Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice.

OBJECTIVE: To explore whether the utility of neurofilament light chain (NfL), as a biomarker to aid amyotrophic lateral sclerosis (ALS) therapy development, would be enhanced by obtaining formal qualification from the US Food and Drug Administration for a defined context-of-use. METHODS: Consensus discussion among academic, industry, and patient advocacy group representatives. RESULTS: A wealth of scientific evidence supports the use of NfL as a prognostic, response, and potential safety biomarker in the broad ALS population, and as a risk/susceptibility biomarker among the subset of SOD1 pathogenic variant carriers. Although NfL has not yet been formally qualified for any of these contexts-of-use, the US Food and Drug Administration has provided accelerated approval for an SOD1-lowering antisense oligonucleotide, based partially on the recognition that a reduction in NfL is reasonably likely to predict a clinical benefit. INTERPRETATION: The increasing incorporation of NfL into ALS therapy development plans provides evidence that its utility-as a prognostic, response, risk/susceptibility, and/or safety biomarker-is already widely accepted by the community. The willingness of the US Food and Drug Administration to base regulatory decisions on rigorous peer-reviewed data-absent formal qualification, leads us to conclude that formal qualification, despite some benefits, is not essential for ongoing and future use of NfL as a tool to aid ALS therapy development. Although the balance of considerations for and against seeking NfL biomarker qualification will undoubtedly vary across different diseases and contexts-of-use, the robustness of the published data and careful deliberations of the ALS community may offer valuable insights for other disease communities grappling with the same issues. ANN NEUROL 2024;95:211-216.

Batoclimab as induction and maintenance therapy in patients with myasthenia gravis: rationale and study design of a phase 3 clinical trial.

Introduction: Batoclimab, a fully human monoclonal antibody that inhibits the neonatal fragment crystallisable receptor, has shown promising phase 2 clinical trial results in patients with generalised myasthenia gravis (gMG). Methods and analysis: In this phase 3, randomised, quadruple-blind, placebo-controlled study, adults with gMG will be randomised 1:1:1 to induction therapy with batoclimab 680 mg, batoclimab 340 mg, or placebo, administered once weekly (QW) for 12 weeks as a subcutaneous injection. The primary endpoint is the change from baseline to week 12 on the Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Batoclimab-treated patients achieving a ≥2-point improvement from baseline on MG-ADL at week 10 or week 12 will be re-randomised to maintenance treatment with batoclimab 340 mg QW, batoclimab 340 mg every other week (Q2W), or placebo for 12 weeks; batoclimab-treated patients with a <2-point improvement at week 10 and week 12 will be switched to placebo for the maintenance period and discontinued thereafter. Placebo-treated patients from the induction period will be re-randomised to batoclimab 340 mg QW or Q2W in the maintenance period. All patients who complete the maintenance period and achieve a ≥2-point improvement from baseline in MG-ADL during ≥1 of the final 2 visits of the induction and/or maintenance periods will continue their current batoclimab dose (or switch to batoclimab 340 mg QW for those on placebo) for a 52-week long-term extension (LTE-1). Patients who complete LTE-1 may enter a second, optional 52-week LTE (LTE-2). Ethics and dissemination: This trial is being conducted in accordance with the International Council for Harmonisation Guideline for Good Clinical Practice, the Declaration of Helsinki, and each site's Institutional Review Board/Independent Ethics Committee. All patients must provide written informed consent. Results from this study will be published in peer-reviewed journals and presented at national and global conferences. Trial registration number: NCT05403541.

Blepharoclonus in Parkinsonism.

