Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
Open accessAbstract
BACKGROUND: mutations. METHODS: mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured. RESULTS: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose. CONCLUSIONS: mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).
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ASO injection is a current standard of care for spinal muscular atrophy and is in five ongoing Phase I trials in ALS, Parkinson's, and Alzheimer's diseases and in Phase III trials for inherited ALS and Huntington's disease.
“ASO injection is a current standard of care for the fatal childhood disease spinal muscular atrophy15 and is in five ongoing Phase I trials in ALS, Parkinson’s, and Alzheimer’s diseases and in Phase III trials for inherited ALS from a mutation in superoxide dismutase16,17 and for Huntington’s disease18.”
From Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB (2021) · cites this paper as [17]
Treating FTD is likely to be most effective when started early, ideally before symptoms appear.
“Experience from Alzheimer’s disease (AD), spinal muscular atrophy (SMA),5 and amyotrophic lateral sclerosis (ALS)6 suggests treating FTD will be most successful if treatment is initiated early in the disease course, ideally prior to the onset of symptoms.”
From Temporal order of clinical and biomarker changes in familial frontotemporal dementia (2022) · cites this paper as [6]
The Characteristics of the Participants section says all trial participants had ALS symptoms at illness onset. The Exploratory Outcomes and discussion describe tofersen results but do not compare treatment started at different disease stages or address treatment before symptoms. Searches for presymptomatic and early treatment found no passage supporting the timing claim. (LLM, conf=0.76)
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“Part A (single ascending dose [9]) and part B (multiple ascending dose [10]) were phase I/II dose-escalation trials conducted to assess the dose of tofersen to be used in part C, the 28-week, double-blind, randomized, placebo-controlled, phase III component of the trial.”
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Self-citationNeurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers
Zucchi, E., Bonetto, V., Sorarú, G., Martinelli, I., Parchi, P., Liguori, R., & Mandrioli, J. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00406-3 · Cited by 107 · see citing works
Julian, T. H., Glascow, N., Barry, A. D. F., Moll, T., Harvey, C., Klimentidis, Y. C., Newell, M., Zhang, S., Snyder, M. P., Cooper‐Knock, J., et al. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103397 · Cited by 108 · see citing works
“For rare forms of ALS which are purely genetically determined, this is already a reality [54].”
BackgroundSelf-citationAdvances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis
Ilieva, H., Vullaganti, M., & Kwan, J. (2023) · BMJ · doi:10.1136/bmj-2023-075037 · Cited by 111 · see citing works
Meyer, T., Schumann, P., Weydt, P., Petri, S., Koc, Y., Spittel, S., Bernsen, S., Günther, R., Weishaupt, J. H., Dreger, M., et al. (2023) · Muscle & Nerve · doi:10.1002/mus.27818 · Cited by 102 · see citing works
Giacomelli, E., Vahsen, B. F., Calder, E. L., Xu, Y., Scaber, J., Gray, E., Dafinca, R., Talbot, K., & Studer, L. (2022) · Cell stem cell · doi:10.1016/j.stem.2021.12.008 · Cited by 97 · see citing works
Antisense Oligonucleotides for the Study and Treatment of ALS
Boros, B. D., Schoch, K. M., Kreple, C. J., & Miller, T. M. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01247-2 · Cited by 100 · see citing works
“At study day 85, SOD1 was reduced in the 40 mg (27%), 60 mg (21%), and 100 mg (36%) groups, demonstrating effective target engagement [29].”
BackgroundMethodInfluentialSelf-citationHemerková, P., & Vališ, M. (2021) · Biomolecules · doi:10.3390/biom11030437 · Cited by 99 · see citing works
“The highest administered dose of the drug led to a reduction in the amount of mutated SOD in the cerebrospinal fluid and also to a decrease in the amount of neurofilaments, a marker of neuronal decay [220].”
