Avidity Biosciences, Inc. ( Nasdaq: RNA), a biopharmaceutical company committed to delivering a new class of RNA therapeutics called Antibody Oligonucleotide Conjugates (AOCs™), today announced the Phase 1/2 FORTITUDE™ clinical trial of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD).
FSHD is a rare, hereditary muscle-weakening condition marked by life-long, progressive loss of muscle function and causes significant pain, fatigue, and disability. AOC 1020 is the second muscle-targeting small interfering RNA (siRNA) AOC from Avidity’s pipeline to advance into clinical development.
Earlier this week, Avidity announced that the U.S. Food and Drug Administration (FDA) cleared the company’s investigational new drug (IND) applications of AOC 1020 for FSHD and AOC 1044 for the treatment of Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (DMD44). The company has now advanced three programs – DM1, FSHD and DMD44 – into clinical development in a 14-month period.
“Advancing AOC 1020 into the Phase 1/2 FORTITUDE study is a significant milestone for the FSHD community and our proprietary AOC platform. People living with FSHD have no approved treatments and experience life-long, progressive loss of muscle function leading to fatigue and disability,” said Sarah Boyce, president and chief executive officer of Avidity. “AOC 1020, our second siRNA AOC, is designed to directly target the disease-causing gene, DUX4, with the goal of treating the underlying biological cause of FSHD. We now have three clinical programs in development for three distinct rare diseases that have no approved therapies.”
FSHD affects approximately 16,000-38,000 people in the United States alone. It is an autosomal dominant disease caused by the abnormal expression of the gene DUX4 (double homeobox 4) that leads to skeletal muscle wasting and progressive loss of muscle function, with symptoms often beginning in adolescence and early adulthood.
“We are grateful for companies like Avidity that are working to address a significant unmet need in the FSHD community,” said Mark A. Stone, chief executive officer at FSHD Society. “Patients as well as their caregivers and families live with the burden of this devastating disease every day and are in desperate need of treatment options that can improve quality of life. As FSHD is a progressive disease, the impact is debilitating and often results in an inability to do everyday activities like brushing teeth or getting dressed. There is a long road ahead, but today marks an important step and gives hope to everyone in our community impacted by FSHD.”
In addition to AOC 1020 and AOC 1044, Avidity is developing AOC 1001 for the potential treatment of myotonic dystrophy type 1 (DM1). AOC 1001 is being evaluated in the Phase 1/2 MARINA™ trial and the MARINA open label-extension study (MARINA-OLE™). Earlier this week, Avidity announced that the FDA placed a partial clinical hold on new participant enrollment in the Phase 1/2 MARINA trial. All current participants, whether they are on AOC 1001 or placebo, may continue in their current dosing cohort and roll over into the MARINA-OLE where they will receive AOC 1001 as planned.
Avidity remains on track to conduct a preliminary assessment of safety, tolerability and key biomarkers in approximately half of the study participants in the Phase 1/2 MARINA trial in the fourth quarter of 2022.
The FORTITUDE™ Phase 1/2 Trial of AOC 1020 in Adults with FSHD
The FORTITUDE trial is a randomized, placebo-controlled, double-blind, Phase 1/2 clinical trial designed to evaluate AOC 1020 in 68 adult participants with FSHD. FORTITUDE will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AOC 1020 administered intravenously, with the primary objective being the safety and tolerability of AOC 1020 in FSHD patients. Activity of AOC 1020 will be assessed using key biomarkers, including magnetic resonance imaging (MRI) measures of muscle volume and composition. Though the Phase 1/2 trial is not statistically powered to assess functional benefit, it will explore the clinical activity of AOC 1020 including measures of mobility and muscle strength as well as patient reported outcomes and quality of life measures. Participants will have the option to enroll in an open-label extension study at the end of the treatment period in the FORTITUDE study.
AOC 1020 is designed to treat the underlying cause of FSHD, which is caused by the abnormal expression of a gene called double homeobox 4 or DUX4. The abnormal expression of DUX4 protein leads to changes in gene expression in muscle cells that are associated with the life-long, progressive loss of muscle function in patients with FSHD. AOC 1020 aims to reduce the expression of DUX4 mRNA and DUX4 protein in muscles in patients with FSHD. AOC 1020 consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DUX4 mRNA. In preclinical studies, a single intravenous dose with the murine version of AOC 1020 prevented development of muscle weakness demonstrated by three functional assays – treadmill running, in vivo force and compound muscle action potential. AOC 1020 is currently in Phase 1/2 development as part of the FORTITUDE™ trial in adults with FSHD.
