First-in-Human Studies of Pharmacokinetics and Safety of Utreloxastat (PTC857), a Novel 15-Lipooxygenase Inhibitor for the Treatment of Amyotrophic Lateral Sclerosis.

Utreloxastat (PTC857) is a 15-lipoxygenase inhibitor being developed to treat amyotrophic lateral sclerosis. This first-in-human study investigated the safety and pharmacokinetics of utreloxastat in healthy volunteers (N = 82) in a double-blind, placebo-controlled trial. The effects of a single ascending dose (100-1000 mg), multiple ascending doses (150-500 mg), and food (500 mg) on the pharmacokinetics and safety of utreloxastat were evaluated. Following single doses, the time to maximum plasma concentration (Cmax ) was observed ≈4 hours after dosing and the terminal half-life ranged from 20 to 25.3 hours. The Cmax and area under the concentration-time curve (AUC) increased slightly over dose proportionally. Following multiple doses (once daily/twice daily), the apparent clearance reduced and terminal half-life was ≥33 hours. There was no apparent difference of exposure following morning or evening doses. Varying diets increased the Cmax and AUCs of utreloxastat but did not alter time to Cmax . There were no gender-based differences in exposure. Utreloxastat showed no marked safety signal following single doses up to 1000 mg and multiple doses over 14 days of 500 mg once daily or 250 mg twice daily. The results support further development of utreloxastat for the treatment of patients with amyotrophic lateral sclerosis at a 250-mg twice-daily dose administered with food.

A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis.

OBJECTIVE: To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS). METHODS: In the randomized, double-blind, placebo-controlled, phase 2 study, ARPEGGIO (A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations in MRI and Clinical Outcomes), eligible patients with PPMS were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016, due to findings of cardiovascular events. RESULTS: A total of 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg vs placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio 0.4; 95% confidence interval, 0.26-0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) vs laquinimod 1.5 mg (66%) and placebo (78%). CONCLUSIONS: Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48. CLINICALTRIALSGOV IDENTIFIER: NCT02284568. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, although well tolerated, laquinimod 0.6 mg did not demonstrate a significant treatment effect on PBVC in patients with PPMS.

Defining responders to therapies by a statistical modeling approach applied to randomized clinical trial data.

BACKGROUND: Personalized medicine is the tailoring of treatment to the individual characteristics of patients. Once a treatment has been tested in a clinical trial and its effect overall quantified, it would be of great value to be able to use the baseline patients' characteristics to identify patients with larger/lower benefits from treatment, for a more personalized approach to therapy. METHODS: We show here a previously published statistical method, aimed at identifying patients' profiles associated to larger treatment benefits applied to three identical randomized clinical trials in multiple sclerosis, testing laquinimod vs placebo (ALLEGRO, BRAVO, and CONCERTO). We identified on the ALLEGRO patients' specific linear combinations of baseline variables, predicting heterogeneous response to treatment on disability progression. We choose the best score on the BRAVO, based on its ability to identify responders to treatment in this dataset. We finally got an external validation on the CONCERTO, testing on this new dataset the performance of the score in defining responders and non-responders. RESULTS: The best response score defined on the ALLEGRO and the BRAVO was a linear combination of age, sex, previous relapses, brain volume, and MRI lesion activity. Splitting patients into responders and non-responders according to the score distribution, in the ALLEGRO, the hazard ratio (HR) for disability progression of laquinimod vs placebo was 0.38 for responders, HR = 1.31 for non-responders (interaction p = 0.0007). In the BRAVO, we had similar results: HR = 0.40 for responders and HR = 1.24 for non-responders (interaction p = 0.006). These findings were successfully replicated in the CONCERTO study, with HR = 0.44 for responders and HR=1.08 for non-responders (interaction p = 0.033). CONCLUSIONS: This study demonstrates the possibility to refine and personalize the treatment effect estimated in randomized studies by using the baseline demographic and clinical characteristics of the included patients. The method can be applied to any randomized trial in any medical condition to create a treatment-specific score associated to different levels of response to the treatment tested in the trial. This is an easy and affordable method toward therapy personalization, indicating patient profiles related to a larger benefit from a specific drug, which may have implications for taking clinical decisions in everyday clinical practice.

Expanded disability status scale progression assessment heterogeneity in multiple sclerosis according to geographical areas.

Using placebo data from 3 randomized multiple sclerosis (MS) trials with uniform inclusion criteria, we investigated heterogeneity of Expanded Disability Status Scale (EDSS) progression by geographical areas. Our analysis revealed a significantly lower EDSS progression in Eastern European countries (10.8%) compared with Western Europe (13.1%) or the USA/Canada (21.4%, p < 0.001); EDSS improvement behaved the same way. This heterogeneity is not explained by differences of baseline variables. No differences were detected on more easily quantifiable measures, the Timed 25-Foot Walk or the Multiple Sclerosis Functional Composite. At a time when disease progression represents the target for future interventions in MS, establishment of more quantitative and objective outcomes remains a key priority of MS research. Ann Neurol 2018;84:621-625.

