Abstract Details

Title FTX-1821 for Treatment of FSHD at its Root Cause: Results of a Clinical Trial in a Dish

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S23 - Genetic Muscle Disorders (4:25 PM-4:36 PM)

Poster/Presentation
Number 006

Background Facioscapulohumeral dystrophy (FSHD) is caused by loss of repression at the D4Z4 locus resulting in mis-expression of the homeobox transcription factor DUX4. DUX4 expression in skeletal muscle activates its downstream transcriptional program resulting in cell death, loss of skeletal muscle and progressive motor disability. Using optimized in vitro myotube culture systems and robust assays to screen a small molecule probe library, we identified and validated a drug target that, when inhibited, reduces or prevents expression of DUX4 and cell death. FTX-1821 is a potent and highly selective small molecule inhibitor of this target resulting in the reduction of DUX4 activity and its downstream transcriptional program preventing cell death without impacting myogenesis.

Objective Assess FTX-1821 inhibition of DUX4 activity and cell death in a population of FSHD1 and FSHD2 patient-derived skeletal muscle cell lines.

Design/Methods A clinical trial in a dish was prospectively designed to investigate the efficacy of FTX-1821. Eleven primary FSHD (8 FSHD1 and 3 FSHD2) and 3 control patient-derived skeletal muscle cell lines were treated with FTX-1821. Four concentrations were tested: 30, 100, 300 and 1000 nM compared to vehicle during myoblast differentiation into myotubes. Investigators were blinded to treatment and FSHD type. DUX4 activity was assessed by measuring mRNA levels of MBD3L2, a well characterized DUX4 target gene. Activated capsase-3 was measured to quantify activation of cell death driven by DUX4 expression.

Results FTX-1821 demonstrated a dose-dependent decrease in MBD3L2 in both FSHD1 and FSHD2 patient-derived skeletal muscle myotubes. Cell death was also strongly inhibited.

Conclusions Treatment with FTX-1821 results in potent dose-dependent reduction of DUX4 activity and prevention of cell death across the full spectrum of patient-derived skeletal muscle cells tested. These results support advancing FTX-1821 into clinical trials for treatment of FSHD at its root cause.

Authors/Disclosures
Michelle L. Mellion, MD PRESENTER	Dr. Mellion has received personal compensation for serving as an employee of PepGen. Dr. Mellion has stock in PepGen.
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Alrabi Tawil, MD, FAAN (University of Rochester Medical Center)	Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kate Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for meRicule. The institution of Dr. Tawil has received research support from Friends of FSH Research. The institution of Dr. Tawil has received research support from FSH Society. The institution of Dr. Tawil has received research support from NIH. The institution of Dr. Tawil has received research support from Fulcrum. Dr. Tawil has received intellectual property interests from a discovery or technology relating to health care.
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Diego Cadavid, MD, FAAN (Verge Genomics)	Dr. Cadavid has received personal compensation for serving as an employee of Verge Genomics. Dr. Cadavid has received personal compensation for serving as an employee of X4 Pharmaceuticals. Dr. Cadavid has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pheno Therapeutics. Dr. Cadavid has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk. Dr. Cadavid has stock in Verge Genomics.
	No disclosure on file

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