In April 2023, over 30 experts and advocates from four countries met in Rome, Italy to discuss unmet needs in endocrine and bone health care for individuals with Duchenne muscular dystrophy (DMD). Despite recent advances in muscle-targeted therapy, long-term glucocorticoids (GC) remain the backbone of treatment for the foreseeable future. This affirms the need to intensify efforts that will mitigate serious complications of GC therapy, including unexpected mortality due to fat embolism syndrome following bone injury and also unrecognized adrenal suppression, early loss of ambulation linked to excess weight and/or fragility fracture, adverse cardiometabolic effects of GC, the psychosocial impact of profound growth and pubertal delay/hypogonadism, and the burden to families arising from monitoring and treating endocrine and skeletal complications of GC therapy. Delegates discussed: 1. The impact of GC therapy on the heart, 2. Predictors of fragility fractures and experience with intravenous and oral bisphosphonates plus teriparatide, 3. The effect of hormonal therapy on muscle-bone health, 4. Adrenal suppression, 5. Weight management, 6. Puberty, sexuality, fertility and gender identity, 7. The impact of early GC initiation, 8. Emerging knowledge about vamorolone (a novel dissociative steroid) and its effects on muscle, bone and endocrine health, and 9. Experiences implementing an endocrine-bone health management strategy nation-wide (in the UK). At the conclusion of the meeting, it was agreed that an endocrine-bone working group should be struck to continue the narrative, following which the International OPTIMIZE DMD Consortium was ignited to move the dial in these important areas.

Background:Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments.Objective: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.Methods: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.Results: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.Conclusions: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.

Purpose: Traditional value assessment frameworks are challenged in comprehensively assessing the societal value new therapies bring to individuals with rare, progressive, genetic, fatal, neuromuscular diseases such as Duchenne muscular dystrophy (DMD). The objective of this study was to identify how value assessment frameworks may need to be adapted to measure the value to society of DMD therapies. Patients and Methods: Three stakeholder groups (6 patient advocates, 4 clinicians, 3 health economists; N = 13) participated in semi-structured interviews around the International Society for Pharmacoeconomics and Outcomes Research's Value Flower, which includes elements to consider within value assessments of healthcare technologies. Results: All stakeholders agreed that traditional value assessment frameworks based on the quality-adjusted life year (QALY) are narrow and will undervalue new DMD therapies. All stakeholders expressed some level of concern that using the QALY as a key metric of value discriminates against patients with severe progressive diseases and disabilities. Some stakeholders saw value in using the QALY for cross-disease comparisons in resource-constrained environments if the methodology was appropriate. All stakeholders recommended considering additional elements of value in decision-making around new DMD therapies. These elements reflect: economic and humanistic costs incurred by patients, caregivers, and families with Duchenne, such as indirect out-of-pocket costs, lost productivity, and family spillovers; meaningful attributes for individuals with disabilities and high unmet need, such as severity of disease, value of hope, and real option value; and factors that contribute to improvements in population health, such as insurance value, equity, and scientific spillovers. Conclusion: These findings highlight the need to expand traditional value assessment frameworks and take a holistic approach that incorporates the perspectives of individuals with Duchenne, caregivers, clinicians, and health economists when assessing the societal value of new DMD therapies. Broadening value assessment will prevent restricted or delayed access to therapies for individuals with Duchenne.