BackgroundCrossing the blood–brain barrier: emerging therapeutic strategies for neurological disease
Pedder, J. H., Sonabend, A. M., Cearns, M. D., Michael, B. D., Zakaria, R., Heimberger, A. B., Jenkinson, M. D., & Dickens, D. (2025) · The Lancet Neurology · doi:10.1016/s1474-4422(24)00476-9 · Cited by 111 · see citing works
Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy
Wang, H., Guan, L., & Deng, M. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1170996 · Cited by 97 · see citing works
Pharmacotherapy for Amyotrophic Lateral Sclerosis: A Review of Approved and Upcoming Agents
Johnson, S. A., Fang, T., Marchi, F. D., Neel, D. V., Weehaeghe, D. V., Berry, J. D., & Paganoni, S. (2022) · Drugs · doi:10.1007/s40265-022-01769-1 · Cited by 97 · see citing works
“They were safe in a human Phase 1–2 trial [105].”
BackgroundHarnessing cerebrospinal fluid circulation for drug delivery to brain tissues
Naseri Kouzehgarani, G., Feldsien, T., Engelhard, H. H., Mirakhur, K. K., Phipps, C., Nimmrich, V., Clausznitzer, D., & Lefebvre, D. R. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.03.002 · Cited by 95 · see citing works
Targeted gene silencing in the nervous system with CRISPR-Cas13
Powell, J. E., Lim, C. K. W., Krishnan, R. S. G., McCallister, T. X., Saporito-Magriñá, C., C., M. A. Z., McPheron, G. D., & Gaj, T. (2022) · Science Advances · doi:10.1126/sciadv.abk2485 · Cited by 94 · see citing works
“While, to date, non–allele-specific targeting for SOD1linked ALS has resulted in no serious side effects and produced evidence of clinical improvement (19), a phase 3 clinical trial designed to evaluate the effectiveness of an intrathecally administered non–allele-specific ASO for HD was recently halted following a re…”
BackgroundInfluentialCombating deleterious phase transitions in neurodegenerative disease
Darling, A. L., & Shorter, J. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2021.118984 · Cited by 85 · see citing works
“Moreover, in a transgenic ALS SOD1-G93A mouse model, there was a robust increase of HspB8 protein levels in the anterior horn cells of the spinal cord that survived to end-stage of disease [232].”
BackgroundInfluentialClinical trials in amyotrophic lateral sclerosis: a systematic review and perspective
Wong, C., Stavrou, M., Elliott, E., Gregory, J. M., Leigh, N. P., Pinto, A. A., Williams, T. L., Chataway, J., Swingler, R. J., Parmar, M., et al. (2021) · Brain Communications · doi:10.1093/braincomms/fcab242 · Cited by 86 · see citing works
“Moreover, the emergence of gene-based treatment approaches for monogenetic causes of amyotrophic lateral sclerosis has already led to genetically stratified treatment trials that bring additional considerations including the nature of the control arm.(67,68) Regardless of how drugs are selected, the pace of growth in…”
Backgroundvan den Berg, L. H., Rothstein, J. D., Shaw, P. J., Babu, S., Benatar, M., Bucelli, R. C., Genge, A. L., Glass, J. D., Hardiman, O. M., Libri, V., et al. (2024) · The Lancet Neurology · doi:10.1016/s1474-4422(24)00216-3 · Cited by 84 · see citing works
Self-citationAbati, E., Manini, A., Comi, G. P., & Corti, S. P. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04408-w · Cited by 84 · see citing works
“Notably, tofersen, an antisense oligonucleotide, recently proved effective in a clinical trial on ALS patients carrying a mutation in the SOD1 gene [6].”
BackgroundJiang, J., Wang, Y., & Deng, M. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1054006 · Cited by 83 · see citing works
“Most adverse events were mild to moderate, including headache, procedural pain, and postlumbar syndrome related to lumbar puncture (Miller et al., 2020).”
BackgroundThompson, A. G., Gray, E., Verber, N. S., Bobeva, Y., Lombardi, V., Shepheard, S. R., Yildiz, Ö., Feneberg, E., Farrimond, L. E., Dharmadasa, T., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac029 · Cited by 82 · see citing works
“Consistent reduction in neurofilament levels has also recently been shown in trials of antisense oligonucleotide therapy in patients harbouring ALS-causing SOD1 mutations, providing an early suggestion that similar changeswill occurwith effective ALS treatment.(10) Our modelling suggested that using plasma NFL in plac…”
Self-citationRandomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
Mandrioli, J., D’Amico, R., Zucchi, E., Biasi, S. D., Banchelli, F., Martinelli, I., Simonini, C., Tartaro, D. L., Vicini, R., Fini, N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40734-8 · Cited by 84 · see citing works
“…fast disease progression to be associated with neuro fi lament decrease over time 29 , other observed an absence of correlation between a drug clinical effect and repeated neuro fi lament measurements 30,31 , others correlated a rise of serum NfL over time to a fast-progressing disease course 32 .”
