We are advancing and expanding our innovative AOC pipeline to offer treatment options for patients and their families across a wide range of therapeutic areas. We have three AOC programs for three distinct rare diseases in clinical development from our muscle disease franchise: myotonic dystrophy type 1 (DM1), facioscapulohumeral muscular dystrophy (FSHD), and Duchenne Muscular Dystrophy (DMD). Our pipeline also includes advancing AOCs to address additional DMD, rare skeletal muscle, and rare precision cardiology programs. We continue to broaden our reach of AOCs in other indications including cardiology and immunology through partnerships.
Facioscapulohumeral Muscular Dystrophy
Facioscapulohumeral muscular dystrophy (FSHD) is a rare, progressive, and relentless hereditary muscle-weakening condition marked by significant pain, fatigue, and disability. It is one of the most common forms of muscular dystrophy, with onset typically in teens and young adults. FSHD affects approximately 16,000 to 38,000 people in the U.S. alone. There are currently no approved therapies to treat the underlying cause of FSHD. Current treatment approaches are focused on support for activities of daily living and mobility, improved functioning and lowering the risk of complications. They include physical therapy, exercise, pain management and orthopedic interventions.
FSHD is characterized by progressive and often asymmetric skeletal muscle loss that initially causes weakness in muscles in the face, shoulders, arms and trunk and progresses to weakness in muscles in the lower body. FSHD is an autosomal dominant genetic disease caused by the abnormal expression of the DUX4 (double homeobox 4) gene primarily in the skeletal muscle. The aberrant expression of the DUX4 activates genes that are toxic to muscle cells and leads to a series of downstream events that result in skeletal muscle wasting and compromised muscle function, including an inability to lift arms for more than a few seconds, loss of ability to show facial expressions, and serious speech impediments. These symptoms cause nearly 20% of people affected by FSHD to become dependent on the use of a wheelchair for mobility by age 50.
FSHD Disease Process:
Delpacibart braxlosiran or del-brax (AOC 1020)
We are developing delpacibart braxlosiran or del-brax (AOC 1020) to treat the underlying cause of facioscapulohumeral muscular dystrophy (FSHD), which is the abnormal expression of the DUX4 gene. Del-brax aims to reduce the expression of DUX4 mRNA and DUX4 protein in muscles in people with FSHD. Del-brax consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DUX4 mRNA. Del-brax is currently in Phase 1/2 development as part of the FORTITUDE™ trial in adults with FSHD. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granted Orphan designation for del-brax and the FDA has granted del-brax Fast Track designation.
Preliminary Data Presented at 2024 FSHD Society International Research Congress
In June 2024, Avidity announced unprecedented data from the Phase 1/2 FORTITUDE™ trial in people living with FSHD. Del-brax data demonstrate unprecedented and consistent reductions of greater than 50% in DUX4 regulated genes, trends of functional improvement, and favorable safety and tolerability in people living with facioscapulohumeral muscular dystrophy (FSHD). Avidity plans to accelerate initiation of registrational cohorts in the FORTITUDE study. The initial assessment from the randomized, double-blind, placebo-controlled Phase 1/2 FORTITUDE trial of del-brax provides a four-month look at the safety and tolerability for all 39 participants across two dose levels (2 mg/kg and 4 mg/kg). For the four-month assessment in the 2 mg/kg cohort, participants received a single-dose of 1 mg/kg del-brax followed by two doses of 2 mg/kg del-brax (siRNA dose), or placebo. Del-brax is the first investigational therapy designed to treat the underlying cause of FSHD, which is caused by the abnormal expression of a gene called double homeobox 4 or DUX4. FSHD is a rare, hereditary disorder marked by life-long, relentless loss of muscle function, significant pain, fatigue, and progressive disability. Currently, there are no approved therapies for the treatment of FSHD.
The Phase 1/2 FORTITUDETM trial is a randomized, placebo-controlled, double-blind trial designed to evaluate single and multiple doses of delpacibart braxlosiran or del-brax (AOC 1020). Dose escalation cohorts A and B are fully enrolled for the Phase 1/2 study in 39 adult participants with facioscapulohumeral muscular dystrophy (FSHD) and the study is ongoing. The Phase 1/2 FORTITUDE trial will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of del-brax administered intravenously, with the primary objective being the safety and tolerability of del-brax in FSHD patients. Activity of del-brax 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 del-brax including measures of mobility and muscle strength as well as patient reported outcomes and quality of life measures. Avidity plans to initiate registrational cohorts in the FORTITUDE study starting in the second half of this year. Participants will have the option to enroll in an open-label extension study at the end of the treatment period in the FORTITUDE study. For more information about the FORTITUDE trial, visit the FORTITUDE study website or visit http://www.clinicaltrials.gov and search for NCT05747924.
