EXPERT CONSENSUS ON TREATMENT GUIDANCE FOR FDA-APPROVED AND SECOND-GENERATION EXON-SKIPPING THERAPIES IN DUCHENE MUSCULAR DYSTROPHY (DMD): A RAND/UCLA MODIFIED DELPHI PANEL
Author(s)
Edward Smith, MD1, Lindsay Alfano, PT, DPT, PCS2, John Brandsema, MD3, Tina Duong, MPT, PhD4, Katherine Mathews, MD5, Leigh Maria Ramos-Platt, MD6, Aravindhan Veerapandiyan, MD7, Brenda Wong, MD8, Craig Zaidman, MD9, Justin Weiss, MPH10, Irina Yermilov, MPH, MS, MD11;
1Rare Disease Research, LLC., Durham, NC, USA, 2Nationwide Children's Hospital, Columbus, OH, USA, 3Children's Hospital of Philadelphia, Philadelphia, NY, USA, 4Stanford University, Palo Alto, CA, USA, 5Iowa Carver School of Medicine, Iowa City, IA, USA, 6Children's Hospital Los Angeles, Los Angeles, CA, USA, 7Arkansas Children's Hospital, Little Rock, AR, USA, 8UMass Memorial Health, Worcester, MA, USA, 9WashU Medicine, St. Louis, MO, USA, 10ADVI Health, Washington, DC, USA, 11ADVI Health, Los Angeles, CA, USA
1Rare Disease Research, LLC., Durham, NC, USA, 2Nationwide Children's Hospital, Columbus, OH, USA, 3Children's Hospital of Philadelphia, Philadelphia, NY, USA, 4Stanford University, Palo Alto, CA, USA, 5Iowa Carver School of Medicine, Iowa City, IA, USA, 6Children's Hospital Los Angeles, Los Angeles, CA, USA, 7Arkansas Children's Hospital, Little Rock, AR, USA, 8UMass Memorial Health, Worcester, MA, USA, 9WashU Medicine, St. Louis, MO, USA, 10ADVI Health, Washington, DC, USA, 11ADVI Health, Los Angeles, CA, USA
OBJECTIVES: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the DMD gene, leading to progressive muscle degeneration. We aimed to characterize the current therapeutic landscape for DMD, including exon-skipping therapies, gene therapy, and givinostat, as well as emerging second-generation exon-skipping agents.
METHODS: Using the RAND/UCLA modified Delphi panel method, nine US experts (seven pediatric neurologists, two physical therapists) rated the likelihood of recommending FDA-approved therapies (eteplirsen, golodirsen, viltolarsen, casimersen, GT, givinostat) and the anticipated clinical value of investigational therapies with Phase 1/2 data (delpacibart zotadirsen, DYNE-251, WVE-N531, and NS-089/NCNP-02). Ratings were completed for four disease stages (early/late ambulatory, early/late non-ambulatory) on a 1-9 scale before and after a virtual meeting. Patients were assumed to be on corticosteroids ± ACE inhibition in all scenarios. Disagreement was defined as >2 panelists rating a scenario on the extremes of the scale (1-3 and 7-9).
RESULTS: Panelists generally supported FDA-approved therapies and most combination approaches for ambulatory and early non-ambulatory patients, though they cautioned against GT followed by approved exon-skippers. Panelists assigned higher anticipated clinical value to second-generation exon-skippers and their potential use in combination with other therapies, based on early data demonstrating improved cardiac delivery and substantially higher dystrophin production. Delpacibart zotadirsen received the highest ratings for ambulatory and early non-ambulatory patients among investigational therapies, based on preliminary data. Disagreement decreased from 36% pre-meeting to 16% post-meeting.
CONCLUSIONS: The panel reached consensus that approved exon-skipping therapies provide modest benefit, particularly in earlier stages, while early data suggest that second-generation exon-skippers may have the potential to offer greater functional improvement. However, trials remain in early stages, and the full risks and benefits of these therapies are not yet known. The findings highlight the rapidly evolving DMD treatment landscape and the need for longitudinal real-world evidence to inform clinical care guidelines and payer decision-making.
METHODS: Using the RAND/UCLA modified Delphi panel method, nine US experts (seven pediatric neurologists, two physical therapists) rated the likelihood of recommending FDA-approved therapies (eteplirsen, golodirsen, viltolarsen, casimersen, GT, givinostat) and the anticipated clinical value of investigational therapies with Phase 1/2 data (delpacibart zotadirsen, DYNE-251, WVE-N531, and NS-089/NCNP-02). Ratings were completed for four disease stages (early/late ambulatory, early/late non-ambulatory) on a 1-9 scale before and after a virtual meeting. Patients were assumed to be on corticosteroids ± ACE inhibition in all scenarios. Disagreement was defined as >2 panelists rating a scenario on the extremes of the scale (1-3 and 7-9).
RESULTS: Panelists generally supported FDA-approved therapies and most combination approaches for ambulatory and early non-ambulatory patients, though they cautioned against GT followed by approved exon-skippers. Panelists assigned higher anticipated clinical value to second-generation exon-skippers and their potential use in combination with other therapies, based on early data demonstrating improved cardiac delivery and substantially higher dystrophin production. Delpacibart zotadirsen received the highest ratings for ambulatory and early non-ambulatory patients among investigational therapies, based on preliminary data. Disagreement decreased from 36% pre-meeting to 16% post-meeting.
CONCLUSIONS: The panel reached consensus that approved exon-skipping therapies provide modest benefit, particularly in earlier stages, while early data suggest that second-generation exon-skippers may have the potential to offer greater functional improvement. However, trials remain in early stages, and the full risks and benefits of these therapies are not yet known. The findings highlight the rapidly evolving DMD treatment landscape and the need for longitudinal real-world evidence to inform clinical care guidelines and payer decision-making.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
HSD8
Topic
Health Service Delivery & Process of Care
Disease
SDC: Neurological Disorders, SDC: Pediatrics, SDC: Rare & Orphan Diseases