P223 Long-term follow-up of onasemnogene abeparvovec gene therapy in patients with spinal muscular atrophy (SMA) type 1
In the phase 1 trial, START, SMA type 1 patients who received the proposed therapeutic dose of onasemnogene abeparvovec (n=12) demonstrated substantially improved outcomes versus natural history. We evaluated long-term safety and efficacy of onasemnogene abeparvovec for patients with SMA type 1 (biallelic SMN1 mutations/deletions; two SMN2 copies) enrolled in the LT-001 study. The primary objective was to evaluate long-term safety assessed by medical history and record review, physical examination, laboratory evaluation, and pulmonary assessments. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: J. Mendell, M. Wigderson, I. Alecu, L. Yang, L. Mehl, A. Connolly Source Type: research
P224 Effect of apitegromab on motor function at 36 months in patients with nonambulatory spinal muscular atrophy aged 2-12 years old
Neuronal degeneration and muscle atrophy contribute to functional decline in spinal muscular atrophy (SMA). Apitegromab inhibits the pro- and latent forms of myostatin, a negative regulator of skeletal muscle growth, directly targeting muscle atrophy. Improvements in motor function measures were observed with apitegromab in Type 2 and nonambulatory Type 3 SMA receiving nusinersen in the phase 2 TOPAZ study. The aim of the present analysis is to determine the effects of apitegromab (20 mg/kg) on muscle function as measured by HFMSE, RULM, and WHO motor development milestones at 36 months in patients with non-ambulatory SMA ...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: T. Crawford, B. Darras, J. Day, D. De Vivo, E. Mercuri, A. Nascimento, E. Mazzone, TOPAZ Study Team, A. Waugh, G. Song, R. Evans, J. Marantz Source Type: research
P225 Longitudinal changes in compound muscle action potential and their association with motor function in infantile-onset SMA children in ENDEAR/SHINE
Compound muscle action potential (CMAP) is a non-invasive, and simple-to-perform electrophysiological technique that can be used to provide physiologic information about motor units. Understanding the longitudinal changes of CMAP and their association with motor function outcomes in children with Spinal Muscular Atrophy (SMA) can help evaluate CMAP as a potential biomarker for therapeutic effects in SMA. Our analysis included 105 participants with infantile-onset SMA who initiated nusinersen in ENDEAR or long-term extension study SHINE (27 Aug 2019 datacut). (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: C. Sumner, B. Youn, M. Farrar, B. Tichler, Z. Berger, C. Zhu, A. Paradis Source Type: research
VP226 Post-hoc analysis of compound motor action potential from clinical trials of intravenous onasemnogene abeparvovec for spinal muscular atrophy
Spinal muscular atrophy (SMA) is characterized by muscle weakness, and, therefore, the progression of the disease and the potential efficacy of therapies can be evaluated by means of electrophysiologic recordings. The compound motor action potential (CMAP) summarizes muscle fiber action potentials, and it correlates with the degree of motor nerve innervation, making it potentially valuable as an SMA biomarker. CMAP was evaluated in three completed clinical trials of intravenous onasemnogene abeparvovec for patients with SMA type 1 and two copies of the survival motor neuron 2 gene (SMN2): START (NCT02122952), STR1VE (NCT03...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: B. McGill, J. Maca, S. Tauscher-Wisniewski, T. Macek Source Type: research
P227 MANATEE: GYM329 (RO7204239) in combination with Risdiplam treatment in patients with spinal muscular atrophy (SMA)
Risdiplam (EVRYSDI ®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA) in more than 90 countries worldwide. GYM329 is an investigational, recycling and antigen-sweeping monoclonal anti-myostatin a ntibody (myostatin is a negative regulator of skeletal muscle growth). In preclinical studies, the combination of GYM329 with an SMN2 splicing modifier demonstrated improved muscle size and strength compared with SMN2 splicing modifier treatment alone. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: T. Duong, B. Darras, J. Morrow, F. Muntoni, L. Servais, M. Rabbia, M. Gerber, H. Kletzl, E. Gaki, S. Fletcher, R. Scalco, K. Wagner, E. Mercuri Source Type: research
