Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA).
Non-ambulatory individuals, aged 18 years or older ...with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1-C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology compound muscle action potential (CMAP), single motor unit size, and motor unit number were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded.
Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21-64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable.
Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.
Objective:
To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical ...function, and motor unit physiology.
Methods:
Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment.
Results:
Six women, seven men (mean age: 37 ± 11, range: 18–59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable.
Conclusions:
Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring
via
improved motor unit reinnervation capacity.
Objective
To test the hypotheses that decomposition electromyography (dEMG) motor unit action potential (MUAP) amplitude and firing rate are altered in SMA; dEMG parameters are associated with ...strength and function; dEMG parameters are correlated with traditional electrophysiological assessments.
Methods
Ambulatory and non‐ambulatory adults with SMA on nusinersen and healthy controls were enrolled. MUAPs were decomposed from multielectrode surface recordings during 30‐s maximum contraction of the abductor digiti minimi (ADM). Isometric strength, upper limb function, patient‐reported function, and standard electrophysiologic measures of the ADM (compound muscle action potential CMAP, single motor unit potential SMUP, motor unit number estimation MUNE) were collected.
Results
dEMG MUAP amplitudes were higher in ambulatory versus control and non‐ambulatory groups and were higher in controls versus non‐ambulatory SMA. In contrast, dEMG firing rates were higher in ambulatory versus non‐ambulatory and control groups but similar between non‐ambulatory and control. dEMG parameters showed moderate to strong positive correlation with strength and function whereas CMAP and MUNE better correlated with function than strength. SMUP did not correlate with strength, function, or dEMG MUAP amplitude. dEMG parameters show overall good test–retest reliability.
Interpretation
dEMG provided reliable, noninvasive measure of MUAP amplitude size and firing rate and revealed divergent patterns across disease severity in adults with SMA. Firing rate enhancement, as seen in milder SMA, may provide a therapeutic avenue for improving function in more severe SMA, where firing rates appear preserved. MUAP amplitude size and firing rate, quantified with dEMG, may be promising monitoring biomarker candidates for noninvasive assessment of SMA.
ObjectiveSpinal muscular atrophy (SMA) is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. Prior work in models and patients has demonstrated electrophysiological ...and morphological defects at the neuromuscular junction (NMJ). Therapeutic development has resulted in clinically available therapies to increase SMN protein levels in patients and improve muscle function. Here we aimed to investigate the effect of SMN restoration (via nusinersen) on NMJ transmission in adults with SMA.MethodsParticipants undergoing nusinersen treatment underwent 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve to assess compound muscle action potential amplitude decrement. Maximum voluntary isometric contraction (MVICT), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT) were assessed for correlations with decrement.ResultsData from 13 ambulatory (7 men/6 women, mean age 40±11 years) and 11 non-ambulatory (3 men/8 women, mean age 38±12 years) participants were analysed. Cross-sectional analyses of RNS decrement were similar at 14 months of nusinersen (−14.2%±11.5%, n=17) vs baseline (−11.9%±8.3%, n=15) (unpaired t-test, p=0.5202). Longitudinal comparison of decrement in eight participants showed no change at 14 months (−13.9%±6.7%) vs baseline (−16.9%±13.4%) (paired t-test, p=0.5863). Decrement showed strong correlations with measures of MVICT, RULM and 6MWT but not age or disease duration.ConclusionAdults with SMA had significant NMJ transmission defects that were not corrected with 14 months of nusinersen treatment. NMJ defects were negatively associated with physical function, and thus may represent a promising target for additive or combinatorial treatments.
Amyotrophic lateral sclerosis (ALS) is a degenerative disease that progressively destroys motor neurons (MNs). Earlier studies identified EphA4, a receptor tyrosine kinase, as a possible ...disease-modifying gene. The complex interplay between the EphA4 receptor and its ephrin ligands in motor neurons and astrocytes has not yet been fully elucidated and includes a putative pro-apoptotic activity of the unbound receptor compared to ephrin-bound receptor. We recently reported that astrocytes from patients with ALS induce cell death in co-cultured MNs. Here we found that first-generation synthetic EphA4 agonistic agent 123C4, effectively protected MNs when co-cultured with reactive astrocytes from patients with ALS from multiple subgroups (sALS and mutant SOD1). Newer generation and more potent EphA4 agonistic agents 150D4, 150E8, and 150E7 provided effective protection at a lower therapeutic dose. Combined, the data suggest that the development of EphA4 agonistic agents provides potentially a promising therapeutic strategy for patients with ALS.
