Treatment Of Duchenne Muscular Dystrophy Research Articles

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.

Identifying hub genes and dysregulated pathways in Duchenne muscular dystrophy

Purpose The aim of this study was to identify the hub genes and dysregulated pathways in the progression of duchenne muscular dystrophy (DMD) and to unveil detailedly the cellular and molecular mechanisms associated with DMD for developing efficacious treatments in the future. Material and methods Three mRNA microarray datasets (GSE13608, GSE38417 and GSE109178) were downloaded from Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) between DMD and normal tissues were obtained via R package. Function enrichment analyses were implemented respectively using DAVID online database. The network analysis of protein-protein interaction network (PPI) was conducted using String. Cytoscape and String were used to analyse modules and screen hub genes. The expression of the identified hub genes was confirmed in mdx mice through using qRT-PCR. Results In total, 519 DEGs were identified, consisting of 393 upregulated genes and 126 downregulated genes. The enriched functions and pathways of the DEGs mainly involve extracellular matrix organization, collagen fibril organization, interferon-gamma-mediated signaling pathway, muscle contraction, endoplasmic reticulum lumen, MHC class II receptor activity, phagosome, graft-versus-host disease, cardiomyocytes, calcium signaling pathway. Twelve hub genes were discovered and biological process analysis proved that these genes were mainly enriched cell cycle, cell division. The result of qRT-PCR suggested that increase in expression of CD44, ECT2, TYMS, MAGEL2, HLA-DMA, SERPINH1, TNNT2 was confirmed in mdx mice and the downregulation of ASB2 and LEPREL1 was also observed. Conclusion In conclusion, DEGs and hub genes identified in the current research help us probe the molecular mechanisms underlying the pathogenesis and progression of DMD, and provide candidate targets for diagnosis and treatment of DMD.

Patient engagement in clinical trial design for rare neuromuscular disorders: impact on the DELIVER and ACHIEVE clinical trials

BackgroundEngaging individuals living with disease in drug development and regulatory processes leads to more thoughtful and sensitive trial designs, drives more informative and meaningful outcomes from clinical studies, and builds trust between the public, government, and industry stakeholders. This engagement is especially important in the case of rare diseases, where affected individuals and their families face many difficulties getting information, treatment, and support. Dyne Therapeutics is developing therapeutics for people with genetically-driven muscle diseases. During the development of potential treatments for Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1), Dyne sought the opinions of individuals living with these diseases to inform its clinical trial design and to decrease the difficulties that participants and families might experience participating in them.MethodsDyne engaged individuals and families living with DMD and DM1 as expert partners in its clinical development programs. Dyne convened panels of affected individuals and care partners/parents of individuals living with DMD (n = 8) or DM1 (n = 18). Workshops focused on how affected individuals and their families evaluate and select clinical trials for participation, the importance, quality, and burden associated with individual trial design elements, participation considerations such as site location and the study visit design, patient privacy, the suitability and scope of travel and participant support programs, and the accessibility of content in the informed consent (or assent) forms. Dyne also engaged the DMD Community Advisory Board (CAB) to collect feedback and advice on designing optimal and meaningful clinical trials and measuring relevant outcomes.ResultsThe issues most important to individuals living with DM1 and DMD regarding clinical trials were the ability to participate/access to the trial, perceptions of benefit and risk of trials and potential treatments, the flexibility of participation, clear communication from the sponsor, availability of information from trusted sources, and patient enrollment. In response to the patient advisory workshops and CAB feedback, Dyne refined clinical trial inclusion/exclusion criteria and clinic visit design, developed a travel service program to address the burden of clinical trial travel and enable long-distance and cross-border participation, planned for home visits when feasible, and allowed for adequate rest before clinic visit initiation and between assessments. Additionally, Dyne developed and implemented a transparent and consistent communications plan (including age-appropriate content) for trial participants and community members, and assessed and adjusted procedures to provide maximum participant comfort and lower anxiety, particularly with younger participants.ConclusionsOngoing communication with the Duchenne CAB and with DMD and DM1 patient advisory committee members allows Dyne to stay current with disease community perspectives and feedback on the needs and preferences of those affected and has provided valuable insights into the participant experience thereby helping Dyne initiate clinical trials that better meet the needs of affected individuals and their families.

