New Advancement Toward The First Primary Endpoint Qualification Of A Digital Endpoint For Duchenne
By Roxana Donisa Dreghici, M.D., Senior Vice President, Head of Clinical Development, Solid Biosciences; Carl Morris, Ph.D., Chief Scientific Officer, Solid Biosciences; and Laurent Servais, Professor of Paediatric Neuromuscular Diseases, MDUK Oxford Neuromuscular Centre and Invited Professor of Child Neurology at Liège University
A defining hallmark of Duchenne muscular dystrophy (Duchenne) is the progressive decline of ambulatory function, with the ability to walk typically lost in patients’ early teenage years. While loss of ambulation radically impacts multiple and diverse aspects of these patients’ lives and the lives of their families, current ambulatory function tests are largely limited to a few specific motions and activities that do not fully reflect how patients are able to engage with activities of daily living.
The two main tests used to assess ambulatory function in clinical trials and clinical management of patients with Duchenne are the 6-Minute Walk Test (6MWT) and the North Star Ambulatory Assessment (NSAA). These tests, which only capture functional data at a single moment in time in the artificial environment of the clinic, are prone to bias and variability that can make interpretation of longitudinal changes difficult. Improving our understanding of these changes is essential for assessing the therapeutic effect of novel treatments for Duchenne and for gaining insight into how patients with Duchenne experience their disease in the context of their lived experiences outside of the clinic.
Novel, patient-centric endpoints using patient-reported outcome measures (PROMs) or wearable technologies offer new approaches to understanding how patients and their families experience Duchenne in their daily lives, an important contrast to standard clinical assessments that measure patients’ strength and mobility at a single moment in time during a clinic visit. In addition to enabling a much broader and continuous assessment of patients’ ambulatory status, these approaches also allow ongoing evaluation without the need for clinic visits — which was especially beneficial during the COVID-19 pandemic when travel and hospital restrictions were in place. One exciting new endpoint that can provide deep insight into how patients with Duchenne experience their disease — and how this experience changes over time or in response to therapy — is Stride Velocity 95th Centile (SV95C).
Introducing SV95C As A Novel Endpoint For Duchenne
SV95C, which represents the fastest spontaneous strides in a patient’s daily life as captured by a wearable device, is an objective assessment of spontaneous peak performance. The assessment is based on the precise measurement of every single stride in the natural environment, from which the lower limit of the 5% most rapid strides is extracted. SV95C is measured using a wearable watch-like device that continuously records motion through magneto-inertial sensors that detect three-dimensional movement. Magneto-inertial sensors include a tri-axial accelerometer, gyrometer, magnetometer, and barometer to measure linear acceleration, angular velocity, magnetic field of movement, and barometric altitude, respectively. Importantly, SV95C is accepted as a secondary endpoint for ambulant patients 5 years of age and above with Duchenne in drug therapeutic studies by the European Medicines Agency (EMA), when captured by a qualified wearable device worn at the ankle. Recently, EMA issued a draft qualification opinion for the qualification of SV95C as a primary endpoint1, which may make SV95C the first primary endpoint formally qualified in Duchenne and the first digital primary endpoint ever approved by a regulatory agency. It is also under review by the FDA for qualification.
Several other endpoints can be extracted from the continuous measurement of lower or upper limbs, such as the walking perimeter, the percentage of running phase, the number of falls, and stair-climbing velocity. Because magneto-inertial sensors provide real-time data on patients’ mobility as they move through their daily lives, assessment of these data has the potential to change our understanding of how patients experience Duchenne outside the clinic and provide better insight into how patients respond to investigational therapies. Importantly, the precision and the calibration of the sensors to obtain a measure that matches regulators’ expectations is essential and, to date, only one device has demonstrated this level of precision and stability.
The EMA acceptance of SV95C as a secondary — and potentially as a primary — endpoint in Duchenne clinical studies in ambulant patients 5 years of age and above was based on data collected from Duchenne patients and from normative controls.2 More recently, data from a Phase 1/2 gene therapy trial in patients with Duchenne (IGNITE DMD) were presented at the 27th International Hybrid Annual Congress of the World Muscle Society.3 These data further demonstrate the utility of SV95C as a novel endpoint for assessing function in ambulant patients with Duchenne.
