Duchenne muscular dystrophy has seen more progress in the past 15 months (give or take) than in the last couple of decades combined. In that time, the Food and Drug Administration has approved three new therapies: Elevidys (delandistrogene moxeparvovec-rokl), the first micro-dystrophin gene therapy; Duvyzat (givinostat), a non-steroidal HDAC inhibitor; and Agamree (vamorolone), a new corticosteroid.
But the currently available treatments all have limitations, many patients are not eligible, and we still have no cure. As the CEO of a biotech firm seeking to accelerate the treatment of rare diseases, and as the mother of a child with DMD, I think many in the field fail to understand that while families now have more hope, they are also more confused than ever.
In the weeks after my son, Caffrey, was first diagnosed with Duchenne four years ago at the age of 10, the fear and grief were overwhelming. I found comfort in fellow families convening in social media groups. These parents have a wealth of information and are a source of great support for each other: exchanging information and ideas about treatments and supportive care, first-hand experience of technologies in trials, and an empathetic ear about the frustrations with each passing failed clinical program. These families have kept me focused on the present with a sense of optimism about the life that my son can have, rather than despair about the one he cannot.
Before the recent emergence of novel treatment approaches, not much had changed for DMD for decades. Now, the dialogue in these DMD groups has experienced a shift. In addition to feeling hopeful, grateful, and excited, Duchenne families like my own are feeling overwhelmed, anxious, confused, and, quite frankly, scared to death. Parents need to step up as advocates for their kids like never before.
Much of this apprehension stems from the decision about whether to seek gene therapy for their child. For the first time ever in Duchenne, this treatment choice could come with a lifetime of considerations and consequences. There is so much we don’t know about how gene therapy works in older patients and those who are nonambulatory, since those groups weren’t included in the clinical trials that led to approval. And the lack of information about safety, particularly related to myocarditis, can be terrifying.
In addition, there is an opportunity cost that comes along with any adeno-associated virus (AAV) formulated product, such as Elevidys, as treatment would create antibodies that will likely render anyone who takes it ineligible for other future AAV-based therapy. This is a crucial consideration since some have doubts about the first generation of micro-dystrophin gene therapies like Elevidys as well as the Pfizer micro-dystrophin therapy. Two Phase 3 trials failed to meet primary endpoints.
Yet the promise of next-generation gene therapies may be too far and uncertain to wait as Duchenne continue its destruction. For DMD families, this is the ultimate question: Is a bird in the hand worth two in the bush?
DMD families need more support so they feel empowered to make effective treatment decisions for their loved ones.
First and foremost, families need help figuring out their therapy priorities. Now that there are multiple treatment options, each family needs to decide what outcomes are most important to them. For some, the priority could be to maintain ambulation for as long as possible. Others might focus on cardiac care since ultimately, it’s heart function that is associated with mortality in Duchenne.
Neurologists need to reframe their dialogue with families to focus on helping them understand their specific goals from treatment and which therapies might be closest to delivering against them. They also need to guide families through the potential treatments on the horizon, either emerging approvals or available through clinical trials, to know the trade-offs of making certain decisions today.
Secondly, neurologists need to provide better guidance on the increasing challenge of polypharmacy in Duchenne. Most of these new treatments were not evaluated in combination with one another, therefore, there is no data to inform if they can be safely used together as part of a comprehensive treatment regimen. This includes questions about the ability to combine gene therapy with exon-skipping treatments for those patients that are amenable. The lack of data is stumping neurologists on how best to guide families.
Families do not have time to wait for additional studies to investigate the combination of these therapies. But insurance providers are taking advantage of this lack of data to selectively reject coverage. We need common-sense guidelines now based on the safety profile and mechanisms of action for each new therapy that can help families make informed decisions with their neurologists about which therapies can be used together to allow patients the best possibility of achieving their treatment goals. We also need mechanisms to ensure this guidance is adopted by insurance providers to avoid further burdening the health care system by creating unnecessary delays and aggravation for families and clinics.
Most importantly, we must recognize that deciding whether to pursue any treatment, especially gene therapy, can be a difficult, even impossible decision for families.
In June, the FDA approved an expanded label for Elevidys, making it available to boys with DMD who are 4 and older. I knew it was likely coming, and I agonized for over a year before the announcement. My son is a few years older than the trial participants, and I wasn’t sure what that would mean. I sought input from several researchers and medical professionals, and tapped into knowledge gained from my biopharma career. But my husband and I also felt that at 14, Caffrey was mature enough to weigh in on the discussion. Interestingly enough, he did not agonize about the choice at all. He was clear on his own treatment priorities and shared his opinion with no hesitation. We have chosen not to seek treatment with Elevidys.
Although we feel comfortable with our choice, we realize that many families will not agree or understand. When the stakes are so high and the decision is so personal, the most critical thing families need is judgment-free support. Living with Duchenne is hard enough. All we can do is make the best decision for our own kid with the information we have today and our treatment priorities in hand.
It has been a historic year, one that makes me so optimistic about the future, but let’s remember that Duchenne is far from being solved.
Ultimately, what patients with Duchenne deserve is a treatment that restores full-length dystrophin, and preferably one that can revert muscle damage, to truly improve long-term outcomes. This remains elusive, even with the recent advancements, and we cannot stop innovating until it is achieved.
Michelle C. Werner is CEO of Alltrna and CEO-partner at Flagship Pioneering. She has held executive roles in the pharmaceutical industry mainly in the oncology field, including Novartis, AstraZeneca, and Bristol Myers Squibb. She is also a member of the rare disease community, currently serving as a board member for the nonprofit organization Rare Disease Renegades.