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•We report on potent and selective EphA4 agents targeting its ligand-binding domain•We used a method that generates neuronal progenitor cells from patient fibroblasts•The agents reverse motor neuron cell death are cellular models of patients with ALS•Our EphA4 agonists can effectively prevent astrocyte-mediated motor neuron toxicity
Medical biochemistry; Molecular biology; Neuroscience
To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history ...of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.
A phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.
Of the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.
Efgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.
This study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.
Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This ...approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in neurology. Here, we describe a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS, with the goal of rapidly identifying novel treatments, biomarkers, and trial endpoints. ANN NEUROL 2022;91:165–175
Introduction/Aims
The Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) was first developed as a secondary functional outcome measure to detect changes over time in patients with spinal ...muscular atrophy (SMA) in clinical trials. Its modified version evaluates 10 activities of daily living. The aim of the study was to analyze modified SMAFRS data using item response theory psychometric models.
Methods
A total of 253 responses from 41 adult patients with ambulatory and non‐ambulatory SMA types 2, 3, and 4 were analyzed. Rasch analysis was used to explore item‐person targeting, fit statistics, category response functioning, dimensionality, and differential item functioning.
Results
Most items had good fitting with the exception of “toileting” and “respiratory.” There were no major floor or ceiling effects, and most items covered a good range of disability with only a negligible breech of uni‐dimensionality from eating, dressing, and respiratory items. Differential item function highlighted differences in toileting, turning, transferring, walking, and respiratory items between ambulatory and non‐ambulatory populations.
Discussion
Despite subtle misfitting of certain items, mainly related to respiratory and bulbar function, overall modified SMAFRS remained a psychometrically stable and unidimensional outcome measure. There were some differences in measuring properties of certain functional items between ambulatory and non‐ambulatory items that need to be taken into consideration in clinical trial design. Overall, the modified SMAFRS is a psychometrically reliable tool in assessment of adult patients with SMA.
Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately ...reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types. Thus, this methodology can facilitate compound testing in a diverse genetic background resulting in a more representative population for therapeutic evaluation. Here, we used established co‐culture assays with motor neurons and reprogrammed patient skin‐derived astrocytes (iAs) to evaluate the effects of (SP‐4‐2)‐2,2’‐(1,2‐dimethyl‐1,2‐ethanediylidene)bisN‐methylhydrazinecarbothioamidato‐κN2,κS(2‐)‐copper (CuATSM), currently in clinical trial for ALS in Australia. Pretreatment of iAs with CuATSM had a differential effect on neuronal survival following co‐culture with healthy motor neurons. Using this assay, we identified responding and non‐responding cell lines for both sporadic and familial ALS (mutant SOD1 and C9ORF72). Importantly, elevated mitochondrial respiration was the common denominator in all CuATSM‐responders, a metabolic phenotype not observed in non‐responders. Pre‐treatment of iAs with CuATSM restored mitochondrial activity to levels comparable to healthy controls. Hence, this metabolic parameter might allow selection of patient subpopulations best suited for CuATSM treatment. Moreover, CuATSM might have additional therapeutic value for mitochondrial disorders. Enhanced understanding of patient‐specific cellular and molecular profiles could help improve clinical trial design in the future.
Main Points
The clinical stage drug CuATSM normalizes aberrant metabolic phenotypes of ALS astrocytes and restores support towards neurons.
Patient samples could be stratified based on this phenotype, indicating that the model system might support clinical trial result interpretation or design.
Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat ...shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis.
This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed.
Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 76% male and 36 24% female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 77% and 70 90%, respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (–3·26, 95% CI –4·15 to –2·36 in the arimoclomol group vs –2·26, –3·11 to –1·41 in the placebo group; mean difference –0·99 95% CI –2·23 to 0·24; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group.
Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design.
US Food and Drug Administration Office of Orphan Products Development and Orphazyme.
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