Utility of Carotid Ultrasonography in Management of an Atypical High Vascular-Risk Patient with Recurrent Calcified Cerebral Embolic Stroke.

OBJECTIVE: To describe a case of recurrent calcified cerebral emboli (CCE)-related acute ischemic stroke (AIS) and the diagnostic utility of plaque morphology characterization on carotid ultrasound. BACKGROUND: CCE are a rare cause of AIS. CCE-related AIS has been previously reported only in high vascular-risk patients such as those with severe carotid stenosis, widespread atheromatous disease, or cardiac valvular disease. CCE-related AIS from a carotid origin has not been reported in patients without carotid stenosis. CASE: A 69-year-old man with no known medical history presented with hemiparesis and aphasia was found to have a curvilinear calcification in the left sylvian fissure on brain imaging, consistent with CCE. Two months later, he developed a second episode of CCE-related AIS. Standard workup, as well as advanced imaging with digital subtraction angiography, revealed no carotid stenosis or valvular disease. Carotid ultrasound demonstrated normal flow velocities but a left carotid heterogeneous plaque with multiple ulcerative craters and lucencies, suggestive of an active thromboembolic source. CONCLUSION: To our knowledge, this is the first case reporting CCE-AIS from carotid origin in a patient with no carotid stenosis. Carotid ultrasound serves a diagnostic role in these patients.

Imaging Acute Ischemic Stroke: Mapping Present and Future Clinical Practice.

Imaging is an increasingly key component of advances in stroke care. Its role in the success of multiple recently reported trials that have now driven new standards of practice highlights its expanding importance in acute stroke management. With significant gains already realized, routine practice only stands to benefit further from additional advances in imaging in the future. The degree to which imaging will impact stroke care, however, is uncertain and complex: multiple aspects of stroke research and its translation into updated practice contribute to it. In this article, a few of these critical issues and questions related to imaging and its potential, both present and future, to drive stroke care forward are addressed.

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Recent successful endovascular stroke trials have provided unequivocal support for these therapies in selected patients with large-vessel occlusive acute ischemic stroke. In this piece, we briefly review these trials and their utilization of advanced neuroimaging techniques that played a pivotal role in their success through targeted patient selection. In this context, the unique challenges and opportunity for advancement in current stroke networks' routine delivery of care created by these trials are discussed and recommendations to change current national stroke system guidelines are proposed.

The goldilocks dilemma in acute ischemic stroke.

Despite the advent of and exciting advances in novel endovascular therapies, t-PA remains the only proven treatment for acute ischemic stroke to date. Although a variety of reasons likely underlie why past trials of endovascular strategies have been unsuccessful, we address in this perspective piece one critical unknown for which a solution is undoubtedly necessary if future ones are to meet with success: determination and selection of patients that are "just right" for endovascular treatments, or the Goldilocks dilemma. Key clinical criteria highlighted in past trials may help provide a solution to this critical problem. However, for them to do so, we propose that they must be applied in service of a model that accounts for the nuanced, dynamic nature of acute ischemic stroke better than the prevailing "time is brain" model. We provide and examine three clinical cases to illustrate this proposal towards solving the Goldilocks dilemma and advancing treatment in acute ischemic stroke. Further, we address our field's ongoing challenge and mission in the meantime to best care for the "not-so-right" patients, by far the majority of the affected stroke population.

Use of perfusion imaging and other imaging techniques to assess risks/benefits of acute stroke interventions.

The advent of multimodal neuroimaging has provided acute stroke care providers with an armamentarium of sophisticated imaging options to utilize for guidance in clinical decision-making and management of acute ischemic stroke patients. Here, we propose a framework and potential algorithm-based methodology for imaging modality selection and utilization for the purpose of achieving optimal stroke clinical care. We first review imaging options that may best inform decision-making regarding revascularization eligibility, with a focus on the imaging modalities that best identify critical inclusion and exclusion criteria. Next, we review imaging methods that may guide the successful achievement of revascularization once it has been deemed desirable and feasible. Further, we review imaging modalities that may best assist in both the noninterventional care of acute stroke as well as the identification of stroke-mimics. Finally, we review imaging techniques under current investigation that show promise to improve future acute stroke management.

A functional MRI study of preparatory signals for spatial location and objects.

