Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy

Mah, Jean K.; Clemens, Paula R.; Guglieri, Michela; Smith, Edward C.; Finkel, Richard S.; Tulinius, M.; Nevo, Yoram; Ryan, Monique M.; Webster, Richard; Castro, Diana; Kuntz, Nancy L.; McDonald, Craig; Damsker, Jesse M.; Schwartz, Benjamin D.; Mengle-Gaw, L.; Jackowski, Stefan A.; Stimpson, Georgia; Ridout, Deborah; Gupta, Vandana Ayyar; Baranello, Giovanni; Manzur, Adnan; Muntoni, Francesco; Gordish‐Dressman, Heather; Leinonen, Mika; Ward, Leanne M.; Hoffman, Eric P.; Dang, Utkarsh J.; Robb, Stephanie; Quinlivan, Ros; Sárközy, Anna; Munot, Pinki; Main, Marion; Abbot, Lianne; Straub, V.; Bertolli, Chiara; Mayhew, Anna; Muni-Lofra, Robert; James, M.; Sodhi, J.; Parasuraman, Deepak; Alhaswani, Zoya; McMurchie, Heather; Rabb, Rosanna; Childs, Anne‐Marie; Pysden, Karen; Pallant, Lindsey; Small, Tiffany; Spinty, Stefan; Madhu, R; Shillington, Alison; Gregson, Sarah; Wraige, Elizabeth; Jungbluth, Heinz; Gowda, Vasantha; Sheehan, Jennie; Hughes, Imelda; Warner, Sinead; Davies, Emily; Willis, Tracey; Kulshrestha, Richa; Emery, Nicholas; Strachan, Kate; Ong, Min; White, Kay; Skone, Kate; Gibbon, Frances; Parsons, Bethan; Majumdar, Anirban; Vijaykumar, K R; Mason, Faye; Frimpong-Ansah, Claire; Naismith, Karen; Burslem, Julie; Horrocks, Iain; Marco, Marina Di; Brown, Sarah M.; Williamson, Sarah; Spencer, Kirstie; Chow, Gabby; Goede, Christian de; Selley, Andrea; Thomas, Nick; Illingworth, Marjorie; Greary, Michelle; Palmer, Jenni; White, Cathy; Greenfield, Kate; Fhirleinn, Grainne Nic; Douglas, Melanie; Tiraputhi, Sandya; Hussain, Nahin; Julien, Yvonne; Ambegaonkar, Gautam; Krishnakumar, Deepa; Taylor, Jacqui; Tewnion, Jane; Stephens, Elma; Chandratre, S; Ramdas, Sithara; Ramjattan, Hayley; Baxter, Alex; Eadie, Clare; Henricson, E.; Abresch, Richard T.; Joyce, Nanette C.; Viswanathan, Venkatarman; Chidambaranathan, S.; Biggar, Douglas W.; McAdam, Laura; Cnaan, Avital; Morgenroth, Lauren P.; Leshner, Robert T.; Tesi-Rocha, C.; Thangarajh, Mathula; Duong, Tina; Kornberg, Andrew J.; Dubrovsky, Alberto; Abdel-Hamid, Hoda; Connolly, Anne M.; Pestronk, Alan; Teasley, Jean; Bertorini, Tulio E.; Kolski, Hanna; Driscoll, Sherilyn W.; Bodensteiner, John B.; Carlo, Jose; Gorni, Ksenija; Lotze, Timothy; Day, John W.; Karachunski, Peter

doi:10.1001/jamanetworkopen.2021.44178

Cited by 49 publications

(2 citation statements)

References 59 publications

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“…Despite continuous therapeutic developments [ 2–5 ], the current standard of care treatment for most DMD boys is glucocorticoid (GC) treatment [ 6 ]. In the UK, boys are prescribed prednisolone/prednisone or deflazacort, with a daily or intermittent (10 days on, 10 days off) regime [ 7 ]; however, other regimes are in use globally [ 8 ] and short-term data from clinical trials have shown that the GC derivative designed to reduce adverse events, Vamorolone, has similar efficacy [ 9 ]. The age at starting GC is also varied, with potential impacts on disease trajectory over time.…”

Section: Introductionmentioning

confidence: 99%

Quantifying Variability in Motor Function in Duchenne Muscular Dystrophy: UK Centiles for the NorthStar Ambulatory Assessment, 10 m Walk Run Velocity and Rise from Floor Velocity in GC Treated Boys

