SMA Researchers and Clinicians from Around the World Gather at the 29th Annual SMA Research & Clinical Care Meeting (2 of 2)

Podium Presentation 18. Spinal muscular atrophy among U.S. Hutterites: Phenotype variability in the setting of conserved ancestral haplotype and four SMN2 copies

Presenter: Kathryn Swoboda, MD ~ Mass General Brigham, Massachusetts, USA

• The Hutterite communities in South Dakota and Montana share a common version of the SMN1 gene, creating an opportunity to study why SMA affects people with similar genetic backgrounds differently.
• In Dr. Swoboda’s study, the researchers found through genetic analysis that of 215 study participants from these Hutterite communities, 75 carried an SMN1 deletion and two or more copies of SMN2. Twenty-one of the 215 participants had SMA.
• Notably, all 21 affected participants had four copies of SMN2. Symptom onset occurred in most affected participants when they were toddlers or young children.
• Consensus has not been reached about if and when to treat newborns with deletion of SMN1 and four or more SMN2 Data from this study supports the argument for early detection, monitoring, and treatment in these individuals.

Podium Presentation 19. Novel mutations identified by newborn screening: Therapeutic hurdles and functional solutions

Presenter: Brunhilde Wirth, PhD ~ University Hospital of Cologne, Germany

• Wirth’s lab identified two novel SMN1 gene variants of unknown significance (VUS) in two symptom-free infants during newborn screening. The families were unsure whether to begin treatment.
• To assess the impact of the VUS, Dr. Wirth’s team collaborated with another lab to create a zebrafish model of SMA. Injecting the fish with mRNA for either variant improved the fish’s health and survival.
• Based partly on these findings, the families chose not to start treatment. Both infants remained symptom-free at 18 months.
• The study underscores the value of developing new SMA models to support diagnosis, guide treatment decisions, and understand different variants of the SMN1

Podium Presentation 20. Exploring quantitative muscle testing among treated adults with spinal muscular atrophy: A real-world perspective

Presenter: Constance de Monts PT, DPT ~ Stanford University, California, USA

• The aim of this study was to track long-term changes in muscle strength and function in adults with SMA who were treated with nusinersen or risdiplam.
• Over approximately two and a half years, Dr. de Monts and her fellow researchers collected data from 56 adults.
• The researchers found that the participants’ muscle strength was generally stable during the study.
• They also identified significant functional gains in elbow flexion for sitters and non-sitters, and elbow extension in sitters. However, knee flexion strength significantly decreased annually in walkers and sitters.
• Because SMA affects people differently and treatment responses vary, more studies like this are needed to understand long-term treatment outcomes in adults with the disease.

Podium Presentation 21. Long-term motor responses to disease-modifying therapies in spinal muscular atrophy (SMA) adults: A prospective study

Presenter: Tina Duong, MPT, PhD ~ Stanford University, California, USA

• In recent years, more adults with SMA have received disease-modifying therapies, but the long-term benefits are just beginning to be understood.
• Duong and her team studied motor function over five years in 207 affected adults with varying abilities who received nusinersen or risdiplam.
• Overall, motor function remained stable, though some functional groups experienced more yearly change in function than others.
• These findings suggest that individual responses to disease-modifying therapy vary, supporting the need for personalized treatment approaches to optimize outcomes for every adult with SMA.

Podium Presentation 22. Longitudinal evaluation of adult patients with type 3 SMA with spinal cord imaging and motor scales: In search of new biomarkers

Presenter: Felipe Franco da Graça MD ~ University of Campinas, Brazil

• A biomarker is a measurable sign in the body that clinicians and researchers can use to track things like disease progression or treatment response in people with SMA.
• In this study, Dr. Franco da Graça used spinal cord magnetic resonance imaging (MRI) and motor function assessments to explore whether MRI could serve as a biomarker in adults with SMA Type 3.
• Two imaging and motor testing sessions were conducted one year apart, and findings from seventeen participants with SMA were compared to those from age-matched controls.
• The researchers found a strong link between spinal cord gray matter area and motor function.
• These results suggest MRI-based gray matter measurements may be a potential non-invasive biomarker for monitoring SMA Type 3.

