Epicrispr Reports Six-Month Clinical Data for EPI-321 Gene Therapy in FSHD
Epicrispr Biotechnologies, a clinical-stage biotechnology company developing epigenetic therapies, has announced updated six-month clinical data from the ongoing first-in-human Phase 1/2 study of EPI-321 in adults with facioscapulohumeral muscular dystrophy (FSHD). The company presented the findings from the first six patients enrolled in the study at the 31st Annual Congress of the World Muscle Society (WMS 2026) in Hiroshima, Japan.
The latest results provide additional evidence on the biological activity, muscle volume and strength outcomes associated with EPI-321, an investigational therapy being developed to address the underlying biology of FSHD. According to Epicrispr, whole-body magnetic resonance imaging (MRI) demonstrated increases in lean muscle volume across total-body, upper-body and lower-body composite muscle groups at six months.
These findings contrasted with the muscle volume declines predicted using an untreated digital twin comparator generated from longitudinal natural history data in FSHD. The most pronounced difference was observed in the upper body, an area in which symptoms of FSHD commonly emerge early in the course of the disease.
Among the six patients treated with EPI-321, upper-body lean muscle volume increased by 3.0% at six months, compared with a predicted 3.5% decline in the matched digital twin comparator.
The MRI findings were accompanied by improvements in measures of muscle strength. Quantitative muscle testing (QMT) showed that patients treated with EPI-321 experienced a 4.1% improvement in upper-body strength, compared with a 0.3% decline observed in a matched external comparator group from the ReSolve FSHD natural history study.
Epicrispr said the results provide additional support for continued investigation of EPI-321 as a potential treatment for FSHD, while emphasizing that the data remain early and will require longer follow-up and evaluation in additional patients.
Muscle Volume Gains Observed Across Body Regions
FSHD is a progressive muscular dystrophy characterized by weakness and loss of skeletal muscle. The disease can affect different muscle groups over time, with weakness often appearing asymmetrically and commonly involving facial, shoulder and upper-body muscles before progressing to additional areas.
For this reason, changes in muscle volume and strength can provide important measures when evaluating an investigational therapy intended to modify disease biology.
In the six patients included in the latest analysis, whole-body MRI showed increases in lean muscle volume across total-body, upper-body and lower-body composite groups after six months of treatment.
The company said these findings represented a reversal of the declines observed in the untreated digital twin comparator. Digital twin methodology can be used in clinical research to model an expected disease trajectory for an individual or group based on longitudinal natural history information.
For the upper-body composite, where FSHD-related manifestations frequently emerge, the difference between observed and predicted outcomes was particularly notable. Patients receiving EPI-321 experienced a 3.0% increase in lean muscle volume, while the matched digital twin predicted a 3.5% decline.
The 6.5-percentage-point difference between the observed treatment group and modeled comparator is being viewed by Epicrispr as an encouraging signal of biological activity, although the small number of patients means the findings will need to be confirmed in larger studies.
Strength Improvements Accompany MRI Findings
The imaging results were accompanied by improvements in quantitative measures of muscle strength.
QMT showed a 4.1% improvement in upper-body strength among EPI-321-treated patients at six months. This compared with a 0.3% decline in the matched external comparator arm derived from the ReSolve FSHD natural history study.
The company also reported results at the individual muscle level. Across all six patients, EPI-321 treatment was associated with an 8.1% increase in elbow extension strength.
The improvement in elbow extension strength occurred alongside a 3.2% increase in lean muscle volume in the elbow extensor muscles.
By comparison, the matched digital twin comparator showed a 1.1% decline in elbow extension strength, while the ReSolve FSHD natural history comparator showed a 9.0% decline in elbow extensor lean muscle volume.
Epicrispr highlighted the fact that strength and MRI measurements moved in the same direction for the same muscle group in this analysis. The company said this represents one of several examples in which increases in muscle volume were accompanied by corresponding improvements in muscle function.
