Background

WVE-004 is an antisense oligonucleotide (ASO) targeting the C9ORF72 mutation that causes amyotrophic lateral sclerosis and frontotemporal dementia. The ASO mediates degradation of hexanucleotide expansion-containing C9ORF72 mRNAs. Both the mRNA and the dipeptide proteins produced from the hexanucleotide repeats are believed to be toxic to neurons, hence the rationale that reducing them will be beneficial.

Wave has reported the production of stereoisomerically pure ASOs that preferentially knock down repeat-containing C9ORF72 mRNAs and preserve normal protein expression (Liu et al., 2021). They previously demonstrated that stereopure ASOs more potently initiate mRNA degradation than standard oligomers with random stereochemistry (Iwamoto et al, 2017).

WVE-004 was tested in motor neurons derived from patient cells and in a transgenic mouse carrying the human C9ORF72 gene with a repeat expansion; results were presented at conferences in 2021 (abstract, ALS News Today coverage). In cultured cells, the ASO reportedly decreased repeat-containing mRNA; in mice, injection into the CSF resulted in reductions of repeat-containing mRNA by 60 to 80 percent in spinal cord and 40 to 50 percent in cortex up to six months later. WVE-004 also diminished dipeptide repeat proteins by approximately 90 percent in the spinal cord and cortex, but did not affect normal protein levels. The data was later published after peer review (Liu et al., 2022).

Findings

In June 2021, Wave began a Phase 1/2 safety study in 42 people with C9ORF72-associated ALS or FTD. Each participant received a single intrathecal injection of 10, 20, 30, or 60 mg WVE-004 or placebo. A multidosing phase administered 10 mg or placebo every four or 12 weeks; followed by an option for open-label extension. The primary outcome was the proportion of patients with adverse events 24 weeks after injection. The trial also measured WVE-004 and C9ORF72-derived glycine-proline dipeptides in CSF at the beginning and end of study. The study ended up enrolling 35 participants. It was performed at 17 sites in Australia, New Zealand, Canada, and Europe. On May 23, 2023, the company reported topline results (press release). Several of the trialed doses were associated with a 50 percent reduction in CSF poly(GP), but no improvement on exploratory clinical outcomes after 24 weeks. In individual participants, poly(GP) levels did not correlate with clinical changes. The company announced it would stop development and terminate an ongoing open-label extension.

For details on this trial, see clinicaltrials.gov.