Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

BACKGROUND: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. METHODS: Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3. RESULTS: Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P<0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P<0.001). The effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship' and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P<0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%). CONCLUSIONS: Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04516291.

Hyperbaric oxygen for late sequelae of carbon monoxide poisoning enhances neurological recovery: case report.

Neuropsychiatric sequelae have been reported in 15%-45% of survivors of carbon monoxide (CO) poisoning. Hyperbaric oxygen (HBO2) therapy reduces the incidence of cognitive and neurological a dysfunction. The efficacy of providing HBO2 beyond the first one to two days after initial insult is unknown. However, some evidence exists for the benefit of this treatment. We report on treating a patient 14 months after CO injury, who responded with markedly improved neurologic status. A 27-year-old scholar was found comatose due to CO poisoning (carboxyhemoglobin = 31.7%). He received five acute HBO2 treatments. After discharge, he developed chorea, Parkinsonism, dystonia, memory loss, slowed processing speed and verbal fluency, leaving him disabled. After the patient reached a clinical plateau, HBO2 was tried again at 90 minutes at 2.4 ATA plus air breaks. Neuropsychological testing was performed at baseline and after each 20 HBO2 cycles, five of which were performed during the period from 14-22 months after CO exposure. After the first 20 treatments, Parkinsonism and dystonia improved. After 40 sessions, further improvements were seen on mental speed, verbal fluency, and fine motor movements. The outcome following 100 treatments was that the patient regained independence, including the ability to drive and to become gainfully employed. Our case calls into question the concept that HBO2 therapy has no role during the chronic phase of CO brain injury. Randomized clinical trials should be considered to evaluate the therapeutic efficacy of HBO2 in patients with neurological sequelae following CO injury.

Inducing LTD-Like Effect in the Human Motor Cortex with Low Frequency and Very Short Duration Paired Associative Stimulation: An Exploratory Study.

Introduction. Paired associative stimulation (PAS) is an established technique to investigate synaptic plasticity in the human motor cortex (M1). Classically, to induce long-term depression- (LTD-) or long-term potentiation-like effects in the human M1, studies have used low frequency and long duration trains of PAS. In the present study, we explored an LTD-like effect using very short duration and low frequency of PAS10 ms protocols in human M1. Methods. Six protocols of low frequency PAS10 ms (ranging from 0.2 Hz to 1 Hz) were investigated with very short durations of 1 and 2 minutes stimulation. Six healthy volunteers were included in each protocol. We obtained motor-evoked potentials from right abductor pollicis brevis muscle before and after applying PAS10 ms up to 30 minutes. After we found PAS10 ms protocol which induced an LTD-like effect, we tested that protocol on additional 5 subjects. Results. One-way repeated-measures ANOVA showed that only the group of 1-minute stimulation of 0.25 Hz induced an LTD-like effect. When adding the additional subjects, the effect remained and lasted for 30 minutes. Conclusion. Low frequency and very short duration of PAS10 ms potentially induced an LTD-like effect in human M1. With further verification, this method might be useful for research relating to synaptic plasticity by reducing the duration of study and minimizing subject discomfort.

Tricks in dystonia: ordering the complexity.

Sensory tricks are various manoeuvres that can ameliorate dystonia. Common characteristics are well known, but their variety is wide, sensory stimulation is not necessarily the critical feature, and their physiology is unknown. To enumerate the various forms of sensory tricks and describe their nature, research findings and theories that may elucidate their neurophysiologic mechanism, we reviewed the literature pertaining to sensory tricks, including variants like motor tricks, imaginary tricks, forcible tricks and reverse sensory tricks. On the basis of this information, we propose a new classification of sensory tricks to include its variants. We highlight neurophysiologic evidence suggesting that sensory tricks work by decreasing abnormal facilitation. We tie this with established dystonia pathogenesis and postulate that sensory tricks decrease abnormally increased facilitation to inhibition ratios in the dystonic brain. It appears worthwhile for patients to search for possible sensory tricks.

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3.

BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF). OBJECTIVE: To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes. METHODS: TRANSLATE-TIMI 70 was a randomized, placebo-controlled trial testing 7 dosing regimens of vupanorsen in 286 adults with hyperlipidemia. A total of 227 patients had HFF measured at baseline and 24 weeks and were included in this analysis. RESULTS: The median HFF at baseline was 8.5%. Vupanorsen led to dose-dependent relative increases in HFF of up to 76% at 24 weeks (p < 0.001), corresponding to an absolute increase of up to 7.0% at the highest dose (p < 0.001). Increases in HFF were numerically greater in patients who had elevated baseline HFF, body mass index, triglycerides, or diabetes. Vupanorsen also increased liver enzymes in a dose-dependent manner, and changes in HFF were moderately positively correlated with changes in aspartate transaminase (AST) (rho = 0.49, p < 0.001) and alanine transaminase (ALT) (rho = 0.50, p < 0.001). CONCLUSION: Vupanorsen, an inhibitor of ANGPTL3 protein synthesis, caused dose-dependent increases in HFF. Increases in HFF were only moderately correlated with elevations in AST and ALT, suggesting that liver enzymes are an imperfect indicator to detect increases in hepatic fat. These results highlight the need to monitor HFF in clinical trials of therapies targeting intracellular ANGPTL3 inhibition, especially those that are targeted to the liver.

Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial.

AIMS: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target. METHODS AND RESULTS: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL. The primary endpoint of this analysis was percentage change in remnant cholesterol (total cholesterol minus directly measured LDL-C minus HDL-C) and VLDL-C (directly measured) over 24 weeks. Two hundred eighty-six patients were enrolled, with a median age of 64 years and 44% female. Median baseline remnant cholesterol and VLDL-C were 42 and 31 mg/dL, respectively (reference: <30 mg/dL). Vupanorsen lowered remnant cholesterol by 42-59% at 24 weeks over placebo (P < 0.001), achieving a median level of 18 mg/dL at the highest dose. Over the same period, VLDL-C was reduced by 52-67% over placebo (P < 0.001), with a median achieved level of 2.5 mg/dL at the highest dose. The effect of vupanorsen on remnant cholesterol and VLDL-C reduction was dose-dependent and directly associated with the degree of ANGPTL3 inhibition: at 90% ANGPTL3 reduction, there was a 61% and 81% decrease in remnant cholesterol and VLDL-C, respectively. CONCLUSION: Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins.

In this randomized controlled trial of 286 participants with elevated triglycerides, treatment with vupanorsen, an ANGPTL3 inhibitor, lowered remnant cholesterol by up to 59% and VLDL cholesterol by up to 67% over placebo. The effect of the treatment was sustained throughout 24 weeks and consistent across key patient subgroups. ANGPTL3 inhibition may be a promising approach to treat patients with elevated triglycerides.

A multi-purpose Japanese phase I study in the global development of vupanorsen: Randomized, placebo-controlled, single-ascending dose study in adults.

Vupanorsen (PF-07285557) is a second-generation tri-N-acetyl galactosamine (GalNAc3 )-antisense oligonucleotide targeted to angiopoietin-like 3 (ANGPTL3) mRNA, shown to reduce lipids and apolipoproteins in subjects with dyslipidemia. To aid bringing innovative drugs to global patients efficiently, a multi-purpose Japanese phase I study was conducted, with integrated development approaches agreed by the Pharmaceuticals and Medical Devices Agency (PMDA). This randomized, double-blind, placebo-controlled, single-ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of vupanorsen administered subcutaneously to Japanese adults (20-65 years) with elevated triglycerides (TG). Participants were randomized (1:1:1) to vupanorsen (80:160 mg) or placebo (N = 4 each). Vupanorsen 160 mg was a first-in-human (FIH) dose level. Vupanorsen was well-tolerated with no treatment-related adverse events reported for either dose. Absorption into the systemic circulation was rapid with median time to maximum concentration (Tmax ) of 3.5 and 2.0 h, for vupanorsen 80 and 160 mg, respectively. Following maximum concentration (Cmax ), vupanorsen underwent multiphasic decline characterized by a relatively fast initial distribution phase followed by slower terminal elimination phase, with elimination half-life (t1/2 ) of 397 and 499 h (80, 160 mg), respectively. Area under the concentration-time curve (AUC) and Cmax increased in a greater than dose-proportional manner. Pharmacodynamic markers (ANGPTL3, TG, and other key lipids) were reduced with vupanorsen versus placebo. Vupanorsen was safe and well-tolerated in healthy Japanese participants with elevated TG. This study provided FIH data for vupanorsen 160 mg. Moreover, the SAD study in Japanese participants fulfilled PMDA bridging requirements, and with the totality of global vupanorsen data, supported the PMDA waiver for a local phase II dose-finding study. ClinicalTrials.gov: NCT04459767.