Such concordance between structural and functional measures may be relevant when evaluating potential disease-modifying effects. However, the company continues to characterize the findings as early clinical evidence requiring further validation.
EPI-321 Designed to Address FSHD Biology
EPI-321 is being evaluated as an epigenetic therapy for FSHD. Epicrispr is developing the program with the goal of addressing the biological mechanisms underlying the disease rather than simply managing its symptoms.
FSHD is associated with abnormal expression of the DUX4 gene in skeletal muscle. In healthy adult skeletal muscle, DUX4 is generally tightly regulated, while inappropriate activation of the gene is believed to contribute to the cascade of molecular events associated with FSHD.
The investigational approach behind EPI-321 is intended to modulate the epigenetic mechanisms associated with the disease-causing biology.
By targeting disease biology at the molecular level, Epicrispr is seeking to develop a treatment that could potentially influence the progressive loss of muscle characteristic of FSHD.
The six-month clinical findings are therefore being evaluated not only for changes in conventional clinical measures but also as evidence that EPI-321 may be producing measurable biological effects in affected muscle.
Safety Profile Remains Manageable
In addition to the preliminary efficacy and biological activity findings, Epicrispr reported that EPI-321 continues to demonstrate a manageable safety and tolerability profile.
The company said that no serious adverse events related to EPI-321 were observed among the six patients included in the updated six-month analysis.
Safety and tolerability remain important considerations for any investigational therapy, particularly for treatments administered systemically. The ongoing Phase 1/2 trial is designed to characterize the safety profile of EPI-321 while also collecting preliminary evidence of biological activity and potential efficacy.
Epicrispr CEO Amber Salzman, Ph.D., said the updated findings build on the initial results observed in the first three patients enrolled in the study.
“As additional patients have reached six months of follow-up, we continue to see a manageable safety profile and encouraging evidence of increased lean muscle volume, including in muscle groups commonly affected by FSHD,” Salzman said.
She added that the company plans to present 12-month data from all patients in the study during the second half of 2027.
Investigators See Encouraging Early Signals
Richard Roxburgh, MB ChB, FRACP, PhD, Associate Professor of Medicine at the University of Auckland and a principal investigator in the EPI-321 clinical trial, said the six-month results are encouraging in the context of the progressive nature of FSHD and the muscle loss experienced by patients over time.
According to Roxburgh, the observation of increased lean muscle volume builds on findings previously reported in the first three patients.
He also emphasized the importance of interpreting the findings in the appropriate clinical context. The current data represent an early-stage analysis from a small patient population, and additional follow-up will be necessary to determine whether the observed changes are sustained and whether they translate into meaningful long-term clinical benefits.
The consistency between MRI and strength measurements, however, supports continued investigation of EPI-321, according to Roxburgh.
Phase 1/2 Trial Now Fully Enrolled
The ongoing open-label Phase 1/2 clinical study is registered under NCT06907875 and is designed to evaluate the safety, tolerability, biological activity and preliminary efficacy of EPI-321 in adults with FSHD.
The trial is now fully enrolled, with six patients treated to date.
Participants received a single intravenous (IV) infusion of EPI-321 at one of two dose levels: 2 × 10¹³ vector genomes per kilogram (vg/kg) or 4 × 10¹³ vg/kg.
The study’s open-label design means that investigators and participants are aware of the treatment being administered. As an early-stage first-in-human study, the primary focus includes assessing safety and tolerability while gathering preliminary information about the therapy’s biological effects.
The inclusion of MRI measurements, quantitative muscle testing and comparisons with natural history data provides the study with multiple methods for assessing potential treatment effects.
Natural History Comparators Provide Additional Context
One of the notable aspects of the updated analysis is the use of external and modeled comparators.
The digital twin comparator was developed using longitudinal FSHD natural history data and was used to estimate the expected trajectory of muscle volume in the absence of treatment for the individual patients.