Podium Presentation 23. Quantitative description of movement and posture in infants with SMA using a wearable sensor suit and a Machine Learning algorithm

Jinseok Oh, PhD ~ Children’s Hospital Los Angeles

• Tools that assess motor function in real-life settings may be particularly useful in detecting subtle but important changes in early child development.
• In his research, Dr. Oh tested the utility of a wearable sensor suit, the Motor Ability Assessment of Infants with a Jumpsuit (MAIJU), in young children with SMA. The MAIJU is designed to record a child’s motor activity throughout an entire day.
• Three infants with SMA, ages 3 to 15 months and treated with nusinersen or onasemnogene abeparvovec, wore the MAIJU during three day-long sessions that occurred over 5–6 months.
• The suit captured six postures and seven movement types among the children. All three children showed increased activity over the course of the study.
• These findings suggest that wearable devices like MAIJU may be valuable for monitoring motor function in young children with SMA.

Podium Presentation 24. Gait speed in SMA: A key vital sign linked to strength and fatigability

Carly Mueller PT, DPT, PCS ~ Columbia University Irving Medical Center, New York, USA

• Gait speed (GS) and gait speed reserve (GSR) — the ability to switch from slow to fast walking — are important indicators of health and function.
• In this study, Dr. Mueller used in-shoe sensors and clinical assessments to measure GS and GSR in 14 ambulatory individuals with SMA and 10 unaffected individuals. Participants were 5 to 64 years of age.
• GS and GSR were both reduced in those with SMA, but the two parameters were not correlated with each other.
• GS was linked to leg strength and fatigability, but GSR was not.
• These findings suggest GS and GSR are useful, complementary tools for assessing motor function and treatment response in ambulatory people with SMA.

Podium Presentation 25. Rasch analysis of the Spinal Muscular Atrophy Person-reported Outcome Measure (SMA-PRO) mobility domain in children and adults with SMA

Amy Pasternak PT, DPT, PCS ~ Boston Children's Hospital, Massachusetts, USA

• The SMA Person-Reported Outcome Measure (SMA-PRO) is a newly developed survey designed to assess functional abilities in people with all types of SMA.
• This study focused on the Mobility domain of the SMA-PRO to determine how well it captured the range of abilities of people with different disease severities.
• A total of 160 caregivers and 80 individuals with SMA (ages 13 and older) completed the Mobility section of the SMA-PRO.
• Having analyzed the completed survey sections, Dr. Pasternak concluded that the questions effectively captured mobility across all SMA types.
• As more people with SMA of all ages and ability levels receive treatment, tools like the SMA-PRO are becoming increasingly important for measuring treatment outcomes.

Podium Presentation 26. Retrospective assessment of feeding and nutrition after 2 years of risdiplam treatment in children with Type 1 SMA using a novel scale

Presenter: Giovanni Baranello MD, PhD ~ UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital Trust, London, UK and Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy

• Ongoing assessment of bulbar function is critical in children with SMA Type 1, but no standard set of assessment tools currently exists.
• The 6-point Children’s Eating and Drinking Activity Scale (CEDAS) evaluates feeding ability by accounting for both sensory and motor needs.
• Baranello and his colleagues used the CEDAS to retrospectively rescore data from 58 children with Type 1 SMA treated with risdiplam in the FIREFISH study.
• At two years, 83% of children fed orally, and most maintained or improved feeding ability. Lower CEDAS scores were associated with more respiratory issues.
• These findings suggest CEDAS may be a valuable tool in assessing bulbar function in children with severe SMA.

