Ways of Capturing Real-life Gains, True Value of SMA Therapy, Still Needed

[Editor’s Note:  This is part of a series of articles into the discovery and development of Evrysdi — SMA’s newly approved disease-modifying therapy and its first oral and at-home one — as well as the scope of SMA issues and treatments. Here we again look at what might lie ahead for SMA,  focusing on needed ways of better capturing patient response in everyday life.]

Now that three targeted treatments are available for spinal muscular atrophy (SMA) — Spinraza (nusinersen), Zolgensma and Evrysdi (risdiplam) — interest is turning to ways to best measure how well patients respond to them, and the degree of improvement a particular therapy brings to everyday life.

In terms that speak to scientists, these measures are called patient-reported and daily life outcomes.

And they may be best attained through tools that track patients over time, rather than via a given day’s test.

In separate interviews with SMA News Today, Richard Finkel, MD, a pediatric neurologist at St. Jude Children’s Research Hospital in Tennessee, and Laurent Servais, MD, PhD, a professor of pediatric neuromuscular diseases at the MDUK Oxford Neuromuscular Centre, discussed what’s ahead in terms of outcome measures in SMA. Both worked on trials for all three SMA treatments.

Richard Finkel, a pediatric neurologist. (Photo courtesy of St. Jude Children’s Research Hospital)

Most current measures of therapy effectiveness in SMA, whether in clinical trials or in the clinic, rely on scales of motor milestones and motor function, which are “in some ways artificial,” Finkel said.

This is especially true when looking at older children, adolescents, and adults with SMA.

“I’m surprised that we still evaluate very complex therapeutic strategies, including gene therapies, by just asking patients to walk during six minutes in a corridor like we did one hundred years ago,” Servais said.

A person can show improvement on a scale on a given day, but how this translates into daily life gains at home, school, or work is far from evident.

“There are many … activities in the real-world setting that really have not been studied very effectively yet,” Finkel said.

Both neurologists are involved in ongoing efforts to “optimize” these tools, including patient-reported and daily life outcomes for SMA. Such measures are expected to help doctors better understand how patients are responding to a therapy, and in making better treatment decisions.

SMA treatments are also expensive and can be burdensome — the gene therapy Zolgensma lists at $2.125 million for a one-time use, and Spinraza is given by a spinal injection every four months. An understanding of patient response and preference should match.

“That’s really the next frontier,” Finkel said.

In this digital age — a time of smartphones, artificial intelligence, and instant data transfer by internet — better “real-life” measures are within reach, these experts said. Measures based on patient or caregiver appraisals could also more ably capture how people are doing each and every day.

“The challenge is, it’s not a one-size-fits-all,” Finkel said. Activities that need to be evaluated in a young child will be “obviously different” from those of a teenager or an adult.

Servais sees wearable devices — wrist or ankle bracelets, vests, orthopedic devices and the like — as a reasonable way of monitoring activity and its degree as SMA patients go about their lives.

“The problem with all the outcome measures that we have today is that they are snapshots of patients’ conditions at very precise moments, the day they come to the hospital,” Servais said. As such, they lack a continuity with daily life. A patient who is feeling “really well” on testing day can “outperform,” making their doctor think all is great. Another who’s simply tired can “underperform,” and an unnecessary change in therapy is made.

Neurologist Laurent Servais. (Photo courtesy of Dr. Servais)

“With wearable devices, we have the opportunity to record patients on a much longer timescale, and so be able to define if the patient is really doing better when we consider him or her on a 30-day or 60-day period,” Servais said.

He emphasized that wearable devices capture data on all aspects of life, and can be easily transferred to a cloud or other platform, allowing physicians to follow patients without a clinic visit — an advantage during the ongoing COVID-19 pandemic.

“I feel that we should start to use the opportunities [offered by] the 21st century to evaluate our patients, because then our evaluations would not only be more powerful, but also more adapted to the challenges of the 21st century,” Servais said.

Wearable devices might also better assess fatigue, an important and often overlooked issue in SMA, Finkel said. The need is to show not only if patients can do something better, but also that they can do it in a sustained way.

“There’s a huge difference between being able to partially do something and being able to completely do something without support … more independently,” Finkel said. It’s the difference between a child being able to lift a spoon to his or her mouth to eat for two or three times before fatiguing, or eating a full meal without help.

“I think these two topics — patient-reported outcomes and real-life daily functioning — really go hand-in-hand,” Finkel said.  Such measures still have to be validated to be of use, he noted, but the U.S. Food and Drug Administration is “very eager” to see them incorporated in clinical trials.

“And it makes sense,” Finkel added. “Because at the end of the day, if a child doesn’t feel better, or function better, then even though you might have gone up a few points on a scale, what does it really mean to that child?

“That’s really the question here.”