The bench to bedside journey of tricyclo-DNA antisense oligonucleotides for the treatment of Duchenne muscular dystrophy.

The development of antisense oligonucleotide (ASO)-based therapeutics has made tremendous progress over the past few years, in particular for the treatment of neuromuscular disorders such as Duchenne muscular dystrophy and spinal muscular atrophy. Several ASO drugs have now reached market approval for these diseases and many more are currently under clinical evaluation. Among them, ASOs made of the tricyclo-DNA originally developed by Christian Leumann have shown particularly interesting properties and demonstrated promise for the treatment of Duchenne muscular dystrophy. In this review, we examine the bench to bedside journey of tricyclo-DNA-ASOs from their early preclinical evaluation as fully phosphorotiated-ASOs to the latest generation of lipid-conjugated-ASOs. Finally we discuss the remaining challenges of ASO-mediated exon-skipping therapy for DMD and future perspectives for this promising chemistry of ASOs.

INNOVATIVE THERAPIES IN REGENERATIVE MEDICINE AND TRANSPLANTATION

Introduction: In the past decade we have observed fast development of a new medical fields including regenerative medicine and reconstructive transplantation of the vascularized composite allografts (VCA). The VCA procedures include the new generation of face transplants, hand transplants and many other organs which opened a new reconstructive option for severely damaged patients. The lecture summarizes the risks and benefits of the VCA transplants specifically in the context of the need for life-long immunosuppression to extend VCA survival. Aim: Novel therapeutic strategies of different cell- based therapies are discussed with special emphasizes on the new generation of the donor-recipient chimeric cells used as a supportive tolerogenic therapy for VCA transplants. Material and Methods: Development of the preclinical studies carried in the experimental animal models for creation of the chimeric cells is outlined. This is followed by the creation of the human hematopoietic chimeric cells of the bone marrow and the Umbilical Cord Blood cells origin, confirming tolerogenic and immunomodulatory properties of these new cell-based therapies for application in theVCA and solod organ transplantation. Further development of chimeric cells in the field of regenerative medicine include creation of the Dystrophin Expressing Chimeric (DEC) cells as a novel therapeutic approach for patients with Duchenne muscular dystrophy (DMD). Results: In preparation to clinical applications DEC cells safety and efficacy was tested in the mdx mouse models of DMD. The safety of DEC biodistribution to the DMD- affected target organs of heart, diaphragm and gastrocnemius muscle was confirmed and correlated with improvement in functional tests assessed by echocardiography, plethysmography and standard tests of muscle strengths. These encouraging results observed in preclinical studies lead to the development of the clinical protocol for DMD patients. Currently the DT-DEC01 therapy was applied to seven DMD patients. Both, safety and efficacy of DT-DEC01 cells was confirmed up to 24 months after systemic intraosseous administration to the DMD patients. Conclusions: This pilot clinical study introduces DEC cells as a novel universal therapeutic approach for treatment of DMD and other muscular dystrophies regardless of gene mutation and ambulatory status of the patients.

Evaluation of pro-regenerative and anti-inflammatory effects of isolecanoric acid in the muscle: Potential treatment of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a devastating degenerative disease of skeletal muscles caused by loss of dystrophin, a key protein that maintains muscle integrity, which leads to progressive muscle degeneration aggravated by chronic inflammation, muscle stem cells’ (MuSCs) reduced regenerative capacity and replacement of muscle with fibroadipose tissue. Previous research has shown that pharmacological GSK-3β inhibition favors myogenic differentiation and plays an important role in modulating inflammatory processes. Isolecanoric acid (ILA) is a natural product isolated from a fungal culture displaying GSK-3β inhibitory properties. The present study aimed to investigate the proregenerative and anti-inflammatory properties of this natural compound in the DMD context. Our results showed that ILA markedly promotes myogenic differentiation of myoblasts by increasing β-Catenin signaling and boosting the myogenic potential of mouse and human stem cells. One important finding was that the GSK-3β/β-Catenin pathway is altered in dystrophic mice muscle and ILA enhances the myofiber formation of dystrophic MuSCs. Treatment with this natural compound improves muscle regeneration of dystrophic mice by, in turn, improving functional performance. Moreover, ILA ameliorates the inflammatory response in both muscle explants and the macrophages isolated from dystrophic mice to, thus, mitigate fibrosis after muscle damage. Overall, we show that ILA modulates both inflammation and muscle regeneration to, thus, contribute to improve the dystrophic phenotype.

