightly for six months. The present analyses of this study consisted of: (1) determination of the distribution of baseline WASO; (2) continuous analysis of the relationship between baseline WASO severity and drug-placebo difference at month 1 and 6; and (3) categorical efficacy analyses of subgroups delimited by the following WASO thresholds: 0, 30, 45, 60, and 90 min. Results The baseline WASO distribution was: ⩽30 = 32.2%; >0 to ⩽45 = 41.5%; >30 to ⩽90 = 33.0%; >45 to ⩽90 = 23.7%; >90 = 22.6%. A relationship between greater baseline WASO severity and a significantly greater drug-placebo difference in efficacy for WASO was evident in both continuous and categorical analyses. Eszopiclone was found to have significant sleep maintenance efficacy at each time point across the entire range of WASO severity studied. Conclusions As illustrated in this analysis, a significant proportion of chronic insomnia patients in efficacy trials that select on the basis of sleep onset latency and total sleep time criteria may have normative-range WASO. However, even in the subgroup with minimal WASO there was a significant sleep maintenance effect. The absence of any sleep maintenance effect in a drug trial may reflect the inclusion of relatively many insomnia patients with no baseline WASO abnormality. However, treatments with therapeutic effects on sleep maintenance, can still demonstrate improvement in sleep maintenance, even in a population not selected for this type of sleep problem, if adequately powered. Future clinical trials intending to examine sleep maintenance should employ WASO selection criteria that would ensure sufficient power to detect a sleep maintenance effect. Drug-placebo difference increased as a function of baseline WASO severity, suggesting that eszopiclone’s clinical effectiveness for insomnia may be enhanced in patients with more severe sleep maintenance symptoms.
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