ulefnersen (ION363) / Ionis, Otsuka - LARVOL DELTA

Otsuka Announces Transformative Phase 3 FUSION Results for Ulefnersen, Bringing the FUS-ALS Community Closer to a Potential Targeted Treatment (Businesswire) - "The study met its primary endpoint, with ulefnersen demonstrating a statistically significant improvement on the primary endpoint assessing functional impairment and survival using a joint rank analysis of time to death or permanent ventilation, time to rescue and change in ALS Functional Rating Scale Revised (ALSFRS-R) score from baseline to Day 505 compared to placebo (p=0.0005), providing evidence from the first-ever placebo-controlled clinical study targeting the underlying genetic cause of FUS-ALS."

P3 data: top line • Amyotrophic Lateral Sclerosis

Update and recommendations on genetic testing for amyotrophic lateral sclerosis in clinical practice: a Brazilian expert view. (PubMed, Front Neurol) - "Establishing the underlying genetic basis in both sporadic and familial ALS is essential, as it enables individualized and family genetic counseling, facilitates the early identification of at-risk or oligosymptomatic relatives, improves the prediction of gene-specific clinical trajectories, and, more recently, determines eligibility for gene-targeted therapies, such as tofersen for SOD1-associated ALS and ulefnersen, currently under clinical investigation, for FUS-associated ALS. However, accumulating clinical evidence has increasingly supported the timely and early implementation of genetic testing as part of the standard clinical management of patients with ALS. In this article, we present the perspective of leading Brazilian neurologists specializing in ALS care regarding the current role of genetic testing in clinical practice."

Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • FUS

Clinical Course Of FUS-ALS: A Retrospective Analysis Of Clinical And Genetic Modifiers (ENCALS 2026) - "NH00004 was designed to characterize the clinical course in a trial-relevant population to inform development of targeted therapies such as ION363.Material and methods NH00004 was a predominantly retrospective, temporally relevant (onset of ALS symptoms ≥January 2000) chart review study including 147 subjects with FUS-ALS from 13 global sites...Restricting to subjects with reported riluzole use did not materially change median event-free estimates (2.2 years, n=53). Among 77 subjects with total ALSFRS-R scores, mean (SD) slope was −1.2 (1.16) points/month. Event rates per 100 subject-years were IV (6.0), NIV (11.4), and PEG (9.1).Conclusion These findings define potential clinical modifiers of progression and provide a well-curated, trial-eligible dataset aligned with interventional criteria to serve as an untreated reference comparator."

Retrospective data • Amyotrophic Lateral Sclerosis • CNS Disorders • Sarcoma • Solid Tumor • FUS

Design & Methodology of FUSION, a Study to Assess Efficacy and Safety of Antisense Oligonucleotide Ulefnersen in Amyotrophic Lateral Sclerosis with Fused in Sarcoma (FUS-ALS) Mutations (ENCALS 2026) - P3 | "Stable background therapies such as riluzole or edaravone are permitted. Results Enrollment is complete with conduct ongoing (ClinicalTrials.gov: NCT04768972). Conclusion This study addresses the substantial unmet need in FUS-ALS, a fatal disease with no available targeted treatments, by evaluating a mutation-specific approach designed to directly address the underlying disease process and potentially alter disease progression."

Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Sarcoma • Solid Tumor • FUS • NEFL

Targeting fused in sarcoma (FUS): a novel antisense strategy for treating idiopathic pulmonary fibrosis. (PubMed, Signal Transduct Target Ther) - "Standard-of-care treatments (pirfenidone, nintedanib) reduced FUS expression in PCLs. In contrast, ION363 promoted functional marker expression and improved morphology in patient-derived 3D alveolospheres. We conclude that FUS is a pivotal regulator of fibrotic signaling in IPF and that targeting FUS via ASO represents a promising therapeutic avenue for IPF."

Journal • CNS Disorders • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • Sarcoma • Solid Tumor • FUS

Ulefnersen for the treatment of FUS-ALS granted U.S. Fast Track designation (Businesswire)

Fast track • Amyotrophic Lateral Sclerosis

2026 Anticipated Highlights Include (Businesswire) - "Results from FUSION study of ulefnersen for Fused in Sarcoma (FUS) Amyotrophic Lateral Sclerosis (ALS) (Otsuka)...Multiple Phase 2 data readouts, including IONIS-MAPTRx (BIIB080) in Alzheimer’s disease (AD) (Biogen) and new Phase 3 clinical trial initiations."

