Delandistrogene moxeparvovec is a recombinant adeno-associated virus rhesus isolate serotype 74 vector-based gene transfer therapy for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed pathogenic variant of the DMD gene. In a subset of patients in the EMBARK (A Gene Transfer Therapy Study to Evaluate the Safety and Efficacy of Delandistrogene Moxeparvovec [SRP-9001] in Participants With DMD) randomized clinical trial, changes in muscle health and pathology were assessed to evaluate the therapeutic impact of the treatment on disease progression. To determine the effect of delandistrogene moxeparvovec on muscle quantitative magnetic resonance (QMR) measures of disease progression in patients in the EMBARK trial. This was a phase 3, double-blind, placebo-controlled (October 2021-September 2023; week 52 cutoff date: September 13, 2023), multicenter randomized clinical trial that included 131 patients. Patients were randomized, and 125 were treated with either delandistrogene moxeparvovec (n = 63) or placebo (n = 62). The current study focused on a subset of patients who underwent muscle QMR imaging. Single-administration intravenous delandistrogene moxeparvovec (1.33 × 1014 vector genome/kg) or placebo. Change from baseline to week 52 in muscle MR was a prespecified exploratory end point. Proton MR spectroscopy (MRS) and 8-point Dixon MR imaging (MRI) measured muscle fat fraction (FF); multislice spin echo MRI measured transverse relaxation time (T2). MRS FF was measured in the soleus and vastus lateralis. MRI FF and T2 were measured in 5 leg muscle locations important for ambulation. A post hoc global statistical test combining all muscles and modalities assessed overall treatment effect. In this exploratory EMBARK analysis, 39 male participants (delandistrogene moxeparvovec, n = 19; placebo, n = 20; mean [SD] age, 6.10 [1.04] years; mean [SD] baseline North Star Ambulatory Assessment total score, 22.99 [3.71] points) underwent muscle MRI. Treated patients showed less disease progression vs placebo on MR measures. Across muscles and modalities, magnitudes of FF change favored delandistrogene moxeparvovec; between-group differences in least-squares mean change ranged from −1.01 (95% CI, −2.79 to 0.77; soleus) to −0.71 (95% CI, −3.21 to 1.80; vastus lateralis) for MRS FF and −3.09 (95% CI, −7.62 to 1.45; vastus lateralis) to −0.44 (95% CI, −4.01 to 3.12; hamstrings) for MRI FF. T2 reductions (improvements; 4 of 5 muscles) were observed in treated patients vs increases (worsening; all muscles) in placebo patients; within-group differences in least-squares mean change ranged from −1.06 (95% CI, −2.10 to −0.02; soleus) to 0.17 (95% CI, −1.76 to 2.10; biceps femoris) in the delandistrogene moxeparvovec group and from 1.12 (95% CI, 0.08-2.16; soleus) to 2.94 (95% CI, 0.84-5.03; quadriceps) in the placebo group. The global statistical test supported treatment benefit (P = .03). Results reveal that QMR outcomes consistently favored delandistrogene moxeparvovec across muscle groups, with treatment leading to decreased fat accumulation and improved T2 vs placebo over 52 weeks. Consistent with treatment effects on functional outcomes observed in the EMBARK trial, these results suggest stabilization or less progression of muscle pathology with delandistrogene moxeparvovec—adding to the totality of evidence supporting disease stabilization or slowing of disease progression with delandistrogene moxeparvovec. ClinicalTrials.gov Identifier: NCT05096221

