Table 1 Ongoing or completed clinical trials of gene therapies for ALS

ASO

Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS [62]

ClinicalTrials.gov number, NCT02623699

In each dose group (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive either 5 doses of toferson or placebo via intrathecal administration over 12 weeks

Primary outcomes: Safety and pharmacokinetics

Secondary outcomes: Changes in cerebrospinal fluid (CSF) SOD1 concentration relative to baseline on day 85

Reduced CSF SOD1 levels at peak levels within 12 weeks

Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS [63]

ClinicalTrials.gov number, NCT02623699

In this Phase 3 trial, adults with SOD1 ALS were randomized in a 2:1 ratio to receive either 8 doses of tofersen (100 mg) or placebo over 24 weeks

Primary outcome: Change from baseline to Week 28 in ALS Functional Rating Scale-Revised (ALSFRS-R) total score among participants predicted to have faster disease progression

Secondary outcome: Changes in total SOD1 protein concentration in CSF, concentration of neurofilament light chain (NfL) in plasma, forced vital capacity, and handheld dynamometry (HHD) of 16 muscle groups

Reduced SOD1 concentration in the CSF and NfL levels in the plasma over 28 weeks

No improvement of clinical endpoints

Associated with adverse events (AEs)

An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study [15]

Clinicaltrials.gov number, NCT01041222

Phase 1, double-blind, placebo-controlled, dose-escalation study. In this study, four dose levels (0.15, 0.5, 1.5, and 3 mg) of ISIS 333611 are sequentially evaluated. Each dose is administered at a rate of 0.25 mL/12 h. Each dose level is studied in a cohort of 8 patients, with 6 randomly receiving active treatment and 2 receiving placebo

Primary outcomes: safety, tolerability, and pharmacokinetics of the ISIS 333611 at four dose levels (safety analysis of dose escalation after Day 8 of the study)

Secondary outcome: NA

When administered intrathecally, the ISIS 333611 has good tolerability with no occurrence of severe AEs

Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD) (FOCUS-C9)

ClinicalTrials.gov number, NCT04931862

Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled study where the experimental group receives intrathecal administration of WVE-004, and the control group receives intrathecal administration of placebo

Primary outcome: Proportion of patients experiencing AEs

Secondary outcomes: Pharmacokinetics (concentration of WVE-004 in CSF) and pharmacodynamics (change in poly-GP levels in CSF relative to baseline)

NA (trial not completed)

Open-label Extension (OLE) Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD)

ClinicalTrials.gov number, NCT05683860

A multicenter, OLE study in which participants receive intrathecal administration of WVE-004

Primary outcome: Safety (number of patients experiencing AEs; number of patients experiencing serious AEs; number of patients who discontinue due to AEs)

Secondary outcomes: NA

NA (trial not completed)

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 number, NCT04288856

An extension study where BIIB078 will be administered in 3 doses during loading phase, approximately 2 weeks apart, followed by maintenance doses administered approximately every 4 weeks via intrathecal infusion

Primary outcome: Number of participants experiencing AEs

Secondary outcomes: Serum concentration of BIIB078; CSF concentration of BIIB078

NA (trial not completed)

A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 in Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis [226]

ClinicalTrials.gov number, NCT03626012

A Phase 1 multiple ascending dose study where BIIB078 is administered in 6 cohorts. The experimental group receives a loading regimen of 3 doses on the first day and subsequently for two more days, followed by 5 maintenance doses over the next five days

The control group receives placebo, with different dosing schedules across cohorts

Primary outcomes: number of participants experiencing AEs and serious adverse events (SAEs)

Secondary outcomes: serum concentration of BIIB078; area under the concentration–time curve from time 0 to infinity (AUC_inf); area under the concentration–time curve from time 0 to the last measurable concentration (AUC_last); maximum observed concentration (C_max); time to reach C_max (T_max); terminal elimination half-life (t_1/2); change from baseline in ALSFRS-R score; change from baseline in percent predicted slow vital capacity (SVC); change from baseline in muscle strength; change from baseline in bulbar strength

Compared to the placebo group, patients in the BIIB078 treatment group showed no reduction in neurofilament levels and did not benefit in terms of clinical outcomes

