Avidity shares interim data from its FORTITUDE trial

“Unprecedented” and “consistent” reductions in DUX4 activity along with improvements in strength and function

by June Kinoshita, FSHD Society

Avidity Biosciences, Inc., a San Diego-based biopharmaceutical company, announced this Wednesday, June 12, that its investigational therapy for facioscapulohumeral muscular dystrophy (FSHD) reduced by more than 50% the expression of genes that are regulated by DUX4—widely viewed as the gene that triggers muscle weakness and degeneration in FSHD. What’s more, the company reported trends showing improvement in muscle strength, reachable workspace, and other outcomes reported by participants and clinicians. Importantly, the therapy has favorable safety and tolerability, and no severe adverse events have been reported.

The data come from the Avidity’s FORTITUDE^TM trial, a Phase 1/ 2 clinical trial of AOC 1020, a molecule that targets the messenger RNA of DUX4. Researchers analyzed data from participants who have been either on a placebo or on AOC 1020 for the first four months of a 48-week dosing period. Avidity also announced delpacibart braxlosiran as the approved international nonproprietary name of AOC 1020, abbreviated as del-brax.

The study’s details will be presented at the FSHD Society’s International Research Congress today in Denver, Colorado, by Jeffrey Statland, MD, Professor of Neurology at the University of Kansas Medical Center and FORTITUDE^™ trial investigator. Amy Halseth, PhD, the FSHD lead at Avidity, will share the results tomorrow morning at the FSHD Connect patient conference in Denver.

In addition, Dr. Statland and the Avidity team will give a webinar hosted by the FSHD Society on Thursday, June 20, at 1:00 p.m. US ET.  Here is Avidity’s letter to the FSHD community, which provides a summary of study findings, the company’s plans, and invites the community to the webinar.

“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 and provided trends of functional improvement in patients with FSHD at the four-month timepoint. These early data would support the notion that del-brax has the potential to change the course of disease for people living with FSHD,” said Statland. There are currently no FDA-approved therapies for FSHD.

“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,” said Sarah Boyce, president and chief executive officer at Avidity. “By directly targeting the root cause of FSHD, we believe that del-brax has the potential to be a first-in-class, best-in-class therapy for people living with FSHD.”

Study details and questions

Avidity’s press release described the study data and interim findings as follows:

The initial assessment from the randomized, double-blind, placebo-controlled Phase 1/2 FORTITUDE trial of del-brax provides a four-month look at the safety and tolerability for all 39 participants across two dose levels (2 mg/kg and 4 mg/kg). For the four-month assessment in the 2 mg/kg cohort, participants received a single-dose of 1 mg/kg del-brax followed by two doses of 2 mg/kg del-brax (siRNA dose), or placebo. Data on DUX4 regulated genes, circulating biomarkers and muscle strength and function were assessed from 12 participants in the 2 mg/kg cohort.

In the Phase 1/2 FORTITUDE study, del-brax demonstrated:

• Greater than 50% mean reductions in DUX4 regulated genes across multiple panels for DUX4 regulated gene expression in muscle
• All participants treated with del-brax showed reductions greater than 20% in DUX4 regulated genes
• Mean reductions of 25% or greater in novel circulating biomarker and creatine kinase
• Trends of functional improvements including increased strength in upper and lower limb muscles, and muscle function as measured by reachable workspace (RWS) compared to placebo and the ReSolve natural history study
• Trends of improvement in patient and clinician reported outcomes
• Favorable safety and tolerability with all adverse events (AEs) mild or moderate, no serious adverse events and no discontinuations

The reference to a “circulating biomarker” that is driven by DUX4 activity caught our eye. Many research teams have been seeking a valid blood biomarker for DUX4 expression. Avidity did not provide details in its press release and we are eager to learn more. Creatine kinase is well-established indicator of muscle damage, so a decrease is a good sign, but it is not specific to the FSHD disease process.

What this means for our community

This is consistent and encouraging data, and we look forward to data from the next cohort of patients, says Lucienne Ronco, PhD, interim chief science officer for the FSHD Society. It’s exciting that positive trends in functional improvements were seen only four months into dosing. Such a fast response raises the hope that Avidity may be able to shorten its trial and move into Phase 3 sooner than it had anticipated. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have granted Orphan designation for del-brax and the FDA has granted del-brax Fast Track designation.

Avidity plans to accelerate initiation of registrational cohorts in the FORTITUDE trial starting in the second half of this year. The Phase 1/2 cohorts of the FORTITUDE trial are fully enrolled. Data generated from the upcoming registrational cohorts will be used as part of the data package evaluated by regulatory agencies for new drug approval. Avidity plans to share additional information about the upcoming trial cohorts with the FSHD community as it becomes available.

We are deeply grateful for the hard work and sacrifice of thousands of individuals living with FSHD who gave blood and muscle samples, filled out countless registry questionnaires, volunteered for natural history studies, lay inside MRI scanners, tested devices, and showed up in all kinds of way. It’s your dedication, your investment in the future, never giving up hope, that has cleared the path through the jungle and brought us to this time of incredible and real promise.