FSHD is a rare genetic muscular disorder, usually presenting with slow progressing and asymmetric muscle weakness. The cause of FSHD is the aberrant expression of the transcription factor DUX4 in skeletal muscle, leading to a series of downstream events that result in skeletal muscle degeneration and wasting. Strategies aimed at reducing DUX4 expression in the skeletal muscle of FSHD patients via oligonucleotides are promising therapeutic approaches. The main challenge that has limited the clinical development of oligonucleotide therapeutics for muscular diseases has been the difficulty of delivering oligonucleotides into muscle cells. Avidity’s AOC platform combines the specificity of monoclonal antibodies with the precision of oligonucleotides to overcome this challenge.
The AOC 1020 therapeutic candidate is comprised of siDUX4.6 conjugated to the human transferrin receptor 1 (TfR1)-targeting monoclonal antibody AV01mAb to facilitate delivery to muscle. The lead DUX4-targeting siRNA, siDUX4.6, was selected based on in vitro screening of a DUX4 siRNA library in 11 FSHD patient-derived muscle cell lines to maximize potency and specificity. In cynomolgus monkey skeletal muscle, AOC 1020 produced a dose-dependent increase in siRNA tissue exposure following a single intravenous dose. At therapeutically relevant doses, the muscle tissue concentration for siDUX4.6 exceeded the IC50 values determined for other TfR1-based AOCs.
The pharmacology of the siDUX4.6 was characterized in ACTA1-MCM; FLExDUX4 mouse model of FSHD expressing human DUX4. Robust activity in muscle was observed 8 weeks after single intravenous dose of murine TfR1 antibody-based DUX4 AOC, with over 75% reduction of DUX4-regulated genes at 6 mg/kg of siRNA dose. Single treatment with DUX4 AOC also resulted in functional improvement of FSHD-related muscle phenotype in this mouse model. Data presented here support the evaluation of AOC 1020 in the Phase 1/2 FORTITUDE trial in adults with FSHD.