NEW YORK – Avidity Biosciences is on track to report the first data readout later this year from a trial of AOC-1044, an antibody-RNA conjugate designed to restore function of the aberrant dystrophin gene known to cause Duchenne muscular dystrophy (DMD).
The San Diego-based company founded in 2013 is developing a roster of so-called antibody oligonucleotide conjugates (AOCs) for rare diseases, hoping to overcome the current limitations of oligonucleotide drugs, and AOC-1044 is one the firm's lead products.
"One of the fundamental challenges [in the RNA therapeutics space] has been how do you deliver RNA therapeutics to cells and tissues types outside of them?" said Avidity President and CEO Sarah Boyce.
Avidity's proposed solution to this challenge, AOCs, combines antibody-mediated cell specificity with the genetic sequence-targeting precision of antisense oligonucleotides (ASOs). The addition of the antibody also extends the half-life of the therapy's RNA component as it passes through a patient's bloodstream.
In the case of drugs for DMD and other muscular dystrophies, like AOC-1044, Avidity uses an antibody that targets the transferring receptor on muscle cells. "Being able to target muscle cells opens up a whole new set of possibilities for people living with these muscular dystrophies," Boyce said.
Matthew Wood, director of Oxford-Harrington Rare Disease Center, known for cutting-edge rare disease research, commented that while antibody-RNA conjugation is novel, RNA conjugation itself is not. "Companies targeting the same diseases, [such as] Sarepta Therapeutics, Pepgen, and Entrada, all have peptide antisense oligonucleotide conjugates, which enhance delivery to muscle but in theory, lack the tissue specificity offered by the antibody conjugates," Wood said.
The US Food and Drug Administration recently granted Avidity's AOC-1044 fast-track designation, which allows the company to interact with the agency more frequently during the development process and potentially seek expedited premarket review. The company is currently evaluating the agent's safety, tolerability, and pharmacokinetic and pharmacodynamic effects at different doses in the Phase I/II Explore44 clinical trial. DMD, a rare and inherited condition characterized by progressively worsening muscle damage and weakness, can be caused by a variety of mutations in the DMD gene that limit production of the dystrophin protein. Avidity is developing AOC-1044 specifically for patients who have exon 44 skipping-amenable disease.
AOC-1044 causes exon 44 of the dystrophin mRNA to be skipped during translation, resulting in a truncated but functional dystrophin protein. While this cannot restore lost muscle tissue, it can in theory slow or prevent further muscle loss.
Avidity currently has approximately $586.3 million in cash, cash equivalents, and marketable securities, which it is using to advance AOC-1044 and its other AOCs in clinical trials. AOC-1001, for example, is Avidity's candidate therapy for myotonic dystrophy type 1 (DM1) and is undergoing testing in a Phase I/II trial. The company presented data from this trial last month at the American Academy of Neurology annual meeting in Boston.
In contrast to AOC-1044, AOC-1001 consists of an antibody conjugated to a small interfering RNA (siRNA), which degrades a long, nonsense molecule of mRNA from an aberrant DMPK gene. The alteration in this case is a nucleotide expansion that results in a long, nonsense mRNA molecule capable of sequestering proteins and enzymes with vital cellular functions.
"That expanded nonsense RNA doesn't code for anything," said Steve Hughes, Avidity's chief medical officer, "but it does sequester other proteins and enzymes that are important to biological function within cells, and that prevents many different functions from happening properly."
Last year, the FDA placed a partial clinical hold on new participant enrollment into the Phase I/II trial of AOC-1001, citing concerns over a serious adverse event reported in one patient. The company recently stated that it is continuing discussions with the FDA and that no further serious adverse events have been reported in the trial.
Wood from Oxford-Harrington Rare Disease Center expressed no surprise that safety concerns have caused bumps in the commercial path for AOC therapies, noting that many questions still remain around the safety, efficacy, and biological effects of these drugs and that "it is not clear yet whether [AOCs] represent a significant advance or not."
Open questions with respect to antibody conjugates, Wood explained, include the degree of tissue specificity they provide; how the levels of receptors vary on target tissue over the course of a disease; whether AOCs interfere with normal receptor function; how long an AOC remains active; how frequently patients will have to be re-dosed; and whether the transferrin system is compatible with re-dosing.
Boyce and Hughes noted that pre-existing antibodies are not an issue with antibody oligonucleotides conjugates.
"AOCs are like other antibody biologics," Hughes said, "they can be chronically dosed."
"The DMD community is closely monitoring the progress of gene therapy programs and there is a high expectation for the approval of the first gene therapy program this month," he said, referring to Sarepta Therapeutics' SRP-9001 (delandistrogene moxeparvovec), which underwent an FDA advisory committee review last week. The agency is expected to issue a decision on Sarepta's marketing application later this month. Ahead of the advisory committee meeting, FDA reviewers had raised concerns that patients for whom the dose of SRP-9001 is inadequate or the drug is ineffective, would not be able to receive another dose or a different AAV-based gene therapy. The advisory committee on Friday narrowly voted in favor of the FDA approving SRP-9001.
According to Kelly, the nonclinical safety and efficacy data for AOCs and other ASO therapies have already generated "significant enthusiasm" among people with DMD.
"These approaches have been shown to target all key muscle groups, [such as] skeletal, diaphragm, and cardiac, to produce very high amounts of exon-skipped protein when compared with the currently approved ASO drugs," he said. "There is a high level of interest in the development programs from patients whose mutations allow them to participate in clinical trials."
Several exon-skipping ASO therapies are currently on the market, including Sarepta's Amondys 45 (casimersen) and Exondys 51 (eteplirsen), and NS Pharma's Viltepso (viltolarsen).
Next, Kelly predicts multi-drug combination therapies will start to enter the standard of care. In that context, CureDuchenne is supporting the development of therapies that improve bone health, preserve muscle function, and provide an alternative to classical steroids.
"AOCs lend themselves well to combination therapies or add-on therapies," Boyce said. "However, we are developing therapeutics for genetically defined rare muscle and cardiology indications where we can directly target the underlying cause of disease like in myotonic dystrophy type 1, Duchenne muscular dystrophy and facioscapulohumeral dystrophy."
In addition to those indications, Avidity has launched programs for an undisclosed cardiac disorder and an undisclosed muscular disease. The firm intends to announce specifics on those programs once it is closer to initiating studies in those areas.