A case of fascioscapulohumeral muscular dystrophy misdiagnosed as Becker's muscular dystrophy for 20 years.

A 60-year-old man diagnosed clinically with Becker's muscular dystrophy 20 years ago by another physician presented with gradually progressive proximal muscle weakness since teenage years. Family history revealed a strong paternal familial inheritance pattern of similar distribution of weakness-face, forearm flexion, knee extension and foot dorsiflexion. Work-ups revealed B12 deficiency and allele 1 deletion in fascioscapulohumeral muscular dystrophy (FSHD) DNA testing. FSHD is the third most common muscular dystrophy. Clinical diagnosis is made from the distinctive pattern of weakness, autosomal-dominant inheritance, and confirmed by genetic testing. This case strongly demonstrates the importance of a thorough and careful clinical evaluation even in a case with a long standing diagnosis.

Using an unbiased symbolic movement representation to characterize Parkinson's disease states.

Unconstrained human movement can be broken down into a series of stereotyped motifs or 'syllables' in an unsupervised fashion. Sequences of these syllables can be represented by symbols and characterized by a statistical grammar which varies with external situational context and internal neurological state. By first constructing a Markov chain from the transitions between these syllables then calculating the stationary distribution of this chain, we estimate the overall severity of Parkinson's symptoms by capturing the increasingly disorganized transitions between syllables as motor impairment increases. Comparing stationary distributions of movement syllables has several advantages over traditional neurologist administered in-clinic assessments. This technique can be used on unconstrained at-home behavior as well as scripted in-clinic exercises, it avoids differences across human evaluators, and can be used continuously without requiring scripted tasks be performed. We demonstrate the effectiveness of this technique using movement data captured with commercially available wrist worn sensors in 35 participants with Parkinson's disease in-clinic and 25 participants monitored at home.

The Impact of Reducing the Number of Wearable Devices on Measuring Gait in Parkinson Disease: Noninterventional Exploratory Study.

BACKGROUND: Measuring free-living gait using wearable devices may offer higher granularity and temporal resolution than the current clinical assessments for patients with Parkinson disease (PD). However, increasing the number of devices worn on the body adds to the patient burden and impacts the compliance. OBJECTIVE: This study aimed to investigate the impact of reducing the number of wearable devices on the ability to assess gait impairments in patients with PD. METHODS: A total of 35 volunteers with PD and 60 healthy volunteers performed a gait task during 2 clinic visits. Participants with PD were assessed in the On and Off medication state using the Movement Disorder Society version of the Unified Parkinson Disease Rating Scale (MDS-UPDRS). Gait features derived from a single lumbar-mounted accelerometer were compared with those derived using 3 and 6 wearable devices for both participants with PD and healthy participants. RESULTS: A comparable performance was observed for predicting the MDS-UPDRS gait score using longitudinal mixed-effects model fit with gait features derived from a single (root mean square error [RMSE]=0.64; R2=0.53), 3 (RMSE=0.64; R2=0.54), and 6 devices (RMSE=0.54; R2=0.65). In addition, MDS-UPDRS gait scores predicted using all 3 models differed significantly between On and Off motor states (single device, P=.004; 3 devices, P=.004; 6 devices, P=.045). CONCLUSIONS: We observed a marginal benefit in using multiple devices for assessing gait impairments in patients with PD when compared with gait features derived using a single lumbar-mounted accelerometer. The wearability burden associated with the use of multiple devices may offset gains in accuracy for monitoring gait under free-living conditions.

Age and environment-related differences in gait in healthy adults using wearables.

Technological advances in multimodal wearable and connected devices have enabled the measurement of human movement and physiology in naturalistic settings. The ability to collect continuous activity monitoring data with digital devices in real-world environments has opened unprecedented opportunity to establish clinical digital phenotypes across diseases. Many traditional assessments of physical function utilized in clinical trials are limited because they are episodic, therefore, cannot capture the day-to-day temporal fluctuations and longitudinal changes in activity that individuals experience. In order to understand the sensitivity of gait speed as a potential endpoint for clinical trials, we investigated the use of digital devices during traditional clinical assessments and in real-world environments in a group of healthy younger (n = 33, 18-40 years) and older (n = 32, 65-85 years) adults. We observed good agreement between gait speed estimated using a lumbar-mounted accelerometer and gold standard system during the performance of traditional gait assessment task in-lab, and saw discrepancies between in-lab and at-home gait speed. We found that gait speed estimated in-lab, with or without digital devices, failed to differentiate between the age groups, whereas gait speed derived during at-home monitoring was able to distinguish the age groups. Furthermore, we found that only three days of at-home monitoring was sufficient to reliably estimate gait speed in our population, and still capture age-related group differences. Our results suggest that gait speed derived from activities during daily life using data from wearable devices may have the potential to transform clinical trials by non-invasively and unobtrusively providing a more objective and naturalistic measure of functional ability.

