Duchenne UK's Project HERCULES has developed a set of tools and evidence to better understand DMD and inform access to medicines and clinical care as well as further research in this field. This patient-led international research collaboration has included clinicians, academic experts, HTA bodies, patient advocacy groups and pharmaceutical industry partners. It has developed a new disease model describing a transfer stage between ambulatory and non-ambulatory disease stages and providing greater granularity about later stages of the disease. It has also developed a bespoke measure of Health-Related Quality of Life (HRQoL) that captures the impact of DMD, and healthcare interventions, on aspects of HRQoL that matter to those living with DMD. This work now underpins the current priorities of Duchenne UK, informing the DMD Hub, DMD Care, and the Duchenne muscular dystrophy data collection platform. The UK Duchenne data platform, launching in early 2025, will be a crucial tool for engaging with patients and collecting their reported outcomes and perspectives. Duchenne UK's involvement in the PaLaDIn project, funded by EU Horizon 2020 and UKRI, aims to revolutionize neuromuscular disease research and care by integrating registry data, patient-reported outcomes, and wearable data through the Interactium platform, while prioritising robust governance for patient consent and data management. This poster will present these key outcomes and how they are being used in ongoing research as well as exploring how this work can underpin future work in improving clinical care and access to new treatments.

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 9.5 years 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

26 Understanding the coronavirus (CoV) antibody landscape in relation to disease and 27 susceptibility is critical for modelling of steps in the next phase during the current covid-19 28 pandemic. In March 2020, during the first month of the epidemic in The Netherlands, we 29 performed cross sectional studies at two time points amongst patients of the Erasmus Medical 30 Centre in Rotterdam, to assess the presence of antibodies against seasonal human 31 coronaviruses (OC43, 229E, NL63, HKU1), emerging zoonotic coronaviruses (SARS, MERS) 32 and SARS-CoV-2 in nine different age groups. We observed minimal SARS-CoV-2 reactivity 33 early March (0.7% of sera), increasing to 3.0%, four weeks later, suggesting probably 34 undetected cases during this early phase of the epidemic. Antibody responses were mostly 35 coronavirus species specific at young age, but possible cross-reactivity between human 36 seasonal CoVs was

Understanding the coronavirus (CoV) antibody landscape in relation to disease and susceptibility is critical for modelling of steps in the next phase during the current covid-19 pandemic. In March 2020, during the first month of the epidemic in The Netherlands, we performed cross sectional studies at two time points amongst patients of the Erasmus Medical Centre in Rotterdam, to assess the presence of antibodies against seasonal human coronaviruses (OC43, 229E, NL63, HKU1), emerging zoonotic coronaviruses (SARS, MERS) and SARS-CoV-2 in nine different age groups. We observed minimal SARS-CoV-2 reactivity early March (0.7% of sera), increasing to 3.0%, four weeks later, suggesting probably undetected cases during this early phase of the epidemic. Antibody responses were mostly coronavirus species specific at young age, but possible cross-reactivity between human seasonal CoVs was observed with increasing age.

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.

There is often a paucity of data in rare diseases to support the development of cost-effectiveness models that fully capture the impact of disease and the benefit of new treatments. Cost-effectiveness models can oversimplify the natural history of disease or rely on assumptions. Project HERCULES is a collaboration between Duchenne UK and eight pharmaceutical companies. One objective of this project was to develop a single, robust cost-effectiveness model for treatments in Duchenne Muscular Dystrophy (DMD). A core multi-state cohort model was developed to facilitate the economic evaluation of new treatments in DMD. Clinically and economically important health states were first determined with input from clinicians, patients and carers. Data were then collected and synthesised to provide a core data set. This data set included transition probabilities for standard of care, health-related quality of life utilities, resource use and cost. Transition probabilities were obtained from a natural history model developed using real-world data. Utilities, resource use and cost were obtained via a burden-of-illness study. A de novo patient reported outcome was also developed to facilitate future estimation of utilities in people with DMD. The model methods and data sources underwent review and critique via EMA early scientific advice, and input from clinicians and experts in health economics and health technology assessment (HTA). Project HERCULES has provided a core model for the economic evaluation of new treatments in DMD that captures the impact of disease, the benefits of treatment, and is based on a robust data set. Project HERCULES illustrates the potential for a paradigm shift in the development of cost-effectiveness models in rare diseases. One in which manufacturers collaborate to generate a robust core economic model and data set, and a standardised methodology is used across HTA submissions.

