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Clinical Trial
. 2023 Jan;30(1):69-86.
doi: 10.1111/ene.15573. Epub 2022 Oct 7.

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial

Ettore Beghi  1 , Elisabetta Pupillo  1 , Elisa Bianchi  1 , Valentina Bonetto  1 , Silvia Luotti  1 , Laura Pasetto  1 , Caterina Bendotti  1 , Massimo Tortarolo  1 , Francesca Sironi  1 , Laura Camporeale  1 , Alexander V Sherman  2 , Sabrina Paganoni  3   4 , Ada Scognamiglio  5 , Fabiola De Marchi  5 , Paolo Bongioanni  6 , Renata Del Carratore  7 , Claudia Caponnetto  8 , Luca Diamanti  9 , Daniele Martinelli  9 , Andrea Calvo  10 , Massimiliano Filosto  11 , Alessandro Padovani  11 , Stefano Cotti Piccinelli  11 , Claudia Ricci  12 , Stefania Dalla Giacoma  12 , Nicoletta De Angelis  12 , Maurizio Inghilleri  13 , Rossella Spataro  14 , Vincenzo La Bella  14 , Giancarlo Logroscino  15   16 , Christian Lunetta  17 , Claudia Tarlarini  17 , Jessica Mandrioli  18   19 , Ilaria Martinelli  19   20 , Cecilia Simonini  19 , Elisabetta Zucchi  19   21 , Maria Rosaria Monsurrò  22 , Dario Ricciardi  22 , Francesca Trojsi  22 , Nilo Riva  23 , Massimo Filippi  23 , Isabella Laura Simone  24 , Gianni Sorarù  25 , Cristina Spera  26 , Lucia Florio  27 , Sonia Messina  28 , Massimo Russo  28 , Gabriele Siciliano  29 , Amelia Conte  30 , Maria Valeria Saddi  31 , Nicola Carboni  31 , Letizia Mazzini  5 ; RNS60-ALS Study Group
Collaborators, Affiliations
Clinical Trial

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial

Ettore Beghi et al. Eur J Neurol. 2023 Jan.

Abstract

Background and purpose: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials.

Methods: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed.

Results: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60.

Conclusions: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.

Keywords: ALS; clinical trial; placebo-controlled; randomized; treatment.

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Conflict of interest statement

E. Beghi reports grants from the Italian Ministry of Health, grants from SOBI, personal fees from Arvelle Therapeutics, outside the submitted work. E. Beghi reports grants from American ALS Association for the conduct of the present study. E. Pupillo reports grants from the Italian Ministry of Health, grants from AIFA, outside the submitted work. A. Sherman reports research grants from the ALS Association, ALS Finding a Cure and the NIH, outside the submitted work. S. Paganoni reports research grants from Amylyx Therapeutics, Revalesio Corporation, UCB/Ra Pharma, Biohaven, Clene, Prilenia, Seelos, the ALS Association, the American Academy of Neurology, ALS Finding a Cure, the Salah Foundation, the Spastic Paraplegia Foundation, the Muscular Dystrophy Association and reports personal consulting fees for advisory panels from Orion and Cytokinetics. All of them are outside the submitted work. M. Filosto reports serving on a scientific advisory board for Amicus, Sanofi, Sarepta; honoraria for speaking engagements for Sanofi, Alnylam. All of them are outside the submitted work.

A. Padovani serves on a scientific advisory board: Director of School of Neurology, University of Brescia; President‐elect of the National Society of Neurology SIN; GE Healthcare, Lilly and Actelion Ltd Pharmaceuticals. Travel funded by a commercial entity: Roche, Ely‐Lilly, Biogen, Zambon, Nutricia, Lundbeck. Serving as a journal editor, associate editor, or on an editorial advisory board: MDPI. Patents held or pending: Method of generation of a diagnostic index for Alzheimer's disease, electronic device for implementing the method and system, 2016. Honoraria for speaking engagements: He has received honoraria from Nutricia, PIAM, Langstone Technology, GE Healthcare, Lilly and Chiesi. Commercial research support: Advisory and served on the Scientific Advisory Board for GE Healthcare, Lilly and Actelion Ltd Pharmaceuticals. Government research support (including funding organization, grant number, and role): He has participated as PI in more than 30 research projects funded by the Ministry of Health and MIUR. Support from a non‐profit foundation or society: CHDI Foundation, Fondazione Cariplo. All of them are outside the submitted work.

G. Logroscino received funds from Roche, Amplifon; he received travel funds for participation in a congress as speaker. All of them are outside the submitted work. C. Lunetta received compensation for consulting services from Neuraltus, Cytokinetics, Mitsubishi Tanabe Pharma Europe and Italfarmaco and has received funds from ARISLA and Italian Ministry of Health. All of them are outside the submitted work. J. Mandrioli received research grants from Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (ARISLA), the Agenzia Italiana del Farmaco (AIFA), the Italian Ministry of Health, Emilia Romagna Regional Health Authority, Roche, Pfizer. All of them are outside the submitted work. F. Trojsi served as a journal editor, associate editor, or on an editorial advisory board: Associate Editor of Frontiers in Neuroscience/Frontiers in Neurology (section Neurodegeneration) (2017–today) and Orphanet Journal of Rare Diseases (BMC/ Springer Nature) (2021); Academic Editor of Brain Sciences (MDPI Ed.) (2021). Fee for consultant: Alnylam Italy Srl (2020). All of them are outside the submitted work.

All other authors report no disclosures.

Figures

FIGURE 1
FIGURE 1
Study flow‐chart: screening, randomization and follow‐up
FIGURE 2
FIGURE 2
Effect plots for MCP‐1, IL‐17, NfL, FOXP3 mRNA at different visit times (in weeks) in each treatment arm (ITT population)
FIGURE 3
FIGURE 3
Effect plots for FVC, FEV1, ALSFRS‐R, ALSAQ40 (eating and drinking) at different visit times (in weeks) in each treatment arm (ITT population)
FIGURE 4
FIGURE 4
Effect plots for NfL and FVC at different visit times in each treatment arm by site of onset (ITT population)
See this image and copyright information in PMC

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