Importance:Delandistrogene moxeparvovec is a recombinant adeno-associated virus rhesus isolate serotype 74 vector-based gene transfer therapy for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed pathogenic variant of the DMD gene. In a subset of patients in the EMBARK (A Gene Transfer Therapy Study to Evaluate the Safety and Efficacy of Delandistrogene Moxeparvovec [SRP-9001] in Participants With DMD) randomized clinical trial, changes in muscle health and pathology were assessed to evaluate the therapeutic impact of the treatment on disease progression. Objective:To determine the effect of delandistrogene moxeparvovec on muscle quantitative magnetic resonance (QMR) measures of disease progression in patients in the EMBARK trial. Design, Setting, and Participants:This was a phase 3, double-blind, placebo-controlled (October 2021-September 2023; week 52 cutoff date: September 13, 2023), multicenter randomized clinical trial that included 131 patients. Patients were randomized, and 125 were treated with either delandistrogene moxeparvovec (n = 63) or placebo (n = 62). The current study focused on a subset of patients who underwent muscle QMR imaging. Intervention:Single-administration intravenous delandistrogene moxeparvovec (1.33 × 1014 vector genome/kg) or placebo. Main Outcomes and Measures:Change from baseline to week 52 in muscle MR was a prespecified exploratory end point. Proton MR spectroscopy (MRS) and 8-point Dixon MR imaging (MRI) measured muscle fat fraction (FF); multislice spin echo MRI measured transverse relaxation time (T2). MRS FF was measured in the soleus and vastus lateralis. MRI FF and T2 were measured in 5 leg muscle locations important for ambulation. A post hoc global statistical test combining all muscles and modalities assessed overall treatment effect. Results:In this exploratory EMBARK analysis, 39 male participants (delandistrogene moxeparvovec, n = 19; placebo, n = 20; mean [SD] age, 6.10 [1.04] years; mean [SD] baseline North Star Ambulatory Assessment total score, 22.99 [3.71] points) underwent muscle MRI. Treated patients showed less disease progression vs placebo on MR measures. Across muscles and modalities, magnitudes of FF change favored delandistrogene moxeparvovec; between-group differences in least-squares mean change ranged from -1.01 (95% CI, -2.79 to 0.77; soleus) to -0.71 (95% CI, -3.21 to 1.80; vastus lateralis) for MRS FF and -3.09 (95% CI, -7.62 to 1.45; vastus lateralis) to -0.44 (95% CI, -4.01 to 3.12; hamstrings) for MRI FF. T2 reductions (improvements; 4 of 5 muscles) were observed in treated patients vs increases (worsening; all muscles) in placebo patients; within-group differences in least-squares mean change ranged from -1.06 (95% CI, -2.10 to -0.02; soleus) to 0.17 (95% CI, -1.76 to 2.10; biceps femoris) in the delandistrogene moxeparvovec group and from 1.12 (95% CI, 0.08-2.16; soleus) to 2.94 (95% CI, 0.84-5.03; quadriceps) in the placebo group. The global statistical test supported treatment benefit (P = .03). Conclusions and Relevance:Results reveal that QMR outcomes consistently favored delandistrogene moxeparvovec across muscle groups, with treatment leading to decreased fat accumulation and improved T2 vs placebo over 52 weeks. Consistent with treatment effects on functional outcomes observed in the EMBARK trial, these results suggest stabilization or less progression of muscle pathology with delandistrogene moxeparvovec-adding to the totality of evidence supporting disease stabilization or slowing of disease progression with delandistrogene moxeparvovec. Trial Registration:ClinicalTrials.gov Identifier: NCT05096221.

The goal of this paper is to estimate an optimal combination of biomarkers for individuals with Duchenne muscular dystrophy (DMD), which provides the most sensitive combinations of biomarkers to assess disease progression (in this case, optimal with respect to standardized response mean (SRM) for 4 muscle biomarkers). The biomarker data is incomplete (missing and irregular) multivariate longitudinal data. We propose a normal model with structured covariance designed for our setting. To sample from the posterior distribution of parameters, we develop a Markov Chain Monte Carlo (MCMC) algorithm to address the positive definiteness constraint on the structured correlation matrix. In particular, we propose a novel approach to compute the support of the parameters in the structured correlation matrix; we modify the approach from [1] on the set of the largest possible submatrices of the correlation matrix, where the correlation parameter is a unique element. For each posterior sample, we compute the optimal weights of our construct. We conduct data analysis and simulation studies to evaluate the algorithm and the frequentist properties of the posteriors of correlations and weights. We found that the lower extremities are the most responsive muscles at the early and late ambulatory disease stages, and the biceps brachii is the most responsive at the nonambulatory disease stage.