Gene Therapy in Amyotrophic Lateral Sclerosis
Fang, T., Je, G., Pacut, P., Keyhanian, K., Gao, J., & Ghasemi, M. (2022) · Cells · doi:10.3390/cells11132066 · Cited by 82 · see citing works
“gov identifier: NCT02623699) and found a dose dependent efficacy with highest dose 100 mg showing the largest of effects at reducing CSF SOD1 concentration, especially in fast progressors of disease [35] (Table 1).”
BackgroundResultBlood-based biomarkers of inflammation in amyotrophic lateral sclerosis
Staats, K. A., Borchelt, D., Tansey, M. G., & Wymer, J. P. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00515-1 · Cited by 73 · see citing works
“ALS; initially by targeting of the SOD1 gene for ALS patients harboring an ALS-causing mutation in this gene in clinical trials [88], and with the additional development of”
BackgroundTDP-43 pathology: From noxious assembly to therapeutic removal
Keating, S. S., Gil, R. S., Swanson, M. E. V., Scotter, E. L., & Walker, A. K. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102229 · Cited by 75 · see citing works
A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?
Xu, X., Shen, D., Gao, Y., Zhou, Q., Ni, Y., Meng, H., Shi, H., Le, W., Chen, S., & Chen, S. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00250-5 · Cited by 77 · see citing works
“group, the ALSFRS-R score of the 100 mg tofersen group seemed to decrease slower than the placebo group [33].”
BackgroundMethodInfluentialJablonka, S., Hennlein, L., & Sendtner, M. (2022) · Neurological Research and Practice · doi:10.1186/s42466-021-00162-9 · Cited by 73 · see citing works
Li, Y., Liu, Y., Yu, X., Xu, Y., Pan, X., Sun, Y. E., Wang, Y., Song, Y.-H., & Shen, Z. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02013-w · Cited by 70 · see citing works
Monine, M. I., Norris, D. A., Wang, Y., & Nestorov, I. A. (2021) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-021-09761-0 · Cited by 67 · see citing works
Self-citationCurrent State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis
Vidovic, M., Müschen, L. H., Brakemeier, S., Machetanz, G., Naumann, M., & Castro‐Gomez, S. (2023) · Cells · doi:10.3390/cells12050736 · Cited by 67 · see citing works
“For patients with SOD1 mutations, tofersen, an antisense oligonucleotide reducing SOD1 protein synthesis, was shown to reduce neurofilament light chain levels in plasma and is already available in many countries in an early access program [84,85]; 3.”
BackgroundTherapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB
Maimon, R., Chillon-Marinas, C., Snethlage, C. E., Singhal, S. M., McAlonis-Downes, M., Ling, K., Rigo, F., Bennett, C. F., Da Cruz, S., Hnasko, T. S., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00864-y · Cited by 62 · see citing works
Self-citationEfficacy and long-term safety of CRISPR/Cas9 genome editing in the SOD1-linked mouse models of ALS
Deng, H., Zhai, H., Shi, Y., Liu, G., Lowry, J., Liu, B., Ryan, É. B., Yan, J., Yang, Y., Zhang, N., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-01942-4 · Cited by 62 · see citing works
Huang, M., Liu, Y., Yao, X., Qin, D., & Su, H. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00416-x · Cited by 68 · see citing works
“ISIS 333611 which targets c.19–38 of wild-type SOD1 , now renamed Tofersen (BIIB067), has entered clinical trials [160] and shown promising results [161–165].”
