Our National Vice-Present of Research, Education and Advocacy, Nicola Worsfold, attended the Parent Project Muscular Dystrophy (PPMD) conference on June 23-26, 2022. Below are summaries of the research and development updates as provided by our industry partners, categorized by the areas of Duchenne research.

Therapies aimed at restoring dystrophin

Exon Skipping (Mutation Specific)

Exon skipping therapies target specific mutations in the DMD gene. The companies’ primary focus is to develop or improve their molecules so the drug can efficiently get into the muscle, promote exon skipping, and produce higher percentages of the dystrophin protein. Each company has a slightly different approach:

Sarepta Therapeutics

Sarepta presented an update on their exon 51 skipping proprietary phosphorodiamidate morpholino oligomer (PMO) and peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), SRP-5051 (vesleteplirsen). The focus was Part B of their PPMO, Study 5051-201, also known as MOMENTUM. Due to a serious adverse event, the Food and Drug Administration (FDA) has put a hold on the clinical trial in the US, however, clinical trials remain open in other sites outside of the United States. Sarepta is working on several different exon programs and has the most extensive portfolio of research in this area at the moment.

Wave Life Sciences

Wave provided an update on their exon 53 skipping molecule that originally failed in 2019, but has since changed the chemistry to what they believe to be more efficient at getting into the muscle. This new molecule is being tested, and its clinical trial is open for enrollment in London, Ontario. Click the button below to learn more about this trial.

Avidity Biosciences

Avidity is relatively new to the Duchenne muscular dystrophy space and working on an exon 44 skipping molecule. Their unique approach to exon skipping combines an oligonucleotide or oligo (a short piece of DNA or RNA) with an antibody attached that targets both skeletal muscle and cardiac muscle to improve the delivery of the drug. They are working on exon 44, 45 and 51 skipping therapies. Exon 44 skipping is the first and is planned to start end of 2022, with others to follow. We will continue to advocate for trial sites in Canada and will update our community as more information becomes available.

Dyne Therapeutics

Dyne is investigating exon skipping for 51, 53, 45 and 44 with others to follow. They will start with DYNE-251 for people living with Duchenne who are amenable to exon 51 in mid-2022. Their chemistry includes an oligo plus an antibody and a linker, specifically targeted to muscle cells, including the cardiac, diaphragm, and smooth muscle. Unfortunately, they received a clinical hold from the FDA before starting their Phase 1 program, however, this was a result of requesting additional information and had nothing to do with a clinical trial or adverse event.

Entrada Therapeutics

Entrada is another relatively new company to the Duchenne space working on ENTR-601-44 for those amenable to exon 44. They are using Endosomal Escape Vehicle (EEV) technology, a small circular peptide linked to their oligo. They are not in the clinic yet but plan to start their program early next year.

PepGen

PepGen is working on an exon 51 molecule. Their phosphorodiamidate morpholino oligomer (PMO) is conjugated to a peptide that enhances delivery to the targeted skeletal, diaphragm, and cardiac muscle. They presented interesting data demonstrating expression in the central nervous system (i.e. drug crossing the blood-brain barrier) and an increased expression of their 51-exon skipping compound in comparison to Sarepta’s Eteplirsen (Exondys 51) in nonhuman primates. Their Phase 1 study started in Canada with healthy volunteers and Phase 2 is planned for the first half of 2023.

BioMarin

BMN-351 is the new exon 51 skipping therapy for BioMarin. You may remember BioMarin was working on Drisapersen, which did not work, and the clinical program was cancelled in 2015. They have now optimized their exon 51 chemistry to be more potent, which will result in more exon skipping and more protein. They plan to file an Investigational New Drug Application (IND) later this year, which will permit them to start their clinical in 2023. We commend BioMarin for not giving up on our Duchenne community, and we will continue to provide updates to this program as information becomes available.

