Weeks before my husband, Sundeep, passed away from ALS, he unexpectedly regained a flicker of movement in one of his limbs. Nothing in his daily regimen or treatments had changed; there was no explanation. With tears in his eyes, he asked me, “Does this mean I’m getting better?” I didn’t know what to say.
When Sundeep was diagnosed with ALS in his mid-40s in 2019, our family was plunged into a new and terrifying reality. We endured relentless grief as, one by one, every ability to move was cruelly taken from him over thirteen months. As his primary caregiver, I became a living record of his experiences.
I remember the changes, both big and small, that went unrecorded —like the day he could no longer do a pull-up, a month before any other symptoms appeared. I also remember the more pronounced declines after his diagnosis: the last time he drove, the last time he fed himself, and the final steps he ever took before falling down several stairs. These milestones of decline are etched into my memory.
The ALS Functional Rating Scale-Revised (ALSFRS-R), the current “gold standard” for assessing progression in ALS drug trials and care settings, is fundamentally limited. It is a 12-question survey that fails to capture subtle and day-to-day fluctuations in function. It also records only a snapshot in time. For example, the ALSFRS-R assigns points for stair climbing, but over 24 hours, Sundeep might have needed assistance or not, depending on his fatigue or the time of day. The scale simply isn’t granular enough.
Obsessed with understanding his progression, I kept a record of his ALSFRS-R scores at home. Recording these numbers several times a week did not alter his care, but I needed to quantify the changes to try to make sense of his disease. The brief regaining of some movement was fleeting and unquantifiable. I remain the only witness. Actigraphy, the collection of movement data through wearable devices, could change this.
We have seen a staggering number of drug trial failures in ALS. Did these drugs fail because they didn’t work or because measurement tools weren’t sensitive and continuous enough? The limitations of the ALSFRS-R have driven recent regulatory whiplash. Amylyx’s Relyvrio was approved based on a phase 2 trial, only to be pulled after a larger phase 3 trial failed to replicate the results. Conversely, the Accelerated Approval of Qalsody in 2023 for SOD1 ALS was a landmark moment, but its trial failed the ALSFRS-R endpoint. Its approval instead relied on the dramatic reduction of a biomarker, neurofilament light. Today, real-world studies report that Qalsody is demonstrably slowing ALS and even improving function.
I wonder whether incorporating digital measures in the trials for both drugs might have detected functional changes earlier and with greater sensitivity. Now that a therapy targeting the underlying cause of a genetic form of the disease has been approved, why isn’t there a dedicated study of digital outcomes in people taking Qalsody? This could provide invaluable insight into what continuous, objective movement data look like in individuals receiving an effective treatment, potentially paving the way for clearer and more meaningful outcome measures.
I had the opportunity to meet Christine Guo, the Chief Scientific Officer at Ametris, a neuroscientist focused on digital health technologies, earlier this year. Christine shared that the same problem was evident from the other side of the clinic door:
“A decade ago, while working on ALS as an academic researcher at the University of Queensland, actigraphy devices were already being explored to develop better outcome measures for ALS. Later, as I transitioned into the pharmaceutical industry, I was struck by how much the field still relied on subjective and imprecise tools to monitor a disease that so clearly demands more sensitive measurement.”
Today, Christine positions the development of novel clinical endpoints for ALS as a top priority. As an innovator dedicated to clinical trial transformation, she understands why the pace of adoption is slower than patients would hope. The validation criteria for regulated trials are extremely rigorous, and rightly so. But there is a balance to strike, and too often perfection becomes the enemy of good. In an industry where the majority of trials fail, decision-makers tend to preserve the status quo. When a trial fails, no one is blamed for having tried something new.
This creates a troubling cycle. In the few trials that have incorporated actigraphy, the data, often collected only as exploratory endpoints, are rarely analyzed because the trial is deprioritized before any analysis can take place; in others, the data are reviewed but ultimately dismissed. In both situations, valuable insights are lost, and the full potential of actigraphy remains unrealized.
Our shared experiences point to the same urgent truth: the way we measure ALS progression is failing patients. We are entering a new era of ALS therapeutics but still relying on the same blunt instruments of measurement.
Sundeep wore a smartwatch for several years. Today, people are widely accustomed to using devices to track health metrics. I conducted a survey of people living with ALS: all 69 respondents were willing to wear an actigraphy device, and 80% were willing to wear two or more. People living with ALS also shared that they believe such measures could monitor their disease and reduce the need for burdensome in-person evaluations. A single trip to our clinic cost hundreds of dollars for an accessible van and left us exhausted for the rest of the day. At-home measurements can ease both the financial and physical burden.
We already have the technology to capture these precious, objective data. It’s time for clinical trials to catch up and use these tools to truly reflect what is happening to a person living with ALS. Without them, we risk missing a breakthrough, and the lived experiences of patients like my husband will remain unrecorded.
Author bio:
Nadia Sethi is CEO of North Star ALS, a nonprofit organization dedicated to connecting people affected by amyotrophic lateral sclerosis (ALS) with research. North Star ALS works to ensure ALS families are meaningfully engaged in research as study participants, contributors to improved research questions and trial design, and informed partners empowered with clear, accurate scientific information. A dentist by training and an ALS advocate for the past seven years, Nadia’s work is deeply personal after losing her husband to ALS. She has spearheaded and participated in numerous ALS-focused scientific initiatives. She also founded and leads a social media community of 10,000+ members focused on sharing current ALS research opportunities and findings. Through North Star ALS, Nadia brings together her clinical background, lived experience, and advocacy to advance ALS science in partnership with the community and research ecosystem.
Photo: designer491, Getty Images