EPI-321 Clinical Trial: Questions For Participants
About the Therapy
What is EPI-321?
EPI-321 is an experimental gene therapy being developed to treat FSHD. It works by switching off harmful DUX4 gene expression, which damages muscle cells.
What is DUX4 and why is it important in FSHD?
In people without FSHD, natural chemical tags called methyl groups are located on DNA near the DUX4 gene, which help to keep DUX4 turned off. This stops the DUX4 protein from building up in muscle cells. In people with FSHD, there aren’t enough of these methyl group tags, so too much DUX4 protein is made, which is a toxic protein that kills muscle cells and causes weakness.
How does EPI-321 switch off the DUX4 gene?
EPI-321 provides a blueprint (a special sequence of DNA) that instructs the muscle cells to make a group of compounds. These compounds work together as tools to switch off DUX4. Some of the compounds help to focus and restrict the activity to the DUX4 gene. The others make up a special “dual system” to restore the natural methyl tags on DNA and block DUX4 activity. This is called epigenetic modification, which helps turn the gene off without changing the DNA. This may protect muscles from further damage.
How is EPI-321 delivered?
EPI-321 is given as a one-time IV infusion (through a vein, usually in your arm). The DNA blueprint is packaged in a viral “carrier” called AAVrh74, which delivers the therapy to muscles.
Why was AAVrh74 chosen?
AAVrh74 has already been used as a viral carrier for gene therapies in more than 1,000 patients with other muscle diseases and is the viral carrier used in an approved gene therapy for another neuromuscular disease. This large experience, including how effectively this viral carrier penetrates muscle cells, suggests that EPI-321 could be effective for FSHD at safe doses.
How long could the therapy last?
Once the therapy restores the natural methyl tags near the DUX4 gene, muscle cells are expected to remember them for their lifetime. Thus, it is expected that EPI-321 only needs to be given one time.
Has EPI-321 been tested before in people?
The ongoing study is the first trial of EPI-321 in humans. So far, preclinical testing has been done in muscle cells obtained from FSHD patients, in animal studies (mice and monkeys), and in lab-grown (engineered) muscle tissue derived from FSHD patients.
What did the preclinical studies show?
EPI-321 increased DNA methyl group tags on the DNA near the DUX4 gene, reduced DUX4 activity, protected muscle cells from dying, and improved muscle strength in preclinical models.
Is the therapy muscle-specific?
Yes. While the viral carrier is known to carry the packaged gene to many different organs, the EPI-321 blueprint is designed with a promoter (a genetic “switch”) that selectively works in muscle cells. So, while muscle cells are instructed to make the compound tools, other tissue types are not. Animal and laboratory testing of EPI-321 showed that its methylating and suppressing activity was restricted to the DUX4 gene in muscle cells, and there was no activity detected in other, non-muscle cell types.
About the Trial
Who can join the trial?
Adults with genetically confirmed FSHD1 who meet certain health requirements. The study team will check eligibility case by case.
Do I need to have a genetic test to be included? If so, will this be provided?
Yes, you must have a genetic test. If you don’t have one, the study will be able to provide the test at no cost to you.
How is the study designed?
It is a dose-escalation study, meaning small groups of patients receive increasing doses to test safety and possible benefit.
Will some people be given a placebo instead of the medicine?
No. All participants will receive the study drug.
What will be measured?
Study doctors will track the following:
- Safety by monitoring for side effects using routine techniques like lab tests, physical exams, interviews, and other diagnostic tests like ECGs and heart ultrasounds
- Muscle strength and function
- DUX4 methylation and activity in muscle biopsies
- Signs of muscle health on magnetic resonance imaging (MRI) and blood tests
How long will participation last?
About one year for the main study, plus long-term safety monitoring for approximately 5 years after receiving EPI-321. This long-term follow-up is standard in gene therapy trials.
What risks are there?
Possible risks include infusion reactions (fever, chills), immune responses which can damage one or more organs, including the liver, kidneys, lungs, heart, or skeletal muscle, or unknown side effects. Participants will be administered immune suppression for several months after receiving EPI-321. This is used in other gene therapies using AAV viral carriers, and it helps to reduce the risk of side effects from the body’s immune response to the gene therapy. Since this is a first-in-human study, the risks of EPI-321 are not fully known. The study team will discuss the potential risks with you as part of the consent form, and you can ask as many questions as needed.
Will I be paid or reimbursed?
Approved travel expenses related to the study will be reimbursed. The study team will provide further details.
What happens next if the study is successful?
If EPI-321 appears safe and effective in the first-in-human study, larger trials will follow to confirm the findings in more patients before it can be approved by regulators.
How do I contact a study site to learn more and sign up?
Go to the clinicaltrials.gov page and scroll down to “Contacts and Locations” to find phone numbers and emails for each study site.