Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial

Cudkowicz, Merit; Genge, Angela; Maragakis, Nicholas J.; Petri, Susanne; Berg, Leonard van den; Aho, Valtteri V.; Sarapohja, Toni; Kuoppamäki, Mikko; Garratt, Chris; Al‐Chalabi, Ammar; Kiernan, Matthew C.; Mathers, Susan; Henderson, Robert D.; Needham, Merrilee; Schultz, David; Löscher, Wolfgang N.; Mitrović, Nenad; Rath, Jakob; Damme, Philip Van; Bleecker, Jan De; Delstanche, Stéphanie; Johnston, Wendy; Zinman, Lorne; O’Connell, Colleen; Matte, Geneviève; Dionne, Annie; Korngut, Lawrence; Turnbull, John; Laaksovirta, Hannu; Jokela, Manu; Tapiola, Tero; Soriani, Marie-Hélène; Couratier, Philippe; Camu, William; Corcia, Philippe; Ludolph, Albert C.; Großkreutz, Julian; Meyer, Thomas; Boentert, Matthias; Schrank, Berthold; Prudlo, Johannes; Untucht, Robert; Hardiman, Orla; Siciliano, Gabriele; Chiò, Adriano; Mazzini, Letizia; Inghilleri, Maurizio; Caponnetto, Claudia; Mora, Gabriele; Pardina, Jesús S. Mora; Muñoz, Eva Farrero; Vázquez-Costa, Juan Francisco; Agüera, Eduardo; Varona, Luís; Andersen, Peter; Ingre, Caroline; Johansson, Rune; Radunović, Aleksandar; Young, Carolyn; Babu, Suma; Shaibani, Aziz; Staff, Nathan P.; Vu, Tuan; Rivner, Michael H.; Scelsa, Stephen N.; Sivakumar, Kumaraswamy; Waheed, Waqar; Heitzman, Daragh; Rana, Sandeep; Pattee, Gary L.; Ajroud‐Driss, Senda; Bayat, Elham; Kasarskis, Edward J.; Lange, Dale J.; Elliott, Michael A.; Harris, Brent T.; Felice, Kevin J.; Pulley, Michael; Kwan, Justin; Brown, M.; Ravits, John; Burford, Matthew; Karam, Chafic; Miller, Timothy M.; Andrews, Jinsy; Levine, Todd; Locatelli, Eduardo; Wymer, James P.; Bedlack, Richard; Fee, Dominic B.; Goyal, Namita; Oskarsson, Björn; McCluskey, Leo; Caress, James B.; Weiss, Michael D.; Quick, Adam; Bromberg, Mark B.; Lacomis, David; Goutman, Stephen A.; Rezania, Kourosh; Guliani, Gaurav; Goslin, Kimberly; Katz, Jonathan

doi:10.1016/s1474-4422(21)00242-8

Cited by 14 publications

(6 citation statements)

References 16 publications

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“…A higher mean CAFS score indicates a better group outcome. The CAFS endpoint was used as the primary endpoint of a dexpramipexole phase III study [ 165 ] and recent studies [ 166 , 167 ].…”

Section: What Is the State Of The Art In Developing Therapies Targeti...mentioning

confidence: 99%

Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy

et al. 2022

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Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS is motor neurons. The success of antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a motor neuron disease, has triggered a paradigm shift in developing ALS therapies. The causative genes of ALS and disease-modifying genes, including those of sporadic ALS, have been identified one after another. Thus, the freedom of target choice for gene therapy has expanded by ASO strategy, leading to new avenues for therapeutic development. Tofersen for superoxide dismutase 1 (SOD1) was a pioneer in developing ASO for ALS. Improving protocols and devising early interventions for the disease are vital. In this review, we updated the knowledge of causative genes in ALS. We summarized the genetic mutations identified in familial ALS and their clinical features, focusing on SOD1, fused in sarcoma (FUS), and transacting response DNA-binding protein. The frequency of the C9ORF72 mutation is low in Japan, unlike in Europe and the United States, while SOD1 and FUS are more common, indicating that the target mutations for gene therapy vary by ethnicity. A genome-wide association study has revealed disease-modifying genes, which could be the novel target of gene therapy. The current status and prospects of gene therapy development were discussed, including ethical issues. Furthermore, we discussed the potential of axonal pathology as new therapeutic targets of ALS from the perspective of early intervention, including intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired axonal transport, aberrant cytoskeleton, and axon branching. We simultaneously discuss important pathological states of cell bodies: persistent stress granules, disrupted nucleocytoplasmic transport, and cryptic splicing. The development of gene therapy based on the elucidation of disease-modifying genes and early intervention in molecular pathology is expected to become an important therapeutic strategy in ALS.

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“…A higher mean CAFS score indicates a better group outcome. The CAFS endpoint was used as the primary endpoint of a dexpramipexole phase III study [ 165 ] and recent studies [ 166 , 167 ].…”

Section: What Is the State Of The Art In Developing Therapies Targeti...mentioning

confidence: 99%

Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy

et al. 2022

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“…Another compound with a similar, but not completely overlapping, mechanism of action, levosimendan, was also studied in a large, Phase 3 study but failed to yield any meaningful benefits. 185 Other pathways involving muscle have attracted preclinical study that has not necessarily resulted in the study of therapeutics in ALS. Most notably, myostatin is secreted by myocytes and negatively regulates skeletal muscle growth through activin receptors.…”

Section: Musclementioning

confidence: 99%

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Maragakis,

de Carvalho,

Weiss

2023

Ann Clin Transl Neurol

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Numerous potential amyotrophic lateral sclerosis (ALS)‐relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS‐relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well‐established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.

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“…The study results did not show a remarkable difference in Slow-vital capacity in patients treated with ALS. Further studies are being conducted to evaluate the role of levosimendan in ALS treatment (Cudkowicz et al, 2021).…”

Section: Levosimendanmentioning

confidence: 99%

Emerging Therapies in Amyotrophic Lateral Sclerosis

Fawad

Tahir

2022

Mol. Med. Com.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of cortical and spinal motor neurons, leading to weakness, muscle atrophy, and, in a substantial number of patients, cognitive impairment. Most patients die within 2 to 5 years of diagnosis. The disease initiates from the death of upper and lower motor neurons leading to a degeneration of motor pathways and the paralytic effects of the disease. The disease has huge economic costs as well. FDA has approved two drugs, riluzole, and edaravone for the treatment of ALS. However, these drugs provide modest benefits in mortality and/or function. Recent developments in the understanding of the underlying pathophysiologic processes that contribute to ALS have led to the development of numerous investigational therapies, with several now in phase 3 trials. This article highlights the epidemiology, pathophysiology, and several current and emerging treatment options for ALS including stem cell therapy.

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Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial

Cited by 14 publications

References 16 publications

Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy

Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Emerging Therapies in Amyotrophic Lateral Sclerosis

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