Developed by Wave Life Sciences, the trial of the investigational treatment, WVE-004, seeks to identify ideal dose level and frequency in patients with C9orf72-associated amyotrophic lateral sclerosis and FTD.
Dosing for multiple patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia began this month, as the phase 1b/2a FOCUS-C9 trial (NCT04931862) kicked off to study the efficacy of WVE-004, an investigational treatment for C9orf72-associated ALS (C9-ALS) and FTD (C9-FTD).
The trial is anticipated to enroll 50 participants, with dose escalation and dosing frequency dependent on analysis from an independent data safety monitoring board. Additional clinical data is expected to be generated through 2022.
Developed by Wave Life Sciences, WVE-004 is a stereopure antisense oligonucleotide, which was designed to target variants containing G4C2, a hexanucleotide repeat expansion associated with the C9orf72 gene. As one of the most common genetic causes of ALS and FTD, both sporadic and inherited, expansion of G4C2 in C9orf72 may be the cause of increased repeat-containing RNA transcripts and abnormally translated dipeptide repeat proteins (DPRs), further leading to neurotoxicity and insufficient C9orf72 protein levels.
The global, multicenter, randomized, double-blind, placebo-controlled trial will assess safety and tolerability of single- and multiple-ascending intrathecal doses of WVE-004, which showed a decrease in repeat-containing RNA transcripts in the spinal cord and cortex during pre-clinical animal trials. Investigators also saw a 90% decrease in dipeptide repeat proteins (DPRs) in the spinal cord and an 80% decrease of DPRs in the cortex during the preclinical phase. C9orf72 protein levels remain relatively unchanged; however, investigators found that reductions in DPRs persisted for at least 6 months.
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According to Michael Panzara, MD, MPH, chief medical officer and head of therapeutics discovery and development, Wave Life Sciences; and Merit Cudkowicz, MD, MSc, chair of the clinical advisory board for the FOCUS-C9 trial, the study is unique due to its adaptive, basket design, which includes people with 2 different forms of C9orf72 mutations, related to either ALS of FTD. Cudkowicz, who is also director of the Sean M. Healey & AMG Center for ALS and chief of neurology at Massachusetts General Hospital, further commented on the study’s innovative look into polyGP DPR proteins in the cerebrospinal fluid, which are elevated in patients with C9-ALS and C9-FTD, and whether treatment with WVE-004 can lower that marker in the trial.
“Depending on the results of this study, this would inform our ability to do a registrational, or a larger study in [ALS and FTD] populations, which would hopefully result in the measurement of positive effects in the clinical endpoints and thus allow it to become a treatment,” Panzara told NeurologyLive. “The study is designed to be adaptive; [it] is designed to change depending on the data and hopefully, accelerate as quickly as possible, because these are 2 devastating diseases with a lot of impact on patients and their families.”
Treatment options for both ALS and FTD are limited, with FOCUS-C9 aiming to identify biomarker changes in protein toxicity, particularly polyGP, to accelerate future studies and elucidate clinically meaningful effects, Panzara said.
According to Cudkowicz, WVE-004 may have potential for positive effects on cognitive and motor function in patients with C9-ALS and C9-FTD. Additionally, as preclinical trials indicated WVE-004 had effects spanning many months and widespread distribution through the central nervous system, Panzara remains hopeful that the molecule could have dramatic impact on disease progression.
“The idea that we can give infrequent doses with long-lasting effects, such that we can alter the course of the disease, potentially, by 1, 2, or 3 administrations in a given year, that changes how people think about [these diseases], from universally fatal to diseases that can be managed, hopefully through the slowing of disability progression,” Panzara said.