Deafness, Autosomal Recessive 4

Typical symptoms include difficulty in running, jumping, and climbing stairs, with most patients requiring a wheelchair in their teenage years. However, the majority of clinical trials for the treatment of DMD rely on timed testing in the clinic, which doesn't necessarily reflect improvement in daily life function, and as such, could result in a lack of robust and sensitive data. Outsourcing Pharma ​ sat down with Christine McSherry, CEO Casimir, a part of Emmes, to understand how a new approach to designing clinical trial outcome measures. The focus is now on quantifying ease of movement rather than speed of movement and is probably more meaningful to patients and less subject to motivational factors, resulting in a truer picture of the trial efficacy. She notes that the cost of Duchenne clinical trial failure is significant, but says that what truly matters is the loss of valuable time experienced by thousands of families. She added tWith previous trial designs that didn’t fully consider the impact of disease heterogeneity – i.e. that a singular and often ‘pre-packed’ trial approach does not fit all patients – clinical outcomes often failed to capture nuanced and significant compensations in movement. McSherry, in addition to co-founding Casimir, is also a carer for a DMD patient, and therefore has first-hand experience of incorporating the patient's viewpoint into clinical research. In fact, she has been supporting families affected by DMD through programming, educational opportunities and ongoing support since 2002. Her experiences are littered with the frustrations of current DMD clinical trial designs, and it ultimately led her to co-found Casimir with another DMD advocate Mindy Leffler. googletag.cmd.push(function () { googletag.display('text-ad1'); }); The thesis of their partnership, they said, was that, with a little flexibility in approach, they could design less intrusive options that would not only improve the patient experience but also produce more reliable outcomes and in turn better treatments. They wanted to prove that virtual trials and home-based assessments did have the potential to breakdown the centralized site-driven organization of clinical trials and shift assessments to the home environment. They believe this then raises the possibility for more meaningful and less burdensome assessments of function, eliminating the need for patients and their families to travel to trial sites, as frequently, and minimizing disruption to their regular routines. OSP: Can you explain what the Duchenne video assessment (DVA) is? ​ McSherry: ​ Put simply DVA is a method of evaluating changes in motor function in patients using videos of patients performing specific tasks at their homes, and the DVA tasks are assigned per functional cohort (severity of the disease). The idea is that the caregiver can record and upload video recordings with the help of an app in natural (real world) settings. The videos are quality-controlled by data monitors and given centralized scoring by certified ‘raters’ – for example, physical therapists familiar with Duchene patients mobility challenges. To give a few examples, the list of specified real-world tasks can range from the ability put on or take off a T-shirt, to raising hands above head, jumping forward, eating 10 bites of food or rolling over in bed. These criteria therefore assess a patient's habitual way of performing meaningful tasks and in turn remove confounds related to travel fatigue, vacation mode, unfamiliar assessors/environment. OSP: How does a real-world assessment help deliver usable trial data? ​ McSherry: ​ DVA trials offer several advantages over traditional clinical outcome assessments, such as physical exams conducted at the clinic, which include timed function testing. The gold standard, North Star Ambulatory Assessment, involves activities like timed running and standing on heels as outcome measures. However, we have learned that performing activities quickly may not necessarily reflect real-world meaningfulness. Instead, we should consider activities such as feeding oneself, repositioning in bed, and moving arms on and off armrests, which can enable individuals to live independently at home.” OSP: What are the advantages in trial design and do they lead to increased specificity of parameters. ​ McSherry: ​ In short yes – absolutely. The reason it is so applicable is that it enables a more objective and standardized assessment of motor function, allowing for the detection of even subtle changes that may not be apparent during a physical exam when evaluating primary or secondary desired endpoints or outcome measures. This means vital improvements in the patient’s condition that were being missed or would go unrecorded in terms of their relevance to a prospective therapy’s approval are also registered. Our hope is that sponsors will also recognise this and be encouraged to use it – it’s really a win-win scenario. We have focussed largely – and rightly – on the patients, but DVA approach also brings tremendous efficiencies as well and reduces the clinical resource need to conduct the trials– put in simple terms it means we can monitor more frequently if the sponsor desires, but also we can capture patients in their own environment, where they feel, function and survive. OSP: Can you give any details of DVA being used in active trials? ​ McSherry: ​ It’s currently being used in nine of Casimir’s clinical trials to assess the efficacy of potential treatments for DMD and for determining any benefit, stabilization and possible progession in the disorder. Additionally, there are development programs underway for other neurodevelopmental indications, including Limb Girdle Muscular Dystrophies, Primary Myocardial Myopathies, and Angelman Syndrome, among others. The potential new disease targets for DVA include Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, Myotonic Dystrophy, and GM1 Gangliosidosis. In fact, DVA has now also been accepted into the FDA’s Initiative with Critical Pathway Institute to be qualifited as an outcome measure for Duchenne. But perhaps, the most significant breakthrough for DVA to date was when Capricor Therapeutics announced it would be using one of the tasks, eat 10 bites, as a secondary outcome measure in the HOPE 3 clinical trial ​. HOPE-3 is a cell-based therapy for DMD, and the study is expected to recruit up to 68 patients. Earlier this year, qualitative interviews with physical therapists to select movement tasks for DVA were published in Physiotherapy Research International ​, marking an important milestone in DVA development. This publication provided peer-reviewed scrutiny of the selection of the movement tasks that comprise the DVA. It, along with other upcoming publications, will be a key component of the information needed for the FDA qualification package to apply for approval and adaptation of the tool in practice for all DMD trials in the future. OSP: Do you have a closing message to other sponsors involved in similar trials? ​ McSherry: ​ It’s become an industry cliché, but to involve the patient and take the feedback from those in the field – in the case of conditions like this, that often means the family and carers. We have all the technology now to do this, we just need a wider acceptance and familiarity for digital video assessments to become the de facto ​ approach in neuromuscular diseases. The most important perspective is that it allows for the integration of the patient experience into the trials and turns this into a positive clinical data point. Unlike other digital measures, the DVA captures meaningful functional data that can be quantified for regulatory review. The most important aspect of any outcome measure should reflect what is most important to patients and their families. We have found that rare disease patients, specifically those with neuromuscular disorders, really want to be like everyone else and not different. Therefore, the two most impactful concepts of interest are independence and socialization. Patients and their families are most affected by the disease and have first-hand experience of the challenges and limitations that the disease imposes on their daily lives. Incorporating this vital viewpoint or data into the trial design allows for more meaningful assessments of function and better treatments. What is most exciting to me is that while we started with DMD the possibilities now are incredibly diverse and obviously other rare neuromuscular diseases will be ‘low hanging fruit’.