Becker muscular dystrophy (BMD) is a progressive disorder and impairs upper extremity (UE) function. The Performance of Upper Limb (PUL) measures UE function in muscular dystrophy, but has a ceiling effect in high-functioning subjects. Yet, fat fraction (FF) values via quantitative magnetic resonance (qMRI) have been used as biomarkers of muscle deterioration. Thus, the study aims to 1) determine if the PUL or qMRI FF can discriminate between functional groups of men with BMD and controls, and 2) assess relationships between PUL scores and qMRI FF. In a cross-sectional study, 56 men with BMD and 9 controls (18-63 yrs) completed PUL 2.0 and whole-body qMRI. Composite FF values for UE (deltoid, biceps & triceps) and whole-body were calculated. To understand the impact of mobility on UE performance, men with BMD were grouped using the 10-m run/walk test. Functional groups were: A) non-ambulatory B) walks – with no increase in speed possible; C) fast walking or jog; or D) run. One-way ANOVA/Kruskal-Wallis and Spearman's rho were used to assess differences between groups and correlations, respectively. Men with BMD scored 18-42 on the PUL. The PUL only detects differences between non-ambulatory (Group A) and high-functioning (Group C: p<0.001; Group D: p=0.02; Controls: p<0.001) groups. However, qMRI UE FF composite can discriminate between low-functioning (Groups A-B) and high-functioning (Groups C-D) men with BMD and whole-body FF composite can discriminate between all BMD functional groups (p<0.001 to 0.02). Higher PUL scores were associated with lower qMRI FF (p<0.05; rho =-0.70 to -0.50) only in low-functioning men with BMD (Groups A&B). Thus, the PUL has utility in assessing UE function in low-functioning men with BMD. Because the PUL may provide limited information about UE impairment in high-functioning men with BMD, it should be used cautiously or together with other biomarkers such as qMRI FF.

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

Delandistrogene moxeparvovec, an rAAVrh74-based gene transfer therapy designed to address absent functional dystrophin by delivering a transgene encoding an engineered micro-dystrophin, is approved in the US, UAE, Qatar, Kuwait, Bahrain, and Oman (March 2024) for ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed DMD mutation. Delandistrogene moxeparvovec showed stabilization of disease trajectory and manageable safety in patients aged ≥4–<8 years in a Phase 3 trial (EMBARK; NCT05096221). We report prespecified, exploratory analyses of muscle magnetic resonance (MR) data from EMBARK Part 1 (Week 52) to test the effect of delandistrogene moxeparvovec on muscle MR measures of disease progression. A subset of patients who received delandistrogene moxeparvovec (1.33×10¹⁴ vg/kg; n=19) or placebo (n=20) underwent quantitative muscle MR, including 8-point Dixon (MR imaging [MRI]) and proton MR spectroscopy (MRS) to measure muscle fat fraction (FF) and multi-slice spin echo imaging to measure transverse relaxation time (T₂). MRS FF was measured in the soleus and vastus lateralis, while MRI T₂ and FF were measured in 5 preselected leg muscles/groups with an important role in ambulation. A global statistical test (GST) combining all muscles and modalities assessed overall treatment effect. Overall, treated patients showed less disease progression vs. placebo. In all muscles, MRI FF and MRS FF magnitude of changes favored the treated group compared with placebo. The placebo group also showed increases (worsening) in T₂ (all muscles) compared with reductions (improvement) in treated patients (4/5 muscles; baseline to Week 52 change ranged from −1.05 to 0.05 msec [delandistrogene moxeparvovec] and 1.11 to 3.02 msec [placebo]). GST supports overall treatment benefit (P=0.0328). Muscle MRI changes were consistent with previously reported timed function tests, suggesting disease stabilization with delandistrogene moxeparvovec.

Bone fragility is highly prevalent in individuals with DMD, and the scope of this problem is likely to increase as patients are treated with corticosteroids for increasing durations. A number of potential interventions may preserve bone in individuals with DMD, however biomarkers to measure the efficacy of these interventions are needed. The purpose of this study was to develop magnetic resonance imaging (MRI) biomarkers of bone quality in DMD. 32 individuals with DMD (12.9 ± 3.8 years old) and 18 unaffected control participants (11.9 ± 2.8 years old) provided informed consent to participate in the study. The DMD group was 100% corticosteroid treated (63% deflazacort, 15% prednisone, 22% prednisolone), with 23% of participants treated with bisphosphonates. 27% of unaffected control participants and 56% of participants with DMD reported a history of fracture. An MR examination including high resolution imaging and Dixon imaging was performed in the distal femur, and MR images were analyzed to extract trabecular and cortical bone parameters and bone marrow fat fraction. Boys with DMD had significantly worse bone quality than unaffected boys as measured by bone marrow fat fraction (0.85 ± 0.10 vs. 0.77 ± 0.08, p=0.03), cortical thickness (1.6 ± 0.7 vs 2.3 ± 0.3 mm, p=0.0006), trabecular bone volume fraction (0.08 ± 0.03 vs 0.14 ± 0.03, p<0.0001), and finite element analysis-estimated bone stiffness (1.5 ± 0.5 vs 2.4 ± 0.4, p<0.001). Additionally, these variables were significantly correlated with both age and duration of corticosteroid use in individuals with DMD. MRI can noninvasively measure trabecular and cortical bone alterations in DMD at the distal femur, a common fracture site in boys with DMD. These measurements may offer a way to track the effects of bone-targeted interventions for DMD and other neuromuscular disorders.

Quantitative model-based clinical trial simulation tools play a critical role in informing study designs through simulation before actual execution. These tools help drug developers explore various trial scenarios in silico to select a clinical trial design to detect therapeutic effects more efficiently, therefore reducing time, expense, and participants' burden. To increase the usability of the tools, user-friendly and interactive platforms should be developed to navigate various simulation scenarios. However, developing such tools challenges researchers, requiring expertise in modeling and interface development. This tutorial aims to address this gap by guiding developers in creating tailored R Shiny apps, using an example of a model-based clinical trial simulation tool that we developed for Duchenne muscular dystrophy (DMD). In this tutorial, the structural framework, essential controllers, and visualization techniques for analysis are described, along with key code examples such as criteria selection and power calculation. A virtual population was created using a machine learning algorithm to enlarge the available sample size to simulate clinical trial scenarios in the presented tool. In addition, external validation of the simulated outputs was conducted using a placebo arm of a recently published DMD trial. This tutorial will be particularly useful for developing clinical trial simulation tools based on DMD progression models for other end points and biomarkers. The presented strategies can also be applied to other diseases.

Microdystrophin gene therapy (GT) shows promise for treating Duchenne muscular dystrophy (DMD), but the results of clinical trials have had mixed results. Magnetic resonance imaging (MRI) data collected 6-24 months after delandistrogene moxeparvovec administration showed preservation of muscle quality in 3 boys with DMD, however the persistence and generalizability of this effect is unknown. The objective of this ongoing longitudinal study is to evaluate MRI-determined muscle fat infiltration in microdystrophin GT-treated boys with DMD relative to an untreated natural history cohort. Muscle fat fraction (FF) was measured using chemical shift-based imaging acquired using a 3T MRI scanner in 6 muscles of the upper and lower legs of 3 microdystrophin GT treated boys with DMD and group age-matched steroid-treated boys with DMD. The longitudinal study included 3 delandistrogene moxeparvovec treated boys with DMD (10.0, 10.6, and 12.1 years) and 71 corticosteroid-treated boys with DMD (11.0 ± 0.9 years). For each GT treated subject, an individual comparator cohort was generated comprising all untreated subjects whose age was ± 0.5 years. 5- or 6-years post-GT administration (range 4.8-6.0 years), muscle FF remained low in GT treated boys, with FF less than 0.20 across all muscles measured including the proximal vastus lateralis (VL) and biceps femoris long head (BFLH) muscles. By contrast, the age-matched comparator cohorts had group mean FF of 0.40 to 0.47 in the VL and 0.60 to 0.63 in the BFLH. Boys treated with delandistrogene moxeparvovec were initially reported to have low fat infiltration 6-24 months after GT administration. More than five years after GT administration, these boys continue to show markedly slowed muscle fat accumulation compared with age-matched non-GT treated boys with DMD.