The study also used a matched external comparator from the ReSolve FSHD natural history study for certain strength and muscle volume analyses.
Natural history datasets can provide important context in rare and progressive diseases, particularly when clinical trials enroll relatively small numbers of participants during early development. By comparing treated patients with expected disease trajectories, researchers can examine whether observed changes differ from the patterns generally associated with disease progression.
However, external comparator analyses do not replace randomized controlled evidence, and differences between study populations, assessments and follow-up can influence comparisons. Larger and controlled clinical studies will ultimately be required to establish the efficacy and durability of EPI-321.
The six-month findings represent an important milestone for Epicrispr as it continues clinical development of EPI-321.
The company plans to continue following patients in the Phase 1/2 study and expects to report 12-month data from all patients in the second half of 2027.
Longer follow-up will be important to determine whether the increases in lean muscle volume observed at six months are sustained over time and whether the associated strength improvements continue. It will also provide additional information about the safety and tolerability of EPI-321 following treatment.
For a progressive disease such as FSHD, durability is a particularly important consideration. A potential disease-modifying therapy would need to demonstrate sustained biological and functional effects over a clinically meaningful period.
Epicrispr’s current findings provide an early indication that EPI-321 may influence measures associated with muscle health in FSHD. The increases in lean muscle volume across body regions, improvements in upper-body QMT and the specific changes in elbow extension strength and muscle volume represent areas the company will continue to evaluate.
The absence of EPI-321-related serious adverse events in the six-patient analysis also supports continued clinical development, although broader safety data will be necessary as the program progresses.
With the Phase 1/2 study now fully enrolled, the next major milestone will be longer-term follow-up. The planned 12-month data could provide additional insight into whether the six-month observations persist and whether EPI-321 has the potential to alter the progression of muscle loss associated with FSHD.
Overall, the updated six-month results strengthen the preliminary clinical dataset for EPI-321 while underscoring the need for continued evaluation. Epicrispr is now positioned to build on these early findings through longer follow-up and future clinical development aimed at determining whether its epigenetic approach can provide a meaningful disease-modifying treatment for people living with facioscapulohumeral muscular dystrophy.
About EPI-321
EPI-321 is an investigational epigenetic therapy that aims to address the underlying molecular mechanisms of FSHD with a one-time dose. Following intravenous administration, EPI-321 is directed to muscle tissue within a single AAV vector, which has been clinically validated for muscle delivery. Preclinical studies on EPI-321 have demonstrated its ability to robustly suppress pathological expression of the DUX4 gene and reduce muscle cell death. EPI-321 previously reported interim data from the Phase 1/2 trial, including statistically significant increases in whole-body lean muscle volume measured by MRI, favorable changes in circulating biomarkers consistent with DUX4 suppression, favorable strength and functional outcomes, and a manageable safety profile.
About Facioscapulohumeral Muscular Dystrophy (FSHD)
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy, affecting more than an estimated 1 million people worldwide. FSHD is a progressive genetic neuromuscular disease characterized by the gradual weakening and loss of skeletal muscle, often beginning in the face, shoulders, and upper arms before progressing to other parts of the body. The disease is caused by aberrant expression of DUX4, a gene that is normally silenced in healthy muscle tissue but becomes activated in individuals with FSHD, leading to muscle damage, inflammation, and progressive muscle degeneration. There are currently no approved disease-modifying therapies for FSHD.
About Epicrispr Biotechnologies
Epicrispr Biotechnologies is a biotechnology company pioneering gene-modulating therapies, leading with treatments for neuromuscular diseases. The company’s proprietary Gene Expression Modulation System (GEMS) enables precise and durable epigenetic modulation of gene expression, unlocking first-in-class treatments for previously untreatable conditions. Epicrispr’s lead program, EPI-321 is in clinical trials for FSHD, and the company is advancing additional gene-modulating therapies.