Because of these encouraging results, VALOR participants were moved to the ongoing open-label extension trial of tofersen (ClinicalTri-als.gov Identifier: NCT03070119), in which both groups were treated with the active agent.
These data suggest that early tofersen treatment might slow decline in faster-progressing patients and stabilize clinical function in slower-progressing patients.18,19 Overall, most adverse events (AEs) in the trial among patients receiving active treatment were of mild or moderate severity, and were largely consistent with either disease progression or lumbar puncture–related complications.18
Because data from VALOR suggested potential benefit from tofersen, the ATLAS trial (ClinicalTrials.gov Identifier: NCT04856982) is investigating the clinical value of presymptomatic treatment and the optimal timing of initiation of therapy.20,21 ATLAS is a phase 3, randomized, placebo-controlled trial that examines the clinical efficacy, safety, and tolerability of tofersen in presymptomatic adult carriers of SOD1 mutation who have an elevated neurofilament light-chain concentration.21 ATLAS will also evaluate the efficacy of tofersen when initiated before, rather than after, ALS manifests clinically. Enrollment is still open for this trial.20,21
Latozinemab, also known as AL001, is a first-in-class monoclonal antibody, administered by IV infusion, that elevates levels of progranulin, a key regulator of the immune activity and lysosomal function in the brain.22,23 Latozinemab limits progranulin endocytosis and degradation by sortilin inhibition.22 Progranulin gene mutations can reduce progranulin expression (by 50 to 70 percent reduction), which may cause neuro-degeneration due to abnormal accumulation of TAR-DNA-binding protein 43 (TDP-43) in the brain cells.22,24 TDP-43 pathology has also been shown to be associated with C9orf72 mutations.23 Although the mechanism is not fully understood, the role of progranulin deficiency in TDP-43 pathology is believed to be associated with neurodegenerative diseases like ALS.11,23,24,43 Previous animal models of chronic neurodegenera-tion have demonstrated how increased progranulin levels can be protective against TDP-43 pathology, increasing neuronal development and survival, thus potentially slowing disease progression.23,24,43 Currently, latozinemab is being investigated in a randomized, double-blind, placebo-controlled, multicenter phase 2 trial (ClinicalTrials.gov Identifier: NCT05053035). Approximately, 45 C90rf72-associated ALS participants (≥ 18 years of age) will receive latozinemab or placebo infusions every 4 weeks (for 24 weeks). Study endpoints include safety, tolerability, PK, PD, as well as plasma, and CSF progranulin levels.25 In previous studies, latozinemab demonstrated encouraging results in frontotemporal dementia (FTD) patients who carry a progranulin mutation. Because FTD was revealed to have significant genetic overlap with ALS, there is disease-modifying potential for latozinemab in ALS patients.23,24
TPN-101 is a nucleoside analog reverse transcriptase inhibitor, administered orally, that was originally developed for human immunodeficiency virus (HIV) treatment. However, due to recent findings suggesting retrotransposon activity contributing to neurodegeneration in TDP-43 mediated diseases, including ALS and FTD, TNP-101 is being repurposed.26 The safety and tolerability of TNP-101 are currently being evaluated in C9orf72-associated ALS and FTD patients (≥ 18 years of age). The study is a randomized, double-blind, placebo-controlled paral-lel-group phase 2a trial (ClinicalTrials.gov Identifier: NCT04993755) The study includes a screening period of 6 weeks, double-blind treatment period of 24 weeks, an open-label treatment period of 24 weeks, and 4 weeks of the post-treatment follow-up visit. Study endpoints include the incidence and severity of spontaneously reported treatment-emergent adverse events (TEAEs) associated with TNP-101 and placebo for a to-tal of 48 weeks.27
ION363 is an investigational ASO, administered by IT injection, that selectively targets one of the FUS mutations (p.P525L), which is responsible for earlier disease onset and rapid ALS progression.28,29 The clinical efficacy of ION363, specifically in clinical function and survival is being assessed in FUS-associated ALS patients (≥ 12 years of age). This randomized phase 3 study (ClinicalTrials.gov Identifier: NCT04768972) includes two parts; part 1 will consist of participants receiving a multi-dose regimen (1 dose every 4-12 weeks) of ION363 or placebo for 61 weeks followed by an open-label extension treatment period in part 2, which will consist of participants receiving ION363 (every 12 weeks) for 85 weeks. The primary endpoint of the study is the change from baseline to day 505 in functional impairment, using ALS Functional Rating Scale-Revised (ALSFRS-R). This measures functional disease severity, specifically in bulbar function, gross motor skills, fine motor skills, and respiratory. The score for all 12 questions can range from 0 (no function) to 4 (full function) with a total possible score of 48.30
Engensis, also known as VM202, is a non-viral gene therapy, administered by intramuscular (IM) injection, that uses a plasmid to deliver the hepatocyte growth factor (HGF) gene to promote HGF protein production. The HGF protein plays a role in angiogenesis, the previous of muscle atrophy, and the promotion of neuronal survival and growth. Based on preclinical studies, increasing HGF protein production has been shown to reduce neurodegeneration, thus potentially halting or slowing ALS progression.31 Currently, the safety of engensis is being evaluated in ALS patients (18-80 years of age) in the REViVALS phase 2a (ClinicalTrials.gov Identifier: NCT04632225)/2b (ClinicalTrial.gov Identifier: NCT05176093).32,33 The ReViVALS trial is a double-blind, randomized, placebo-controlled, multi-center study. The phase 2a study endpoints include the incidence of TEAEs, treatment-emergent serious adverse events (TESAEs), injection site reactions, and clinically significant labor-atory values post-treatment (engensis vs placebo group) for 180 days.33 A phase 2b study will evaluate the long-term safety of engensis for an additional 6 months. Study endpoints include the incidence of AEs, changes from baseline in ALSFRS-R scores to evaluate improvement in muscle function, changes from baseline in quality of life using the ALS patient assessment questionnaire, time to all-cause mortality compared to placebo, etc.32
Spinal muscular atrophy
SMA is a hereditary lower motor-neuron disease caused (in 95% of cases) by deletions or, less commonly, by mutations of the survival motor neuron 1 (SMN1) gene on chromosome 5q13 that encodes the SMN protein.6 Reduction in expression of the SMN protein causes motor neurons to degenerate.36-38 Because of a large inverted duplication in chromosome 5q, two variants of SMN (SMN1 and SMN2) exist on each allele. The paralog gene, SMN2, also produces the SMN protein – although at a lower level (10% to 20% of total SMN protein production) than SMN1 does.
A single nucleotide substitution in SMN2 alters splicing and suppresses transcription of exon 7, resulting in a shortened mRNA strand that yields a truncated SMN protein product.6,37,39 SMA is classified based on age of onset and maximum motor abilities achieved, ranging from the most severe (Type 0) to mildest (Type 4) disease.36,40 Because SMA patients lack functional SMN1 (due to polymorphisms), disease severity is determined by copy numbers of SMN2.6,39