North Star Ambulatory Assessment (NSAA) is increasingly being utilized to assess efficacy of interventions in muscular dystrophies. Furthermore, proton magnetic resonance spectroscopy (1H-MRS) measures of fat fraction have been shown to be sensitive to disease progression and treatments in Duchenne muscular dystrophy (DMD). However, the relationship between NSAA and MR measures of fat fraction are less established. Therefore, in this study we evaluated NSAA and fat fraction measures of lower extremity muscles in a longitudinal study of DMD. A total of 90 subjects (age 5-17 at baseline) with DMD from the ImagingNMD project were included in this study with time points acquired yearly for up to 3 years. Single voxel 1H-MRS data were acquired at 3T using stimulated echo acquisition mode (STEAM) with relaxation corrections to measure fat fraction from the soleus and vastus lateralis. Relationships among measures were evaluated using non-parametric correlation and probability analyses. There was a strong relationship between NSAA total score and fat fraction of the soleus (ρ = -.78, p<0.01) and vastus lateralis (ρ = -.85, p<0.01). Three-year longitudinal changes in fat fraction correlated with NSAA total score changes (ρ = -.37, p=0.01). Further, the loss of ability to perform the more difficult tasks in the NSAA occurred at a lower fat fraction (e.g., running, 50% probability to perform task, vastus lateralis fat fraction 0.35) than less challenging tasks (e.g., standing, vastus lateralis fat fraction 0.60). Overall, NSAA was strongly correlated with muscle fat fraction evaluated with 1H-MRS, and our findings are consistent with the notion that muscle fat fraction can be used to predict functional abilities included in NSAA.

Becker muscular dystrophy (BMD) results in fat replacement of skeletal muscle and impaired functional performance. Quantitative magnetic resonance (qMR) imaging of muscle fat fraction (FF) has been used as a biomarker of muscle deterioration in muscular dystrophies. Specifically, qMR whole-body imaging (WBI) can quickly analyze multiple muscles and develop FF composites. The North Star Assessment for limb-girdle type muscular dystrophies (NSAD), has the potential to assess motor function in men with BMD across a wide range of abilities. Thus, we aimed to 1) assess the relationship between qMR FF and NSAD scores, and 2) determine qMR FF cut-off values for loss of performance on NSAD tasks that require gluteal and thigh muscle contractions. 41 men with BMD (18-62 years) completed 3-point Dixon qMR WBI and the NSAD. GlutThigh was calculated as the average FF of the right gluteus maximus, gluteus medius/minimus, quadriceps femoris, and hamstrings. The relationship between GlutThigh and function was assessed using Spearman's rho. GlutThigh cut-off values to discriminate men able or unable to perform each NSAD task were calculated using the receiver operating characteristic (ROC) and the Youden Index. Men with BMD had GlutThigh values from 0.08-0.89 (median: 0.58). Higher GlutThigh was strongly associated with lower NSAD scores (rho=-0.93; p<0.001). GlutThigh cut-off values ranged from 0.27 for rise from squat and running to 0.82 for standing and showed 83-100% sensitivity and 67-100% specificity. In men with BMD, higher GlutThigh values are strongly associated with poorer NSAD performance and more challenging NSAD tasks have lower GlutThigh cut-offs. GlutThigh cut-off values have high sensitivity and specificity to detect NSAD task failures across a wide range of men with BMD. Thus, qMR WBI GlutThigh provides important insight into functional performance in men with BMD and may serve as a functionally relevant biomarker of disease status in future clinical trials.

