Paulo Fontoura

To assess putative antidepressant and procognitive effects of decoglurant, a selective metabotropic glutamate receptor type 2/3 (mGlu2/3) negative allosteric modulator, as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in patients with partially refractory major depressive disorder (MDD), diagnosed using DSM-IV-TR criteria.

Biomarkers for autism spectrum disorder (ASD) are lacking but would facilitate drug development for the core deficits of the disorder. We evaluated markers proposed for characterization of differences in social communication and interaction in adults with ASD versus healthy controls (HC) for utility as biomarkers. Data pooled from an observational study and baseline data from a placebo-controlled study were analyzed. Between-group differences were observed in eye-tracking tasks for activity… Mehr anzeigen

Biomarkers for autism spectrum disorder (ASD) are lacking but would facilitate drug development for the core deficits of the disorder. We evaluated markers proposed for characterization of differences in social communication and interaction in adults with ASD versus healthy controls (HC) for utility as biomarkers. Data pooled from an observational study and baseline data from a placebo-controlled study were analyzed. Between-group differences were observed in eye-tracking tasks for activity monitoring, biomotion, human activity preference, composite score (p = 0.0001-0.037) and pupillometry (various tasks, p = 0.017-0.05). Impaired olfaction was more common in the ASD sample versus HC (p = 0.018). Our preliminary results suggest the potential use for stratification and response sub-analyses outcome-prediction of specific eye-tracking tasks, pupillometry and olfaction tests in ASD trials. Weniger anzeigen

We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on… Mehr anzeigen

We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD). Weniger anzeigen

There are no approved pharmacological therapies to address the core symptoms of autism spectrum disorder (ASD), namely, persistent deficits in social communication and social interaction and the presence of restricted, repetitive patterns of behaviors, interests, or activities. The neuropeptide vasopressin has been implicated in the regulation of social behaviors, and its modulation has emerged as a therapeutic target for ASD. The phase 2 VANILLA clinical trial reported here evaluated… Mehr anzeigen

There are no approved pharmacological therapies to address the core symptoms of autism spectrum disorder (ASD), namely, persistent deficits in social communication and social interaction and the presence of restricted, repetitive patterns of behaviors, interests, or activities. The neuropeptide vasopressin has been implicated in the regulation of social behaviors, and its modulation has emerged as a therapeutic target for ASD. The phase 2 VANILLA clinical trial reported here evaluated balovaptan, an orally administered selective vasopressin V1a receptor antagonist, in 223 men with ASD and intelligence quotient ≥70. The drug was administered daily for 12 weeks and was compared with placebo. Participants were randomized to placebo (n = 75) or one of three balovaptan dose arms (1.5 mg, n = 32; 4 mg, n = 77; 10 mg, n = 39). Balovaptan treatment was not associated with a change from baseline compared with placebo at 12 weeks in the primary efficacy endpoint (Social Responsiveness Scale, 2nd Edition). However, dose-dependent and clinically meaningful improvements on the Vineland-II Adaptive Behavior Scales composite score were observed for participants treated with balovaptan 4 or 10 mg compared with placebo. This was driven principally by improvements in the Vineland-II socialization and communication scores. Balovaptan was well tolerated across all doses, and no drug-related safety concerns were identified. These results support further study of balovaptan as a potential treatment for the socialization and communication deficits in ASD. Weniger anzeigen

Autism Spectrum Disorder (ASD) lacks validated measures of core social functions across development stages suitable for clinical trials. We assessed the concurrent validity between ASD clinical measures and putative biomarkers of core deficits, and their feasibility of implementation in human studies. Potential biomarkers included eye-tracking, olfaction, and auditory and visual emotion recognition assessed via the Affective Speech Recognition test (ASR) and Reading-the-Mind-in-the-Eyes Test… Mehr anzeigen

Autism Spectrum Disorder (ASD) lacks validated measures of core social functions across development stages suitable for clinical trials. We assessed the concurrent validity between ASD clinical measures and putative biomarkers of core deficits, and their feasibility of implementation in human studies. Potential biomarkers included eye-tracking, olfaction, and auditory and visual emotion recognition assessed via the Affective Speech Recognition test (ASR) and Reading-the-Mind-in-the-Eyes Test (RMET). Weniger anzeigen

Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger… Mehr anzeigen

Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials. We evaluated basimglurant, a potent and selective mGluR5 NAM, in a 12-week, double-blind, parallel-group study of 183 adults and adolescents (aged 14-50, mean 23.4 years) with FXS. Individuals with an FMR1 full mutation were randomized to placebo or one of two doses of basimglurant. The primary efficacy endpoint was the change from baseline in behavioral symptoms using the Anxiety Depression and Mood Scale (ADAMS) total score. All treatment arms showed marked behavioral improvements from baseline to week 12 with less improvement in the basimglurant 1.5 mg arm than placebo; however, basimglurant 0.5 mg was inferior to placebo in the ADAMs total score. Treatment with basimglurant was overall well-tolerated. A higher incidence of adverse events classified as psychiatric disorders were reported in patients treated with basimglurant, including three patients with hallucinations or psychosis. In this phase 2 clinical trial, basimglurant did not demonstrate improvement over placebo. Evaluation of the overall risk-benefit in younger patient populations is an important consideration for the design of potential further investigations of efficacy with this class of medications. Weniger anzeigen

Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer's disease (AD). The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical… Mehr anzeigen

Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer's disease (AD). The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. Weniger anzeigen

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a)… Mehr anzeigen

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18-45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Weniger anzeigen

Results of a Ph2 trial of olesoxime in SMA type 2 and 3 patients, showing slowing of motor function deterioration over 2 years of treatment.

