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ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS. CAPTURE ALS: the comprehensive analysis platform to understand, remedy and eliminate ALS. [Extracted from the article]

Abstract Mechanical hyperalgesia is a clinically-relevant form of pain sensitization that develops through largely unknown mechanisms. TRPA1, a Transient Receptor Potential ion channel, is a sensor of pungent chemicals that may play a role in acute noxious mechanosensation and cold thermosensation. We have developed a specific small molecule TRPA1 inhibitor (AP18) that can reduce cinnameldehyde-induced nociception in vivo. Interestingly, AP18 is capable of reversing CFA-induced mechanical hyperalgesia in mice. Although TRPA1-deficient mice develop normal CFA-induced hyperalgeisa, AP18 is ineffective in the knockout mice, consistent with an on-target mechanism. Therefore, TRPA1 plays a role in sensitization of nociception, and that compensation in TRPA1-deficient mice masks this requirement.

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., Competing Interests: Declaration of interests MB reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association; as well as consulting fees from Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and UniQure. The University of Miami licensed some of MB's research data to Biogen to aid in the design of the ATLAS trial; MB receives a royalty payment received by the University of Miami as part of this licensing agreement. DR received consulting fees from Orphazyme for biostatistical consulting services for the ORARIALS-01 protocol. LHvdB reports consulting fees from Amylyx, Biogen, Ferrer, Corcept, Orion, and Orphazyme, as well as payment for scientific advisory board activities from Takeda. AC reports grants from the Italian Ministry of Health, the Italian Ministry of University and Research, the European Commission, Biogen, and the ALS Association; as well as consulting fees from Mitsubishi Tanabe, Biogen, Roche, Sanofi, Denali Pharma, Cytokinetics, Eli Lilly, and Amylyx Pharmaceuticals; he has received a research grant from Biogen. PMA report grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Ulla-Carin Lindquist Foundation, NEURO, the Brain Foundation, and the European Commission; as well as consulting fees from Biogen, Avrion, Arrowhead, Regeneron, uniQure, Orphazyme, and Roche. P-FP reports meeting and travel support from Orphazyme. PVD reports grant from CSL Behring; speakers fees from Biogen and Amylyx; and participation in advisory boards for Biogen, CSL Behring, Alexion Pharmaceuticals, Ferrer, QurAlis, Cytokinetics, Argenx, UCB, Muna Therapeutics, Alector, Augustine Therapeutics, and VectorY. SP reports grants from Cytokinetics, Biogen, and Roche; consulting fees from Cytokinetics, Amylyx, Biogen, Roche, and Zambon; payment or honoraria from Biogen, Zambon, Roche, Amylyx, Italfarmaco, and Desitin; meeting and travel support from Biogen, Desitin, Zambon, Amylyx, Italfarmaco, PTC Therapeutics, and Ferrer; and participation in data safety monitoring boards or advisory boards for ORION Pharma, Amylyx, Biogen, Roche, and Zambon. SL reports consulting fees from Biogen and Amylyx; and participation in a data safety monitoring board (chair) for Neurosense Therapeutics. NAG reports grants from Abcuro, Amylyx, Alexion, Annelixis, Annexon, Brainstorm Cell Therapeutics, Calico, Cytokinetics, Fulcrum, Healey, Janssen, Kezar, Medicinova, MT Pharma, Octapharma, PTC, Sanofi, and Transposon; consulting fees from Abcuro, Alexion, Amylyx, Annexon, Argenx, Astrazeneca, CSL Behring, Fulcrum, Kezar, MT Pharma, Sanofi Genzyme, Sarepta, and UCB; and speakers fees from Argenx and CSL. CQ reports grants from Sanofi, Biogen, and Amylyx; consultant fees from Amylyx and Biogen; and honoraria from Seattle Science Foundation. AG reports consulting fees from Medtronic, Atlantic Research Group, Calico, Apellis, Anexon, ALS Pharmaceuticals, QurAlis, Orion, Sanofi Genzyme, Ionis, Wave Life Therapies, Anelixis, Roche, Cytokinetics, Mitsubishi Tanabe Pharma, Amylyx, Alexion, UCB, Ra Pharmaceuticals (now UCB Biosciences), Biogen, Eli Lilly, and Amicus Therapeutics; support for attending meetings and travel from Amylyx, Mitsubishi Tanabe Pharma, QurAlis, Alexion, and ALS Pharmaceuticals; has a leadership role in ALS Canada; has stock or stock options in QurAlis; and has received equipment, materials, drugs, medical writing, gifts or other services from Amylyx. LZ reports grants from ALS Canada, Amylyx, Biogen, and Mitsubishi Tanabe Pharma; consulting fees from Amylyx, Cytokinetics, Mitsubishi Tanabe Pharma, Neurosense, and Biogen; and participation in a data safety monitoring board (chair) for Amylyx. CS reports speakers fees from Mitsubishi Tanabe Pharma Canada; participation in an advisory board for Biogen; and unpaid roles in Canadian ALS Research Consortium and Scientific Medical Advisory Board for ALS Canada. CN received compensation for consultant fees and training activities by Biogen, Roche, Genzyme, and Mitsubishi Tanabe. JMS reports grants from NINDS, ALS Association, AB Sciences, Acorda Therapeutics, Alector, Amylyx, Biogen, Cytokinetics Incorporated, Ionis, Mitsubishi Tanabe Pharma America, Quralis, PTC, Sanofi, Wave, and Myolex; consulting fees from Amylyx, Cytokinetics, Denali, GSK, Mitsubishi Tanabe Pharma America, Neurosense, Orthogonal, Pinteon, RRD, Acurastem, Revalasio, Apellis, Novartis, Sanofi, and Immunity Pharma; participation in data safety monitoring boards or advisory boards for Swanbio and Braingate; and stock or stock options in Aural Analytics. MRT reports salary support from the Motor Neurone Disease Association; royalties or licences from Oxford University Press, Oneworld, and Karger; speakers' honoraria from University of Miami; and participation in advisory board for Biogen and Novartis. JW reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association. TH, MAG, TB, RB, HD, and CS are previous employees of Orphazyme. MK-K reports research support from the JPND by the National Center for Research and Development, and from E-Rare by the National Science Center of Poland. MK-K also reports paid consulting fees from Amylyx, Ferrer, and Cytokinetics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed., Methods: The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal., Results: Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database., Conclusions: ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key Messages What is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population. What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research , practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with motor neuron loss as a defining feature. Despite significant effort, therapeutic breakthroughs have been modest. MN-166 (ibudilast) has demonstrated neuroprotective action by various mechanisms: inhibition of proinflammatory cytokines and macrophage migration inhibitory factor, phosphodiesterase inhibition, and attenuation of glial cell activation in models of ALS. Early-phase studies suggest that MN-166 may improve survival outcomes and slow disease progression in patients with ALS. This article describes the rationale and design of COMBAT-ALS, an ongoing randomized, double-blind, placebo-controlled, multicenter Phase IIb/III study in ALS. This study is designed to evaluate the pharmacokinetics, safety and tolerability and assess the efficacy of MN-166 on function, muscle strength, quality of life and survival in ALS.