Considerations For Using SV95C In Clinical Trials Of Duchenne And Other Neuromuscular Diseases
Evaluation of SV95C in the EMA qualification trials and in clinical trials of novel Duchenne therapies has provided important insights into the use of this endpoint in clinical settings. Several of these insights relate to the device used to capture SV95C data and underscore the importance of ease of use, comfort, and compatibility with the daily activities of the patients who will be wearing the device. Refinements have been made to the first-generation wearable device used to measure SV95C in response to patient feedback, including making the device smaller, more comfortable, and waterproof, all of which enhance the social and emotional acceptance of the device among young boys.
Another insight gained using SV95C devices in the IGNITE Duchenne trial is the importance of determining an appropriate period of time for data collection. Patients should only be asked to use a wearable device for the minimum period needed to gain accurate insight into their patterns of movement in daily life. Based on the IGNITE experience, sufficient data can be captured in weeks, rather than months, reducing the burden of clinical trial participation for patients and their families.
Focusing On Patient Centricity In Duchenne Therapeutic Development
A growing body of data supports the use of SV95C as a more informative primary endpoint for assessing ambulatory function in clinical trials of novel Duchenne therapies. Other real-time assessments of ambulatory function may also better inform our understanding of how patients with Duchenne experience their disease over time and how novel therapies impact ambulatory function in daily living. The physician, patient, industry, and regulatory communities need to continue working collaboratively to develop, evaluate, and deploy novel endpoints that enable a more comprehensive understanding of how investigational therapies impact ambulatory function for patients with Duchenne. The preliminary experience gained using SV95C in clinical trials of novel Duchenne therapies may provide a foundation for further innovation that can help improve outcomes for patients with Duchenne and other neuromuscular disorders.
References:
- European Medicines Agency. Draft qualification opinion for stride velocity 95th centile as primary endpoint in studies in ambulatory Duchenne muscular dystrophy studies. February 20, 2023. Available at: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/draft-qualification-opinion-stride-velocity-95th-centile-primary-endpoint-studies-ambulatory_en.pdf
- Haberkamp M, Moseley J, Athanasiou D, deAndres-Trelles F, Elferink A, Rosa MM et al. European regulators’ views on a wearable-derived performance measurement of ambulation for Duchenne muscular dystrophy regulatory trials. Neuromuscular Disorders. 2019;29(7):514-516.
- Servais L, Gonzalez JP, Morris CA, Shieh PB, Byrne BJ, Annoussamy M, Donisa Dreghici R. DMD patients treated with SGT-001 microdystrophin gene therapy improve in the objective endpoint of spontaneous walking velocity. World Muscle Society Congress, 2022
About The Authors:
Roxana Donisa Dreghici, M.D., is the senior vice president, head of clinical development at Solid Biosciences. She has served in senior scientific leadership roles at F. Hoffmann La Roche, Santhera, Novartis, Novo Nordisk, and Quintiles, most recently as global development lead/associate group medical director for neuromuscular diseases for F. Hoffmann La Roche in Basel, Switzerland. A native of Romania, Dreghici received her medical degree from Iuliu Hațieganu University of Medicine and Pharmacy, Romania.
Carl Morris, Ph.D., is chief scientific officer at Solid Biosciences. He is responsible for overseeing all of the company’s clinical programs. Previously, Morris was a senior director for Pfizer’s Rare Disease Research Unit, leading its efforts in neurologic diseases and muscle biology programs. Before that, he was an assistant professor at Boston University School of Medicine and was founding faculty member for their Muscle and Aging Research Unit. Morris completed his postdoctoral fellowship in the Department of Physiology at the University of Pennsylvania and holds a B.A. in biology from Franklin Pierce College and a Ph.D. in physiology from UCLA.
Laurent Servais, M.D., Ph.D., is a professor of pediatric neuromuscular diseases at the MDUK Oxford Neuromuscular Centre and invited professor of child neurology at Liège University. Previously, he was head of clinical trials and database services at the Institute of Myology in Paris, where he served most recently as head of the Institute of Muscle-Oriented Translational Innovation. He also was previously head of the Neuromuscular Centre in Liège, Belgium. Dr. Servais has been principal investigator in numerous clinical trials, most recently in testing treatments for Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and Angelman syndrome. He also leads the newborn screening program for SMA in southern Belgium. Dr. Servais received his M.D. from Louvain Medical School, Brussels, and his Ph.D. in neuroscience from Free University of Brussels, Belgium, followed by residencies in child neurology at the Free University of Brussels and Robert Debré Hospital, Paris.