Duchenne muscular dystrophy (DMD) is a rare progressive life-limiting genetic neuromuscular disorder. There is no cure, so interventions focus on maintaining or improving paediatric quality of life (QoL). Evidence suggests that existing preference-based measures (PBMs) may be inadequate for assessing QoL in DMD. Project HERCULES is developing a new PBM in DMD. This consists of three stages: 1) Concept elicitation; 2) Refining the descriptive system; and 3) Valuation. Here we describe the results of Stages 1 and 2a. In Stage 1, we undertook 18 semi-structured interviews with people with DMD of varying ages and clinical severity. We used Framework Analysis to identify themes and develop an initial descriptive system. In Stage 2a, cognitive debriefing interviews were undertaken with patients (n=10), parents (n=10), and clinicians (n=8) to refine the draft questionnaire. In Stage 1, seven QoL domains were important in DMD, which included physical aspects, daily activities, identity, autonomy, healthcare and support, feelings and emotions, and social relationships. A draft 43-item questionnaire was developed. In Stage 2a, the draft questionnaire was refined following cognitive debriefing. This included an assessment of content validity, covering item wording, response options, and questionnaire instructions. This resulted in a 27-item draft measure to be tested quantitatively in a national psychometric survey (Stage 2b). We have developed a draft 27-item questionnaire with high content validity for assessing QoL in people with DMD. Initial work highlighted challenges in research in a rare paediatric, life-limiting condition. Whilst there is support for a new PBM in this area, due to the subject matter, it can be difficult for some families to participate in qualitative interviews. There were differing views as to which items should be included in the new PBM. Final item selection for the new PBM will be informed by the psychometric survey.

Project HERCULES is a collaboration between Duchenne UK and eight pharmaceutical companies; pooling resources and expert input to develop a core cost-effectiveness model for Duchenne Muscular Dystrophy (DMD). Whilst model users would utilise the same structure, flexibility was required to accommodate different interventions, treatment effects, comparators, patient populations and types of analysis. Due to the collaborative nature of the project, the challenge was to develop the model without disclosure of confidential information or breaching competition rules. A multi-state cohort model was developed with health states informed by clinicians, patients and carers. Data were collected and synthesised to provide a core data set. To avoid the need to share commercially sensitive information on pipeline products, contributing manufacturers and clinical experts discussed all possible treatment effects of future therapies in DMD. Input from the manufacturers, HTA experts and health economists also identified the characteristics of a therapy, decision problem and audience that would necessitate flexibility within the core model. In addition, manufacturers had the opportunity for one-to-one discussions with the developers to ensure the model met their individual needs. The cost-effectiveness model developed includes flexibility to evaluate different emerging treatments in DMD. The user can define their decision problem: patient population, intervention, comparator, type of analysis and perspective. They can define modelling assumptions, including cycle length, time horizon and the health states in which the intervention is received. Most importantly, the model includes functionality to accommodate different treatment effects. Interventions can slow or halt progression, improve function loss or cure, reduce or avoid the use of steroids, and/or avoid acute events. This case study illustrates the potential for collaboration between manufacturers in rare diseases to develop a robust, core cost-effectiveness model which meets the needs of the different manufacturers without compromising confidentiality.

Project HERCULES is a collaborative global project set up by Duchenne UK, a patient organisation, to bring together pharmaceutical companies, academia, HTA bodies, clinicians, and patients to build tools and evidence at a disease level for use in HTA focused on Duchenne Muscular Dystrophy. Duchenne UK leads a multistakeholder international collaboration developing a Quality of Life metric that better captures important aspects of Quality of Life for people living with DMD, a natural history model, a burden of illness study and an economic model. These workstreams are supported by leading academics and consultants who are working together to ensure that each. Alongside the progress of individual workstreams, the poster will describe as the benefits and challenges of the Project HERCULES approach. This will include the challenges of having a diverse, dispersed, international evidence base, facing a lack of mortality data in a disease which is 100% fatal, the use of quality of life metrics in a paediatric progressive condition, creation of a disease level model suitable for different interventions and agreement on what is important in burden of illness. The benefits of this approach include presenting a credible, comprehensive, peer reviewed suite of evidence that best reflects patient and clinical experience. Working with world leaders in their respective fields ensures high quality outputs readily adaptable to the needs of HTA systems. This is a cost and time effective approach for all parties in a rare yet heavily researched disease population.

Project HERCULES is an innovative international multi-stakeholder collaboration led by Duchenne UK that aims to simplify the way evidence is generated for Health Technology Assessment (HTA) for Duchenne Muscular Dystrophy (DMD). The generation of robust data for DMD treatments is hampered by the scarcity of patients and limited resources. Project HERCULES has developed evidence and tools to support international HTA and reimbursement decisions. These include a critical review of commonly used Quality of Life metrics, demonstrating their inappropriateness for DMD; the development of a new, DMD specific Quality of Life metric in collaboration with patients, carers and expert clinicians to measure the Quality of Life of those living with DMD; development of a DMD specific disease model based on data analysis that maps trial data, natural history data and other patient data against meaningful clinical outcomes that can be incorporated into HTA; a burden of illness study, an economic model and HTA educational tools and support. Clinician and patient involvement are central to Project HERCULES and this has led to a new understanding of which aspects of DMD are most significant to patients, families, carers and clinical teams. For example, our research has identified a new, clinically relevant stage in the disease model between late ambulatory and early non-ambulatory stages when weight bearing is still possible and transfer from and to the wheelchair is still manageable. This stage marks a transition in clinical care and support needs but is not well captured by the current disease model. The impact of these findings on clinical practice and monitoring of disease progression are worth further discussion. Project HERCULES represents a paradigm that could have benefits beyond DMD, particularly for other rare neurodegenerative conditions. The poster will describe this unique collaboration and highlight emerging findings and consider their possible impact on clinical practice.

By establishing a core set of measures to be assessed and reported in a burden of illness (BOI) study we aim to improve the usefulness of future health research. The objective of this study was to inform data collection to assess the economic burden and disease-specific health-related quality of life (HRQOL) impact of Duchenne muscular dystrophy (DMD) in the United Kingdom (UK). First, we identified outcomes reported in previous research through a targeted review of the literature and gap analysis. Second, project HERCULES steering committee (SC) participants were invited to take part in a modified Delphi survey in which participants rated the importance of candidate measures. A two round modified Delphi process was followed, and at each round, participants rated an exhaustive list of outcomes on a five-point Likert scale. Participants also had the opportunity to leave comments and make suggestions for other measures to be included in the BOI study. In the second-round, participants were presented with anonymised results from the previous round and were then invited to revise their responses. Each round was completed by 8 SC participants. SC participants consisted of parents of people with DMD, patient advocates, clinicians and other health professionals. Participants rated 182 research measures across 15 domains including prescribed treatments, consultations, hospitalisations, tests and procedures, transport, home improvements and patient-reported outcome measures. The highest median rated measures after the second round included fractures, adverse effects of corticosteroids and wheelchair use. Our methodology presents a rigorous and pragmatic approach toward developing BOI studies. This study collated the views of the SC to produce a valid and robust set of research measures. The findings will inform a future BOI study to quantify the impact of DMD in the UK and to describe more comprehensively, the societal implications of DMD, not previously reported.

Duchenne Muscular Dystrophy (DMD) is a rare genetic muscle wasting disorder that mainly affects boys, typically diagnosed from around the age of 2. Patients will require care from a number of specialities due to the wide ranging effect of the disease – not just from neuromuscular specialists, but respiratory specialists, cardiologists, endocrinologists, physiotherapists and more. Additionally as sufferers are mostly children and young adults, there is an impact on the family, as well as a societal costs. To understand the evidence on this burden we conducted a series of literature reviews to identify the available evidence to populate economic models. To identify relevant literature, we first searched for burden of illness studies directly, recognising that evidence may already exist. We then performed searches for areas likely to impacted by DMD to find studies that may look at each aspect. Searches were performed to identify inpatient and acute care resource use, other medical costs (for example wheelchairs and medical devices), other governmental costs, impacts on the cost of living, education, productivity losses, and the impact on families. 61 hits were retrieved for burden of illness studies, with a further 1,454 from additional searches. After review 36 studies were found to contain relevant information on at least one area. Whilst the amount of information was large for a rare disease there were notable limitations. In particular whilst many studies reported the cost of illness, few disaggregated this by the resources used and unit price applied – limiting its generalisability. A further limitation was that few papers reported results by disease stage – a requirement for modelling. Whilst there is a large volume of data on the burden (particularly the cost) of DMD, to provide inputs for economic modelling further research – either novel or involving reanalysis of existing studies, will be required.