BackgroundProtein aggregation and its affecting mechanisms in neurodegenerative diseases
Wu, J., Wu, J., Chen, T., Cai, J., & Ren, R. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105880 · Cited by 61 · see citing works
“Two patients with a pure SOD1 c.335dupG variant showed similar symptoms, including quadratic spatiality, progressive loss of locomotion, and hyperreflexia, with symptoms starting in early childhood (Mueller et al., 2020; Miller et al., 2020).”
Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy
Montojo, M. G., Fathi, S., Norato, G., Smith, B., Rowe, D. B., Kiernan, M. C., Vucic, S., Mathers, S., van Eijk, R. P. A., Santamaria, U. A., et al. (2021) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2021.117358 · Cited by 58 · see citing works
The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration
Opie-Martin, S., Iacoangeli, A., Topp, S. D., Abel, O., Mayl, K., Mehta, P. R., Shatunov, A., Fogh, I., Bowles, H., Limbachiya, N., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34620-y · Cited by 58 · see citing works
“15 It is not clear what impact therapy will have on people carrying variants associated with a longer disease duration, although if effective, the therapy should halt progression altogether.”
Self-citationBlood biomarkers in ALS : challenges, applications and novel frontiers
Sturmey, E., & Malaspina, A. (2022) · Acta Neurologica Scandinavica · doi:10.1111/ane.13698 · Cited by 56 · see citing works
The sense of antisense therapies in ALS
Daele, S. H. V., Masrori, P., Damme, P. V., & Bosch, L. V. D. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.12.003 · Cited by 58 · see citing works
The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis—Frontotemporal Dementia
Scarian, E., Fiamingo, G., Diamanti, L., Palmieri, I., Gagliardi, S., & Pansarasa, O. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.841394 · Cited by 54 · see citing works
Cullen, N. C., Novák, P., Tosun, D., Kováčech, B., Hanes, J., Kontseková, E., Fresser, M., Ropele, S., Feldman, H., Schmidt, R., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104923 · Cited by 55 · see citing works
“11,12 The CDR-SB and ADCS-MCI-ADL are widely employed as clinical Sex (% male/female) a 41.4 outcome measures in AD trials; and would be expected to be less sensitive to treatment effects than biomarkers.”
MethodInfluentialAbu‐Rumeileh, S., Baiardi, S., Ladogana, A., Zenesini, C., Bartoletti‐Stella, A., Poleggi, A., Mammana, A., Polischi, B., Pocchiari, M., Capellari, S., et al. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-323826 · Cited by 55 · see citing works
“29 The discussion of the present results should also consider the current clinical scenario.”
Inflammasome Contribution to the Activation of Th1, Th2, and Th17 Immune Responses
Martynova, E. V., Rizvanov, A. A., Urbanowicz, R. A., & Khaiboullina, S. F. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.851835 · Cited by 54 · see citing works
Pan, Y., & Nicolazzo, J. A. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15802 · Cited by 49 · see citing works
Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers
Dorst, J., Weydt, P., Brenner, D., Witzel, S., Kandler, K., Huss, A. M., Herrmann, C. H., Wiesenfarth, M., Knehr, A., Günther, K., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104521 · Cited by 53 · see citing works
Self-citationvan Roon‐Mom, W., Ferguson, C. M., & Aartsma-Rus, A. M. (2023) · Nucleic Acid Therapeutics · doi:10.1089/nat.2023.0027 · Cited by 53 · see citing works
The presymptomatic phase of amyotrophic lateral sclerosis: are we merely scratching the surface?
Chipika, R. H., Siah, W. F., McKenna, M. C., Shing, S. L. H., Hardiman, O. M., & Bede, P. (2020) · Journal of Neurology · doi:10.1007/s00415-020-10289-5 · Cited by 53 · see citing works
The 2022 Lady Estelle Wolfson lectureship on neurofilaments
Petzold, A. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15682 · Cited by 49 · see citing works
“Nf stoichiometry changes in ALS (Khalil et al., 2018).”
