Spring, 2022

Sarepta recently provided a community letter detailing updates on our LGMD programs and pipeline. In this communication, we shared the following LGMD 2B/R2 (SRP-6004, dysferlinopathy) program update: Sarepta plans to initiate a proof-of-concept study in late 2022 while conducting additional manufacturing efforts in tandem. To respond to questions from the LGMD 2B/R2 patient, caregiver, and advocacy community that we received in recent weeks, we are providing a brief question and answer (Q&A) below with the aim of clarifying expected activities in 2022 to advance development of SRP-6004. We look forward to updating the community when plans are further finalized.

What is SRP-6004?
SRP-6004 is Sarepta’s investigational gene therapy being developed for the treatment of LGMD 2B/R2. Like all of Sarepta’s investigational LGMD gene therapies, SRP-6004 is designed to express the full-length protein that is missing, addressing the root cause of disease. To do this, SRP-6004 needs to comprise the full-length dysferlin transgene. There is a unique complexity with the full-length dysferlin transgene: it is too large to fit inside the selected vector – the vector essentially serves as a vehicle; responsible for carrying the transgene directly into the cell. Sarepta’s proposed solution is to use a dual-vector approach. In a dual-vector approach, two halves of the large transgene are delivered via two different vectors, as opposed to a single vector delivering one transgene. When dosed, the goal is for an individual to receive both vectors and the components of the full transgene, which is intended to produce full-length dysferlin protein in muscle cells.

For more information on the intended mechanism of action for SRP-6004, please visit the section starting at 1:08:10 in our presentation, Sarepta Therapeutics LGMD Pipeline Update given at the September 2021 International LGMD Conference. For more information on the general roles of the vector and transgene in gene therapy, please see our GT-FAQ video series.

Can Sarepta share the status of the LGMD 2B/R2 clinical development program?
Sarepta previously completed a first in-human clinical trial of SRP-6004, in which two participants received SRP-6004 gene therapy treatment through intramuscular injection (NCT02710500). To achieve distribution of gene therapy throughout the body rather than a single muscle, Sarepta has since decided to move forward with a different route of administration for SRP-6004, which is systemic (full-body) intravenous infusion. We are currently designing a proof-of-concept study for systemic dosing for SRP-6004 in individuals diagnosed with LGMD2B/R2. Our goal is to start this trial before the end of 2022.

What is a proof-of-concept study?
A proof-of-concept clinical trial is an early-stage study with human participants. The study data is used to generate initial evidence (or “proof”) of clinical safety and biological activity in a specific patient population (in this case in the LGMD 2B/R2 patient population). Results from proof-of-concept studies provide important information about how a treatment may work in later stages of drug development when larger groups of patients are dosed.

What is a proof-of-concept study trying to accomplish?
Proof-of-concept clinical work is needed to evaluate the risk/benefit analysis of novel investigational treatments before advancing to later phases of clinical development. Preclinical work utilizes animal studies; however, animal study findings need to be confirmed through in-human clinical trials. Human clinical trial participants are more complex than animals, and this type of data collected is considered critical for novel investigational treatments such as gene therapy. The foundational proof-of-concept work is needed to advance LGMD2B/R2 research and development.

How does proof-of-concept work advance research and development for LGMD 2B/2R patients?
To continue advancing SRP-6004 research efforts for the potential treatment of LGMD2B/2R, it is imperative we establish positive biological activity, meaning that we see expression of the full-length dysferlin transgene utilizing our dual vector approach, and that we begin to understand the safety profile of the treatment. If the results from the proof-of-concept study can demonstrate sufficient clinical safety and biological activity of SRP-6004 in LGMD 2B/R2 patients, Sarepta will then be able to evaluate next steps for further clinical study. Sarepta plans to move the proof-of-concept work for SRP-6004 forward in tandem with our manufacturing efforts (as highlighted in the February 25, 2022 community letter). For gene therapy, the manufacturing aspects of development can often create bottlenecks to clinical development. By advancing our manufacturing process in parallel, Sarepta aims to be poised for subsequent clinical development, pending the results from the proof-of-concept studies and discussions with regulators.

What can Sarepta share about the design of the proof-of-concept study?
Please note that the design of the study is not yet final and is subject to change as Sarepta receives feedback on our study design from key stakeholders. While we don’t have the final details to share at this time on the study design, proof-of-concept studies typically involve small numbers of patients. Sarepta understands that the decision to participate in a gene therapy study is one that individuals should make in consultation with their treating physician, family, and loved ones. We look forward to sharing further details of the study in the future so individuals living with LGMD 2B/2R can make informed decisions whether to participate in this study if they are eligible.

How can the community expect to receive Sarepta updates?
We recognize that the community is eager to learn the eligibility criteria, locations, and other specific information about the study. We are committed to sharing those details when the information is available. Sarepta anticipates providing a webinar update to the patient community in the future when details of the proof-of-concept study are established. If you/your loved one has questions or would like to connect, you may email [email protected], join limbgirdle.com/stay-connected* or follow us on our social media channels.

How can an individual with a LGMD2B/R2 diagnosis participate in a community-led patient registry?
Patient registries are essential to rare disease research, serving a critical role in the ability to develop a foundational understanding of LGMD and the number of people who are living with this disease. Sarepta encourages the patient community to stay connected to the Jain Foundation Dysferlin Registry by joining their LGMD2B/R2 registry database. The Dysferlin Registry is a free patient registry exclusively for individuals who have been genetically diagnosed with dysferlinopathy, also referred to as LGMD2B, LGMDR2, Miyoshi Myopathy 1, through the identification of mutations in the DYSF gene.

What resources are available to the broader LGMD community?
Sarepta encourages the LGMD patient/caregiver community to stay connected to Patient Advocacy organizations. A list of organizations may be found here: https://www.lgmd-info.org/resources/ lgmd-organizations/. You may also email [email protected] if you would like support finding an organization with which to connect.

*Please note that limbgirdle.com is intended for US audiences only.