Clinical data • New P3 trial • Alzheimer's Disease • Amyotrophic Lateral Sclerosis

Longitudinal profiling of transcriptomic and proteomic changes in biofluids of FUS-ALS patients treated with FUS antisense oligonucleotide (ALS-MND 2025) - "These toxic, insoluble aggregates are strongly implicated in FUS-ALS pathogenesis ( 2 ), which has led to the development of jacifusen, a FUS-silencing antisense oligonucleotide (ASO) therapy for FUS-ALS ( 3 , 4 )...ScRNA-seq revealed a shift over the course of treatment in which CD4þ T cells are reduced in CSF and PBMCs and myeloid cells are increased (i.e., CSF dendritic cells and PBMC CD14þ monocytes). Together with flow cytometry data, proportions of cytotoxic CD4þ and CD8þ T cells in PBMCs correlated negatively with CSF NfL concentration and positively with ALSFRS-R. Indeed, we observed consistently high levels of cytotoxic memory and effector T cells in a presymptomatic carrier."

Clinical • Amyotrophic Lateral Sclerosis • Sarcoma • Solid Tumor • CSF NfL • FUS • NEFL

FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS) (clinicaltrials.gov) - P3 | N=89 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders • Oncology • Sarcoma • Solid Tumor • FUS

Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series. (PubMed, Lancet) - "The findings suggest the safety and possible efficacy of jacifusen for treating FUS-ALS. The efficacy of jacifusen is being further evaluated in an ongoing clinical trial."

Journal • Amyotrophic Lateral Sclerosis • Back Pain • CNS Disorders • Muscular Dystrophy • Musculoskeletal Pain • Oncology • Pain • Sarcoma • Solid Tumor • FUS • NEFL

Jacifusen for FUS-ALS: molecular effects and clinical outcomes in a case series. (PubMed, Lancet) - No abstract available

Clinical data • Journal

Otsuka gains global licensing rights from Ionis to ulefnersen (The Pharma Letter) - "Otsuka Pharmaceutical...announced that it has entered into an exclusive worldwide licensing agreement with Ionis Pharmaceuticals...for rights to manufacture and market Ionis' ulefnersen (ION363), a drug candidate under development for the treatment of patients with amyotrophic lateral sclerosis (ALS) caused by mutation of the fused in sarcoma (FUS) gene."

Licensing / partnership • Amyotrophic Lateral Sclerosis • CNS Disorders

Longitudinal analysis of immune cell changes in FUS- ALS patients treated with a FUS antisense oligonucleotide (ALS-MND 2024) - "Objectives: Now, the efficacy of FUS ASO (i.e. jacifusen) is being tested further in an expanded access program in which paired blood and CSF samples are collected... Analysis of sequencing data revealed significant changes to immune cell (e.g. cytotoxic T cell) frequencies, phenotypes, and clonal expansion across treatment, highlighting a biphasic trajectory with a more inflammatory stage at earlier, compared to later, treatment time points. Validation approaches highlighted further differences between participants who did and did not have an observable response to treatment."

Clinical • Immune cell • IO biomarker • Amyotrophic Lateral Sclerosis • CNS Disorders • Oncology • Sarcoma • Solid Tumor • FUS

Biogen and Ionis Announce Topline Phase 1/2 Study Results of Investigational Drug in Amyotrophic Lateral Sclerosis (GlobeNewswire) - P1/2 | N=99 | ALSpire (NCT04494256) | Sponsor: Biogen | "Biogen Inc...announced the decision to terminate development of BIIB105 (ION541) an investigational antisense oligonucleotide (ASO) for amyotrophic lateral sclerosis (ALS) based on topline results from the Phase 1/2 ALSpire study. BIIB105 was designed to reduce expression of ataxin-2 (ATXN2) protein...However, over the 6-month placebo-controlled period, treatment with BIIB105 did not result in a reduction in levels of plasma neurofilament light chain (NfL), a marker of neurodegeneration and neuronal damage. Additionally, BIIB105 did not demonstrate an impact on clinical outcome measures of function, breathing, and strength...'Ionis continues to be committed to the ALS community and is advancing our Phase 3 ulefnersen program.'....The companies will present the BIIB105 Phase 1/2 data at the upcoming European Network to Cure ALS..."

