Therapeutic options for Duchenne muscular dystrophy: hope or hype?

Recently, the parents of a young boy with Duchenne muscular dystrophy (DMD) asked me about new emerging treatment options for their son. He has been on vamorolone as a disease-modifying treatment as part of an expanded access program after completing a clinical trial 2 years ago. Even though he is currently stable and in the early ambulatory phase of the disease, his parents are well-informed regarding the challenges ahead, and they are seeking alternative treatment to help slow disease progression. They are not alone in this journey. I received similar requests from many other DMD families on a regular basis.

DMD is a fatal X-linked recessive disease caused by pathogenic variants in the DMD gene. ¹ It is the most common childhood muscular dystrophy, with an estimated incidence of 1 in 3500 male births, and a prevalence of 4.8 in 100,000 males worldwide. ² Loss of dystrophin disrupts the dystrophin glycoprotein complex and leads to progressive muscle degeneration, with loss of independent ambulation by early adolescence, followed by decline in upper limbs function, scoliosis, cardiomyopathy, and respiratory insufficiency, with death occurring during the third or fourth decade of life. There is presently no cure for DMD. Comprehensive guidelines published in 2010, and further updated in 2018, have helped standardize the global care of DMD.^3,4

Thus far, several DMD therapies have received accelerated approval through the United States Food and Drug Administration (US FDA), the European Medicine Agency (EMA), and/or other regulatory authorities in several countries. Ataluren was conditionally approved by the EMA since July 2014 for ambulatory patients with DMD caused by nonsense mutations (~13% of DMD). It binds to the ribosomal RNA subunits and impairs the recognition of premature stop codon, thus allowing the translation and production of a modified dystrophin protein. ⁵ An earlier phase III ataluren confirmatory trial (NCT01826487) suggested potential benefit in a subset of participants at risk of ambulatory decline (as defined by 6-minute walk distance between 300 and 400 m at baseline). ⁶ Long-term real-world data from the global STRIDE Registry showed that treatment with ataluren delayed the age at loss of ambulation among individuals with nonsense mutation DMD (nmDMD). ⁷ However, the EMA recently reconfirmed its recommendation to not renew the conditional marketing authorization for Ataluren in October 2024 after the latest study (NCT03179631) failed to confirm Ataluren’s efficacy among nmDMD patients. ⁸ It is pending further review by the European Commission as well as the FDA.

Currently approved exon skipping drugs target DMD mutations amendable to exons 51, 53, or 45 skipping to produce a truncated dystrophin protein. Eteplirsen, a phosphoramidate morpholino oligomer (PMO), received accelerated approval by the FDA in 2016 for exon 51 skipping (~14% of DMD). Long-term follow-up of the original 12 treated patients suggested a delay in time to loss of ambulation (by median of ~2 years) and less decline in pulmonary function when compared to external controls. ⁹ Other exon-skipping PMOs including Golodirsen, ¹⁰ Viltolarsen ¹¹ (both exon 53 skipping, ~8% of DMD), and Casimersen ¹² (exon 45 skipping, ~9% of DMD) were similarly approved by the FDA between 2019 and 2021 based on modest increase in dystrophin expression on muscle biopsies obtained from a small number of treated patients; their long-term clinical benefits are still being assessed.

Delandistrogene moxeparvovec is the first approved gene therapy for DMD patients 4 years and older. Its initial accelerated approval by the FDA in June 2023 and subsequent expanded approval a year later caused significant controversy within the scientific community. ¹³ It uses an adeno-associated virus (AAVrh74) vector to deliver a micro-dystrophin gene to enable the production of a modified dystrophin protein. Early phase clinical studies of delandistrogene moxeparvovec suggested functional stabilization in four young boys with DMD (mean age at treatment, 5.1 years) 4 years after receiving treatment. ¹⁴ A larger phase III randomized placebo trial (NCT05096221) did not meet its primary endpoint (change in North Star Ambulatory Assessment score at 52 week) among those who received delandistrogene moxeparvovec (n = 63) compared to placebo (n = 65). ¹⁵ However, mean micro-dystrophin expression at week 12 (n = 31) and key secondary efficacy endpoints (changes in time to rise and time to walk/run 10 m) at week 52 numerically favored treatment. ¹⁵ Patients with elevated antibody titers to rAAVrh74 (>1:400) were not eligible for treatment. As well, those with mutations in exon 8 and/or exon 9 of the DMD gene were excluded due to risk of severe immune-mediated myositis. Individuals who received microdystrophin gene therapy may not be eligible to participate in other DMD clinical trials, particularly those involving different genetic therapy approaches. Long-term safety and efficacy data on delandistrogene moxeparvovec are currently pending.