Models developed in Microsoft EXCEL of increasing complexity are being used as an integral part of the submission process for new pharmaceutical products and for technical assessments produced by national agencies. The credibility of the health economic models utilised depends on their validity. Firstly, in terms of reflecting the appropriate clinical process using the correct data and assumptions and secondly, in terms of ensuring a correct functioning of the model based on the relationships between variables and formulas embedded in the model. In this research, the authors concentrate on the latter aspect of validating health economic models. While recognising that models should be validated, there is a paucity of detailed techniques available in the literature that show researchers and users of health economic models how to validate them. Hence, we have attempted to develop a methodological framework that may be helpful to both those reviewing complex models and to model developers themselves who could incorporate validation processes while they develop their own models. The authors have reviewed the literature, looked at other disciplines (e.g. finance) where modelling plays a central role, investigated different software options in addition to the inbuilt validation tools in EXCEL. The evolving methodology has been applied to a number of existing real-life models in order to develop a consistent approach. By applying the developed methodology, errors have been identified at the design/review stage in a number of budget impact and cost-effectiveness models of varying degrees of complexity. A consistent approach to validation is a useful tool to test the often highly complex processes and relationships with thousands of formulas in health economic models. It may also encourage modellers to take a more disciplined and organised approach in the development process and give increased confidence to end-users that the models they are using can be relied upon.

discounted at 5%. Annual and lifetime direct and indirect costs, in US dollars (USD), were determined on a per patient basis, and were then projected to the overall Colombian type-2 diabetes mellitus population. RESULTS: The estimated annual total cost of type 2 diabetes mellitus was $2.7 billion USD from the societal perspective. From the ministry of health perspective, the annual estimated cost was $921 million USD. The annual direct cost per patient was $288 USD, and the annual indirect cost per patient was $559 USD The distribution of this cost over the different model disease stages was as follows: diabetes treatment, 47%; cardiac and coronary disease, 24%; stroke, 15%; retinopathy, 2%, nephropathy 3%; and amputation, 9%. Macrovascular complications comprised 86% of the annual direct costs and 95% of the annual indirect costs of type 2 diabetes mellitus. CONCLUSION: The economic burden of type 2 diabetes mellitus in Columbia is comparable to results for other countries. The developed model showed a logical disease progression.

The second known case of sporotrichosis caused by Sporothrix schenckii var. luriei in a patient living in Piacenza, Italy is described. In the absence of cultures, the diagnosis was based on histologic studies. Stained tissue sections (Hematoxylin and eosin, & Gomori methenamine silver) revealed hyaline, large, thick walled tissue form cells that had divided by septation or a budding process. These forms, along with the striking "eyeglass" configuration of incompletely separated cells that were also present, are the diagnostic features of this apparently rare variety. The use of a fluorescent antibody reagent, specific for S. schenckii, confirmed the identity of the etiologic agent.

Urethral exudate from human males with gonococcal urethritis was transferred to the urethras of three male chimpanzees. The chimpanzees developed gonococcal urethritis, as demonstrated by the presence of a purulent urethral exudate containing gram-negative intracellular diplococci and the recovery of Neisseria gonorrhoeae on bacteriological culture media. The gonococcal urethritis was then transferred from chimpanzee to chimpanzee. One chimpanzee developed gonococcal conjunctivitis, presumably by auto-inoculation. All animals developed complement-fixing antibodies to N gonorrhoeae in their sera. It appears, therefore, that an animal model of gonococcal urethritis has been established.