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 number, NCT04768972

A multicenter Phase 1–3 study where the experimental group receives ION363 via lumbar intrathecal infusion every 12 weeks. In the first part, there is a 60-week double-blind treatment period with additional loading doses at 4 weeks. The open-label extension (Part 2) continues for 84 weeks with doses every 12 weeks and an additional loading dose 4 weeks after the first dose. In Part 3, patients may continue open-label ION363 every 12 weeks for up to 3 years, until ION363 is approved in their country/region, or until the sponsor terminates the development program, whichever is earlier

The control group receives placebo via lumbar IT infusion every 12 weeks with an additional loading dose at 4 weeks during the 60-week double-blind treatment period (Part 1)

Primary outcome: change in functional disability from baseline (Day 1 of Part 1) to day 505 of the study

Secondary outcomes: Change from baseline to day 505 of the study in Amyotrophic Lateral Sclerosis Specific Quality of Life—Revised (ALSSQOL-R) score; survival and ventilation-free survival; clinical SVC, HHD, concentration of NfL in CSF, and concentration of FUS in CSF

NA (trial not completed)

A Study to Assess the Safety, Tolerability, and Effect on Disease Progression of BIIB105 in Participants With Amyotrophic Lateral Sclerosis (ALS) and Participants With the ALS Ataxin-2 (ATXN2) Genetic Mutation (ALSpire)

ClinicalTrials.gov number, NCT04494256

A Phase 1/2 multiple ascending dose study with a long-term open-label extension. In the experimental group, during Part 1, participants receive BIIB105 intrathecally as 3 loading doses over the first day and the following two days, followed by two maintenance doses over the subsequent two days. In Part 2, dosing continues according to cohorts

The control group receives placebo administered according to cohort schedules

Primary outcome: number of participants experiencing AEs and SAEs

Secondary outcomes for different parts:

Part 1: Serum and CSF concentration of BIIB105; Area under the concentration–time curve from time 0 to infinity (AUC_inf) of serum concentration; Area under the concentration–time curve from time 0 to the last measurable concentration (AUC_last) of serum concentration; etc

Part 1 combined with Part 2: Serum concentration of BIIB105; Change from baseline in plasma NfL levels; etc

NA (trial not completed)

RNAi

Safety, Tolerability, and Exploratory Efficacy Study of Intrathecally Administered Gene Therapy AMT-162 in Adult Participants With SOD1 Amyotrophic Lateral Sclerosis (SOD1-ALS)

ClinicalTrials.gov number, NCT06100276

Phase 1/2 multicenter, single ascending dose study exploring three dose levels of AMT-162, with approximately 6 to 12 participants in total. Each participant receives a single dose of AMT-162 via intrathecal infusion and will undergo follow-up for up to 5 years following administration of AMT-162

Primary outcome: safety and tolerability of intrathecal administration of AMT-162 in participants with SOD1-ALS

Secondary outcomes: immune responses to AMT-162 and dropout rates following intrathecal administration of AMT-162; efficacy of intrathecal AMT-162, including changes from baseline in percent predicted SVC, HHD scores, and serum levels of NfL protein

NA (trial not completed)

Safety and Tolerability of RAG-17 in the Treatment of Amyotrophic Lateral Sclerosis Patients With SOD1 Gene Mutation

ClinicalTrials.gov number, NCT06556394

An open-label, single-center, first-in-human dose escalation study where patients initially receive 60 mg of RAG-17. If within 14 days following the first dose there are no AEs or SAEs, patients may proceed to dose escalation every 30 mg every 14 days during an observation period. The study plans to increase doses 3 to 4 times until reaching the dose-limiting toxicity, with the optimal dose used for a continuous 6-month treatment period. Subsequent doses for continuous treatment will be selected between the safe dose and maximum tolerated dose as the optimal continuous treatment dose

Primary outcomes: AEs and SAEs;

Clinical laboratory parameters (blood and urine tests);

Physiological parameters—vital signs;

Revised ALSFRS-R;

System-specific examinations (neurological, respiratory, digestive, circulatory);

Electrocardiogram results.

Secondary outcomes: SOD1 protein levels;

Plasma NFL levels;

Pharmacokinetic changes of RAG-17;

Mechanical ventilation time;

Mortality.

NA (trial not completed)

CRISPR-Cas9

NA

NA

NA

NA