FSHD treatment del-brax (formerly AOC 1020) aids muscle function

After 3 doses, DUX4-regulated gene activity more than halved over placebo

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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AOC 1020, an investigational treatment by Avidity Biosciences that’s now called delpacibart braxlosiran, or del-brax, helped adults with facioscapulohumeral muscular dystrophy (FSHD) grow stronger muscles and extend their arms farther than they could four months earlier.

These are early data from FORTITUDE (NCT05747924), a three-part Phase 1/2 clinical trial that’s testing how safe del-brax is for treating FSHD and how well it works over a placebo on measures of muscle strength and function, among others.

Avidity plans to move quickly to gain enough data to seek del-brax’s approval. The treatment holds U.S. fast track and orphan drug designations, which are intended to help speed its clinical development and regulatory review.

“With the unprecedented del-brax data from the FORTITUDE trial, we are now focused on accelerating our registrational plans as we understand the urgency to develop a treatment for people living with FSHD who have no treatment options,” Avidity President and CEO Sarah Boyce said in a company press release. According to a recent webcast for investors and analysts, biomarker and functional groups within FORTITUDE that are designed to help support its approval should start this year.

FSHD is caused by an abnormal activation of the DUX4 gene that results in the DUX4 protein building up to toxic levels in muscle cells, leading to muscle weakness mainly in the face, shoulders, and upper arms. There are no approved medications to treat FSHD.

A so-called antibody-oligonucleotide conjugate, del-brax is made up of an antibody that binds to the transferrin receptor 1 in muscles cells and is attached to a small interfering RNA, or siRNA, that reduces DUX4 mRNA, a molecule that carries genetic instructions from DNA.

Turning off DUX4 mRNA should keep DUX4 from building up and ease symptoms. In FSHD mouse model studies, a single dose of such an antibody-oligonucleotide conjugate prevented muscle weakness compared with a placebo, helping mice run longer distances.

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Early results of FORTITUDE trial

In FORTITUDE, 39 adults with FSHD, ages 18-65, were randomly assigned to five infusions of del-brax at 2 or 4 mg/kg, or a placebo, given directly into the bloodstream over nine months. After a year, the participants can enter an open-label extension where everyone is given del-brax.

Eight patients were given the lower del-brax dose, with the first of the five infusions being given at half the dose, 18 were given the higher dose, and 13 the placebo. Treatment-related side effects were mild or moderate and occurred with each del-brax dose (50%) and the placebo (23.1%). The most common side effects were fatigue, rash, anemia, and chills.

Early data on measures of muscle strength and function are only available for the eight patients given the lower del-brax dose and four given the placebo. After three doses of del-brax, the activity of genes regulated by DUX4 in muscle was more than halved compared with the placebo, suggesting it may turn off DUX4 mRNA.

“As the first therapy to directly target DUX4, it is very encouraging to see that the del-brax data demonstrate consistent reductions in DUX4 regulated genes,” said Jeffrey M. Statland, MD, a professor of neurology at the University of Kansas Medical Center in Kansas City.

Statland, who’s an investigator for FORTITUDE, presented the data in the oral presentation “Interim Results from FORTITUDE, a Randomized Phase 1/2 Trial Evaluating AOC 1020 in Adults with FSHD” at this year’s FSHD Society International Research Congress, June 13–14, in Denver.

A new FSHD biomarker to monitor treatment response

Researchers also identified a new biomarker regulated by DUX4 that’s seen at higher levels with FSHD. Because it can be measured in the blood, it may provide an easy way to monitor the response to del-brax and also serve as an endpoint for its accelerated approval, Statland said.

In patients given del-brax, the levels of the new biomarker dropped by an average 25% from the start of the trial to the four-month point. A similar reduction, by an average of 30%, was observed in creatine kinase, a biomarker of muscle damage.

Moreover, the patients given del-brax showed improved Quantitative Muscle Testing (QMT) scores, which measure muscle strength, in both upper and lower limbs. When tested for reachable workspace after four months, the patients also moved their arms more freely and reached farther than those given the placebo.

“Early data showing trends in del-brax to improve muscle strength and function are very encouraging for patients with FSHD who are in need of treatments,” said Statland, who noted they “support the notion that del-brax has the potential to change the course of disease.”

Both patients and doctors reported clinical improvements and less severe symptoms based on Global Impression of Change or Severity scales, which rely on perceptions. Those given del-brax, but not the placebo, also reported better quality of life than four months earlier.

Avidity is also developing AOC 1044, an investigational treatment for Duchenne muscular dystrophy amenable to exon 44 skipping, and AOC 1001, for people with myotonic dystrophy type 1, who’ve reported gains in muscle strength in a clinical trial.

The FSHD program “is our third rare muscle disease program to show delivery to muscle and target engagement and [the] second … to provide signs of functional improvement,” Boyce said, adding the company’s approach may be “revolutionizing the delivery of RNA therapeutics.”