Stride velocity 95th centile (SV95C) is a wearable-derived endpoint representing the 5% fastest strides taken during everyday living. In July 2023, SV95C received European Medicines Agency (EMA) qualification for use as a primary endpoint in trials of patients with Duchenne muscular dystrophy (DMD) aged ≥ 4 years-becoming the first digital endpoint to receive such qualification. We present the data supporting this qualification, providing insights into the evidentiary basis of qualification as a digital clinical outcome assessment. Clinical trials, natural history studies, and patient surveys (ages 5 - 14 years) showed that SV95C is accurate, valid, reliable, sensitive, and clinically meaningful. SV95C significantly correlated with traditional DMD assessments, increased rapidly after steroid initiation (0.090 m/s 3 months post-treatment), and declined steadily in patients on stable steroid regimens. Compared with traditional assessments, SV95C demonstrated earlier sensitivity to disease progression (3 vs 9 months) and greater sensitivity at 12 months. Distribution- and anchor-based approaches revealed a change of - 0.10 to - 0.20 m/s as clinically meaningful. The EMA qualification of SV95C illustrates the willingness of regulators to accept novel digital endpoints for drug approval, setting an important precedent for the evidentiary basis of regulatory digital endpoint qualification that could transform clinical development in disorders affecting movement.

BACKGROUND:Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy. METHODS:In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 108 CDCs) or placebo intravenously every 3 months for a total of four infusions. Clinicians, caregivers, patients, and clinical operations personnel were fully masked to treatment groups. The primary outcome was the change in mid-level elbow Performance of Upper Limb version 1.2 (PUL 1.2) score at 12 months, assessed in the intention-to-treat population. Safety was assessed in all individuals who received an investigational product. This trial is registered with ClinicalTrials.gov, NCT03406780. FINDINGS:Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7-59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred. INTERPRETATION:CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy. FUNDING:Capricor Therapeutics.

In the US, gene therapy companies, as with all biopharmaceutical companies, are not required by law or regulation to provide their investigational products to patients via non-trial preapproval (expanded) access. However, we believe that gene therapy companies, in particular, have a moral obligation to develop policies regarding such access, historically known as “compassionate use.” Gene therapies are predominantly intended for patients with serious or life-threatening rare diseases for which there are limited treatments;1 this should compel companies to develop product-specific non-trial preapproval access policies.

Background In clinical trials for rare diseases, such as Duchenne muscular dystrophy, clinical outcome assessments (COA) used to assess treatment benefit are often generic and may not be sensitive enough to detect change in specific patient populations. Thus, there is a need for disease specific COAs that track meaningful change among individuals. When developing such measures, input from clinicians, caregivers and patients is critical for assessing clinically relevant concepts and ensuring validity of the measure. Method The aim of this study was to develop two Duchenne-specific global impression items for use in clinical trials. The development of the Duchenne Clinical Global Impression of Change (CGI-C) and Caregiver Global Impression of Change (CaGI-C) was informed by findings from concept elicitation (CE) interviews with clinicians, caregivers and individuals with Duchenne. Through cognitive debriefing (CD) interviews, clinicians and caregivers evaluated draft CGI-C and CaGI-C items to ensure relevance and understanding of the items and instructions. Suggestions made during the CD interviews were incorporated into the finalized CGI-C and CaGI-C measures. Results The symptoms most frequently reported by clinicians, caregivers and individuals with Duchenne were muscle weakness, fatigue, cardiac difficulties and pain. Regarding physical functioning, all three populations noted that small changes in functional ability were meaningful, particularly when independence was impacted. Caregivers and clinicians reported that changes in speed, endurance and quality of movement were important, as was improvement in the ability of individuals to keep up with their peers. A change in the ability to complete everyday activities was also significant to families. These results were used to create two global impression of change items and instruction documents for use by clinicians (CGI-C) and caregivers (CaGI-C). Overall, both items were well understood by participants. The descriptions and examples developed from the CE interviews were reported to be relevant and appropriate for illustrating different levels of meaningful change in patients with Duchenne. Modifications were made based on caregiver and clinician CD feedback . Conclusions As part of a holistic measurement strategy, such COA can be incorporated into the clinical trial setting to assess global changes in relevant symptoms and functional impacts associated with Duchenne.

