Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study

INTRODUCTION: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. METHODS: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. RESULTS: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. CONCLUSIONS: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients

Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study

Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. Methods: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. Results: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. Conclusions: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients

The Differing Effects of Sleep on Ictal and Interictal Network Dynamics in Drug‐Resistant Epilepsy

Objective: Sleep has important influences on focal interictal epileptiform discharges (IEDs), and the rates and spatial extent of IEDs are increased in non‐rapid eye movement (NREM) sleep. In contrast, the influence of sleep on seizures is less clear, and its effects on seizure topography are poorly documented. We evaluated the influences of NREM sleep on ictal spatiotemporal dynamics and contrasted these with interictal network dynamics. Methods: We included patients with drug‐resistant focal epilepsy who underwent continuous intracranial electroencephalography (iEEG) with depth electrodes. Patients were selected if they had 1 to 3 seizures from each vigilance state, wakefulness and NREM sleep, within a 48‐hour window, and under the same antiseizure medication. A 10‐minute epoch of the interictal iEEG was selected per state, and IEDs were detected automatically. A total of 25 patients (13 women; aged 32.5 ± 7.1 years) were included. Results: The seizure onset pattern, duration, spatiotemporal propagation, and latency of ictal high‐frequency activity did not differ significantly between wakefulness and NREM sleep (all p > 0.05). In contrast, IED rates and spatial distribution were increased in NREM compared with wakefulness (p < 0.001, Cliff's d = 0.48 and 0.49). The spatial overlap between vigilance states was higher for seizures (57.1 ± 40.1%) than IEDs (41.7 ± 46.2%; p = 0.001, Cliff's d = 0.51). Interpretation: In contrast to its effects on IEDs, NREM sleep does not affect ictal spatiotemporal dynamics. This suggests that once the brain surpasses the seizure threshold, it will follow the underlying epileptic network irrespective of the vigilance state. These findings offer valuable insights into neural network dynamics in epilepsy and have important clinical implications for localizing seizure foci

A spatial perturbation framework to validate implantation of the epileptogenic zone

Abstract Stereo-electroencephalography (SEEG) is the gold standard to delineate surgical targets in focal drug-resistant epilepsy. SEEG uses electrodes placed directly into the brain to identify the seizure-onset zone (SOZ). However, its major constraint is limited brain coverage, potentially leading to misidentification of the ‘true’ SOZ. Here, we propose a framework to assess adequate SEEG sampling by coupling epileptic biomarkers with their spatial distribution and measuring the system’s response to a perturbation of this coupling. We demonstrate that the system’s response is strongest in well-sampled patients when virtually removing the measured SOZ. We then introduce the spatial perturbation map, a tool that enables qualitative assessment of the implantation coverage. Probability modelling reveals a higher likelihood of well-implanted SOZs in seizure-free patients or non-seizure free patients with incomplete SOZ resections, compared to non-seizure-free patients with complete resections. This highlights the framework’s value in sparing patients from unsuccessful surgeries resulting from poor SEEG coverage

Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial.

BACKGROUND Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. METHODS FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. FINDINGS Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0·0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%). INTERPRETATION Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam. FUNDING F Hoffmann-La Roche

Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy

International audienceObjective: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU.Methods: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study.Results: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment.Interpretation: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam

Isolation and characterization of the novel Popeye gene family expressed in skeletal muscle and heart

Andree B, Hillemann T, Kessler-Icekson G, et al. Isolation and characterization of the novel Popeye gene family expressed in skeletal muscle and heart. DEVELOPMENTAL BIOLOGY. 2000;223(2):371-382.We identified a novel gene family in vertebrates which is preferentially expressed in developing and adult striated muscle. Three genes of the Popeye (POP) family were detected in human and mouse and two in chicken. Chromosomal mapping indicates that Pop1 and Pop3 genes are clustered on mouse chromosome 10, whereas Pop2 maps to mouse chromosome 16. We found evidence that POP1 and POP3 in chicken may also be linked and multiple transcript isoforms are generated from this locus. The POP genes encode proteins with three potential transmembrane domains that are conserved in all family members. Individual POP genes exhibit specific expression patterns during development and postnatally. Chicken POP3 and mouse Pop1 are first preferentially expressed in atrium and later also in the subepicardial compact layer of the ventricles. Chicken POP1 and mouse Pop2 are expressed in the entire heart except the outflow tract. All three Pop genes are expressed in heart and skeletal muscle of the adult mouse and lower in lung. Pop1 and Pop2 expression is upregulated in uterus of pregnant mice. Like the mouse genes, human POP genes are predominantly expressed in skeletal and cardiac muscle. The strong conservation of POP genes during evolution and their preferential expression in heart and skeletal muscle suggest that these novel proteins may have an important function in these tissues in vertebrates. (C) 2000 Academic Press

A prospective international Aspergillus terreus survey: An EFISG, ISHAM and ECMM joint study

Objectives: A prospective international multicentre surveillance study was conducted to investigate the prevalence and amphotericin B susceptibility of Aspergillus terreus species complex infections. Methods: A total of 370 cases from 21 countries were evaluated. Results: The overall prevalence of A. terreus species complex among the investigated patients with mould-positive cultures was 5.2% (370/7116). Amphotericin B MICs ranged from 0.125 to 32 mg/L, (median 8 mg/L). Conclusions: Aspergillus terreus species complex infections cause a wide spectrum of aspergillosis and the majority of cryptic species display high amphotericin B MICs.Fil: Risslegger, Brigitte. Universidad de Innsbruck; AustriaFil: Zoran, Tamara. Universidad de Innsbruck; AustriaFil: Lackner, Michaela. Universidad de Innsbruck; AustriaFil: Aigner, María. Universidad de Innsbruck; AustriaFil: Sanchez Reus, Ferrán. Hospital de la Santa Creu I Sant Pau; EspañaFil: Rezusta, Antonio. Universidad de Zaragoza; EspañaFil: Chowdhary, Anuradha. University of Delhi; IndiaFil: Alcacer Sanchez, Juan Manuel. Hospital de la Santa Creu I Sant Pau;Fil: Taj Aldeen, Saad Jaber. Hamad Medical Corporation; QatarFil: Arendrup, Maiken C.. Universidad de Copenhagen; DinamarcaFil: Oliveri, Salvatore. Università degli Studi di Catania; ItaliaFil: Kontoyiannis, Dimitrios P.. The University of Texas MD Anderson Cancer Center; Estados UnidosFil: Alastruey Izquierdo, Ana. Universidad Carlos III de Madrid. Instituto de Salud; EspañaFil: Lagrou, Katrien. Katholikie Universiteit Leuven; BélgicaFil: Lo Cascio, Giuliana. Azienda Ospedaliera Universitaria Integrata; ItaliaFil: Meis, Jacques F.. Canisius Wilhelmina Hospital; Países BajosFil: Buzina, Walter. Medical University of Graz; AustriaFil: Farina, Claudio. ASST Papa Giovanni XXIII. Microbiology Institute; ItaliaFil: Drogari Apiranthitou, Miranda. Universidad Nacional y Kapodistriaca de Atenas; GreciaFil: Grancini, Anna. Cà Granda Ospedale Maggiore Policlinico; ItaliaFil: Tortorano, Anna Maria. Università degli Studi di Milano; ItaliaFil: Willinger, Birgit. Universidad de Viena; AustriaFil: Hamprecht, Axel. Universitat Zu Köln; AlemaniaFil: Johnson, Elizabeth. Public Health England. Mycology Reference Laboratory; Reino UnidoFil: Klingspor, Lena. Karolinska Huddinge Hospital; SueciaFil: Arsic Arsenijevic, Valentina. University of Belgrade; SerbiaFil: Cornely, Oliver A.. Universitat Zu Köln; AlemaniaFil: Meletiadis, Joseph. Universidad Nacional y Kapodistriaca de Atenas; GreciaFil: Prammer, Wolfgang. Klinikum Wels-Grieskirchen; AustriaFil: Tullio, Vivian. Università di Torino; ItaliaFil: Vehreschild, Jörg Janne. Universitat Bonn; Alemania. Universitat Zu Köln; AlemaniaFil: Trovato, Laura. Università degli Studi di Catania; ItaliaFil: Lewis, Russell E.. Universidad de Bologna; ItaliaFil: Segal, Esther. Tel Aviv University; IsraelFil: Rath, Peter Michael. Universitat Essen; AlemaniaFil: Hamal, Petr. Universtity Hospital Olomouc; República Checa. Palacky University Olomouc; República ChecaFil: Rodríguez Iglesias, Manuel. Universidad de Cádiz; EspañaFil: Roilides, Emmanuel. Aristotle University School of Health Sciences; GreciaFil: Arikan Akdagli, Sevtap. Hacettepe University; TurquíaFil: Chakrabarti, Arunaloke. Postgraduate Institute of Medical Education and Research; IndiaFil: Colombo, Arnaldo L.. Universidade Federal de Sao Paulo; BrasilFil: Fernández, Mariana Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Martin Gomez, M. Teresa. Vall d’Hebron University Hospital; EspañaFil: Badali, Hamid. Mazandaran University of Medical Sciences; IránFil: Petrikkos, Georgios. European University Cyprus; ChipreFil: Klimko, Nikolai. North Western State Medical University; RusiaFil: Heimann, Sebastian M.. Universitat Zu Köln; AlemaniaFil: Houbraken, Jos. Fungal Biodiversity Centre; Países BajosFil: Uzun, Omrum. Hacettepe University Medical School; TurquíaFil: Edlinger, Michael. Universidad de Innsbruck; AustriaFil: de la Fuente, Sonia. Hospital Ernest Lluch Martin; EspañaFil: Lass Flörl, Cornelia. Universidad de Innsbruck; Austri

Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study

Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types&nbsp;1–3 SMA. Here, an analysis was performed after all patients had received at least 1&nbsp;year of treatment with risdiplam. Methods: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6&nbsp;months and 60&nbsp;years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2&nbsp;years of treatment. Results: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0&nbsp;years (1–60&nbsp;years) and 39.1&nbsp;kg (9.2–108.9&nbsp;kg), respectively. About 63% of patients aged 2–60&nbsp;years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale–Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. Conclusions: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients