Wave Life Sciences Ltd are running in the Phase 1b/2a FOCUS-C9 clinical trial evaluating WVE-004 as an investigational treatment for C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD).
Wave Life Sciences Ltd is a US-based clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases.
C9-ALS and C9-FTD are believed to be caused by multiple factors related to the G4C2 expansion in the C9ORF72 gene. The expansion may lead to accumulation of repeat-containing RNA transcripts and aberrantly translated dipeptide repeat proteins (DPRs) leading to neurotoxicity, as well as insufficient levels of C9orf72 protein, affecting normal regulation of neuronal function and the immune system. C9orf72 mutations are reported to be found in 40% of people with familial ALS, and 8% to 10% of those with sporadic ALS.
C9orf72 normally makes three mRNA variants called V1, V2, and V3. Repeat expansions in V1 and V3 lead to the disease-causing DPRs and lower amounts of healthy C9orf72 proteins, which play vital roles in neural and immune system function.
WVE-004 is an antisense oligonucleotide, meaning that it is a short strand of nucleotides that can specifically target other RNA molecules — in this case, the mRNA molecules corresponding to V1 and V3. By attaching itself to those mRNA molecules, WVE-004 is designed to mark them for destruction, leaving only the healthy V2 protein to carry out its work within cells.
The medication’s specificity to V1 and V3 was validated in preclinical studies performed in mice altered to carry the mutated human C9orf72 gene. The candidate therapy successfully removed over 90% of the DPRs in the spinal cord, and over 80% of DPRs around the brain, of these mice. This effect lasted for at least six months.
The FOCUS-C9 trial is a global, multicentre, randomised, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety and tolerability of single- and multiple-ascending intrathecal doses (an injection into the spinal canal) of WVE-004 for people with C9-ALS and/or C9-FTD. Additional objectives include measurement of polyGP DPR proteins in the cerebrospinal fluid (CSF), plasma and CSF pharmacokinetics (PK), and exploratory biomarkers and clinical outcomes. The FOCUS-C9 trial is expected to enrol approximately 50 participants. It is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee.
WVE-004 is an investigational medication not currently approved for use in patients with ALS in any country worldwide. A possible treatment resulting from this study is likely years away.
The Australian site for this study is;
The Perron Institute, Nedlands, Western Australia, Australia, 6009
Principal Investigator: Merrilee Needham, MBBS, PhD, FRACP
Further information is available here