Ultrasound as Diagnostic Tool for Diaphragmatic Myoclonus.

BACKGROUND: Diaphragmatic myoclonus is a rare disorder of repetitive diaphragmatic contractions, acknowledged to be a spectrum that includes psychogenic features. Electromyography has been the diagnostic tool most commonly used in the literature. METHODS: To test if we could perform a noninvasive technique to delineate the diaphragm as the source of abnormal movements and demonstrate distractibility and entrainability, we used B-mode ultrasound in a patient with diaphragmatic myoclonus. RESULTS: Ultrasound imaging clearly delineated the diaphragm as the source of her abdominal movements. We were able to demonstrate entrainability of the diaphragm to hand tapping to a prescribed rhythm set by examiner. CONCLUSION: We recommend the use of ultrasound as a noninvasive, convenient diagnostic tool for further studies of diaphragmatic myoclonus. We agree with previous findings that diaphragmatic myoclonus may be a functional movement disorder, as evidenced by distractibility and entrainability demonstrated on real-time video with ultrasonography.

Temporal discrimination threshold with healthy aging.

The temporal discrimination threshold (TDT) is the shortest interstimulus interval at which a subject can perceive successive stimuli as separate. To investigate the effects of aging on TDT, we studied tactile TDT using the method of limits with 120% of sensory threshold in each hand for each of 100 healthy volunteers, equally divided among men and women, across 10 age groups, from 18 to 79 years. Linear regression analysis showed that age was significantly related to left-hand mean, right-hand mean, and mean of 2 hands with R-square equal to 0.08, 0.164, and 0.132, respectively. Reliability analysis indicated that the 3 measures had fair-to-good reliability (intraclass correlation coefficient: 0.4-0.8). We conclude that TDT is affected by age and has fair-to-good reproducibility using our technique.

FDA Regulation of Neurological and Physical Medicine Devices: Access to Safe and Effective Neurotechnologies for All Americans.

The United States Food and Drug Administration (FDA) ensures that patients in the U.S. have access to safe and effective medical devices. The Division of Neurological and Physical Medicine Devices reviews medical technologies that interface with the nervous system. This article addresses how to navigate the FDA's regulatory landscape to successfully bring medical devices to patients.

Intraoperative neurophysiology in deep brain surgery for psychogenic dystonia.

Psychogenic dystonia is a challenging entity to diagnose and treat because little is known about its pathophysiology. We describe two cases of psychogenic dystonia who underwent deep brain stimulation when thought to have organic dystonia. The intraoperative microelectrode recordings in globus pallidus internus were retrospectively compared with those of five patients with known DYT1 dystonia using spontaneous discharge parameters of rate and bursting, as well as movement-related discharges. Our data suggest that simple intraoperative neurophysiology measures in single subjects do not differentiate psychogenic dystonia from DYT1 dystonia.

Clinical Response to IncobotulinumtoxinA, after Demonstrated Loss of Clinical Response to OnabotulinumtoxinA and RimabotulininumtoxinB in a Patient with Musician's Dystonia.

Botulinum toxin is a mainstay therapy for dystonia. Formulations available are three types of botulinumtoxinA and one type of botulinumtoxinB.1 Antibodies can develop against the toxin, leading to treatment failure. IncobotulinumtoxinA (Xeomin; Merz Pharmaceuticals GmbH, Frankfurt, Germany) is differentiated from other types of botulinumtoxinA preparations by being free from complexing proteins, speculated to make the product less antigenic.2.

Progressive personality and language changes in a 62-year-old woman.

A 62-year-old woman with no known psychiatric illness had a 1.5-year history of progressive personality and language changes, leading to a loss of functional independence. Laboratory results revealed elevated autoimmune antibodies. She did not improve on high-dose steroid therapy and continued to deteriorate to her death, 2.5 years after symptom onset.