Objective: Behavioral variant frontotemporal dementia (bvFTD), is commonly considered the cognitive presentation of the frontotemporal dementia-motor neuron disease (FTD-MND) spectrum disorder. We evaluated the prevalence of primary progressive aphasia in a series of pathologically confirmed cases of FTD-MND spectrum. Methods: Pathologically confirmed cases of frontotemporal lobar degeneration-motor neuron disease (FTLD-MND) were obtained from the UCSF brain bank. Cases were analyzed for presence of language impairment via retrospective chart review of research visits that include neurologic exam, in-depth cognitive testing and magnetic resonance imaging (MRI) imaging. Forty one cases were included. Thirty two were diagnosed with FTD-MND, while nine cases were diagnosed as MND-only from clinical evaluation. Results: Ten FTLD-MND cases (31%) presented with prominent or isolated language involvement consistent with a diagnosis of primary progressive aphasia (PPA), which we called progressive aphasia with motor neuron disease (PA-MND). Of these, three cases that mirrored the non-fluent variant of PPA (nfvPPA) were named nfvPA-MND. The imaging pattern of these nfvPA-MND showed atrophy strictly confined to the frontal and anterior temporal language cortical areas. Another group of seven cases that resembled patients with the semantic variant PPA (svPPA) were named svPA-MND. The group of svPPA-MND on imaging analysis showed selective atrophy of the temporal lobe and orbitofrontal cortex. Conclusions: Language impairment was a frequent phenotype of FTD-MND associated with focal atrophy patterns within the language networks. This data suggest patients with FTD-MND can present quite often with language phenotype of nfvPPA and svPPA, as opposed to exclusive bvFTD symptoms.