VP228 Post-hoc analyses of prednisolone use and hepatotoxicity in clinical trials of intravenous onasemnogene abeparvovec
Onasemnogene abeparvovec (OA) is a one-time intravenous gene replacement therapy approved for treatment of SMA. Acute serious liver injury, acute liver failure, and aminotransferase elevations can occur with OA and are acknowledged potential risks for OA that may be immune-mediated. Here, we report the findings from post-hoc analyses exploring differences in hepatotoxicity outcomes based on starting dose of 1 vs. 2 mg/kg/day, the time course of prednisolone administration and comparisons to protocol guidelines and shifts in ALT/AST values or other aspects of hepatotoxicity before and during the tapering period. (Source: Ne...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: T. Macek, S. Wen, E. O'Brien, I. Alecu, S. Tauscher-Wisniewski, B. McGill Source Type: research
P229 Adult SMA REACH: a clinical network to standardize the collection of data to enable integrated and longitudinal analysis of clinical and patient-reported data
Adult SMA REACH is a longitudinal observational study collecting clinical data and outcome measures for Spinal Muscular Atrophy (SMA) patients aged ≥16 years with genetically confirmed 5q SMA. The Adult SMAREACH network was set up in alongside SMA REACH UK and the UK SMA Patient Registry. The integration of the three UK SMA databases will advance our understanding of the impact of care and new therapies on the natural history of the disease a nd ensure continuity of data collection throughout transition. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: R Muni Lofra, S. Segovia, T. Elwell, J. Yau, L. Murphy, C. Blewitt, S. Fitzsimmons, C Marini Bettolo, Adult SMA REACH Network Source Type: research
P230 Safety update: Risdiplam clinical trial program for spinal muscular atrophy (SMA)
Risdiplam (EVRYSDI ®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre‑mRNA splicing modifier approved for the treatment of SMA in over 90 countries worldwide. The risdiplam clinical development program consists of four clinical trials: 1) FIREFISH (NCT02913482) in infants wit h Type 1 SMA (inclusion criteria [IC]: aged 1–7 months at enrollment). 2) SUNFISH (NCT02908685) in patients with Types 2/3 SMA (IC: aged 2–25 years at enrollment). 3) JEWELFISH (NCT03032172) in patients with SMA (IC: aged 6 months–60 years at enrollment) who previously received RG7800 (RO68852 47), nusi...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: G. Baranello, C. Chiriboga, L. Servais, B. Darras, J. Day, N. Deconinck, M. Farrar, R. Finkel, E. Bertini, J. Kirschner, M. Rasson, M. Mazurkiewicz-Be łdzińska, D. Vlodavets, S. Bader-Weder, K. Gorni, B. Jaber, W. Yeung, G. Papp, R. Scalco, E. Mercuri, Source Type: research
P231 Early intervention and speed-to-effect in spinal muscular atrophy type 1 following onasemnogene abeparvovec gene replacement therapy
Spinal muscular atrophy (SMA) type 1 is a severe genetic neuromuscular disease that is caused by a defect in the survival motor neuron 1 (SMN1) gene, and that leads to rapid deterioration of motor neurons when left untreated. Onasemnogene abeparvovec is a one-time gene replacement therapy approved for treatment of SMA. Durable efficacy has been demonstrated in clinical trials and long-term follow-up studies. Here, we highlight the speed of post-treatment effect of onasemnogene abeparvovec. We assessed the early post-treatment impact of onasemnogene abeparvovec on motor function in symptomatic infants with SMA type 1, as me...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: W. Toro, S. Reyna, S. Ritter, A. Patel, N. Mumneh, O. Dabbous Source Type: research
P232 Bioavailability and bioequivalence of Risdiplam tablets in healthy volunteers
Risdiplam (EVRYSDI ®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA) in over 90 countries worldwide. Currently, risdiplam is administered as an oral solution, which provides flexibility for tail oring the dosing regimen in paediatric patients. However, all patients with a body weight ≥20 kg receive a 5 mg dose. The oral solution is constituted from powder by a pharmacist and, for a dose of 5 mg, a volume of 6.6 mL has to be drawn up in an oral syringe by the patient or their caregiver eve ry day. (...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: H. Kletzl, K. Heinig, B. Jaber, B. Lomeli, W. Yeung, A. Young, H. Coleman, D. Morrison Source Type: research