Applying Lessons Learned from Developing Exon Skipping for Duchenne to Developing Individualized Exon Skipping Therapy for Patients with Neurodegenerative Diseases

AbstractAntisense oligonucleotides (ASOs) are short, modified pieces of DNA that are chemically modified. They can be used to induce exon skipping and treat Duchenne muscular dystrophy (DMD) patients by interfering with the splicing process so mutated dystrophin transcripts become readable allowing production of partially functional dystrophin proteins, rather than nonfunctional dystrophins. After over 2 decades of research, 4 ASOs are FDA approved for DMD, but clinical effects are suboptimal due to limited delivery to skeletal muscle. At the same time, ASOs for brain diseases result in much more functional impact, because local delivery allows higher exposure to the target tissue at a low dose and infrequent treatment regimen. This has opened the way to develop ASOs in an individualized setting, as was exemplified by the development of Milasen to treat a patient with CLN7 Batten disease.In this perspective paper I will share my personal journey as one of the pioneers of ASO-mediated exon skipping development for DMD, currently applying expertise gained and lessons learned along the way to develop exon skipping ASOs for eligible patients with genetic brain diseases in a national and international setting.1 Duchenne and Antisense-Mediated Exon Skipping2 Opportunities for Treating Central Nervous System Diseases and Developing Individualized ASOs for Central Nervous System Diseases3 Collaborative Spirit to Develop Individualized Treatments Globally4 Global Implementation5 Concluding Remarks

Vamorolone: First Approval.

Vamorolone (AGAMREE®) is an oral, selective, dissociative corticosteroid developed by ReveraGen BioPharma and Santhera Pharmaceuticals for the treatment of patients with muscular dystrophy. Vamorolone was approved in October 2023 for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older in the USA and received a positive opinion in the EU in October 2023 for the treatment of DMD in patients 4 years of age and older. This article summarizes the milestones in the development of vamorolone leading to this first approval for DMD.

Networking to Optimize Dmd exon 53 Skipping in the Brain of mdx52 Mouse Model.

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that disrupt the open reading frame and thus prevent production of functional dystrophin proteins. Recent advances in DMD treatment, notably exon skipping and AAV gene therapy, have achieved some success aimed at alleviating the symptoms related to progressive muscle damage. However, they do not address the brain comorbidities associated with DMD, which remains a critical aspect of the disease. The mdx52 mouse model recapitulates one of the most frequent genetic pathogenic variants associated with brain involvement in DMD. Deletion of exon 52 impedes expression of two brain dystrophins, Dp427 and Dp140, expressed from distinct promoters. Interestingly, this mutation is eligible for exon skipping strategies aimed at excluding exon 51 or 53 from dystrophin mRNA. We previously showed that exon 51 skipping can restore partial expression of internally deleted yet functional Dp427 in the brain following intracerebroventricular (ICV) injection of antisense oligonucleotides (ASO). This was associated with a partial improvement of anxiety traits, unconditioned fear response, and Pavlovian fear learning and memory in the mdx52 mouse model. In the present study, we investigated in the same mouse model the skipping of exon 53 in order to restore expression of both Dp427 and Dp140. However, in contrast to exon 51, we found that exon 53 skipping was particularly difficult in mdx52 mice and a combination of multiple ASOs had to be used simultaneously to reach substantial levels of exon 53 skipping, regardless of their chemistry (tcDNA, PMO, or 2'MOE). Following ICV injection of a combination of ASO sequences, we measured up to 25% of exon 53 skipping in the hippocampus of treated mdx52 mice, but this did not elicit significant protein restoration. These findings indicate that skipping mouse dystrophin exon 53 is challenging. As such, it has not yet been possible to answer the pertinent question whether rescuing both Dp427 and Dp140 in the brain is imperative to more optimal treatment of neurological aspects of dystrophinopathy.