Frontotemporal dementia refers to a group of progressive neurodegenerative syndromes usually caused by the accumulation of pathological tau or TDP-43 proteins. The effects of these proteins in the brain are complex, and each can present with several different clinical syndromes. Clinical efficacy trials of drugs targeting these proteins must use endpoints that are meaningful to all participants despite the variability in symptoms across patients. There are many candidate clinical measures, including neuropsychological scores and functional measures. Brain imaging is another potentially attractive outcome that can be precisely quantified and provides evidence of disease modification. Most imaging studies in frontotemporal dementia have been cross-sectional, and few have compared longitudinal changes in cortical volume with changes in other measures such as perfusion and white matter integrity. The current study characterized longitudinal changes in 161 patients with three frontotemporal dementia syndromes: behavioural variant frontotemporal dementia (n = 77) and the semantic (n = 45) and non-fluent (n = 39) variants of primary progressive aphasia. Visits included comprehensive neuropsychological and functional assessment, structural MRI (3 T), diffusion tensor imaging, and arterial spin labelled perfusion imaging. The goal was to identify measures that are appropriate as clinical trial outcomes for each group, as well as those that might be appropriate for trials that would include more than one of these groups. Linear mixed effects models were used to estimate changes in each measure, and to examine the correlation between imaging and clinical changes. Sample sizes were estimated based on the observed effects for theoretical clinical trials using bootstrapping techniques to provide 95% confidence intervals for these estimates. Declines in functional and neuropsychological measures, as well as frontal and temporal cortical volumes and white matter microstructure were detected in all groups. Imaging changes were statistically significantly correlated with, and explained a substantial portion of variance in, the change in most clinical measures. Perfusion and diffusion tensor imaging accounted for variation in clinical decline beyond volume alone. Sample size estimates for atrophy and diffusion imaging were comparable to clinical measures. Corpus callosal fractional anisotropy led to the lowest sample size estimates for all three syndromes. These findings provide further guidance on selection of trial endpoints for studies in frontotemporal dementia and support the use of neuroimaging, particularly structural and diffusion weighted imaging, as biomarkers. Diffusion and perfusion imaging appear to offer additional utility for explaining clinical change beyond the variance explained by volume alone, arguing for considering multimodal imaging in treatment trials.

Tuberous sclerosis complex (TSC), a heritable neurodevelopmental disorder, is caused by mutations in the TSC1 or TSC2 genes. To date, there has been little work to elucidate regional TSC1 and TSC2 gene expression within the human brain, how it changes with age, and how it may influence disease. Using a publicly available microarray dataset, we found that TSC1 and TSC2 gene expression was highest within the adult neo-cerebellum and that this pattern of increased cerebellar expression was maintained throughout postnatal development. During mid-gestational fetal development, however, TSC1 and TSC2 expression was highest in the cortical plate. Using a bioinformatics approach to explore protein and genetic interactions, we confirmed extensive connections between TSC1/TSC2 and the other genes that comprise the mammalian target of rapamycin (mTOR) pathway, and show that the mTOR pathway genes with the highest connectivity are also selectively expressed within the cerebellum. Finally, compared to age-matched controls, we found increased cerebellar volumes in pediatric TSC patients without current exposure to antiepileptic drugs. Considered together, these findings suggest that the cerebellum may play a central role in TSC pathogenesis and may contribute to the cognitive impairment, including the high incidence of autism spectrum disorder, observed in the TSC population.