Stimpson,

Ridout,

Wolfe

et al. 2024

JND

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Background Boys with Duchenne Muscular Dystrophy (DMD) display heterogeneous motor function trajectory in clinics, which represents a significant obstacle to monitoring. Objective: In this paper, we present the UK centiles for the North Star Ambulatory Assessment (NSAA), the 10 m walk/run time (10MWR) and velocity (10MWRV), and the rise from floor time (RFF) and velocity (RFFV) created from a cohort of glucocorticoid treated DMD boys between the age of 5 and 16 years. Methods: Participants were included from the UK NorthStar registry if they had initiated steroids (primarily deflazacorts/prednisolone, intermittent/daily) and were not enrolled in an interventional trial. Assessments were included if the participant had a complete NSAA, the timed tests had been completed or the corresponding items were 0, or the participant was recorded as non-ambulant, in which case the NSAA was assumed 0. Results: We analysed 3987 assessments of the NSAA collected from 826 participants. Of these, 1080, 1849 and 1199 were imputed as 0 for the NSAA, RFFV and 10MWRV respectively. The 10th, 25th, 50th, 75th and 90th centiles were presented. The NSAA centiles showed a peak score of 14, 20, 26, 30 and 32 respectively, with loss of ambulation at 10.7, 12.2 and 14.3 years for the 25th, 50th and 75th centiles, respectively. The centiles showed loss of rise from floor at 8.6, 10.1 and 11.9 years and a loss of 10MWR of 0 at 8.9, 10.3 and 13.8 years for the 25th, 50th and 75th centiles, respectively. The centiles were pairwise less correlated than the raw scores, suggesting an increased ability to detect variability in the DMD cohort. Conclusions: The NSAA, 10MWR and RFF centiles may provide insights for clinical monitoring of DMD boys, particularly in late ambulatory participants who are uniformly declining. Future work will validate the centiles in national and international natural history cohorts.

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Section: Introductionmentioning

confidence: 99%

Quantifying Variability in Motor Function in Duchenne Muscular Dystrophy: UK Centiles for the NorthStar Ambulatory Assessment, 10 m Walk Run Velocity and Rise from Floor Velocity in GC Treated Boys

Stimpson,

Ridout,

Wolfe

et al. 2024

JND

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“…Vamorolone was well tolerated at doses up to 6.0 mg/kg/d, with only 5 of the 46 patients stopping the study early and for unrelated causes. Glucocorticoid-treated DNHS individuals experienced a significant growth delay compared to vamorolone-treated participants, whose height percentiles remained consistent throughout time (0.37 percentile/month; 95% CI, 0.23 to 0.52 percentile/month) [ 74 ]. Once vamorolone completes its clinical trials successfully, it will be available to serve DMD patients.…”

Section: Possible Therapeutic Approachesmentioning

confidence: 99%

Molecular and Biochemical Therapeutic Strategies for Duchenne Muscular Dystrophy

Krishna,

Prashant,

Kumar

et al. 2024

Neurology International

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Significant progress has been achieved in understanding Duchenne muscular dystrophy (DMD) mechanisms and developing treatments to slow disease progression. This review article thoroughly assesses primary and secondary DMD therapies, focusing on innovative modalities. The primary therapy addresses the genetic abnormality causing DMD, specifically the absence or reduced expression of dystrophin. Gene replacement therapies, such as exon skipping, readthrough, and gene editing technologies, show promise in restoring dystrophin expression. Adeno-associated viruses (AAVs), a recent advancement in viral vector-based gene therapies, have shown encouraging results in preclinical and clinical studies. Secondary therapies aim to maintain muscle function and improve quality of life by mitigating DMD symptoms and complications. Glucocorticoid drugs like prednisone and deflazacort have proven effective in slowing disease progression and delaying loss of ambulation. Supportive treatments targeting calcium dysregulation, histone deacetylase, and redox imbalance are also crucial for preserving overall health and function. Additionally, the review includes a detailed table of ongoing and approved clinical trials for DMD, exploring various therapeutic approaches such as gene therapies, exon skipping drugs, utrophin modulators, anti-inflammatory agents, and novel compounds. This highlights the dynamic research field and ongoing efforts to develop effective DMD treatments.

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Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy

et al. 2022

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IMPORTANCECorticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life.OBJECTIVE To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD).DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. INTERVENTIONSThe study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. MAIN OUTCOMES AND MEASURESStudy outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test.RESULTS Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo −0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, −1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. CONCLUSIONS AND RELEVANCEIn this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care.

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Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy

Abstract: This nonrandomized controlled trial examines efficacy of vamorolone treatment for Duchenne muscular dystrophy among boys compared with glucocorticoid treatment.

Cited by 49 publications

References 59 publications

Quantifying Variability in Motor Function in Duchenne Muscular Dystrophy: UK Centiles for the NorthStar Ambulatory Assessment, 10 m Walk Run Velocity and Rise from Floor Velocity in GC Treated Boys

Quantifying Variability in Motor Function in Duchenne Muscular Dystrophy: UK Centiles for the NorthStar Ambulatory Assessment, 10 m Walk Run Velocity and Rise from Floor Velocity in GC Treated Boys

Molecular and Biochemical Therapeutic Strategies for Duchenne Muscular Dystrophy

Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy

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