Successful delivery of RNA to muscle occurs in trial for myotonic dystrophy
Click Here to Manage Email Alerts
Avidity Biosciences Inc. announced positive data from a phase 1/2 trial, which successfully delivered RNA into muscle for the first time in a study that aimed to treat patients with myotonic dystrophy, the company said in a press release.
The delivery of siRNA into muscle reinforces the potential of the company’s antibody oligonucleotide conjugate (AOC) platform and expands the ability to address targets and diseases previously unreachable with existing RNA therapies, according to Avidity.
AOC 1001 is the company’s lead clinical program that uses the AOC platform to address the root cause of myotonic dystrophy type 1 (DM1), which has no current approved treatments, the company stated.
“Myotonic dystrophy is a genetic disease,” Art Levin, PhD, chief scientific officer at Avidity, told Healio. “It is passed on from parents to children, and one of the really devastating things about this disease is that it tends to get worse over the generations. Sometimes parents or grandparents are only diagnosed when they have an offspring who is more severely affected. The reason that happens is because there is a mutation in a gene called the DMPK.”
According to Levin, over time the mutation gets worse from generation to generation. The mutation in this instance is that there is a triple nucleotide repeat in the patient’s DNA, which is then translated into a messenger RNA, he said.
“The messenger RNA for DMPK will have increasing numbers of these triple nucleotide repeats,” Levin said. “In this case [for] this disease, unlike Huntington’s [disease], the triple nucleotide repeats our CUGs in the messenger RNA, and it is actually this messenger RNA that is the toxic basis for the disease. So, the more CUG repeats you have, you tend to have a more severe disease.”
According to Levin, the hypothesis behind the phase 1/2 trial was that if he and colleagues could find a way to remove the “toxic” messenger RNA, then the course of the disease would change.
According to the company release, AOC 1001 consists of a proprietary monoclonal antibody that binds to transferrin receptor 1 conjugated with a siRNA targeting DMPK mRNA to address the underlying cause of DM1.
The study was a randomized, double-blind, placebo-controlled trial that assessed safety and tolerability of 38 participants and key biomarkers in 19 participants. Participants received a single dose of 1 mg/kg AOC 1001, two doses of 2 mg/kg AOC 1001 or placebo.
The authors reported a meaningful DMPK reduction in 100% of participants who received AOC 1001, with a mean reduction of 45% in DMPK among all participants.
“This is just an early look at the first two doses in this clinical trial. This is just a midpoint analysis,” Levin said. “We are continuing to collect data, but we are extraordinarily encouraged by the fact that in a muscle disease, we can see improvement as quickly as this early assessment in our clinical trial.”
In September 2022, the FDA placed a partial clinical hold on new participant enrollment in the trial because of a serious adverse event that was reported in one patient who received a 4 mg/kg dose of AUC 1001, the release stated. However, all active participants have been able to continue their current dosing.
According to Levin, if a treatment for DM1 eventually came out of this, it will “have broad effects on the quality of life for these patients.”
He continued, “Being able to reverse this potentially should have some remarkable promise for this patient population, who are currently unserved by any approved therapies.”
Avidity has three distinct rare disease programs in clinical trials — AOC 1001 for DM1; AOC 1020, which is advancing to clinical phase 1/2 trial for the treatment of facioscapulohumeral muscular dystrophy; and AOC 1044, which also is advancing to a phase 1/2 trial for the treatment of Duchenne muscular dystrophy mutations amenable to Exon 44 skipping.