Clinical • Discontinued • P1/2 data • Amyotrophic Lateral Sclerosis • CNS Disorders

Frequency of SOD1 and FUS mutations in a multicenter screening program in Germany – implication for early access program and clinical trial enrollment (ALS-MND 2023) - "Background: Genetic testing of ALS patients is becoming increasingly relevant – given the treatment option with the antisense oligonucleotide (ASO) Tofersen for SOD1-related ALS, the ongoing clinical trial for FUS-related ALS (ION363 study) and the emerging of other gene-related interventions. In an observational period of only 18 months, 1514 patients were included in the genetic screening program. 38 patients with SOD1 mutation were found (2.5%). Most SOD1 mutation carriers (75%) had no family history of ALS and were therefore classified as apparently sporadic ALS."

Clinical • Alzheimer's Disease • CNS Disorders • Dementia • FUS • SOD1

Allele selective FUS targeted antisense oligonucleotide therapeutic development for ALS (ALS-MND 2023) - P3 | "An AO therapeutic that reduces FUS expression is currently undergoing clinical trial for FUS-ALS (ION363, NCT04768972) and shows significant promise, reducing expression of all FUS transcripts... TMOs were significantly more allele selective than MOE modified gapmers of the same sequences, as measured by droplet digital PCR. For example, 72 hours post-transfection with a lead AO sequence (CV1b) at 10 nM, expression of the non-target allele was not significantly different from control treated cells for the MOE or TMO. There was, however, significantly more reduction of the target allele after transfection with the TMO, with expression at 17.1% of control levels compared to the 35.9% seen with the MOE (p = 0.038)."

Amyotrophic Lateral Sclerosis • FUS

A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS) (clinicaltrials.gov) - P3 | N=77 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Sep 2025 ➔ Mar 2028 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders • Oncology • Sarcoma • Solid Tumor • FUS

Orphan Designation: Treatment of amyotrophic lateral sclerosis (ALS) (FDA) - Date Designated: 08/15/2023

Orphan drug • Amyotrophic Lateral Sclerosis • CNS Disorders

"Anna….a story of hope fulfilled. https://t.co/OMz7adkFhU #endALS #jacifusen #FusALS #mnd #genetic #ALS #Neurology @alsnewstoday @n_lorem @ColumbiaMed @NYTHealth @gatesfoundation @JAMANeuro @CBSHealth @HuffPostScience @novapbs @ProjectALSorg @harvardmed" (,@mRNAdisrupts)

Amyotrophic Lateral Sclerosis

"We are on the same ION363 protocol as Anna! #Jacifusen" (,@TeamJacobWV)

"It’s my privilege! In memory of @JaciHerm_22 💖 #Jacifusen #ALS warrior. @BPMonia @DrStanleyCrooke @alsadvocacy @alsnewstoday @RareDiseases @n_lorem" (,@mRNAdisrupts)

Amyotrophic Lateral Sclerosis • Rare Diseases

A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS) (clinicaltrials.gov) - P3 | N=77 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Mar 2024 ➔ Sep 2025 | Trial primary completion date: Mar 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders • Oncology • Sarcoma • Solid Tumor • FUS

Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. (PubMed, Nat Med) - "In a patient with ALS with a FUSP525L mutation, we provide preliminary evidence that repeated intrathecal infusions of ION363 lower wild-type and mutant FUS levels in the central nervous system, resulting in a marked reduction in the burden of FUS aggregates that are a pathological hallmark of disease. In mouse genetic and human clinical studies, we provide evidence in support of FUS silencing as a therapeutic strategy in FUS-dependent ALS and FTD."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology • Oncology • Sarcoma • Solid Tumor • FUS

A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS). (clinicaltrialsregister.eu) - P2/3; N=64; Sponsor: Ionis Pharmaceuticals, Inc.

Clinical • New P2/3 trial • Amyotrophic Lateral Sclerosis • CNS Disorders • Oncology • Sarcoma • Solid Tumor • FUS

[VIRTUAL] SESSION 363: Benefits of Remote Management and Patient-reported Outcomes in Delivering CPAP Therapy (ERS 2021) - No abstract available

Clinical • Patient reported outcomes