Real-World Experience With Duchenne Muscular Dystrophy Gene Therapy
In honor of World Duchenne Awareness Day, held September 7, several experts have provided their insights on the real-world experience of gene therapy’s use in Duchenne muscular dystrophy.
Sarepta Therapeutics’ delandistrogene moxeparvovec-rokl (marketed as Elevidys), an adeno-associated virus (AAV) vector-based gene therapy for patients with Duchenne muscular dystrophy (DMD), was originally granted FDA approval under an accelerated approval pathway for a limited indication on June 22, 2023: ambulatory patients aged 4 to 5 years with DMD and a confirmed mutation in the DMD gene, excluding patients with any deletion in exon 8 and/or exon 9.1 Later, on June 20, 2024, the FDA approved the gene therapy for use in a broader indication: ambulatory patients (via traditional approval) and nonambulatory patients (via accelerated approval) with a confirmed mutation in the DMD gene who are 4 years of age or older and who do not have any deletion in exon 8 or exon 9 in the gene.2
Elevidys is the most recent of several new options to come into the DMD paradigm within recent years, joining other treatments option such as exon-skipping therapy. Although these treatments are disease-modifying and have the potential for a transformative impact, none of them are curative, and they each carry their own risks. Furthermore, the uptake of Elevidys by the community is just beginning.
Nevertheless, in observance of World Duchenne Awareness Day, held annually on September 7, CGTLive® has reached out to several experts to learn about the real-world experience of gene therapy’s use in DMD thus far. Insights from experts interviewed by CGTLive’s sister site, NeurologyLive®, are also included.
Elevidys: Balancing Risks and Rewards
CGTLive spoke to John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia, about how the FDA’s approval of Elevidys changed the treatment landscape for DMD, how the experience of integrating the gene therapy into clinical practice has gone so far, and how doctors should help patients and families choose the right treatment option for DMD going forward. Brandsema explained how Elevidys fits into the rapidly expanding landscape of care for the disease, noting that the therapy offers patients the opportunity to get back a functional, although truncated, version of the gene that is mutated and nonfunctional in their own genome. He then went over the known safety risks of the therapy, as well as potential risks that are not yet confirmed. He emphasized the need for more long-term data, especially for older patients, as many patients treated thus far have been on the younger end of the spectrum.
Brandsema also discussed issues of access to Elevidys and other treatment options for DMD, noting that not all of the options are universally covered by patients' insurance and that some of the precautions and infrastructure that need to be in place to treat patients with gene therapy slow down the rate at which new patients can receive Elevidys. He also discussed the importance of age of treatment, noting that early treatment may help prevent further neurodegenerative effects of the disease, and as such comes with a sense of urgency, but that healthcare providers want to be able to provide the product to all patients and families who are interested, both those who are younger and older. As such, making decisions can be a balancing act. Brandsema also touched on the potential to combine multiple treatment options, such as gene therapy and exon-skipping therapy, for subsequent treatment of the same patients. He noted, however, that this may prove challenging from the perspective of insurance coverage and from the perspective of monitoring for adverse events (AEs), as the ability to attribute AEs to one treatment or the other may be confounded.
Making Decisions in the Face of Rapidly Expanding Treatment Options
In addition to the new therapeutic options for DMD that have been approved over the past 5 or so years, a large number of clinical trials for novel DMD therapeutics, such as gene-editing therapies, are currently ongoing. As such, patients and their families may not only choose between FDA-approved options, but also between enrolling in one of several active clinical trials, as well.
CGTLive spoke to Barry J. Byrne, MD, PhD, the chief medical advisor of Muscular Dystrophy Association (MDA) and a physician-scientist at the University of Florida, to get his perspective on both the real-world experience with Elevidys’ integration into clinical practice and his view on treatment decision-making in the aforementioned world of new commercial and investigational treatment options. Byrne emphasized that this is a difficult time for decision-making with the number of options available and that doctors will need to play an active role in helping patients and their families to pick the treatment path that is right for them. He discussed several promising investigational treatments that are being evaluated by various companies and institutions right now and pointed out that the potential for combination treatments may expand the breadth of decision-making even further. Byrne also noted the importance of work being done by several muscular dystrophy advocacy groups, such as the MDA Gene Therapy Support Group, to distribute relevant educational information and materials to the patient community.
Limitations of Current Therapies and the Promise of Gene Therapy to Address Unmet Needs
Besides gene therapy, exon-skipping therapy is one of the primary approaches for treating DMD, with 4 FDA-approved drugs available; although, they only cover about 30% of patients because of specific genetic mutation requirements, according to a conversation NeurologyLive had with Emma Ciafaloni, MD, who serves as a professor of neurology and pediatrics at University of Rochester Medical Center.
In a news network interview, Ciafaloni told NeurologyLive that these treatments require weekly IV infusions, but advancements in next-generation exon-skipping drugs may lead to more effective therapies with less frequent dosing. In addition, Ciafaloni said that significant progress is being made in gene replacement therapies, where mini or microdystrophin genes are engineered to be small enough for delivery via AAV vectors, potentially offering a one-time IV infusion solution for broader patient populations.
Efforts in the Duchenne Community to Educate Patients on Gene Therapy
In another recent interview with NeurologyLive, Michael Kelly, PhD, the chief scientific officer at CureDuchenne, and Deborah Miller, the CEO and founder of CureDuchenne, discussed a webinar focused on a new treatment for DMD, hosted by the organization in English and Spanish for the Duchenne community after the FDA approved the expansion label for Elevidys.3 The duo talked about how Diana Castro, MD, a neuromuscular specialist at the Neurology & Neuromuscular Care Center, shared her insights about its mechanism and the practical realities of treatment administration in the webinar. The webinar discussion emphasized the importance of educating both clinicians and families about the drug’s benefits and risks. In the discussion, Kelly highlighted the important role of physicians' experiences and the ongoing efforts of pharmaceutical companies to streamline drug access for patients.
During the conversation, Miller expressed her initial surprise and optimism about the expanded approval of Sarepta’s gene therapy, emphasizing the essential need for more treatment options in the DMD community. Both Kelly and Miller stressed the importance of patient choice in treatment, especially in a disease as progressive as DMD. Although they celebrated the progress made, they acknowledged the limitations of current gene therapy and shared their organizations' commitment to furthering research, including exploring new approaches like nonviral gene therapies and exon-skipping technologies.
The Big Picture
On the whole, it is an exciting time for the field of neuromuscular disease, as more and more disease-modifying treatments for devastating disorders like DMD become available to patients, and an even greater number are in or entering clinical trials. Although this is reason for optimism, the lack of an approved therapy that is curative and the different risks associated with the different treatment modalities, renders the decision-making process for treatment paths more complicated than ever for treating physicians, patients, and their families.
As an addendum to the interviews with Brandsema and Byrne, CGTLive asked each whether they had any messages to share with the clinician and patient communities for World Duchenne Awareness Day this year.
“I would first like to wish everyone in the DMD community a very happy World Duchenne Awareness Day,” Brandsema said. “I think that we’ve come a long way as a community in terms of having new hope for a different experience of this disease based on both our strides with genetically-targeted as well as muscle-targeted therapies, but we still have a lot of work to do together as a community to have the best possible life lived with DMD.”
“World Duchenne Awareness Day is really an opportunity for us as a provider community to reflect on all the new options there are for treatment,” Byrne said. “I think it will be fun to celebrate those developments—and the treatment landscape keeps improving. I think the provider community certainly welcomes that as do patients because it will ultimately really improve the lives of all those living with DMD and Becker muscular dystrophy, so we’re excited to contribute to that celebration.”