Background and Objectives: In clinical practice, we have observed that patients with Parkinson disease (PD) often have blepharoclonus, but its prevalence is not well described in the literature. Understanding the relative frequencies of blepharoclonus in PD and atypical parkinsonian syndromes may shed light on the diagnostic utility of this clinical sign. We aimed to assess (1) the frequency of blepharoclonus in patients with PD in a single-center cohort; (2) the association of blepharoclonus with disease stage, tremor severity, and non-motor symptoms; and (3) the frequency of blepharoclonus in synucleinopathy vs non-synucleinopathy-associated parkinsonism. Methods: We prospectively enrolled 85 patients, 75 with PD and 10 with atypical parkinsonism. Blepharoclonus was considered present if eyelid fluttering was sustained for >5 seconds after gentle eye closure. For each patient, demographics were collected, and we completed selected questions from the MDS-UPDRS (Unified Parkinson's Disease Rating Scale) part 2, REM Sleep Behavior Disorder Questionnaire, and MDS-UPDRS part 3 tremor assessments and recorded the presence/absence of dyskinesia. Results: 63 of 75 patients with PD (84%) had blepharoclonus. Among the 10 patients with atypical parkinsonism, 5 had synucleinopathy syndromes. Blepharoclonus was present in 3 of 5 patients with synucleinopathy and 0 of 5 patients with non-synucleinopathy-associated parkinsonian syndromes. Discussion: Blepharoclonus is prevalent in our PD cohort, suggesting possible utility as a clinical marker for PD. The absence of blepharoclonus in a patient with parkinsonism may suggest a non-synucleinopathy (e.g., tauopathy). Analysis of a larger cohort of both PD and atypical parkinsonism would be needed to establish whether blepharoclonus distinguishes PD from atypical parkinsonism, or synucleinopathy from non-synucleinopathy.

Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Survey.

BACKGROUND: With more than 103 million cases and 1.1 million deaths, the COVID-19 pandemic has had devastating consequences for the health system and the well-being of the entire US population. The Rare Diseases Clinical Research Network funded by the National Institutes of Health was strategically positioned to study the impact of the pandemic on the large, vulnerable population of people living with rare diseases (RDs). OBJECTIVE: This study was designed to describe the characteristics of COVID-19 in the RD population, determine whether patient subgroups experienced increased occurrence or severity of infection and whether the pandemic changed RD symptoms and treatment, and understand the broader impact on respondents and their families. METHODS: US residents who had an RD and were <90 years old completed a web-based survey investigating self-reported COVID-19 infection, pandemic-related changes in RD symptoms and medications, access to care, and psychological impact on self and family. We estimated the incidence of self-reported COVID-19 and compared it with that in the US population; evaluated the frequency of COVID-19 symptoms according to self-reported infection; assessed infection duration, complications and need for hospitalization; assessed the influence of the COVID-19 pandemic on RD symptoms and treatment, and whether the pandemic influenced access to care, special food and nutrition, or demand for professional psychological assistance. RESULTS: Between May 2, 2020, and December 15, 2020, in total, 3413 individuals completed the survey. Most were female (2212/3413, 64.81%), White (3038/3413, 89.01%), and aged ≥25 years (2646/3413, 77.53%). Overall, 80.6% (2751/3413) did not acquire COVID-19, 2.08% (71/3413) acquired it, and 16.58% (566/3413) did not know. Self-reported cases represented an annual incidence rate of 2.2% (95% CI 1.7%-2.8%). COVID-19 cases were more than twice the expected (71 vs 30.3; P<.001). COVID-19 was associated with specific symptoms (loss of taste: odds ratio [OR] 38.9, 95% CI 22.4-67.6, loss of smell: OR 30.6, 95% CI 17.7-53.1) and multiple symptoms (>9 symptoms vs none: OR 82.5, 95% CI 29-234 and 5-9: OR 44.8, 95% CI 18.7-107). Median symptom duration was 16 (IQR 9-30) days. Hospitalization (7/71, 10%) and ventilator support (4/71, 6%) were uncommon. Respondents who acquired COVID-19 reported increased occurrence and severity of RD symptoms and use or dosage of select medications; those who did not acquire COVID-19 reported decreased occurrence and severity of RD symptoms and use of medications; those who did not know had an intermediate pattern. The pandemic made it difficult to access care, receive treatment, get hospitalized, and caused mood changes for respondents and their families. CONCLUSIONS: Self-reported COVID-19 was more frequent than expected and was associated with increased prevalence and severity of RD symptoms and greater use of medications. The pandemic negatively affected access to care and caused mood changes in the respondents and family members. Continued surveillance is necessary.

Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.

BACKGROUND AND OBJECTIVES: The term "ALS Reversal" describes patients who initially meet diagnostic criteria for amyotrophic lateral sclerosis (ALS) or had clinical features most consistent with progressive muscular atrophy (PMA) but subsequently demonstrated substantial and sustained clinical improvement. The objective of this genome-wide association study (GWAS) was to identify correlates of this unusual clinical phenotype. METHODS: Participants were recruited from a previously created database of individuals with the ALS Reversal phenotype. Whole-genome sequencing (WGS) data were compared with ethnicity-matched patients with typically progressive ALS enrolled through the CReATe Consortium's Phenotype-Genotype-Biomarker (PGB) study. These results were replicated using an independent ethnically matched WGS data set from Target ALS. Significant results were further explored with available databases of genetic regulatory markers and expression quantitative trait loci (eQTL) analysis. RESULTS: WGS from 22 participants with documented ALS Reversals was compared with the PGB primary cohort (n = 103) and the Target ALS validation cohort (n = 140). Two genetic loci met predefined criteria for statistical significance (two-sided permutation p ≤ 0.01) and remained plausible after fine-mapping. The lead single nucleotide variant (SNV) from the first locus was rs4242007 (primary cohort GWAS OR = 12.0, 95% CI 4.1 to 34.6), which is in an IGFBP7 intron and is in near-perfect linkage disequilibrium with a SNV in the IGFBP7 promoter region. Both SNVs are associated with decreased frontal cortex IGFBP7 expression in eQTL data sets. Notably, 3 Reversals, but none of the typically progressive individuals (n = 243), were homozygous for rs4242007. The importance of the second locus, located near GRIP1, is uncertain given the absence of an associated effect on nearby gene transcription. DISCUSSION: We found a significant association between the Reversal phenotype and an IGFBP7 noncoding SNV that is associated with IGFBP7 expression. This is biologically relevant as IGFBP7 is a reported inhibitor of the insulin growth factor-1 (IGF-1) receptor that activates the possibly neuroprotective IGF-1 signaling pathway. This finding is limited by small sample size but suggests that there may be merit in further exploration of IGF-1 pathway signaling as a therapeutic mechanism for ALS. TRIAL REGISTRATION INFORMATION: This study was registered with ClinicalTrials.gov (NCT03464903) on March 14, 2018. The first participant was enrolled on June 22, 2018.

Mismatch between clinically defined classification of ALS stage and the burden of cerebral pathology.

This study aimed to investigate the clinical stratification of amyotrophic lateral sclerosis (ALS) patients in relation to in vivo cerebral degeneration. One hundred forty-nine ALS patients and one hundred forty-four healthy controls (HCs) were recruited from the Canadian ALS Neuroimaging Consortium (CALSNIC). Texture analysis was performed on T1-weighted scans to extract the texture feature "autocorrelation" (autoc), an imaging biomarker of cerebral degeneration. Patients were stratified at baseline into early and advanced disease stages based on criteria adapted from ALS clinical trials and the King's College staging system, as well as into slow and fast progressors (disease progression rates, DPR). Patients had increased autoc in the internal capsule. These changes extended beyond the internal capsule in early-stage patients (clinical trial-based criteria), fast progressors, and in advanced-stage patients (King's staging criteria). Longitudinal increases in autoc were observed in the postcentral gyrus, corticospinal tract, posterior cingulate cortex, and putamen; whereas decreases were observed in corpus callosum, caudate, central opercular cortex, and frontotemporal areas. Both longitudinal increases and decreases of autoc were observed in non-overlapping regions within insula and precentral gyrus. Within-criteria comparisons of autoc revealed more pronounced changes at baseline and longitudinally in early- (clinical trial-based criteria) and advanced-stage (King's staging criteria) patients and fast progressors. In summary, comparative patterns of baseline and longitudinal progression in cerebral degeneration are dependent on sub-group selection criteria, with clinical trial-based stratification insufficiently characterizing disease stage based on pathological cerebral burden.

Temporal and spatial progression of microstructural cerebral degeneration in ALS: A multicentre longitudinal diffusion tensor imaging study.

OBJECTIVE: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS. METHODS: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses. RESULTS: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts. CONCLUSIONS: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.

ALSUntangled #73: Lion's Mane.

Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.

The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.

Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study.

BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS. METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed. FINDINGS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator. INTERPRETATION: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS. FUNDING: Biogen.

ALSUntangled #75: Portable neuromodulation stimulator therapy.

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.

Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.