Podium Presentation 27. First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy

Presenter: Genis Prat Ortega, PhD ~ University of Pittsburgh, Pennsylvania, USA

• Primary sensory afferents are nerves that send signals from the skin, muscles, and organs to the brain and spinal cord. In SMA, the loss of these signals causes motor neurons to fire less often, which leads to decreased muscle function.
• In this study, Dr. Ortega and his team implanted electrodes along the spine to stimulate primary sensory afferents in the arms or legs of three ambulatory and three non-ambulatory adults with SMA, respectively.
• After four weeks of stimulation, both groups experienced improvements in muscle strength and endurance, even after spinal cord stimulation was turned off.
• In the future, technologies like spinal cord stimulation may be used in combination with existing disease modifying therapies to address current unmet needs like muscle weakness and fatigue.

Podium Presentation 28: PIERRE Clinical Trial: Safety and performance of ThecaFlex DRX™: An implantable intrathecal catheter and subcutaneous port system for repeated intrathecal delivery of nusinersen

Presenter: Kathrin Meyer PhD ~ Alcyone Therapeutics, Massachusetts, USA

• Certain treatments for neurological diseases, like nusinersen, must be administered directly into the spinal fluid through lumbar puncture. For patients with complex spinal anatomy, repeated lumbar punctures can be difficult and uncomfortable.
• To make treatment administration easier, Alcyone Therapeutics has created a device called the ThecaFlex DRx™ System. The device is made up of a small tube and a drug delivery port that are inserted surgically.
• The PIERRE study aims to assess the safety and effectiveness of the ThecaFlex DRx™ for repeated nusinersen delivery in people with SMA aged 3 and older.
• In Stage 1 of the trial, the ThecaFlex DRx™ worked as expected when used in 10 participants. Stage 2 is now enrolling up to 80 people in the U.S. and Europe.
• New drug delivery devices like the ThecaFlex DRx™ may reduce treatment burden for people with SMA.

Podium Presentation 29: Taldefgrobep alfa in spinal muscular atrophy: Results of the Phase 3 RESILIENT Study

Presenter: Lindsey Lee Lair ~ Biohaven Pharmaceuticals, Inc. Connecticut, USA

• Because the myostatin protein blocks muscle growth, inhibiting myostatin may be one way to encourage muscle growth in people with SMA.
• In Phase 3 of the RESILIENT study, participants with SMA who were 4-21 years old received weekly injections of either a myostatin inhibitor called “taldefgrobep alphaor” or a placebo. Participants continued their pre-existing disease modifying therapy regimen during the study.
• Lair and her fellow researchers found that motor function generally improved in participants. However, these improvements were not significantly greater than those measured in participants who received a placebo.
• In-depth data analysis revealed that factors like race and baseline myostatin level may have affected how much a participant’s motor function improved from taldefgrobep alpha treatment.
• Myostatin inhibitors like taldefgrobep alpha may be developed as “add-on” therapies to be used alongside existing disease modifying treatments for optimal health outcomes.

Podium Presentation 30: NURTURE Study: Long-term benefits of nusinersen in presymptomatic spinal muscular atrophy (SMA) over 8-years of follow-up

Presenter: Nancy L Kuntz, MD ~ Ann & Robert H. Lurie Children’s Hospital of Chicago, Illinois, USA

• Prior research has established that early diagnosis and treatment of newborns with SMA is key to optimal short-term outcomes for patients and families. The long-term effects of early intervention with disease modifying therapy are not as well understood.
• NURTURE was a long-term, open-label safety and efficacy study of nusinersen treatment in 22 infants with SMA who had either two or three copies of SMN2. Infants were 6 weeks of age or younger at first nusinersen dose, and they were still receiving nusinersen treatment at approximately 8 years of age.
• Kuntz and her colleagues found that all participants sat without support and stood with assistance during the study. Many participants achieved motor milestones at age-appropriate timepoints and retained them throughout the study.
• These findings underscore the importance of early diagnosis and treatment---ideally before symptoms develop---to optimize long-term outcomes in infants with SMA.