BackgroundMethodInfluentialKetabforoush, A. H. M. E., Chegini, R., Barati, S., Tahmasebi, F., Moghisseh, B., Joghataei, M. T., Faghihi, F., & Azedi, F. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114378 · Cited by 52 · see citing works
Trist, B. G., Fifita, J. A., Hogan, A. L., Grima, N., Smith, B. N., Troakes, C., Vance, C. A., Shaw, C. E., Al‐Sarraj, S., Blair, I. P., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01421-9 · Cited by 50 · see citing works
“Current therapies targeting disordered SOD1 and pathological TDP-43 in ALS patients primarily aim to reduce expression levels [31], stabilize protein structure [3, 38, 49], correct protein mislocalization [6] or enhance clearance mechanisms [9].”
BackgroundImamura, K., Izumi, Y., Nagai, M., Nishiyama, K., Watanabe, Y., Hanajima, R., Egawa, N., Ayaki, T., Oki, R., Fujita, K., et al. (2022) · EClinicalMedicine · doi:10.1016/j.eclinm.2022.101707 · Cited by 50 · see citing works
De novo mutations in SOD1 are a cause of ALS
Müller, K., Oh, K., Nordin, A., Panthi, S., Kim, S. H., Nordin, F., Freischmidt, A., Ludolph, A. C., Ki, C., Forsberg, K., et al. (2021) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2021-327520 · Cited by 49 · see citing works
“The findings of increasing number of sALS cases to have a genetic underpinning coupled with the promising results from new bespoken gene therapies 40 make us revise our previous opinion.”
Self-citationCerebrospinal fluid biomarkers of disease activity and progression in amyotrophic lateral sclerosis
Dreger, M., Steinbach, R., Otto, M., Turner, M. R., & Großkreutz, J. (2022) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2021-327503 · Cited by 49 · see citing works
Saini, A., & Chawla, P. A. (2023) · European Journal of Neurology · doi:10.1111/ene.16140 · Cited by 49 · see citing works
The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis
Liu, J., Zhou, F., Guan, Y., Meng, F., Zhao, Z., Su, Q., Bao, W., Wang, X., Zhao, J., Huo, Z., et al. (2022) · Cells · doi:10.3390/cells11030572 · Cited by 49 · see citing works
Genetic testing in motor neurone disease
Dharmadasa, T., Scaber, J., Edmond, E., Marsden, R., Thompson, A., Talbot, K., & Turner, M. R. (2022) · Practical Neurology · doi:10.1136/practneurol-2021-002989 · Cited by 48 · see citing works
Targeting RNA with synthetic oligonucleotides: Clinical success invites new challenges
Hofman, C. R., & Corey, D. R. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.09.005 · Cited by 51 · see citing works
The impact of age on genetic testing decisions in amyotrophic lateral sclerosis
Mehta, P. R., Iacoangeli, A., Opie-Martin, S., van Vugt, J. J. F. A., Khleifat, A. A., Bredin, A., Ossher, L., Andersen, P. M., Hardiman, O. M., Mehta, A. R., et al. (2022) · Brain · doi:10.1093/brain/awac279 · Cited by 48 · see citing works
“There is mounting evidence that for those with an identified genetic basis to their ALS, effective treatment may soon be possible.(4,5)”
Self-citationBarresi, V., Musmeci, C., Rinaldi, A., & Condorelli, D. F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168875 · Cited by 47 · see citing works
Helm, J., Schöls, L. J., & Hauser, S. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14081708 · Cited by 47 · see citing works
α-Synuclein: A Promising Biomarker for Parkinson’s Disease and Related Disorders
Hatano, T., Okuzumi, A., Matsumoto, G., Tsunemi, T., & Hattori, N. (2024) · Journal of Movement Disorders · doi:10.14802/jmd.24075 · Cited by 48 · see citing works
“Additionally, when evaluating the effectiveness of treatments for amyotrophic lateral sclerosis, such as SOD1 antisense oligonucleotides, 88 the combination of Amylyx and sodium phenylbutyrate, 89 and C9orf72 antisense oligonucleotides, 90 the development of surrogate markers that align with the…”
BackgroundPaving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective
Klockgether, T., Ashizawa, T., Brais, B., Chuang, R., Dürr, A., Fogel, B. L., Greenfield, J., Hagen, S., Jardim, L. B., Jiang, H. F., et al. (2022) · Movement Disorders · doi:10.1002/mds.29032 · Cited by 47 · see citing works
“Such ASOs already underwent successful early-phase clinical trials in Huntington’s disease and superoxide dismutase 1 amyotrophic lateral sclerosis (SOD1 ALS).(5,6) However, subsequent phase 3 trials did not prove clinical efficacy, but a positive effect on fluid biomarkers in SOD1 ALS (https:// investors.”
BackgroundBiomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis
Katzeff, J. S., Bright, F., Phan, K., Kril, J. J., Ittner, L. M., Kassiou, M., Hodges, J. R., Piguet, O., Kiernan, M. C., Halliday, G. M., et al. (2022) · Brain · doi:10.1093/brain/awac077 · Cited by 48 · see citing works
“ever, a correlation between treatment and clinical outcomes could not be drawn due to the small study size.(63) Therefore, the use of SOD1 as a biomarker may lie primarily in determining the pharma-”
BackgroundConsiderations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design
Fournier, C. N. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01271-2 · Cited by 45 · see citing works
“Recent studies highlight these uncertainties; the phase 1–2 study of Tofersen in SOD1 ALS showed reduction of neurofilament light chains with treatment without a corresponding benefit on clinical outcome measures [99], while the AMX0035 study showed benefit on its primary clinical outcome measure without a significant…”
Result
- Authors
- Miller, T., Cudkowicz, M., Shaw, P. J., Andersen, P. M., Atassi, N., Bucelli, R. C., Genge, A., Glass, J., Ladha, S., Ludolph, A. L., Maragakis, N. J., McDermott, C. J., Pestronk, A., Ravits, J., Salachas, F., Trudell, R., Van Damme, P., Zinman, L., Bennett, C. F., Lane, R., Sandrock, A., Runz, H., Graham, D., Houshyar, H., McCampbell, A., Nestorov, I., Chang, I., McNeill, M., Fanning, L., Fradette, S., & Ferguson, T. A.
- Affiliations
- From the Washington University School of Medicine, St. Louis (T.M., R.C.B., A.P.); the Healey Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston (M.C., N.A.), and Biogen, Cambridge (A.S., H.R., D.G., H.H., A.M., I.N., I.C., L.F., S.F., T.A.F.) — both in Massachusetts; the Sheffield Institute for Translational Neuroscience, University of Sheffield, and NIHR Sheffield Biomedical Research Centre and Clinical Research Facility, University of Sheffield and Sheffield Teaching...
- Harvard University (US)
- Montreal Neurological Institute and Hospital (CA)
- Barrow Neurological Institute (US)
- Biogen (United States) (US)
- ORCID
- Cudkowicz, Merit
- Shaw, Pamela J.
- Andersen, Peter M.
- Atassi, Nazem
- Bucelli, Robert C.
- Genge, Angela
- Glass, Jonathan
- Ladha, Shafeeq
- Maragakis, Nicholas J.
- McDermott, Christopher J.
- Pestronk, Alan
- Ravits, John
- Trudell, Randall
- Zinman, Lorne
- Bennett, C. Frank
- Lane, Roger
- Runz, Heiko
- Graham, Danielle
- McCampbell, Alexander
- Nestorov, Ivan
- Chang, Ih
- Fradette, Stephanie
- Ferguson, Toby A.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-07-09
- Volume
- 383
- Issue
- 2
- Pages
- 109-119
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3040840440
- Cited by
- 565
- References
- 27
- Citations by year
- 2026: 64 · 2025: 73 · 2024: 87 · 2023: 90 · 2022: 130 · 2021: 83 · 2020: 36 · 2019: 1
- FWCI
- 36.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Funders
- National Institute for Health and Care Research (NF-SI-0617-10077)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- tofersen, antisense oligonucleotides, amyotrophic lateral sclerosis, SOD1, intrathecal administration, pleocytosis, dose escalation
- MeSH terms
- Superoxide Dismutase-1, Adult, Amyotrophic Lateral Sclerosis, Dose-Response Relationship, Drug, Double-Blind Method, Female, Headache, Humans, Injections, Spinal, Intermediate Filaments, Leukocytosis, Male, Middle Aged, Mutation, Oligonucleotides, Vital Capacity, Oligonucleotides, Antisense, Disease Progression
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