Replenishing NAD+ content reduces aspects of striated muscle disease in a dog model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in DMD gene and loss of the protein dystrophin, which ultimately leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Among the developed therapeutic strategies for DMD, gene therapy approaches partially restore micro-dystrophin or quasi-dystrophin expression. However, despite extensive attempts to develop definitive therapies for DMD, the standard of care remains corticosteroid, which has only palliative benefits. Animal models have played a key role in studies of DMD pathogenesis and treatment development. The golden retriever muscular dystrophy (GRMD) dog displays a phenotype aligning with the progressive course of DMD. Therefore, canine studies may translate better to humans. Recent studies suggested that nicotinamide adenine dinucleotide (NAD+) cellular content could be a critical determinant for striated muscle function. We showed here that NAD+ content was decreased in the striated muscles of GRMD, leading to an alteration of one of NAD+ co-substrate enzymes, PARP-1. Moreover, we showed that boosting NAD+ content using nicotinamide (NAM), a natural NAD+ precursor, modestly reduces aspects of striated muscle disease. Collectively, our results provide mechanistic insights into DMD.

Positive results from a first-in-human study supporting continued development of PGN-EDO51 for the treatment of duchenne muscular dystrophy (DMD)

Positive results from a first-in-human study supporting continued development of PGN-EDO51 for the treatment of duchenne muscular dystrophy (DMD)

Developing a Natural History Model for Duchenne Muscular Dystrophy.

The aim of this study was to pool multiple data sets to build a patient-centric, data-informed, natural history model (NHM) for Duchenne muscular dystrophy (DMD) to estimate disease trajectory across patient lifetime under current standard of care in future economic evaluations. The study was conducted as part of Project HERCULES, a multi-stakeholder collaboration to develop tools to support health technology assessments of new treatments for DMD. Health states were informed by a review of NHMs for DMD and input from clinicians, patients and caregivers, and defined using common outcomes in clinical trials and real-world practice. The primary source informing the NHM was the Critical Path Institute Duchenne Regulatory Science Consortium (D-RSC) database. This was supplemented with expert input obtained via an elicitation exercise, and a systematic literature review and meta-analysis of mortality data. The NHM includes ambulatory, transfer and non-ambulatory phases, which capture loss of ambulation, ability to weight bear and upper body and respiratory function, respectively. The NHM estimates patients spend approximately 9.5years in ambulatory states, 1.5 years in the transfer state and the remainder of their lives in non-ambulatory states. Median predicted survival is 34.8 years (95% CI 34.1-35.8). The model includes a detailed disease pathway for DMD, including the clinically and economically important transfer state. The NHM may be used to estimate the current trajectory of DMD in economic evaluations of new treatments, facilitating inclusion of a lifetime time horizon, and will help identify areas for further research.

Impact of the Inhibition of Organic Anion Transporter on Tricyclo-DNA-Mediated Exon Skipping in the mdx Mouse Model.

Antisense-mediated exon skipping is one of the most promising therapeutic strategies for Duchenne muscular dystrophy (DMD) and some antisense oligonucleotide (ASO) drugs have already been approved by the U.S. FDA for DMD. The potential of this therapy is still limited by several challenges including the poor distribution of ASOs to target tissues. Indeed, most of them accumulate in the kidney and tend to be rapidly eliminated after systemic delivery. We hypothesized here that preventing renal clearance of ASO using organic anion transporter (OAT) inhibitor could increase the bioavailability of ASOs and thus their distribution to target tissues and ultimately their efficacy in muscles. Mdx mice were, therefore, treated with ASO with or without the OAT inhibitor named probenecid. Our findings indicate that OAT inhibition, or at least using probenecid, does not improve the therapeutic potential of ASO-mediated exon-skipping approaches for the treatment of DMD.

Considering the Promise of Vamorolone for Treating Duchenne Muscular Dystrophy.

