There was plenty of ingenuity and grit on display in Denver
by June Kinoshita, FSHD Society
Many scientists who work on FSHD spend their days bent over test tubes and computers, so this year’s International Research Congress (IRC), on June 13-14, opened with a bracing talk by Jeff Johnston, who has lived with the diagnosis for the past 25 years.
“We humans value independence so much that we are willing to die for it,” Johnston noted. “With FSHD, I’ve lost a lot of independence. I’m a 54-year-old man who can no longer live by himself.” He said the COVID pandemic – the isolation, loss of cherished activities, anxiety about the future – gave ordinary people a taste of “what it’s like to live with FSHD.”
Johnston’s remarks underscored how FSHD is not a benign condition, as it is sometimes depicted in textbooks. As he thanked the audience, he impressed upon them the urgency and life-changing impact of their research.
Clinical trial landscape
The hot news of the IRC was Avidity’s announcement of interim data four months into their Phase 1/2 trial of their RNA therapy called “del-brax” (see related story).
Alexandra Collin de l’Hortet of Epic Bio shared what she called “robust evidence” for EPI-321 as a potential gene therapy for treating FSHD by permanently suppressing DUX4. “We intend to submit an IND application [to the FDA] and are looking forward to commencing first-in-human trials in 2024,” she said.
Oxana Beskrovnaya, PhD, of Dyne Therapeutics, reported that the company’s lead candidate, DYNE-302, “resulted in dose-dependent and robust reduction of the DUX4 transcriptome … that lasted up to three months, with benefit on muscle structure and function” in a mouse model of FSHD.
DYNE-302 is similar to Avidity’s del-brax, in that it employs an antibody to deliver an siRNA (small interfering RNA) to muscle, where it blocks DUX4 expression. The Avidity findings are a cause for optimism that DYNE-302 will also be beneficial, but its commercial success may depend on additional factors such as safety, tolerability, and how long-lasting the effects are. Dyne has not announced a time frame for starting a clinical trial.
On the horizon
Lindsay Wallace and colleagues at Nationwide Children’s Hospital shared progress on an RNA-based therapy combining mi405, identified in their lab as a potent inhibitor of DUX4, with AAV-SLB-101, the adeno-associated virus capsid (surface protein) used by Solid Biosciences in their Duchenne gene therapy. The team showed the construct, ARM-201, is a potent reducer of DUX4 in mice. ARM-201 is the lead FSHD candidate of Armatus Bio.
Sharif Tabebordbar of Kate Therapeutics described creating artificial microRNA sequences, finding the sequence that was most potent at reducing DUX4 expression, and pairing it with a muscle-targeting Myo-AAV to deliver the miRNA into a mouse model of FSHD. Their compound improved the mice’s ability to run on a treadmill, reduced FSHD-like pathology in the muscles, and lowered DUX4 levels. On the strength of these data, the company plans to keep developing their gene therapy candidate for FSHD.
Anti-inflammatory drugs, specifically those targeting IL-6, were mentioned as potential therapies for FSHD, and one such drug is currently in a clinical trial in France in a study led by Sabrina Sacconi.
Emanuele Mocciaro and Davide Gabellini described small-molecule drugs that silence/target a region of the genome involved in activating DUX4. Two of these drugs are currently in clinical trials for leukemia. Safety and tolerability from these trials will no doubt inform whether these drugs would be good candidates for treating FSHD.
Tools for trials
One topic of keen interest is the Reachable Workspace (RWS), which was selected as a primary outcome for Fulcrum Therapeutics’ Phase 3 clinical trial. RWS measures how high and how far, back and forth, a person can reach their arms while seated. But regulatory agencies like the FDA will likely demand evidence that changes in RWS line up with changes in patients’ quality of life.
Support for this claim was presented by Leo Wang, MD, from the University of Washington. He analyzed data on 168 adults who participated for two years in the ReSolve natural history study of FSHD. The study found a strong correlation between declines in RWS and muscle strength, and a moderate correlation with difficulties in daily activities that require arm mobility.
Chantal Coles at Murdoch Children’s Research Institute in Melbourne, Australia, is conducting an analysis of circulating immune cells as the community seeks to understand the role of the immune system in FSHD. Her “Immune Atlas” will be a valuable tool to support muscle recovery after DUX4 reduction.
A strong push to characterize pediatric FSHD is underway with three clinical centers worldwide (Kansas; Nice, France; and Melbourne, Australia) carrying out long-term natural history studies combined with MRI imaging and molecular muscle characterization to help researchers understand early disease onset and the impact of FSHD on human development.
How does one get a 54 year old male into the studies.
Recently diagnosed in April 2024
Go to clinicaltrials.gov and search for FSHD.
Yes, as stated, go to clinicaltrials.gov. Then where it asks for the condition you type FSHD. Don’t worry about the other boxes, just click Search. All the different studies will show up, each in it’s own little box. You can click on the study to learn more about it. At the bottom of each little box is a link that shows other locations. Click on it and see ifnthere is a location near you, or close enough that you’re willing to travel to.
Although these drugs sound encouraging for possible treatment/cure for FSHD, I’m so disappointed we still don’t have a date/year for one of these treatments to be available to all patients who suffer with this disease. For more than five years, I have been following trials and research for a treatment/ cure as I decline and struggle to do life every minute of the day. I keep reading encouraging data, but know announcement of when a drug will be available to ALL patients with FSHD. We need help now, please give us something!!!!!🙏
I think your comment is exactly what the vast majority of people with FSHD think. If FSHD had the urgency of Covid, we would already have access to losmapimod and it would only be months to Avidity’s del-brax instead of the many years if not a decade or more that it likely will be. “FSHD urgency” is what we have instead. This is where the system that could deliver a therapy could care less about our extreme urgency or the time frame of our lives.
Yes, as stated, go to clinicaltrials.gov. Then where it asks for the condition you type FSHD. Don’t worry about the other boxes, just click Search. All the different studies will show up, each in it’s own little box. You can click on the study to learn more about it. At the bottom of each little box is a link that shows other locations. Click on it and see if there is a location near you, or close enough that you’re willing to travel to.
Fair warning. I’ve communicated with several companies doing trials, I’m willing to go anywhere and do anything…but that doesn’t mean you get in a trial. Most of the trials are very small, like 1-2 patients per site. I’ve been ghosted by coordinators (I’m sure they are very busy!) and many of the locations listed are not actually looking for patients currently.