The use of digital health products has gained considerable interest as a new way to improve therapeutic research and development. Although these products are being adopted by various industries and stakeholders, their incorporation in clinical trials has been slow due to a disconnect between the promises of digital products and potential risks in using these new technologies in the absence of regulatory support. The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium hosted a public workshop to address challenges and opportunities in this field. Important characteristics of tool development were addressed in a series of presentations, case studies, and open panel sessions. The workshop participants endorsed the usefulness of an evidentiary criteria framework, highlighted the importance of early patient engagement, and emphasized the potential impact of digital monitoring tools and precompetitive collaborations. Concerns were expressed about the lack of real‐life validation examples and the limitations of legacy standards used as a benchmark for novel tool development and validation. Participants recognized the need for novel analytical and statistical approaches to accommodate analyses of these novel data types. Future directions are to harmonize definitions to build common methodologies and foster multidisciplinary collaborations; to develop approaches toward integrating digital monitoring data with the totality of the data in clinical trials, and to continue an open dialog in the community. There was a consensus that all these efforts combined may create a paradigm shift of how clinical trials are planned, conducted, and results brought to regulatory reviews.

Introduction: In this study we investigate associations between genotypic and sociodemographic factors and the age of diagnosis of Duchenne muscular dystrophy (DMD). Methods: Data were collected from the Duchenne Registry from 2007 to 2019, and then used to assess the impact genotype, race/ethnicity, neighborhood poverty levels, and other sociodemographics factors have on the age of diagnosis of DMD patients without a known family history, using univariate and multivariable linear regression. Results: The mean age of diagnosis was 4.43 years. Non-Caucasian patients and patients from high-poverty neighborhoods were older at diagnosis (P < .01). Increased year of birth was associated with decreasing age of diagnosis (P < .001). Specific genetic mutation subtypes were associated with later ages of symptom onset and diagnosis (P = .005). Discussion: After adjusting for genotype and year of birth, the average age of diagnosis was significantly later for traditionally at-risk patients.

Project HERCULES is an international patient led multi stakeholder collaboration developing tools and evidence supporting HTA for new treatments for Duchenne Muscular Dystrophy (DMD) including a bespoke Quality of Life metric, a natural history model, a burden of illness study and a core economic model. The evidence reflects patient experience and patients and patient organisations can shape the framework for HTA in DMD. This has led to a new paradigm for developing evidence for HTA and an improved understanding of DMD impacting on HTA decisions. Project HERCULES is led by Duchenne UK with a core team including two parents of boys with DMD, one of whom is also a health economist. This unique combination brings health economics and HTA expertise combined with the lived patient experience to deliver this ambitious health economics research programme. Patient organisation leadership enables access to data sources and expertise which may be inaccessible for individual researchers. An iterative approach to the individual workstreams ensures each workstream has high levels of patient involvement, shaping outcomes to embody actual patient and family experience. This patient led approach has led to each workstream of Project HERCULES better reflecting the true impact of DMD:•Identification of a previously undefined disease stage between the traditional stages of late ambulatory and early non ambulatory•Development of a bespoke Quality of Life metric•An economic model encompassing the actual experience of patients and families•A burden of illness study focussing on what is most impactful on patients and families.•Identification of future research priorities reflecting what is important to patients. Project HERCULES has demonstrated the potential impact of patient led evidence generation in a rare disease for use in HTA.

Translational medicine works through the definition of unmet medical needs, their understanding and final resolution. In this complex and multi-disciplinary process patients have always been regarded as “end-users” or no more than “data provider.” Considering that the translational practice is nowadays highly inefficient (i.e., large intellectual and economical resources are wasted with limited impact on people health) here we propose to reverse the process: start from patients, engage them, and keep them at the center. A new partnership needs to be formed between the patients and the health care professionals, as well as the treating physicians, to make the most out of the current “health resources.” New patient-centric approaches are emerging but they remain isolated phenomena often difficult to implement. Here—with this perspective—we aim at thinking differently and learning from new experiences. We will provide some successful examples of change, and we will discuss new approaches to create a radical change in the way translational medicine is managed and how this would significantly impact people health and health care systems.