Results of the OPERA 1 and 2 clinical trials of Ocrelizumab in RMS

Results of the ORATORIO trial of ocrelizumab in PPMS, the first trial to show positive results in the treatment of this aggressive form of Multiple Sclerosis.

Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD). To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally… Mehr anzeigen

Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD). To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline. Weniger anzeigen

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a)… Mehr anzeigen

The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18-45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=-0.8, p=0.03) and fear (ES=-0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=-0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. Weniger anzeigen

Results of the MARIGOLD trial of basimglurant as an adjunctive therapy for treatment resistant depression.

First time highly specific RNA splicing modifiers have been found. Profound efficacy in animal models of spinal muscular atrophy provide great therapeutic potential.

Realizing that 60% to 80% of dopaminergic nigrostriatal neurons are nonfunctional at the time of clinical diagnosis, there is an emerging consensus that disease-modifying treatments should be initiated in the earliest stages of Parkinson's disease (PD). To date, clinical trial designs and metrics in PD have been focused on motor symptoms as the core feature of the clinical disease. To identify earlier or "pre-motor" populations in PD, new markers have been proposed. We address the prerequisites… Mehr anzeigen

Realizing that 60% to 80% of dopaminergic nigrostriatal neurons are nonfunctional at the time of clinical diagnosis, there is an emerging consensus that disease-modifying treatments should be initiated in the earliest stages of Parkinson's disease (PD). To date, clinical trial designs and metrics in PD have been focused on motor symptoms as the core feature of the clinical disease. To identify earlier or "pre-motor" populations in PD, new markers have been proposed. We address the prerequisites needed to use these pre-motor markers in clinical trials for the selection of subjects, definition of populations, and monitoring of disease progression. This may require the development of new diagnostic criteria potentially based on non-motor clinical signs, imaging techniques, or biological features, all requiring discussion in a regulatory framework. Questions addressed include: Which steps must be taken to gain a broad consensus in the field from academic opinion leaders, patient advocacy groups, regulatory bodies, and industry? How do we prevent the selection of subgroups, which may not be representative of the full disease spectrum? Is there a way forward in personalized medicine? How do we balance risk and benefit in an at-risk population? While many tools are available, a concerted effort is required to develop integrated data sets, as well as to achieve the necessary standardization for multicenter clinical trials. To this end, public-private consortia (including academic centers, patient advocacy groups, and industry) will be of crucial importance to prospectively investigate and define the best tools and treatment paradigms. Weniger anzeigen

Amatus Lusitanus, a Portuguese Jew who gained notoriety as one of the most famous physician-scientists in XVI century Europe published collections of case histories--Centuriae--describing his most interesting patients. The Renaissance was a transitional period for medicine and the neurological sciences, which if still dominated by the humoral and ventricular-pneumatic doctrines, were taking the first steps away from them. We analysed the Centuriae for neurological and psychiatric cases in order… Mehr anzeigen

Amatus Lusitanus, a Portuguese Jew who gained notoriety as one of the most famous physician-scientists in XVI century Europe published collections of case histories--Centuriae--describing his most interesting patients. The Renaissance was a transitional period for medicine and the neurological sciences, which if still dominated by the humoral and ventricular-pneumatic doctrines, were taking the first steps away from them. We analysed the Centuriae for neurological and psychiatric cases in order to appreciate neurological practice in this period and selected one hundred which fit those diagnostic categories. The Centuriae contain cases of CNS infection and trauma, epilepsy, apoplexy and depressed states of consciousness (including coma, carus, lethargy and cataphora), headache and vertigo, tumours, cranial nerve paralysis, melancholy, anatomical and physiological observations, as well as a short treatise on cranial traumatology. The most relevant observations point to the importance of the brain parenchyma in cognition, provide original observations of epidemic lethargic encephalitis, describe the neurological consequences of syphilis, including the first description of tertiary syphilis, attempt to distinguish mania from melancholy, extensively describe medical and surgical treatment of cranial trauma, document the first use of anatomical dissection to study a case of brain abscess, negate Galen's view of the optic nerves as hollow, and describe the use of new drugs such as guaiac wood for the treatment of headache. The Centuriae not only provide insight into neurological clinical practice in the XVI century, but also emphasize the role of Amatus Lusitanus as an important precursor of this discipline, given his numerous original observations. Weniger anzeigen