A randomized, double blinded, placebo controlled, multicenter Phase 3 clinical trial (Epidys; NCT02851797) examined the safety and efficacy of givinostat, an orally active histone deacetylase inhibitor in development, in ambulant boys with Duchenne muscular dystrophy (DMD). A total of 179 DMD boys aged ≥6 years at baseline were enrolled and treated for 18 months. The primary efficacy assessment was the time to climb 4 standard stairs (4SC). The primary endpoint was complemented by six key secondary efficacy endpoints: NSAA, time to rise from floor, 6MWT, knee extension and elbow flexion muscle strength, and a biomarker consisting of fat fraction of the vastus lateralis (VL) measured by magnetic resonance spectroscopy (MRS) which has proven to be sensitive to disease progression in DMD and predictive of loss of ambulation. The Epidys Study met its primary endpoint and givinostat demonstrated a statistically significant difference in change from baseline at 18 months in 4SC (GLSmean ratio [SD] = 0.86 [0.071]; p=0.0345). Overall, treatment effect estimates relating to the key secondary endpoints consistently favored givinostat over placebo supporting the primary endpoint result. VL fat fraction, measured by MRS, showed significant less fat infiltration in givinostat treated subjects over 18 months compared to placebo (Difference in LS means (givinostat-placebo): -2.92%; nominal p-value: 0.035). Participants in the placebo group had an average VL fat fraction increase of 10.6% while patients treated with givinostat had an increase of 7.6%. MRS VL fat fraction results were confirmed using quantitative imaging of water and fat (Dixon Imaging). The treatment effect of givinostat was demonstrated in each of the selected 5 thigh muscles/muscle groups (VL, nominal p-value: 0.0033; biceps femoris long head, nominal p-value: 0.0235; semitendinosus and quadriceps, nominal p-value: 0.0009 each; and hamstrings, nominal p-value: 0.0026). Givinostat treatment in DMD patients showed a good tolerability profile. In conclusion, the Epidys Study met its primary endpoint with consistent results in the key secondary endpoints. Quantitative MR measures of muscle fat infiltration showed that givinostat ameliorates muscle deterioration in patients with DMD. Givinostat tolerability profile in Epidys Study was in line with results in previous studies in DMD and in other diseases. These results also support the use of quantitative MR biomarkers in clinical trials. A randomized, double blinded, placebo controlled, multicenter Phase 3 clinical trial (Epidys; NCT02851797) examined the safety and efficacy of givinostat, an orally active histone deacetylase inhibitor in development, in ambulant boys with Duchenne muscular dystrophy (DMD). A total of 179 DMD boys aged ≥6 years at baseline were enrolled and treated for 18 months. The primary efficacy assessment was the time to climb 4 standard stairs (4SC). The primary endpoint was complemented by six key secondary efficacy endpoints: NSAA, time to rise from floor, 6MWT, knee extension and elbow flexion muscle strength, and a biomarker consisting of fat fraction of the vastus lateralis (VL) measured by magnetic resonance spectroscopy (MRS) which has proven to be sensitive to disease progression in DMD and predictive of loss of ambulation. The Epidys Study met its primary endpoint and givinostat demonstrated a statistically significant difference in change from baseline at 18 months in 4SC (GLSmean ratio [SD] = 0.86 [0.071]; p=0.0345). Overall, treatment effect estimates relating to the key secondary endpoints consistently favored givinostat over placebo supporting the primary endpoint result. VL fat fraction, measured by MRS, showed significant less fat infiltration in givinostat treated subjects over 18 months compared to placebo (Difference in LS means (givinostat-placebo): -2.92%; nominal p-value: 0.035). Participants in the placebo group had an average VL fat fraction increase of 10.6% while patients treated with givinostat had an increase of 7.6%. MRS VL fat fraction results were confirmed using quantitative imaging of water and fat (Dixon Imaging). The treatment effect of givinostat was demonstrated in each of the selected 5 thigh muscles/muscle groups (VL, nominal p-value: 0.0033; biceps femoris long head, nominal p-value: 0.0235; semitendinosus and quadriceps, nominal p-value: 0.0009 each; and hamstrings, nominal p-value: 0.0026). Givinostat treatment in DMD patients showed a good tolerability profile. In conclusion, the Epidys Study met its primary endpoint with consistent results in the key secondary endpoints. Quantitative MR measures of muscle fat infiltration showed that givinostat ameliorates muscle deterioration in patients with DMD. Givinostat tolerability profile in Epidys Study was in line with results in previous studies in DMD and in other diseases. These results also support the use of quantitative MR biomarkers in clinical trials.

Although regulatory agencies encourage inclusion of imaging biomarkers in clinical trials for Duchenne muscular dystrophy (DMD), industry receives minimal guidance on how to use these biomarkers most beneficially in trials. This study aims to identify the optimal use of muscle fat fraction biomarkers in DMD clinical trials through a quantitative disease-drug-trial modeling and simulation approach. We simultaneously developed two multivariate models quantifying the longitudinal associations between 6-minute walk distance (6MWD) and fat fraction measures from vastus lateralis and soleus muscles. We leveraged the longitudinal individual-level data collected for 10 years through the ImagingDMD study. Age of the individuals at assessment was chosen as the time metric. After the longitudinal dynamic of each measure was modeled separately, the selected univariate models were combined using correlation parameters. Covariates, including baseline scores of the measures and steroid use, were assessed using the full model approach. The nonlinear mixed-effects modeling was performed in Monolix. The final models showed reasonable precision of the parameter estimates. Simulation-based diagnostics and fivefold cross-validation further showed the model's adequacy. The multivariate models will guide drug developers on using fat fraction assessment most efficiently using available data, including the widely used 6MWD. The models will provide valuable information about how individual characteristics alter disease trajectories. We will extend the multivariate models to incorporate trial design parameters and hypothetical drug effects to inform better clinical trial designs through simulation, which will facilitate the design of clinical trials that are both more inclusive and more conclusive using fat fraction biomarkers.

Becker Muscular Dystrophy (BMD) results in impaired function of dystrophin and leads to fat replacement of skeletal muscle impacting function. There is a growing interest in drug development for BMD, and biomarkers that characterize muscle quality and their relationships to function are needed. Quantitative magnetic resonance (qMR) imaging of muscle fat fraction (FF) is highly reliable and sensitive to disease progression in muscular dystrophy. Whole-body quantitative three-point Dixon (3PD) imaging (WBI) has efficient acquisition and the ability to analyze multiple muscles to develop body segment-specific FF composites. Using WBI qMR, we aimed to 1) characterize skeletal muscle using FF composites, and 2) identify relationships among FF composites and function in men with BMD. We hypothesized that FF composites of the upper (UE) and lower (LE) extremity and the trunk would be moderately correlated with the Performance of Upper Limb (PUL), North Star Assessment for Dysferlinopathy (NSAD), and pulmonary function tests (PFTs), respectively. In 29 men with BMD (18 to 61 years), we measured FF composites of the muscles of the right proximal UE (deltoid and biceps brachii), LE (gluteus maximus, gluteus medius/minimus, psoas, quadriceps femoris, and hamstrings), and trunk (rectus abdominus, obliques, and paraspinals). Relationship between FF and function was assessed using the Spearman Rank correlation coefficient (rs). Men with BMD had FF composites ranging from 9% to 78% (median: 20%) for UE, 7% to 81% (median: 57%) for LE, and 9% to 76% (median: 41%) for trunk. Relationships were identified between UE FF composite and PUL scores (rs=-0.76; p<0.001), LE FF composite and NSAD scores (rs=-0.93; p<0.001), and trunk FF composite and PFTs (forced vital capacity [FVC], forced expiratory volume [FEV1], and peak cough flow [PCF]; rs=-0.47 to -0.48; p=0.03). Body segment-specific relationships with function suggest that WBI qMR FF is a meaningful biomarker in men with BMD. Becker Muscular Dystrophy (BMD) results in impaired function of dystrophin and leads to fat replacement of skeletal muscle impacting function. There is a growing interest in drug development for BMD, and biomarkers that characterize muscle quality and their relationships to function are needed. Quantitative magnetic resonance (qMR) imaging of muscle fat fraction (FF) is highly reliable and sensitive to disease progression in muscular dystrophy. Whole-body quantitative three-point Dixon (3PD) imaging (WBI) has efficient acquisition and the ability to analyze multiple muscles to develop body segment-specific FF composites. Using WBI qMR, we aimed to 1) characterize skeletal muscle using FF composites, and 2) identify relationships among FF composites and function in men with BMD. We hypothesized that FF composites of the upper (UE) and lower (LE) extremity and the trunk would be moderately correlated with the Performance of Upper Limb (PUL), North Star Assessment for Dysferlinopathy (NSAD), and pulmonary function tests (PFTs), respectively. In 29 men with BMD (18 to 61 years), we measured FF composites of the muscles of the right proximal UE (deltoid and biceps brachii), LE (gluteus maximus, gluteus medius/minimus, psoas, quadriceps femoris, and hamstrings), and trunk (rectus abdominus, obliques, and paraspinals). Relationship between FF and function was assessed using the Spearman Rank correlation coefficient (rs). Men with BMD had FF composites ranging from 9% to 78% (median: 20%) for UE, 7% to 81% (median: 57%) for LE, and 9% to 76% (median: 41%) for trunk. Relationships were identified between UE FF composite and PUL scores (rs=-0.76; p<0.001), LE FF composite and NSAD scores (rs=-0.93; p<0.001), and trunk FF composite and PFTs (forced vital capacity [FVC], forced expiratory volume [FEV1], and peak cough flow [PCF]; rs=-0.47 to -0.48; p=0.03). Body segment-specific relationships with function suggest that WBI qMR FF is a meaningful biomarker in men with BMD.