P233 Zolgensma in spinal muscular atrophy: a Toronto paediatric hospital experience
Spinal muscular atrophy (SMA) is a neuromuscular disorder that is characterized by loss of motor neurons leading to progressive muscle weakness and atrophy. SMA is a lifelong disorder that impacts a person's quality of life and leads to significant morbidity and mortality. Since the addition of SMA on Newborn Screening programs, healthcare professionals have been able to intervene and provide therapies to infants prior to symptom onset of SMA. A favourable approach to therapy is Zolgensma, a one-time gene therapy approved for the treatment of SMA in Ontario to newborns who are 6 months of age or less. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: E. Nigro, H. Gonorazky Source Type: research
P234 Effect of Apitegromab on pedi-cat and promis-fatigue questionnaire at 36-months in patients with spinal muscular atrophy
Spinal muscular atrophy (SMA) is characterized by neuronal degeneration and muscle atrophy. Apitegromab inhibits the pro- and latent forms of myostatin, a negative regulator of skeletal muscle growth and is being investigated in SMA, directly targeting muscle atrophy. The TOPAZ Phase 2 study of apitegromab showed improvements in muscle function and PEDI-CAT and PROMIS measures in patients with SMA Type 2 and nonambulatory Type 3, suggesting the potential of restoring muscle strength to improve patient/caregiver reported outcomes. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: T. Crawford, B. Darras, J. Day, J. Krueger, E. Mercuri, A. Nascimento, A. Pasternak, T. Duong, Topaz Study Team, L. Liu, M. Sadanowicz, S. Baver Source Type: research
P319 Histopathological features and autophagy aspects of Ku+ myositis
Ku+ myositis is one of the rarer forms of myositis, with antibodies that are associated with many forms of connective tissue disease and the clinical picture of the patients often varies. A few histopathological examinations have shown a broad picture with inflammatory or necrotizing aspects, but a precise description and characterization of Ku+ myositis is still lacking. Therefore, the aim of this study was to perform a detailed histopathological and transcriptional examination of muscle samples from Ku+ patients with myositis to uncover possible pathophysiological mechanisms/commonalities. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: C. Preusse, M. Holzer, U. Schneider, A. Sch änzer, S. Léonard-Louis, O. Benveniste, J. Weis, K. Claeys, B. Schoser, F. Montagnese, A. Uruha, M. Huber, L. Gallay, N. Streichenberger, K. Mrusche, W. Stenzel Tags: MYOSITIS Source Type: research
P320 VMA21 conditional knockout mice model XMEA with myopathy and dysfunctional autophagy
X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive disorder caused by mutations in the vacuolar membrane ATPase activity 21 (VMA21) gene, which is necessary for vacuolar ATPase assembly in the lysosomal lumen. This defect leads to de-acidified lysosomes and vacuolar pathology. XMEA affects only males, with females being carriers. At present, no mouse models of XMEA have been reported. We generated VMA21 floxed mice using CRISPR/Cas9. These mice were crossed to mice expressing CreERT2 under an HSA promoter to generate VMA21 muscle-specific knockout mice. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: M. Inoue, S. Pittman, A. Findlay, C. Weihl Source Type: research
P321 Exploring hand and upper limb function in patients with inclusion body myositis
This study describes functional hand impairments as measured by performance-based outcome measures in a cross-sectional sample of 74 patients with IBM. Subjects completed a series of outcome measures (Functional Dexterity Test (FDT), Performance of the Upper Limb (PUL), and Sollerman Hand Function Test (SHFT)) alongside a collection of patient reported outcomes (PROs). (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: S. Hunn, L. Alfano, M. Seiffert, C. Weihl Source Type: research