This commentary provides an independent consideration of data related to the drug vamorolone (VBP15) as an alternative steroid proposed for treatment of Duchenne muscular dystrophy (DMD). Glucocorticoids such as prednisone and deflazacort have powerful anti-inflammatory benefits and are the standard of care for DMD, but their long-term use can result in severe adverse side effects; thus, vamorolone was designed as a unique dissociative steroidal anti-inflammatory drug, to retain efficacy and minimise these adverse effects. Extensive clinical trials (ongoing) have investigated the use of vamorolone for DMD, with two trials also for limb-girdle muscular dystrophies including dysferlinopathy (current), plus a variety of pre-clinical trials published. Vamorolone looks very promising, with similar efficacy and some reduced adverse effects (e.g., related to height) compared with other glucocorticoids, specifically prednisone/prednisolone, although it has not yet been directly compared with deflazacort. Of particular interest to clarify is the optimal clinical dose and other aspects of vamorolone that are proposed to provide additional benefits for membranes of dystrophic muscle: to stabilise and protect the sarcolemma from damage and enhance repair. The use of vamorolone (and other glucocorticoids) needs to be evaluated in terms of overall long-term efficacy and cost, and also in comparison with many candidate non-steroidal drugs with anti-inflammatory and other benefits for DMD.

Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman-Diamond syndrome cells.

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.

Türkiye'de Duchenne/Becker Musküler Distrofisi Kohortunda Distrofin Gen Delesyonları ve Duplikasyonlarının Dağılımı

Duchenne Muscular Dystrophy (DMD) is the most prevalent muscle disease in children, and unfortunately, currently there are no effective treatments for either DMD or Becker Muscular Dystrophy (BMD). Nevertheless, targeted gene therapy treatments have recently emerged, and genetic diagnoses is now the basis of treatment. In addition, genetic and prenatal diagnosis have significantly reduced the incidence rates of these diseases. The aim of this study was to identify the most common deletion and duplication regions in the Turkish population using the Multiplex Ligation-dependent Probe Amplification (MLPA) method, as well as to determine the suitability of patients for current treatments and identify new treatment target regions based on the findings. In clinical practice, data from 103 patients with Duchenne and Becker muscular dystrophy who have been identified with the deletion/duplication using the Multiplex Ligation-dependent Probe Amplification (MLPA) method, as well as 35 participants carrying the deletion/duplication for these diseases, were analyzed. The aim was to detect the most common deletion/duplication regions of the Dystrophin gene in the Turkish population. The majority of patients had deletions (89.9% in males and 75% in females), while a smaller percentage had duplications. The most common deletions occurred in exons 50 and 49, while the most common duplication was in exon 7. The deletions in exons 45-52 accounted for over half of all deletions, and most deletions involved 5 or less exons. The longest deletions involved 30 exons and were found in 2 patients. The findings of this research have provided valuable insights into the prevalence of deletions and duplications in the dystrophin gene among individuals in our population. The results indicate that a significant proportion of patients may be eligible for treatments that are not yet widely available. This study highlights the critical role of population-specific data in advancing the field of dystrophin gene-based therapies.

Early Cost-Utility Analysis of Ataluren and Eteplirsen in the Treatment of Duchenne Muscular Dystrophy in Egypt

ObjectivesAtaluren and eteplirsen are orphan drugs that delay progression of Duchenne muscular dystrophy in mutation-specific subgroups. They have yet to be approved in Egypt but are expected to reach the market soon. This study describes 2 cost-utility models comparing the drugs with the standard of care. MethodsWe used a partition-survival model with 5 states based on the ambulatory status to model a cohort of ambulatory patients at the age of 5 years. Baseline curves were obtained from a published model; then the ambulation loss curve was updated using the Kaplan-Meier curve of the standard of care from a study by McDonald et al. Other curves were updated by calibration to this curve. Costs and utilities were from a local study. Deterministic and probabilistic sensitivity analyses were conducted. Prices were estimated based on other orphan drugs’ prices. ResultsIn the base case, ataluren 1000 mg and eteplirsen 50 mg/mL resulted in an incremental cost-effectiveness ratio of EGP 51 745 605 and EGP 69 652 533/quality-adjusted life-year, respectively, at their hypothetical prices of EGP 308 600 for ataluren 30-sachet pack and EGP 62 800 for eteplirsen 10 mL vial. The incremental cost-effectiveness ratio was sensitive to health state utilities but not to state costs. At EGP 911 719/quality-adjusted life-year threshold, the value-based prices were EGP 4680 for ataluren 1000 mg and EGP 733 for eteplirsen 10 mL vial. ConclusionsBased on these models, there is a huge gap between the prices of orphan drugs and their value-based prices, which highlights the need for major policy reforms in the assessment and pricing of orphan drugs.