We investigated preparatory signals for spatial location and objects in normal observers using functional magnetic resonance imaging (fMRI). Activity for attention-directing cues was separated from activity for subsequent test arrays containing the target stimulus. Subjects were more accurate in discriminating a target face among distracters when they knew in advance its location (spatial directional cue), as compared to when the target could randomly appear at one of two locations (spatial neutral cue), indicating that the spatial cue was used. Spatially specific activations occurred in a region at the intersection of the ventral intraparietal sulcus and transverse occipital sulcus (vIPS-TOS), which showed significantly stronger activation for rightward- than leftward-directing cues, while other fronto-parietal areas were activated by the cue but did not show spatial specificity. In visual cortex, activity was weak or absent in retinotopic occipital regions following attention-directing cues and this activity was not spatially specific. In a separate task, subject discriminated a target outdoor scene among distracters after the presentation of spatial neutral cues. There was no significant difference in dorsal frontoparietal activity during the face versus scene discrimination task. Also, there was only weak evidence for selective preparatory activity in ventral object-selective regions, although the activation of these regions to the subsequent test array did depend upon which discrimination (face or place) was performed. We conclude first that under certain circumstances, spatial cues that produce strong behavioral effects may modulate parietal-occipital regions in a spatially specific manner without producing similar modulations in retinotopic occipital regions. Second, attentional modulations of object-selective regions in temporal-occipital cortex can occur even though preparatory object-selective modulations of those regions are absent or weak.

Quantitative analysis of attention and detection signals during visual search.

Prior work has distinguished regions in the intraparietal sulcus (IPs) and frontal eye field (FEF) involved in the voluntary control of attention, from more ventral regions in the temporoparietal junction (TPJ) involved in target detection. The present results show that when subjects search for and detect a visual target stimulus among nontargets, these regions show sensory-, search-, and detection-related signals that both confirm and refine these functional distinctions. The different signals were isolated by an additive model that accounted for a large fraction of BOLD (blood oxygenation level-dependent) signal modulation over the brain. Both IPs and FEF were activated during search through nontargets, consistent with a role in maintaining attention-related signals during search. However, unlike FEF, IPs also showed stimulus-related activations, and may combine signals related to sensory and task-dependent components of salience. Although IPs-FEF showed search-related activations, the TPJ was deactivated during search. TPJ activations were confined to detection-related signals. These results provide a much stronger dissociation between the TPJ and IPs-FEF than previous work, while indicating functional differences between frontal and parietal regions that are often coactivated in studies of attention. Finally, continuous flow models of information processing predict that during search, signals from missed targets should be fed from sensory to associative regions rather than being gated by the decision criterion. Correspondingly, missed targets significantly activated parietal (e.g., right TPJ) and frontal (e.g., anterior insula, anterior cingulate) regions, although with a smaller magnitude than detected targets. Surprisingly, many cortical regions showed equivalent signals from detected targets and the completion of target-absent trials, reflecting a widespread signal unrelated to motor execution.

Word retrieval learning modulates right frontal cortex in patients with left frontal damage.

Previous studies have suggested that recovery or compensation of language function after a lesion in the left hemisphere may depend on mechanisms in the right hemisphere. However, a direct relationship between performance and right hemisphere activity has not been established. Here, we show that patients with left frontal lesions and partially recovered aphasia learn, at a normal rate, a novel word retrieval task that requires the damaged cortex. Verbal learning is accompanied by specific response decrements in right frontal and right occipital cortex, strongly supporting the compensatory role of the right hemisphere. Furthermore, responses in left occipital cortex are abnormal and not modulated by practice. These findings indicate that frontal cortex is a source of top-down signals during learning.

Two attentional processes in the parietal lobe.

We report fMRI evidence for two attentional processes in parietal cortex. Subjects matched a feature, cued by a word, to a test display of moving colored dots. Either color (red, green) or motion direction (left, right) was cued on mixed scans while only one dimension was cued on blocked scans. An event-related paradigm separated the preparatory activity generated by the cue from the subsequent activity related to the test display. One attentional process specified task information while a second process was motion selective. During the cue period, a pure effect of task specification was observed in left frontal cortex while combined effects of task specification and motion selectivity were observed in left posterior parietal cortex. The frontal task-specification signal may have been the source of the corresponding signal in parietal cortex. Effects of task specification generalized over cue dimension, indicating that the information was coded in a sufficiently abstract form to affect color and motion processing. During the subsequent test period, task-specification and motion-selective signals were again observed in left parietal cortex. Task specification did not significantly affect occipital motion-selective regions, such as MT+, however, indicating that this process did not influence the lower cortical tier of the motion processing stream. These results provide evidence for general and specialized task representations within left parietal cortex during task preparation and execution.

Reactivation of networks involved in preparatory states.

We report an endogenous signal that has a widespread cortical distribution and is time-locked to the termination of a sustained state of task-readiness. In three event-related functional magnetic resonance imaging (fMRI) experiments, subjects saw an arrow cue that predicted either the direction of motion or the location of a subsequent test stimulus. A reactivation of the BOLD (blood oxygenation level-dependent) signal occurred at the termination of the state of readiness in occipital regions that were transiently activated by the cue and in frontal-parietal regions that maintained an attentional set over the trial. Moreover, a delayed activation occurred in prefrontal and temporo-parietal regions that did not initially respond to the cue and that have been implicated in re-orienting attention to novel sensory events. These latter regions may have generated control signals that ended the state of readiness in regions active during the cue period. These results indicate that terminating a state of readiness produces a widely distributed cortical signal and suggest that areas involved in a preparatory state may be maintained as a network which can be modulated as a whole.