Olney, N, Wertz, T, LaPorta, Z, Mora, A, Serbas, J, and Astorino, TA. Comparison of acute physiological and psychological responses between moderate-intensity continuous exercise and three regimes of high intensity interval training. J Strength Cond Res 32(8): 2130-2138, 2018-High-intensity interval training (HIIT) elicits similar physiological adaptations as moderate-intensity continuous training (MICT) despite less time commitment. However, there is debate whether HIIT is more aversive than MICT. This study compared physiological and perceptual responses between MICT and 3 regimes of HIIT. Nineteen active adults (age = 24.0 ± 3.3 years) unfamiliar with HIIT initially performed ramp exercise to exhaustion to measure maximal oxygen uptake (V[Combining Dot Above]O2max) and determine workload for subsequent sessions, whose order was randomized. Sprint interval training (SIT) consisted of six 20-second bouts of "all-out" cycling at 140% of maximum watts (Wmax). Low-volume HIIT (HIITLV) and high-volume HIIT (HIITHV) consisted of eight 60-second bouts at 85% Wmax and six 2-minute bouts at 70% Wmax, respectively. Moderate-intensity continuous training consisted of 25 minutes at 40% Wmax. Across regimes, work was not matched. Heart rate (HR), V[Combining Dot Above]O2, blood lactate concentration (BLa), affect, and rating of perceived exertion (RPE) were assessed during exercise. Ten minutes postexercise, Physical Activity Enjoyment (PACES) was measured via a survey. Results revealed significantly higher (p ≤ 0.05) V[Combining Dot Above]O2, HR, BLa, and RPE in SIT, HIITLV, and HIITHV vs. MICT. Despite a decline in affect during exercise (p < 0.01) and significantly lower affect (p ≤ 0.05) during all HIIT regimes vs. MICT at 50, 75, and 100% of session duration, PACES was similar across regimes (p = 0.65), although it was higher in women (p = 0.03). Findings from healthy adults unaccustomed to interval training demonstrate that HIIT and SIT are perceived as enjoyable as MICT despite being more aversive.

AVANIR Pharmaceuticals Inc, under license from Irisys Research & Development, is developing AVP-923 (Zenvia, Neurodex) for the treatment of pseudobulbar affect (PBA; in collaboration with Medison Pharma Ltd) and neuropathic pain associated with diabetic peripheral neuropathy. PBA, the main indication of AVP-923, is a neurological disorder characterized by uncontrollable and unpredictable episodes of laughing and/or crying. AVP-923 consists of a combination of the NMDA antagonist/sigma1 receptor agonist dextromethorphan hydrobromide (DM) and the cytochrome P450 2D6 (CYP2D6) enzyme inhibitor quinidine sulfate (Q). DM has been under investigation for several years as a neuroprotective agent in stroke, neurosurgery and amyotrophic lateral sclerosis (ALS); however, it is rapidly metabolized by CYP2D6, reducing the drug's bioavailability at neuronal targets. The inclusion of Q inhibits the rapid first-pass metabolism of DM to increase systemic concentrations of the drug in the plasma and, in theory, increase the potential efficacy. The initial clinical data for AVP-923 in the treatment of PBA demonstrated the combination was effective, but exhibited significant side effects. Of particular concern to the FDA were increased QTc intervals reported in patients dosed with a 30-/30-mg dose of DM/Q. A subsequent phase III clinical trial assessing a lower dose of AVP-923 (20 or 30 mg DM/10 mg Q) for the treatment of PBA in patients with ALS or multiple sclerosis was implemented by AVANIR and demonstrated a favorable safety profile of AVP-923 while maintaining efficacy. Pending approval of the data from the FDA, AVP-923 would be the first FDA-approved treatment for PBA.

Mechanical hyperalgesia is a clinically-relevant form of pain sensitization that develops through largely unknown mechanisms. TRPA1, a Transient Receptor Potential ion channel, is a sensor of pungent chemicals that may play a role in acute noxious mechanosensation and cold thermosensation. We have developed a specific small molecule TRPA1 inhibitor (AP18) that can reduce cinnameldehyde-induced nociception in vivo. Interestingly, AP18 is capable of reversing CFA-induced mechanical hyperalgesia in mice. Although TRPA1-deficient mice develop normal CFA-induced hyperalgeisa, AP18 is ineffective in the knockout mice, consistent with an on-target mechanism. Therefore, TRPA1 plays a role in sensitization of nociception, and that compensation in TRPA1-deficient mice masks this requirement.