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Preclinical data published in Molecular Therapy Nucleic Acids demonstrate that WVE-004 potently reduces C9orf72 transcriptional variants and poly(GP) dipeptide repeat proteins in mice for at least six months while maintaining C9orf72 protein levels
Recently reported clinical data from ongoing Phase 1b/2a FOCUS-C9 trial of WVE-004 suggest these preclinical data translate in the clinic
CAMBRIDGE, Mass., April 25, 2022 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced the publication of preclinical data for WVE-004, the company’s clinical candidate for C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD), in Molecular Therapy Nucleic Acids (MTNA). The paper includes in vivo data demonstrating that WVE-004 led to potent, sustained reductions in pathogenic C9orf72 RNA transcripts and poly(GP) dipeptide repeat proteins (DPRs) for six months in C9 BAC transgenic mice after only two doses, without altering C9orf72 protein levels. The paper, titled “Preclinical evaluation of WVE-004, an investigational stereopure antisense oligonucleotide for the treatment of C9orf72-associated ALS or FTD,” is available here.
WVE-004 is currently being investigated in the Phase 1b/2a FOCUS-C9 clinical trial in individuals with C9-ALS and/or C9-FTD. Wave recently shared initial, positive data from the study (here), demonstrating target engagement with potent, durable reductions of poly(GP) after low, single doses.
“On the heels of the first clinical data from FOCUS-C9, we are excited to be publishing our preclinical data for WVE-004, which helped enable accurate prediction of pharmacodynamically active starting doses in patients with C9-ALS/FTD,” said Michael Panzara, MD, MPH, Chief Medical Officer and Head of Therapeutics Discovery and Development at Wave Life Sciences. “These preclinical data demonstrate that WVE-004 distributes widely throughout the CNS in mice, potently and durably lowering the toxic transcripts and poly(GP) driven by a C9orf72 expansion mutation. We also recently reported our first human data from FOCUS-C9 where low, single doses of WVE-004 significantly reduced CSF poly(GP) levels, which were still declining after three months, suggesting translation of the preclinical data to the clinic. We are looking forward to sharing additional clinical data from the WVE-004 program this year.”
WVE-004 is a stereopure antisense oligonucleotide designed with Wave’s proprietary chemistry, including PN backbone chemistry modifications (PN chemistry), to selectively target transcriptional variants containing a hexanucleotide repeat expansion (G4C2) associated with the C9orf72 gene, thereby sparing C9orf72 protein. A G4C2 expansion in C9orf72 is the most common known genetic cause of the sporadic and inherited forms of ALS and FTD. Despite being distinct disorders, studies have found that ~20-50% of patients have both C9-ALS and C9-FTD. The overlap in genetics, pathology and clinical presentation has led to the idea that these diseases are manifestations of a clinical spectrum.
C9-ALS and C9-FTD are believed to be caused by multiple factors related to the G4C2 expansion. The expansion leads to production of modified sense and antisense transcripts that can form nuclear RNA foci and encode DPRs, which are believed to drive disease pathology. Additionally, the G4C2 expansion can decrease expression of C9orf72 protein, affecting regulation of neuronal function and the immune system.
Data from the MTNA publication include:
