Treatment Of Duchenne Muscular Dystrophy Research Articles

Discovery of Quinazoline and Quinoline-Based Small Molecules as Utrophin Upregulators via AhR Antagonism for the Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of a dystrophin protein. Elevating utrophin, a dystrophin paralogue, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Herein, we report the design and synthesis of novel quinazoline and quinoline-based small molecules as potent utrophin modulators screened via high throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of 70 molecules, upregulates utrophin 2.7-fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02's efficacy was further validated through DMD patient-derived cells, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by an increased MyHC expression. ADME evaluation supports SG-02's oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population.

Pharmacoinformational, gerontoinformational and chemoreactomic analysis of the molecule of citrulline malate, carnitine, sulbutiamine and meldonium to identify the molecular mechanisms of antiasthenic action

The pathophysiology of asthenia is very complex and is associated with chronic kidney disease, heart failure, chronic obstructive pulmonary disease, sarcopenia, bacterial and viral pathogens, micronutrient nutritional imbalances, hypothyroidism, etc. Asthenia can occur with excessive (for a given patient) physical, mental or mental stress and adaptation disorders or be iatrogenic in nature (in particular, due to taking medications that contribute to increased loss of vitamins and microelements), incl. due to unwanted drug interactions. The complex nature of the pathophysiology of asthenia necessitates the use of a differentiated approach aimed at eliminating the main cause of asthenia in a given patient. If asthenia is associated primarily with disorders of energy metabolism, then the pathophysiological treatment is the use of nutrients that support intracellular synthesis - such as citrulline, citrulline malate, the main mechanisms of action of which are supporting the urea cycle, increasing the excretion of ammonium ions, reducing the concentration lactate in the blood. The paper presents the results of a comparative pharmacoinformatic and chemoreactomic analysis of citrulline, citrulline malate (CM), carnitine, sulbutiamine and meldonium. The profile of pharmacological effects of citrulline/CM was significantly different from the profiles of other molecules. For citrulline/CM, cholinergic, antidepressant, and lipid-modifying effects have been identified and an antiasthenic effect has been suggested when used in the treatment of Duchenne muscular dystrophy and for disorders of carbohydrate metabolism. Unlike other molecules, CM and carnitine do not contribute to the loss of vitamins and minerals. Inhibition of the CM serotonin 5HT3A receptor may improve vestibulation because blockers of 5-HT3 receptors concentrated in neurons of the vestibular apparatus, improves tests of balance and walking in an experiment in mice. A positive dose-dependent effect of citrulline and CM on the lifespan of a number of model organisms has been shown. Chemoreactomic analysis of molecular receptor proteins indicated new molecular mechanisms of the antiasthenic action of CM: inhibition of serotonin receptors, calcium sensor protein receptors, chemokine receptors, lipopolysaccharides (toll receptors), nociceptin, glutamate, orexin, purines and prostanoids, biosynthesis of NF-kB and TNFα.

Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.

Assessing Pharmacogenomic loci Associated with the Pharmacokinetics of Vamorolone in Boys with Duchenne Muscular Dystrophy.

Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti-inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP-glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid-naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A4*22, CYP3A4*1B), CYP3A5 (CYP3A5*3), and UGT1A1 (UGT1A1*60) utilizing population PK modeling. A one-compartment model with zero-order absorption (Tk0, duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25-6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population Tk0 was 3.14 h yielding an average zero-order absorption rate (k0) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on Tk0). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD.

Vamorolone: revolutionizing Duchenne muscular dystrophy treatment

Duchenne muscular dystrophy (DMD) is a severe inherited neuromuscular disorder characterized by a dystrophin gene mutation, leading to progressive muscle weakness and structural degradation. Current management strategies focus on multidisciplinary approaches to mitigate symptoms and enhance quality of life. Conventional glucocorticoids present challenges due to their complex nature and severe side effects. Vamorolone, a first-in-class dissociative steroidal drug recently Food and Drug Administration (FDA) - approved, distinguishes itself through enduring anti-inflammatory effects with reduced safety concerns. Pharmacologically, Vamorolone's mechanism of action, differentiating it from traditional corticosteroids, involves selective glucocorticoid receptor (GR) modulation and mineralocorticoid receptor (MR) antagonism, offering improved safety and tolerability. Notably, its unique Δ9,11 modification prevents adverse receptor interactions, demonstrating superior safety in inhibiting inflammation across various cell types. This article explores Vamorolone's pharmacokinetics, drug interactions, and adverse effects, underscoring its well-tolerated profile with reversible hypothalamic-pituitary-adrenal axis suppression as a notable concern. Comparative studies against prednisone reveal Vamorolone's efficacy in improving muscle strength with minimal side effects, validated through the pivotal Phase IIb VISION-DMD study. Ultimately, Vamorolone has attained a breakthrough status in DMD treatment. Its endorsement by the FDA underscores Vamorolone as a transformative linchpin, heralding a new era in revolutionizing DMD care.

Casimersen (AMONDYS 45™): An Antisense Oligonucleotide for Duchenne Muscular Dystrophy.

Casimersen (AMONDYS 45TM) is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer subclass developed by Sarepta therapeutics. It was approved by the Food and Drug Administration (FDA) in February 2021 to treat Duchenne muscular dystrophy (DMD) in patients whose DMD gene mutation is amenable to exon 45 skipping. Administered intravenously, casimersen binds to the pre-mRNA of the DMD gene to skip a mutated region of an exon, thereby producing an internally truncated yet functional dystrophin protein in DMD patients. This is essential in maintaining the structure of a myocyte membrane. While casimersen is currently continuing in phase III of clinical trials in various countries, it was granted approval by the FDA under the accelerated approval program due to its observed increase in dystrophin production. This article discusses the pathophysiology of DMD, summarizes available treatments thus far, and provides a full drug review of casimersen (AMONDYS 45TM).

RGX-202, an Investigational Gene Therapy for the Treatment of Duchenne Muscular Dystrophy: Interim Clinical Data (S21.005)

RGX-202, an Investigational Gene Therapy for the Treatment of Duchenne Muscular Dystrophy: Interim Clinical Data (S21.005)

Efficacy and Tolerability of Ivabradine for Cardiomyopathy in Patients with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an intractable X-linked myopathy caused by dystrophin gene mutations. Patients with DMD suffer from progressive muscle weakness, inevitable cardiomyopathy, increased heart rate (HR), and decreased blood pressure (BP). The aim of this study was to clarify the efficacy and tolerability of ivabradine treatment for DMD cardiomyopathy.A retrospective analysis was performed in 11 patients with DMD, who received ivabradine treatment for more than 1 year. Clinical results were analyzed before (baseline), 6 months after, and 12 months after the ivabradine administration.The initial ivabradine dose was 2.0 ± 1.2 mg/day and the final dose was 5.6 ± 4.0 mg/day. The baseline BP was 95/64 mmHg. A non-significant BP decrease to 90/57 mmHg was observed at 1 month but it recovered to 97/62 mmHg at 12 months after ivabradine administration. The baseline HR was 93 ± 6 bpm and it decreased to 74 ± 12 bpm at 6 months (P = 0.011), and to 77 ± 10 bpm at 12 months (P = 0.008). A linear correlation (y = 2.2x + 5.1) was also observed between the ivabradine dose (x mg/day) and HR decrease (y bpm). The baseline LVEF was 38 ± 12% and it significantly increased to 42 ± 9% at 6 months (P = 0.011) and to 41 ± 11% at 12 months (P = 0.038). Only 1 patient with the lowest BMI of 11.0 kg/m2 and BP of 79/58 mmHg discontinued ivabradine treatment at 6 months, while 1-year administration was well-tolerated in the other 10 patients.Ivabradine decreased HR and increased LVEF without lowering BP, suggesting it can be a treatment option for DMD cardiomyopathy.

Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete. Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745-0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred. Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. Italfarmaco.

Screening for Duchenne muscular dystrophy in newborns in the Ningxia region

To evaluate the incidence rate of Duchenne muscular dystrophy (DMD) in the male newborns in the Ningxia region and establish a critical threshold for screening DMD in newborns to distinguish between the normal population and affected individuals. A total of 10 000 male newborns were screened using immunofluorescence analysis of creatine kinase isoenzyme concentrations in heel spot dried blood specimens. Newborns with the concentrations higher than the critical threshold were recalled for serum creatine kinase measurements. Genetic testing was performed to confirm diagnosis in cases showing abnormalities. Among the screened 10 000 male newborns, two were confirmed to have DMD through genetic testing, resulting in a preliminary estimated incidence rate of 1/5 000 for male newborns in the Ningxia region. The critical threshold for creatine kinase isoenzyme concentration in newborns in this region was determined to be 468.57 ng/mL. Screening for DMD in newborns is feasible in the Ningxia region. Early screening, diagnosis, and treatment of DMD can improve the quality of life for affected individuals and help families make informed decisions regarding further pregnancies.

Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy and contextualization with natural history controls.

Eteplirsen, approved in the US for patients with Duchenne muscular dystrophy (DMD) with exon 51 skip-amenable variants, is associated with attenuated ambulatory/pulmonary decline versus DMD natural history (NH). We report overall survival in a US cohort receiving eteplirsen and contextualize these outcomes versus DMD NH. US patients with DMD receiving eteplirsen were followed through a patient support program, with data collected on ages at eteplirsen initiation and death/end of follow-up. Individual DMD NH data were extracted by digitizing Kaplan-Meier (KM) curves from published systematic and targeted literature reviews. Overall survival age was analyzed using KM curves and contextualized with DMD NH survival curves; subanalyses considered age groups and duration of eteplirsen exposure. Overall survival time from treatment initiation was also evaluated. A total of 579 eteplirsen-treated patients were included. During a total follow-up of 2119 person-years, median survival age was 32.8 years. DMD NH survival curves extracted from four publications (follow-up for 1224 DMD NH controls) showed overall pooled median survival age of 27.4 years. Eteplirsen-treated patients had significantly longer survival from treatment initiation versus age-matched controls (age-adjusted hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.44-0.98; p < .05). Longer treatment exposure was associated with improved survival (HR, 0.15; 95% CI, 0.05-0.41; p < .001). Comparisons using different DMD NH cohorts to address common risks of bias yielded consistent findings. Data suggest eteplirsen may prolong survival in patients with DMD across a wide age range. As more data become available, the impact of eteplirsen on survival will be further elucidated.

Trilobatin contributes to the improvement of myopathy in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) occurs due to genetic mutations that lead to a deficiency in dystrophin production and consequent progressive degeneration of skeletal muscle fibres, through oxidative stress and an exacerbated inflammatory process. The flavonoid trilobatin (TLB) demonstrates antioxidant and anti-inflammatory potential. Its high safety profile and effective action make it a potent therapy for the process of dystrophic muscle myonecrosis. Thus, we sought to investigate the action of TLB on damage in a DMD model, the mdx mouse. Eight-week-old male animals were treated with 160 mg/kg/day of trilobatin for 8 weeks. Control animals were treated with saline. Following treatment, muscle strength, serum creatine kinase (CK) levels, histopathology (necrotic myofibres, regenerated fibres/central nuclei, Feret's diameter and inflammatory area) and the levels of catalase and NF-κB (western blotting) of the quadriceps (QUA), diaphragm (DIA) and tibialis anterior (TA) muscles were measured. TLB was able to significantly increase muscle strength and reduce serum CK levels in dystrophic animals. The QUA of mdx mice showed a reduction in catalase and the number of fibres with a centralized nucleus after treatment with TLB. In the DIA of dystrophic animals, TLB reduced the necrotic myofibres, inflammatory area and NF-κB and increased the number of regenerated fibres and the total fibre diameter. In TA, TLB increased the number of regenerated fibres and reduced catalase levels in these animals. It is concluded that in the mdx experimental model, treatment with TLB was beneficial in the treatment of DMD.

Spending on Targeted Therapies for Duchenne Muscular Dystrophy

This study estimates public and private spending on genetically targeted treatments for Duchenne muscular dystrophy during years in which the drugs were marketed without completed confirmatory studies.

Correction of human nonsense mutation via adenine base editing for Duchenne muscular dystrophy treatment in mouse

Duchenne muscular dystrophy (DMD) is the most prevalent herediatry disease in men, characterized by dystrophin deficiency, progressive muscle wasting, cardiac insufficiency, and premature mortality, with no effective therapeutic options. Here, we investigated whether adenine base editing can correct pathological non-sense point mutations leading to premature stop codons in the dystrophin gene. We identified 27 causative nonsense mutations in our DMD patient cohort. Treatment with adenine base editor (ABE) could restore dystrophin expression by direct A-to-G editing of pathological nonsense mutations in cardiomyocytes generated from DMD patient-derived induced pluripotent stem cells. We also generated two humanized mouse models of DMD expressing mutation-bearing exons 23 or 30 of human dystrophin gene. Intramuscular administration of ABE, driven by ubiquitous or muscle-specific promoters could correct these non-sense mutations in vivo, albeit with higher efficiency in exon 30, restoring dystrophin expression in skeletal fibers of humanized DMD mice. Moreover, a single systemic delivery of ABE with human sgRNA could induce body-wide dystrophin expression and improve muscle function in rotarod tests of humanized DMD mice. These findings demonstrate that ABE with human sgRNAs can confer therapeutic alleviation of DMD in mice, providing a basis for development of adenine base editing therapies in monogenic diseases.

Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs. The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy. The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

The role of ataluren in the treatment of ambulatory and non-ambulatory children with nonsense mutation duchenne muscular dystrophy - a consensus derived using a modified Delphi methodology in Eastern Europe, Greece, Israel and Sweden.

This paper details the results of an evaluation of the level of consensus amongst clinicians on the use of ataluren in both ambulatory and non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The consensus was derived using a modified Delphi methodology that involved an exploration phase and then an evaluation phase. The exploration phase involved 90-minute virtual 1:1 interviews of 12 paediatric neurologists who cared for 30-120 DMD patients each and had patient contact every one or two weeks. The respondents managed one to ten nmDMD patients taking ataluren. The Discussion Guide for the interviews can be viewed as Appendix A. Following the exploration phase interviews, the interview transcripts were analysed by an independent party to identify common themes, views and opinions and developed 43 draft statements that the Steering Group (authors) reviewed, refined and endorsed a final list of 42 statements. Details of the recruitment of participants for the exploration and evaluation phases can be found under the Methods section. A consensus was agreed (> 66% of respondents agreeing) for 41 of the 42 statements using results from a consensus survey of healthcare professionals (n = 20) experienced in the treatment of nmDMD. The statements with a high consensus suggest that treatment with ataluren should be initiated as soon as possible to delay disease progression and allow patients to remain ambulatory for as long as possible. Ataluren is indicated for the treatment of Duchenne muscular dystrophy that results from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older (see Summary of Product Characteristics for each country).

Evolving Role of Viltolarsen for Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is one of the most prevalent X-linked inherited neuromuscular disorders, with an estimated incidence between 1 in 3500 and 5000 live male births. The median life expectancy at birth is around 30years due to a rapid and severe disease progression. Currently, there is no cure for DMD, and the standard of care is mainly palliative therapy and glucocorticoids to mitigate symptoms and improve quality of life. Recent advances in phosphorodiamidate morpholino antisense oligonucleotide (PMO) technology has proven optimistic in providing a disease-modifying therapy rather than a palliative treatment option through correcting the primary genetic defect of DMD by exon skipping. However, as a result of the high variance in mutations of the dystrophin gene causing DMD, it has been challenging to tailor an effective therapy in most patients. Viltolarsen is effective in 8% of patients and accurately skips exon53, reestablishing the reading frame and producing a functional form of dystrophin and milder disease phenotype. Results of recently concluded preclinical and clinical trials show significantly increased dystrophin protein expression, no severe adverse effects, and stabilization of motor function. In summary, viltolarsen has provided hope for those working toward giving patients a safe and viable treatment option for managing DMD. This review summarizes an overview of the presentation, pathophysiology, genetics, and current treatment guidelines of DMD, pharmacological profile of viltolarsen, and a summary of the safety and efficacy with additional insights using recent clinical trial data.

Characteristics of Patients Receiving Novel Muscular Dystrophy Drugs in Trials vs Routine Care

The US Food and Drug Administration approved eteplirsen for Duchenne muscular dystrophy (DMD) in 2016 based on a controversial pivotal study that demonstrated a limited effect on the surrogate measure of dystrophin production. Other DMD treatments in the same class followed. To assess how patients receiving novel DMD treatments in postapproval clinical settings compare with patients in the clinical trials. This cross-sectional study collected data on patients who initiated 1 of 4 novel DMD treatments (eteplirsen, golodirsen, viltolarsen, and casimersen) using national claims databases of commercially insured (Merative MarketScan and Optum's Clinformatics Data Mart Database [CDM]) and Medicaid patients between September 19, 2016, and March 31, 2022. Patients were followed for 1 year after the date of first use of any novel DMD treatment. In addition, patients in pivotal DMD drug trials were identified for comparison. Age, sex, race and ethnicity, region, and DMD stage of patients receiving novel DMD treatment. The main outcome was health care costs and drug discontinuation as measured using descriptive statistics. A total of 223 routine care patients initiating novel DMD drugs (58 in MarketScan, 35 in CDM, and 130 in Medicaid) were identified. Among the 106 patients in the pivotal trials, the mean (SD) age was 8.5 (2.0) years (range, 4.0-13.0 years), which was younger than the mean age of patients in routine care (MarketScan: 13.7 [7.0] years [range, 1.8-33.3 years; P < .001]; CDM: 11.9 [5.7] years [range, 0.6-23.6 years; P < .001]; Medicaid: 13.4 [6.5] years [range, 1.8-46.1 years; P < .001]). The proportion of female patients identified in postapproval clinical settings was 2.9% (n = 1) in CDM (vs 34 male patients [97.1%]) and 1.5% (n = 2) in Medicaid (vs 128 male patients [98.5%]), which was not different from the pivotal trials. While nearly all patients in the pivotal trials had DMD disease stage 1 or 2 when initiating the DMD treatments (103 [97.2%]), in the postapproval clinical setting, slightly more than one-third of patients were in disease stage 3 or 4 (MarketScan, 17 [36.2%; P < .001]; CDM, 13 [41.9%; P < .001]; Medicaid, 54 [47.0%; P < .001]). The payer's cost for novel DMD treatments varied across the databases, with a mean (SD) of $634 764 ($607 101) in MarketScan, $482 749 ($582 350) in CDM, and $384 023 ($1 165 730) in Medicaid. Approximately one-third of routine care patients discontinued the treatments after approximately 7 months (mean [SD], 6.1 [4.4], 6.9 [3.9], and 7.2 [4.3] months in MarketScan, CDM, and Medicaid, respectively). These findings raise questions about the translation of DMD drug trial findings to routine care settings, with patients in routine care discontinuing the treatment within 1 year and payers incurring substantial expenses for these medications. More data are needed on whether these high costs are accompanied by corresponding clinical benefits.

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

This perspective article is concerned with the question of how proteomics, which is a core technique of systems biology that is deeply embedded in the multi-omics field of modern bioresearch, can help us better understand the molecular pathogenesis of complex diseases. As an illustrative example of a monogenetic disorder that primarily affects the neuromuscular system but is characterized by a plethora of multi-system pathophysiological alterations, the muscle-wasting disease Duchenne muscular dystrophy was examined. Recent achievements in the field of dystrophinopathy research are described with special reference to the proteome-wide complexity of neuromuscular changes and body-wide alterations/adaptations. Based on a description of the current applications of top-down versus bottom-up proteomic approaches and their technical challenges, future systems biological approaches are outlined. The envisaged holistic and integromic bioanalysis would encompass the integration of diverse omics-type studies including inter- and intra-proteomics as the core disciplines for systematic protein evaluations, with sophisticated biomolecular analyses, including physiology, molecular biology, biochemistry and histochemistry. Integrated proteomic findings promise to be instrumental in improving our detailed knowledge of pathogenic mechanisms and multi-system dysfunction, widening the available biomarker signature of dystrophinopathy for improved diagnostic/prognostic procedures, and advancing the identification of novel therapeutic targets to treat Duchenne muscular dystrophy.

The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice. This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase1b/2 trial assessing safety (NCT02515669) and a phase2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686). In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score). The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events. NCT02145234, NCT02515669, NCT03039686.