In the last few years, the Duchenne muscular dystrophy (DMD) therapeutic landscape has undergone a dramatic evolution. More therapies are in clinical development today than ever before, each one aiming to treat DMD in a different way in order to halt or slow the disease’s devastating effects. This September marks the two-year anniversary of the first disease-modifying DMD therapy ever approved by the Food and Drug Administration (FDA), Sarepta Therapeutics’ Exondys 51, an exciting milestone for the DMD community that ushered in a new era of possibility.
Sept. 7 is World Duchenne Awareness Day, and although there is still more research to be done to cure DMD, we’re excited about the increasing number of impactful therapies advancing through the clinic, many of which can trace their origins back to MDA-funded research. As it stands, more than 25 DMD therapies are currently between Phase 1 and Phase 3 trials, an astounding number considering that just a few years ago there were only a handful. And this number is only going to grow in the coming years.
Transformative therapies on the horizon
Some of the most exciting experimental therapies in development are those that target the underlying DMD genetic mutation. These therapies are designed to partially restore the DMD gene by either replacing or correcting it, and they rely on cutting-edge technologies that include gene therapy, exon skipping and gene editing. Researchers in Duchenne and other neuromuscular diseases have been at the forefront of innovating these new types of therapies, and we are now seeing these novel approaches enter and broaden the pipeline.
The first of these, gene replacement therapy, has seen its share of ups and downs. But significant progress has been made in recent years, and three companies (Sarepta, Solid Biosciences and Pfizer) have recently moved into clinal-stage testing. Preliminary results in patients and in animal studies have been encouraging, hinting at the possibility that gene therapy may robustly improve expression of the DMD gene product (dystrophin), which in turn may protect muscles from damage and slow or stop the loss of function. While many important hurdles must be cleared before these therapies can be approved, the potential exists for them to someday be transformative.
Another class of therapies that continue to make gains are exon skipping drugs, which are designed to partially restore function of the DMD gene. What is worth noting is that each exon skipping drug is designed to target a specific underlying genetic defect, and therefore a subset of DMD patients. For example, Exondys 51 is designed for use by 13 percent of all DMD patients and is effective only for those whose DMD gene mutations are amenable to exon 51 skipping. But now there are four drug companies (Sarepta, Wave Life Sciences, Daiichi Sankyo and NS Pharma) who have exon skipping therapies in development that collectively target five new exons for skipping (exons 53, 52, 50, 45 and 44). If all are successful, a total of 43 percent of DMD patients may someday have access to an exon skipping therapy.
The third gene targeting approach is gene editing, including CRISPR. This approach is similar to exon skipping in that it is designed to address specific mutations in a subset of patients, but researchers hope it may be more effective. Early stage animal testing of CRISPR, including those conducted by Exonics Therapeutics, suggests that partial correction of the DMD gene may be achieved at higher rates and result in greater expression of dystrophin. Importantly, further animal studies are needed to confirm this, and to determine if CRISPR is safe enough for clinical trials to begin.
MDA’s commitment to funding groundbreaking DMD research
MDA has always been committed to supporting the fundamental research necessary for groundbreaking therapies to be discovered in the lab. For several decades, MDA has funded work to harness the power of gene therapy and exon skipping, and we are now starting to see this research come to fruition. And when early-stage gene editing techniques burst onto the scene in 2010, MDA began supporting development of these techniques in the hope of one day producing therapies for DMD — therapies that are now close to entering the clinic.
As we watch with anticipation during this exciting time in drug discovery, we also have our eyes set on the next generation of DMD breakthroughs. We are funding several research projects that have the potential to build on previous scientific advances and, in some cases, radically transform therapeutic approaches altogether.
Readers can visit MDA’s grants page to see what we are currently funding and get a holistic sense of the latest advances in DMD research today. However, there are several projects worth highlighting:
• Melissa Spencer, Ph.D., at the University of California, Los Angeles is investigating the use of nanoparticles to deliver CRISPR to the DMD gene. Nanoparticles have the potential to offer a more effective alternative to the AAV-mediated delivery approach that is currently in use for CRISPR and other gene replacement therapies.
• James Novak, Ph.D., at Children’s National Medical Center is looking into the role that macrophages play in influencing the delivery of exon skipping drugs into muscle. His work could inform better ways of using or designing exon skipping drugs.
• Caroline LeGuiner, Ph.D., at the University of Nantes aims to develop a gene replacement therapy that targets the heart muscle in DMD patients. If successful, this therapy may someday be used to slow the progressive development of dilated cardiomyopathy.
Matching therapies to clinical trials
With so many DMD trials entering the clinic, it is important for patients to be aware of the clinical trial landscape and participate in these trials if eligible. Many times, clinical trials are delayed as patients who qualify for the trial criteria cannot be easily found.
MDA’s clinical trial finder tool is a great way to see the different trials currently recruiting patients. After answering a few questions related to your or your child’s condition, you will be able to see the available trials that meet your criteria and will be given the contact information for those studies. The site also offers an FAQ section about participating in clinical trials, a checklist of questions to ask your doctor and a video of a family describing their clinical trial experience.
Harnessing data to expedite clinical trials
After launching a neuromuscular disease registry in 2013 that has enrolled and tracked more than 3,000 patients — including more than 650 with DMD — MDA has enhanced the registry’s technology. Renamed the NeuroMuscular ObserVational Research (MOVR) Data Hub Cooperative, MOVR will be a central registry that aggregates medical, patient-reported and genetic data. This registry will be rolled out at 25 MDA Care Centers this fall, with participation from an additional 25 Care Centers in the spring. Eventually, all MDA Care Centers will use MOVR, leveraging MDA’s unparalleled clinical reach and expertise.
MOVR has the potential to greatly influence patient care and research. From a clinical-care perspective, capturing a robust set of data from patients will enable care to be refined so that standards can be updated and best practices adopted. This is especially important for DMD, as new drugs and other treatments are changing the course of disease and clinical care is continually being refined in real time.
MOVR will also facilitate research. One goal of MOVR is to further clarify our understanding of DMD’s course, including how specific genetic mutations affect the timing and severity of symptoms. And as stated before, many therapies in the pipeline are designed for a specific subset of patients. MOVR captures genetic information that, coupled with a patient’s other medical data, can be used to quickly match patients with appropriate clinical trials.
In pursuit of a cure
There is no question that this is an exciting time in the history of DMD research. The pace of discovery is accelerating and the number of DMD drugs entering the clinic is growing exponentially. As MDA responds to and funds the breakthroughs taking place every day in labs throughout the world, our commitment remains unchanged. We will not rest until all these breakthroughs one day add up to a cure that our DMD community deserves.