ulefnersen (ION363) / Ionis, Otsuka - LARVOL DELTA

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

"We also entered our late-stage pipeline with the initiation of pivotal studies for ION363 in patients with FUS-#ALS. And the ION373 in patients with #Alexandersdisease. #raredisease #neurotwitter #MedTwitter #neurolgy #ALSAwarenessMonth $ions $biib" (@IonisDisrupts)

Clinical • Amyotrophic Lateral Sclerosis • Rare Diseases

[VIRTUAL] Ethical Issues in Individualized Antisense Oligonucleotide Therapies (ASGCT 2021) - "In fact, that year saw the development of two custom-made ASO therapies, both for ultrarare neurological disorders: milasen, named for a girl with a unique genetic mutation associated with Batten disease, and jacifusen, named for a young woman with an extremely rare mutation associated with early onset ALS...The justice questions will be much harder to manage, given the enduring inequities in access to healthcare in the US and globally. Educating all stakeholders in individualized ASOs about the attendant ethical considerations will go a long way toward establishing policies and practices to protect the safety of and ensure justice for patients."

Clinical • CNS Disorders • Gene Therapies

"For Ion 363-Jacifusen, we need Expanded Access Programa too." (@Ana99788279)

Ionis initiates Phase 3 trial of novel antisense medicine to treat leading cause of juvenile-onset ALS (PRNewswire) - “Ionis Pharmaceuticals…announced the initiation of a Phase 3 clinical trial of ION363 in patients with amyotrophic lateral sclerosis (ALS) with mutations in the fused in sarcoma gene (FUS)....Part one of the trial will consist of patients randomized to receive a multi-dose regimen of ION363 or placebo for 29 weeks, followed by part two, which will be an open-label period in which all patients in the trial will receive ION363 for 73 weeks.”

New P3 trial • Amyotrophic Lateral Sclerosis • CNS Disorders

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=64; Recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Enrollment open • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • 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) (clinicaltrials.gov) - P3; N=64; Not yet recruiting; Sponsor: Ionis Pharmaceuticals, Inc.

Clinical • New P3 trial • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Oncology • Sarcoma • Solid Tumor • FUS

Ionis Pharmaceuticals, Inc. (IONS) Q3 2020 Earnings Call Transcript (The Motley Fool) - “The Phase 1/2 study of ION541, our first medicine designed to address nearly all forms of ALS regardless of family history, is well under way. The Phase 3 study of Tofersen in patients with SOD1-ALS is progressing with data expected in the second half of next year.…Biogen plans to initiate a study of Tofersen in pre-symptomatic SOD1-ALS patients with the potential to delay or prevent disease onset. The Phase 1/2 study of IONIS-C9Rx in patients with C9-ALS remains on track for data next year. And ION363, our first Ionis-owned ALS medicine for the treatment of ALS patients with mutations in the FUS gene, remains on track to enter a registrational study next year.”

New trial • P1/2 data • P3 data • Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders

Ionis Is A Long On Neurological Medicines Pipeline (SeekingAlpha) - “Tofersen: Phase 3 VALOR study underway (data expected 2021). IONIS-C9Rx: Phase 1/2 study ongoing in C9- familial ALS (data expected 2021). ION363, Ionis-owned targeting FUS on track to initiate a Phase 1/2 study in FUS-ALS in late 2020/early 2021. ION541 targeting ATXN2 in sporadic ALS on track to initiate a Phase 1/2 study in 2H20.”

New P1/2 trial • P1/2 data • P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders

Collaboration funds experimental therapy for rare FUS-ALS (ALS News Today) - “Eight patients will receive jacifusen, an experimental therapy for amyotrophic lateral sclerosis (ALS) caused by FUS gene mutations, under a joint effort from the ALS Association, Project ALS, and Columbia University’s Eleanor and Lou Gehrig ALS Center. The new clinical research program, which will be supported by a two-year, $900,000 commitment from the ALS Association and Project ALS, aims to be the first step in developing a comprehensive strategy to treat rare forms of ALS.”

Financing • Licensing / partnership

ALS association, project ALS to fund drug trial for ALS patients with rare gene mutations (Eurekalert) - “The drug, called jacifusen, is an investigational therapy for patients with mutations in a gene called FUS. Such gene mutations cause some of the most aggressive forms of ALS... The ALS Association is providing $650,000 for the project and Project ALS is providing $250,000. Additional support for ongoing pre-clinical studies of jacifusen and FUS-associated ALS…”

Biomarker • Financing