ObjectiveNo treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD.MethodsMales aged 18–65 years with a diagnosis of BMD confirmed by genetic testing were randomized 2:1 to 12 months treatment with givinostat or placebo. The primary objective was to demonstrate statistical superiority of givinostat over placebo for mean change from baseline in total fibrosis after 12 months. Secondary efficacy endpoints included other histological parameters, magnetic resonance imaging and spectroscopy (MRI and MRS) measures, and functional evaluations.ResultsOf 51 patients enrolled, 44 completed treatment. At baseline, there was greater disease involvement in the placebo group than givinostat, based on total fibrosis (mean 30.8 vs. 22.8%) and functional endpoints. Mean total fibrosis did not change from baseline in either group, and the two groups did not differ at Month 12 (least squares mean [LSM] difference 1.04%; p = 0.8282). Secondary histology parameters, MRS, and functional evaluations were consistent with the primary. MRI fat fraction in whole thigh and quadriceps did not change from baseline in the givinostat group, but values increased with placebo, with LSM givinostat–placebo differences at Month 12 of −1.35% (p = 0.0149) and −1.96% (p = 0.0022), respectively. Adverse events, most mild or moderate, were reported by 88.2% and 52.9% patients receiving givinostat and placebo.ConclusionThe study failed to achieve the primary endpoint. However, there was a potential signal from the MRI assessments suggesting givinostat could prevent (or slow down) BMD disease progression.

Abstract Objective Magnetic resonance (MR) measures of muscle quality are highly sensitive to disease progression and predictive of meaningful functional milestones in Duchenne muscular dystrophy (DMD). This investigation aimed to establish the reproducibility, responsiveness to disease progression, and minimum clinically important difference (MCID) for multiple MR biomarkers at different disease stages in DMD using a large natural history dataset. Methods Longitudinal MR imaging and spectroscopy outcomes and ambulatory function were measured in 180 individuals with DMD at three sites, including repeated measurements on two separate days (within 1 week) in 111 participants. These data were used to calculate day‐to‐day reproducibility, responsiveness (standardized response mean, SRM), minimum detectable change, and MCID. A survey of experts was also performed. Results MR spectroscopy fat fraction (FF), as well as MR imaging transverse relaxation time (MRI‐T2), measures performed in multiple leg muscles, and had high reproducibility (Pearson's R > 0.95). Responsiveness to disease progression varied by disease stage across muscles. The average FF from upper and lower leg muscles was highly responsive (SRM > 0.9) in both ambulatory and nonambulatory individuals. MCID estimated from the distribution of scores, by anchoring to function, and via expert opinion was between 0.01 and 0.05 for FF and between 0.8 and 3.7 ms for MRI‐T2. Interpretation MR measures of FF and MRI T2 are reliable and highly responsive to disease progression. The MCID for MR measures is less than or equal to the typical annualized change. These results confirm the suitability of these measures for use in DMD and potentially other muscular dystrophies.