Wednesday, August 16, 2023
Avidity Biosciences, Inc. has reported that the U.S. Food and Drug Administration (FDA) granted Orphan Drug designation to their investigational therapy, AOC 1044. This therapy is being developed to treat Duchenne muscular dystrophy (DMD) in individuals whose mutations allow for exon 44 skipping (DMD44). DMD is a rare genetic condition characterized by progressive muscle damage due to the absence of dystrophin protein, usually manifesting from a young age. Notably, there are currently no approved treatments that specifically address exon 44. Avidity Biosciences, known for its work with Antibody Oligonucleotide Conjugates (AOCs™), is committed to advancing innovative RNA therapeutics.
AOC 1044 is currently under investigation in the Phase 1/2 EXPLORE44™ clinical trial, focusing on individuals with DMD44. This marks the initial step among several AOCs in Avidity's pipeline intended for DMD treatment. The anticipated outcomes from the EXPLORE44 trial's segment involving healthy volunteers are projected to be disclosed in the fourth quarter of 2023. Concurrently, Avidity is actively enrolling participants with DMD44 for inclusion in the study. Notably, in April 2023, AOC 1044 was granted the FDA's Fast Track designation for addressing DMD44.
Dr. Steve Hughes, Avidity's Chief Medical Officer, expressed satisfaction with the FDA's granting of both Orphan Drug and Fast Track designations to AOC 1044. He emphasized the critical significance of advancing innovative treatments for those affected by DMD, particularly considering the lack of therapies targeting the fundamental cause of DMD44. The mechanism behind AOC 1044 involves the specific skipping of exon 44 of the dystrophin gene, thus facilitating the generation of functional dystrophin protein. Avidity is eagerly looking forward to advancing the clinical development of AOC 1044 and expediting its safe introduction to patients.
Avidity's distinctive AOCs meld the precision of oligonucleotide therapy with the specificity of monoclonal antibodies (mAbs), creating a novel approach for tackling conditions that were previously resistant to treatment using RNA-based therapeutics. In the context of DMD, this disorder emerges from a genetic mutation that obstructs the synthesis of dystrophin protein, which normally shields muscle cells during contractions. The absence of functional dystrophin leads to the weakening, tearing, inflammation, and gradual loss of muscle function in muscle cell membranes. AOC 1044 is designed to deliver phosphorodiamidate morpholino oligomers (PMOs) to both skeletal and cardiac muscle tissues. These PMOs work around the mutation by prompting the skipping of exon 44 in the dystrophin gene, thereby enabling the production of functional dystrophin protein.
The FDA's Office of Orphan Products Development confers orphan status to facilitate the development of medicines for rare disorders that impact fewer than 200,000 individuals in the United States. Orphan Drug designation offers several advantages, including exclusive marketing rights upon regulatory approval, exemption from FDA application fees, and tax credits for qualifying clinical trials.
The EXPLORE44 trial constitutes a Phase 1/2 clinical investigation of AOC 1044, designed with a randomized, double-blind, placebo-controlled format. The principal aim is to gauge the safety, tolerance, pharmacokinetics, and pharmacodynamic effects of AOC 1044. This evaluation encompasses both healthy volunteers and individuals with DMD mutations amenable to exon 44 skipping (DMD44), involving the administration of AOC 1044 through intravenous delivery.
Approximately 40 healthy volunteers and 24 participants with DMD44, ranging in age from seven to 27, are projected to be enrolled in the trial. Throughout the study, the assessment will encompass exon skipping and the levels of dystrophin protein in participants affected by DMD44. A subsequent extension study will also be an option for participants with DMD44 who wish to continue their involvement after the initial trial phase.
Duchenne muscular dystrophy (DMD) is a genetic ailment that leads to the absence of functional dystrophin, a crucial protein for upholding the integrity of muscle cell membranes. This deficiency triggers stress, tears in muscle cell membranes, and consequent muscle cell demise, culminating in the gradual decline of muscle function. Dystrophin also acts as a foundation for a cluster of proteins connecting the internal and external elements of muscle cells, serving as a shock absorber. Individuals grappling with DMD confront progressive muscle weakness that commonly commences during early childhood.
As the disorder advances, individuals with DMD encounter challenges related to mobility and breathing. Eventually, the muscles essential for cardiac and respiratory functions cease to operate. People living with DMD often rely on specialized assistance and support throughout their lives, given the substantial impact on their physical capabilities. Regrettably, life expectancy for individuals affected by DMD is notably shortened. Despite existing approved treatments, there remains a considerable gap in addressing the condition's demands.
DMD is recognized for its monogenic, X-linked, recessive inheritance pattern, primarily affecting males. The global occurrence is estimated at approximately one in every 3,500 to 5,000 male births.
AOC 1044 is intricately designed to carry phosphorodiamidate morpholino oligomers (PMOs) to the heart and skeletal muscle tissues. The specific purpose of this design is to trigger exon 44 skipping within the dystrophin gene. This strategic maneuver facilitates the production of dystrophin in individuals grappling with Duchenne muscular dystrophy (DMD) who possess mutations amenable to exon 44 skipping (DMD44).
DMD is marked by gradual muscle deterioration and associated weakness, stemming from mutations impacting dystrophin, a crucial protein safeguarding muscle cells from harm during contractions. Notably, AOC 1044 stands out due to its composition, featuring a proprietary monoclonal antibody interacting with the transferrin receptor 1 (TfR1). This antibody is coupled with a PMO targeting exon 44.
In an impressive feat, active AOC 1044 demonstrated enduring capabilities in inducing exon skipping in a preclinical model mirroring DMD. Furthermore, it spurred the production of functional dystrophin protein in both skeletal muscle and heart tissue. This accomplishment was achieved through a single intravenous dose.
Presently, AOC 1044 is in the midst of Phase 1/2 development through the EXPLORE44™ trial. This trial is primarily centered on individuals carrying DMD mutations that lend themselves to exon 44 skipping as a prospective treatment avenue.