tadnersen (BIIB078) / Ionis, Biogen - LARVOL DELTA

Antisense oligonucleotides are broadly distributed but do not provide sustained suppression of G4C2 pathology in c9ALS patients (ALS-MND 2024) - P1 | "This study resolves important knowledge gaps in our understanding of BIIB078 distribution and efficacy in patient tissues and provides evidence that despite broad BIIB078 ASO distribution throughout the CNS, G4C2 expansion pathology was not significantly altered"

Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders • NEFL • STMN2

Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study. (PubMed, Lancet Neurol) - P1 | "On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS."

Journal • P1 data • PK/PD data • Amyotrophic Lateral Sclerosis • Cardiovascular • CNS Disorders • Pain • Pulmonary Embolism • Respiratory Diseases

Identification of Artificial microRNAs Targeting C9orf72 Sense and Antisense Transcripts for ALS Treatment (ASGCT 2024) - "A recent clinical trial utilizing an oligonucleotide antisense (ASO, BIIB078) targeting the G4C2 sense repeat RNA assessed the hypothesis of gain of toxic function...Our preliminary characterization indicates a potential advantage in concurrently expressing miRNAs targeting both sense and antisense strands to lower C9orf72 expression. Dual silencers demonstrating efficacy in both assays are selected for future development of Adeno-Associated Virus (AAV) gene therapy to treat C9orf72 HRE-caused ALS."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Gene Therapies • TARDBP

Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB078 Administered to Previously Treated Adults C9ORF72-Associated Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P1 | N=75 | Terminated | Sponsor: Biogen | Trial completion date: Jul 2023 ➔ May 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jul 2023 ➔ May 2022; There was no evidence of benefit across efficacy endpoints in the randomized trial, 245AS101. Accordingly, Biogen has made the difficult decision to discontinue the BIIB078 program including this open label extension trial, 245AS102.

Trial completion date • Trial primary completion date • Trial termination • Amyotrophic Lateral Sclerosis • CNS Disorders

Biogen and Ionis Announce Topline Phase 1 Study Results of Investigational Drug in C9orf72 Amyotrophic Lateral Sclerosis (GlobeNewswire) - P1 | N=106 | NCT03626012 | Sponsor: Biogen | "In this Phase 1 study, BIIB078 was generally well-tolerated. The adverse events (AEs) were mostly mild to moderate in severity and occurred at a similar rate across BIIB078 and placebo groups. The most common AEs were fall, procedural pain and headache. BIIB078 did not meet any secondary efficacy endpoints and it did not demonstrate clinical benefit....Based on these results, the BIIB078 clinical development program will be discontinued, including its ongoing open-label extension study....The primary objective of the study was to assess safety and tolerability. Secondary efficacy endpoints included ALS Functional Rating Scale–Revised, Slow Vital Capacity, Hand-Held Dynamometry, and the Iowa Oral Pressure Instrument."

P1 data • Trial suspension • Amyotrophic Lateral Sclerosis • CNS Disorders

"📰🧪🔬📊 @biogen @ionispharma rilasciano i risultati dello studio fase 1 #BIIB078 per la #SLA #C9ORF72. Ringraziamo a tutti i partecipanti e i ricercatori per il loro impegno. 🇮🇹⬇️ https://t.co/pdkAqYYlUo" (@ConslancioOnlus)

Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB078 Administered to Previously Treated Adults C9ORF72-Associated Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P1 | N=90 | Active, not recruiting | Sponsor: Biogen | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders

A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 in Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1; N=106; Completed; Sponsor: Biogen; Active, not recruiting ➔ Completed

Clinical • Trial completion • Amyotrophic Lateral Sclerosis • CNS Disorders

A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 in Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1; N=114; Active, not recruiting; Sponsor: Biogen; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders

A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 in Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1; N=114; Recruiting; Sponsor: Biogen; Active, not recruiting ➔ Recruiting

Enrollment open • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders

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

First Patient Enrolled in Phase 1 Gene Therapy Study in Ireland (ALS News Today) - “A Phase 1 clinical trial of a gene-based therapy for amyotrophic lateral sclerosis (ALS) is now recruiting patients in one of its European centers.”

Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders

How Ionis' antisense drugs could help combat ALS and dementia (FierceBiotech) - “Many ALS and FTD cases are linked to the abnormal expansion of nucleotide G4C2 repeats in C9orf72, which results in the transcription of different proteins, including poly(GR). Antisense oligonucleotides—single-stranded RNAs that are designed to inhibit the translation of target mRNA into harmful proteins—are considered to be a promising approach to combating the problem. Biogen’s Ionis-partnered BIIB078, an antisense oligonucleotide targeting TDP-43, is in a phase 1 trial in adults with C9orf72-associated ALS, with data expected next year.”

P1 data • 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

Ionis reports first quarter 2020 financial results and recent business achievements (Streetinsider.com) - “Ionis Pharmaceuticals…today reported its financial results for the first quarter of 2020 and recent business highlights….Two medicines granted Fast Track Designation by the U.S. FDA…IONIS-C9Rx for the treatment of C9orf72-ALS…Initiate a first-in-human study of ION541 in patients with sporadic ALS, conducted by Biogen”

Fast track designation • New trial • Amyotrophic Lateral Sclerosis • CNS Disorders • Proteinopathy

"$BIIB fresh new pipeline? New programs MS:BTK inh SMA: BIIB078/110/100 Pain: BIIB095 Ophtalmology: BIIB111/112 Neurocognitive disorders: BIIB104 Out MS: BIIB098 Ophthalmolog: BIIB087 Acute neurology: Natalizumab AD: Elembecestast Switch Parkinson to AD & Dementia: BIIB092 https://t.co/Vr96h9huu9" (@BursatilBiotech)

Alzheimer's Disease • CNS Disorders • Dementia • Gene Therapies • Genetic Disorders • Movement Disorders • Pain • Parkinson's Disease • Tauopathies And Synucleinopathies

Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB078 Administered to Previously Treated Adults C9ORF72-Associated Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P1; N=90; Enrolling by invitation; Sponsor: Biogen; Not yet recruiting ➔ Enrolling by invitation

Enrollment open

Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB078 Administered to Previously Treated Adults C9ORF72-Associated Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P1; N=90; Not yet recruiting; Sponsor: Biogen

Clinical • New P1 trial

Ionis’ neurological franchise marks year of achievement (PRNewswire) - “Enrolling the first patient in a pivotal study of IONIS-HTTRx (RG6042) for patients with Huntington's Disease (HD) by Roche….Advancing tofersen, a drug designed to reduce production of superoxide dismutase 1 (SOD1) in patients with amyotrophic lateral sclerosis (ALS), to a phase 3 pivotal trial by Biogen…Advancing an ongoing study by Biogen of IONIS-C9Rx (BIIB078) targeting the C9orf72 mutation in ALS…”

Enrollment status • New P3 trial • Trial status

A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 in Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1; N=80; Active, not recruiting; Sponsor: Biogen; Trial completion date: Jul 2022 ➔ Sep 2021; Trial primary completion date: Jul 2022 ➔ Sep 2021

Clinical • Trial completion date • Trial primary completion date

A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 in Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1; N=80; Active, not recruiting; Sponsor: Biogen; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed