Antisense Oligonucleotide for Potential Treatment of C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Decreases Dipeptide Repeat Proteins

In the ongoing phase 1b/2a FOCUS-C9 clinical trial (NCT04931862) of an antisense oligonucleotide (ASO) (WVE-004; Wave Life Sciences, Cambridge, MA) for potential treatment of C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia, target engagement and safety were observed. 

This trial used an adaptive trial design to optimize dose level and frequency rapidly based on early indicators of target engagement. Potent, durable reductions in cerebrospinal fluid (CSF) levels of dipeptide repeat proteins were observed in all active treatment groups. Participants treated with 30 mg of the ASO vs placebo had a 34% reduction in poly(GP) dipeptide proteins at day 85 (P=.011). 
 
“FOCUS-C9 was designed to deliver an early indication of target engagement so that we could rapidly optimize the dose and move toward the next stage of development,” said Michael Panzara, MD, MPH, chief medical officer, Wave Life Sciences. “Based on our preclinical pharmacokinetic / pharmacodynamic modeling, we expected that relatively low doses would engage target; however, seeing this level of poly(GP) knockdown 3 months after a single 30 mg dose exceeded our expectations. We expect poly(GP) to be further reduced with repeat administrations.”

Adverse events were balanced across treatment groups, including placebo, and were mostly mild-to-moderate in intensity. Sever or serious adverse events occurred in 4 participants, 1 of whom was treated with placebo. Of these adverse events, 1 was treatment-emergent and the others were related to ALS or administration of the treatment. No treatment-associated elevations in CSF white blood cell counts or protein or other notable laboratory abnormalities were seen 
 
The ASO is delivered intrathecally and is designed to target selectively transcriptional variants containing a hexanucleotide repeat expansion (G4C2) associated with the C9orf72 gene, thereby sparing normal C9orf72 protein.