12 Jul Avidity Shares Promising Interim Data from its FORTITUDE Trial

By Justin Cohen, PhD

Avidity Biosciences recently announced exciting interim results from their randomized, double-blind, placebo-controlled Phase 1/2 FORTITUDE trial in facioscapulohumeral muscular dystrophy (FSHD). Termed delpacibart braxlosiran or del-brax for short, this first-in-class therapy is a muscle targeting antibody bound to a payload that targets DUX4, the toxic protein that causes FSHD. Once attached to the cell, the delivered payload inhibits DUX4 RNA,
addressing the basis of the disease.

While this initial trial is intended to assess the safety and efficacy of del-brax, of which no serious/severe adverse effects were reported, several outcome measures related to the therapeutic potential of the treatment were still quantified. One of the most anticipated is the impact on DUX4 regulated genes, something that was not demonstrated with losmapimod, the therapeutic Fulcrum used in their ReDUX4 trial, the first clinical trial to address the root cause of
FSHD. Excitingly, del-brax showed greater than 20% reduction in DUX4 associated genes for each patient and on average there was a more than 50% decrease across multiple gene panels, including the panel used in Fulcrum’s trial. It is uncertain why a reduction in DUX4 was demonstrated for del-brax and not losmapimod as MRI was used to guide muscle biopsy selection in both. One possibility could be differences in fat content of the muscles.

Avidity also examined signs of muscle health. This was done by measuring levels of creatine kinase (CK) in the blood. This compound is often elevated in muscular dystrophies and is an indicator of muscle damage. Promisingly, CK decreased by 30% in the del-brax group compared to placebo control. However, most interesting in terms of circulating compounds is an a novel DUX4-regulated biomarker. A compound that correlates with FSHD that can be
measured in the blood would be a major help for clinical trials as it would reduce the need for muscle biopsies and can allow for more frequent measurement of a therapy’s effectiveness. While the name of this compound has not been revealed, del-brax reduced levels by 25%. Hopefully more information about this biomarker is released soon so it can be applied to other FSHD clinical trials.

Most vital for patients is whether there is an impact on muscle function and excitingly there are trends towards improvement. Upper and lower limb muscles both showed improvement in strength. Importantly, the reachable workspace test, which measures upper limb range of motion and is a key outcome of the Fulcrum trials, was also improved compared to placebo. Lastly, patient self-assessment and clinician assessment indicated improvement.

As exciting as these results are, a caveat is that only 12 patients were assessed. Larger numbers of patients will be needed to be confident in the results. To this end, Avidity is concurrently testing a larger dose of del-brax after which a bigger trial with greater numbers of participants is planned to focus on muscle function. Overall, these results show great promise and with many other drugs in the pipeline we are in a new era of FSHD therapy.