Vamorolone is a novel glucocorticoid with anti-inflammatory and membrane stabilization effects on skeletal muscle. A double-blind, randomized, placebo- and prednisone-controlled trial (NCT03439670) of steroid-naïve DMD boys (n = 121, divided into four treatment groups) age 4 to <7 years showed that high dose (6 mg/kg/day) vamorolone had similar efficacy as prednisone after 24 weeks of treatment. The trial met the primary end point for change from baseline to week 24 time to stand velocity for high-dose vamorolone and the first 4 sequential secondary end points. ¹⁶ Improvements of motor outcomes seen with high-dose vamorolone at week 24 were maintained at week 48 after treatment; bone morbidities of prednisone including growth stunting and decline in serum bone biomarkers were reversed when treatment transitioned to vamorolone. ¹⁷ It was approved by the FDA in October 2023 for DMD patients ⩾2 years of age, followed by the EMA in December 2023 and the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA) in January 2024 for those 4 years and older.

Givinostat is the latest approved oral treatment for DMD patients with all genetic variants. It works by inhibiting classes I and II histone deacetylases, thus reducing inflammation and potentially slowing muscle degeneration. ¹⁸ It received FDA approval in March 2024, and by the MHRA in December 2024 for ambulant boys ⩾6 years of age with DMD after a randomized 18-month phase III (NCT02851797, n = 179) study showed that givinostat-treated participants had less decline in muscle function, as measured by time to climb four stairs, compared to placebo. ¹⁹ The key secondary endpoints did not differ between groups after multiplicity adjustment. The long-term safety and efficacy of givinostat in DMD is part an ongoing extension study. It is currently under review by the EMA.

Unfortunately, these new DMD therapies are currently not approved in many countries outside of the EU, United Kingdom, or United States, in part due to limited long-term efficacy data and high costs. ²⁰ Most studies were based on relatively small number of participants and used surrogate endpoints for treatment efficacy. ²⁰ These therapies are all very expensive; the estimated cost of eteplirsen can exceed $1 million USD per year, and delandistrogene moxeparvovec is priced at $3.2 million USD for a one-time treatment, thus beyond the reach of most patients apart from those living in economically affluent countries. Furthermore, pharmaceutical companies may delay submission to countries outside of the United States or the European Union due to smaller markets with less financial incentives, and therefore of lower priority status. Early or expanded access programs are available to patients who completed previous clinical trials to provide ongoing treatment until such therapies receive regulatory approval.

In Canada, once a new drug receives regulatory approval from Health Canada, it must go through review by Canada’s Drug Agency or equivalent provincial bodies and health technology assessment to further determine its clinical efficacy and cost-effectiveness, followed by pricing negotiations before final funding decisions by provincial/territorial governments, thus adding further delay to drug access. Participation in clinical trials meanwhile would allow patients to try new emerging therapies; however, it remains to be determined whether these new experimental therapies will succeed in meeting the intended outcomes or demonstrate a substantial impact on disease progression over time; there may also be many unforeseeable serious adverse effects. Significant unmet medical needs remain for patients with DMD, with many desperately seeking alternate therapeutic options. None of the currently approved therapies address the cognitive and behavior comorbidities, or other extra-muscular manifestations of DMD. Physicians should stay informed to support families and to guide decisions on accessing new therapies.

As my young patient’s specific DMD mutation is not amendable to exon-skipping, nonsense mutation suppression, or microdystrophin gene therapy, the parents are hoping to access givinostat for their child. However, as givinostat is currently not available in Canada except as part of a clinical trial, the parents may pursue it in other countries where it is already approved. They understand that the excessive costs of new DMD therapies will pose a significant barrier to drug access. Meanwhile, the parents are agreeable to receiving standard of care for their son, including immunizations against preventable illnesses, and continuing with glucocorticoid as a disease modifying treatment. Hopefully, there will be more effective treatment options for them and other DMD families soon.