Gene Therapy (Mini/Micro Dystrophin)

There was no new information presented from the companies working on gene therapies; however, here are the highlights from the broad gene therapy discussions:

1. Gene therapies aim to help the body produce more dystrophin, the protein missing in Duchenne. Each investigational gene therapy has a slightly different way of doing this.
2. Depending on where your mutation is on the DMD gene, you may be producing a very small amount of dystrophin. Some part of the DMD gene is being translated into protein, but because it’s not doing it properly, whatever parts are made are quickly broken down and eliminated. What’s important here is that these individuals recognize some part of the dystrophin protein (albeit a small part) and are less likely to have an immune response to gene therapy. Some individuals who have larger mutations at the beginning of the DMD gene are completely naive to the dystrophin protein and are at higher risk of a potentially serve immune response to gene therapies. This is a class effect which means all current gene therapies under investigation are facing this immunoresponse issue and, therefore, why some individuals with large mutations occurring at the beginning of the gene are being excluded from clinical trials. 
3. When gene therapy is helping the body make more dystrophin, it can only prevent future damage from happening and can not change what is already lost. This is why gene therapy is targeting young boys with less muscle damage and more function. It is still not clear how gene therapies might benefit older populations. Furthermore, the older you are, the more likely you will have antibodies to the AAV vectors, and because you have a more mature immune system, you may be at higher risk of side effects with gene therapy. More research is needed to understand this better.
4. Approximately 100 patients with Duchenne have been treated collectively across all current gene therapy programs worldwide as of June 2022. Safety data is accumulating, but there is still much more to learn.
5. There is a need to understand more about the longevity of gene therapies. Muscle cells are regenerative, and any new microdystrophin introduced through gene therapy will be lost in new muscle cells when they regenerate. So how long does it last? Lots of research is happening to try to figure out how to retreat patients with gene therapy.

Therapies addressing the symptoms of Duchenne

Not Mutation Specific

Capricor Therapeutics

Capricor is investigating CAP-1002, a unique therapy derived from healthy heart cells. These cells are thought to act on the immune system and have anti-inflammatory, antifibrotic, and regenerative effects on skeletal and heart muscle cells. The therapy is given as an infusion four times a year and targets those with Duchenne who are ten years of age and older and no longer walking. They presented impressive 1-year extension data from their clinical trial program that showed a slowing of disease progression by 70% as measured from the upper limb function test (PUL). This treatment could be used in combination with other treatments like exon skipping or gene therapy.

Their HOPE-3 clinical trial for CAP-1002 is now open for enrollment in the US only. More information on this trial can be found on our Clinical Trial Finder Tool.

Astellas Pharma

ASP0367 is their investigation drug thought to improve mitochondrial function and energy, thereby improving muscle health and function. It is an oral therapy and could be given in combination with exon skipping or gene therapy. Their Phase 1b trial is open in the US only for those living with Duchenne between the ages of 8-16, both walking and not walking.

Edgewise Therapeutics

EDG-5506 is under investigation as it is thought to protect specific fast twitch muscle fibres and prevent long-term damage. It is an oral medication, well tolerated, with positive results in Becker muscular dystrophy as confirmed in their Phase 1 trial. Their Becker study and a natural history study are open for enrollment, with their Phase 2 study starting soon. They are planning on starting a Phase 2 clinical trial for boys with Duchenne aged 4-9 years old, who are still walking, on a stable dose of steroids, and can also be on exon skipping therapy later this year. You can learn more on our Clinical Trial Finder Tool or click the button below to read the latest on their website.

Italfarmaco

Italfarmaco presented their Phase 3 study results from givinostat, a histone deacetylase (HDAC) inhibitor which reduces muscle tissue damage, cell death, chronic inflammation, and fibrosis. The results showed statistical significance on all their endpoints for participants who are still walking. They demonstrated preservation of muscle mass and delay in disease progression as measured by the four stair climb and North Star Ambulatory Assessment (NSAA). This investigational drug is an oral suspension with a good safety profile that was well tolerated.

Do you have questions about the above information? Please don’t hesitate to email research@defeatduchenne.ca.