Podium Presentation 31. DEVOTE Part C Results: Exploring higher doses of nusinersen in nusinersen-experienced participants with spinal muscular atrophy

Presenter: Richard S. Finkel, MD ~ St. Jude Children's Research Hospital, Tennessee, USA

• DEVOTE is a three-part clinical trial designed to evaluate the safety and tolerability of a higher-dose regimen of nusinersen in participants with SMA.
• The third phase of the study enrolled 40 participants with SMA, aged 4 to 65 years, who had been receiving the standard regimen of nusinersen (12 mg loading/12 mg maintenance) for at least one year.
• Participants received one 50 mg loading dose of nusinersen approximately four months after their last 12 mg maintenance dose. They also received a 28 mg maintenance dose on days 121 and 241 of the study.
• Finkel and his fellow researchers determined that adverse events during the 50 mg/28 mg regimen were similar to those that occurred during the 12mg/12 mg regimen.
• These data indicate that individuals receiving the standard nusinersen regimen may safely be transitioned to the higher regimen, which may increase treatment options for people with SMA.

Podium Presentation 32: Efficacy and safety of apitegromab in individuals with type 2 and type 3 spinal muscular atrophy evaluated in the phase 3 SAPPHIRE trial

Presenter: Basil T. Darras, MD ~ Department of Neurology, Boston Children's Hospital, Massachusetts, USA

• Apitegromab is an antibody that inhibits myostatin, a protein that restricts muscle growth.
• Phase 3 of the SAPPHIRE study was conducted to determine the safety and efficacy of apitegromab in non-ambulatory patients with SMA Type 2 or Type 3 who were receiving nusinersen or risdiplam.
• 188 participants aged 2 to 21 years received apitegromab or a placebo every four weeks for twelve months.
• Darras and his colleagues observed statistically significant improvements in motor function in participants who received apitegromab.
• Improvements were generally consistent across age, disease-modifying therapy, age of therapy initiation, and region of residence.
• These results suggest that the clinical benefits of myostatin-targeted therapies like apitegromab may complement the benefits of existing disease modifying treatments.

Podium Presentation 33: Intrathecal onasemnogene abeparvovec for patients with spinal muscular atrophy: Phase 3, randomized, sham-controlled, double-blind STEER study

Presenter: Crystal M. Proud, MD ~ Children’s Hospital of the King’s Daughters, Virginia, USA

• Intrathecal (spinal) administration of the gene therapy, onasemnogene abeparvovec, is under development for the treatment of children and teens with SMA. The drug is currently administered intravenously into the bloodstream.
• The aims of Phase 3 of the STEER study were to investigate the safety and efficacy of intrathecal onasemnogene abeparvovec in children and teens with SMA who had not previously received disease modifying therapy. Participants were between 2 and 18 years old and were able to sit but had never walked.
• Over 52 weeks, 126 participants received either intrathecal onasemnogene abeparvovec or a sham procedure. A sham procedure mimics the process used to deliver a drug, but the drug itself is not actually given.
• Proud and her fellow researchers found that treatment with onasemnogene abeparvovec resulted in statistically significant improvement in motor function compared with the sham procedure.
• Developing new ways to administer disease-modifying therapies may expand treatment options and improve outcomes for individuals with SMA and their families.

Podium Presentation 34: Intrathecal Onasemnogene abeparvovec for treatment-experienced patients with SMA: Phase 3b, open-label STRENGTH study

Presenter: Jennifer M. Kwon MD, MPH ~ American Family Children’s Hospital, University of Wisconsin School of Medicine and Public Health, USA

• Prior clinical trials have evaluated the safety and efficacy of intrathecal onasemnogene abeparvovec in patients with SMA who had never before received a disease modifying therapy for SMA.
• The STRENGTH study, Phase 3b, evaluated the safety and efficacy of intrathecal onasemnogene abeparvovec in patients with SMA who had previously received but were no longer receiving nusinersen or risdiplam.
• Participants were 27 children and teens with SMA aged between 2 and 18 years old who were able to sit but had never walked independently
• Kwon and her team found that intrathecal onasemnogene abeparvovec had a favorable safety profile, consistent with results from earlier studies of the drug.
• They also determined that the majority of participants maintained existing motor function, while some participants gained new motor function.
• These results indicate that intrathecal onasemnogene abeparvovec may be a therapeutic option for children and teens who have already been treated with nusinersen or risdiplam.