Clinical Research and Drug Development Session Highlights from 2024 Annual SMA Research & Clinical Care Meeting

Podium Presentation 1. Swallowing Physiology and Function in Untreated Patients with Spinal Muscular Atrophy Type 1: Establishing Natural History Reference Values

Katlyn McGrattan, PhD ~ University of Minnesota, Minneapolis, MN, USA

Main Points:

• Dysphagia, or difficulty swallowing, is often a major symptom of SMA Type 1. However, dysphagia in infants with SMA Type 1 is not well-characterized, and there are no standardized ways to measure swallowing function in these infants.
• To develop an understanding of how swallowing is impaired in untreated infants with SMA Type 1, Dr. McGrattan and her fellow researchers analyzed data from clinical exams completed at 13 international hospitals. They were able to identify three biomechanical deficits that impaired the infant’s ability to swallow.
• These findings can help form an understanding of the biomechanics of dysphagia in untreated infants in SMA Type 1. This understanding may help researchers and clinicians develop a standardized way to assess whether treatment prevents and/or improves dysphagia in infants with Type 1 SMA.

 

Podium Presentation 2. Newborn Screening in SMA Motor Function Project (NBS-SMART): Achieving Consensus on Motor Function Outcomes

Kristin J. Krosschell PT, DPT  ~ Northwestern University, IL, United States

Main Points:

• The recent widespread implementation of newborn screening for SMA, along with the FDA-approval of three disease modifying treatments, has resulted in more infants with SMA being treated early in life. As they develop, these infants are achieving previously unattainable motor functions.
• Krosschell and her colleagues brought together physical therapists, occupational therapists, physicians, and other experts in SMA clinical care from around the world. The group’s objective was to decide on a set of core outcome measures made up of the most accurate and thorough tests for assessing motor function in infants and children who receive SMA therapeutics early in life.
• Using the Delphi survey method, which is a way to achieve informed consensus within a group, the experts created a motor function outcome measure toolkit. As the use of this toolkit becomes standard practice, it will enable information from different SMA research and clinical care centers to be shared and compared.

 

Podium Presentation 3. Motor Unit Index (MUNIX) as a Biomarker of Progression in 5q-Spinal Muscular Atrophy Types 3 and 4

Rodrigo Holanda Mendonça MD, PhD ~ Hospital das Clinicas da Universidade de Sao Paulo, Brazil

Main Points:

• The motor unit number index (MUNIX) is a method for determining the number and size of motor units in a given muscle by measuring the electrical impulse that occurs in response to stimulation by a motor neuron.
• Holanda Mendonça and his group sought to determine if MUNIX could be used to detect disease progression after four years in untreated and treated individuals with SMA Types 3 or 4. Using MUNIX, the researchers were able to measure the number of motor units lost in untreated participants. They also determined that MUNIX scores remained stable in participants treated with disease modifying therapy, suggesting that no motor units were lost.
• These findings suggest that MUNIX may be used to monitor disease progression and treatment effects in people with Type 3 and Type 4 SMA.

 

Podium Presentation 4. SMA Community-Based Experience with the 12-Tier Functional Ability Scale for Evolving Spinal Muscular Atrophy

Meghan Moore Burk PT, DPT ~ Children's Hospital Colorado, CO, United States & Rocky Mountain University of Health Professions, UT, United States

Main Points:

• As more people with SMA receive disease modifying treatments, there is a need for new ways to describe individuals’ disease status and level of ability.
• Moore Burk and her fellow researchers have begun to develop a new survey designed to classify SMA type by functional level. To test the reliability of the scale, called “SMA-EVOLVE,” the researchers asked people with SMA or their caregivers to use it to assess themselves. They also asked a physical therapist or physician with expertise in SMA to assess each participant using the survey. Most participants had received or were receiving treatment.
• The researchers found that using the SMA-EVOLVE, participants and the physical therapists/physicians who evaluated them generally reached the same conclusions about which type of SMA participants had according to the new scale. Participants also indicated that the scale was easy to use and accurately reflected their functional ability.
• Tools like the SMA-EVOLVE may help clinicians understand the unique needs of each person with SMA and provide them with the most appropriate care.

Podium Presentation 5. Rapid Risdiplam Initiation in Newborns with Spinal Muscular Atrophy (SMA): A Multicenter, Retrospective Cohort Study

Natalie Goedeker DNP, CPNP ~ Washington University in St. Louis School of Medicine, MO, United States

Main Points:

• In May of 2022, the FDA expanded the approval of the disease modifying therapy, Risdiplam, to infants two months of age and younger.
• Goedeker and her colleagues reviewed the records of infants who had received risdiplam an average of 11 days after birth---the majority of these infants later received an additional disease modifying therapy. The researchers found that as of February 2024, all but one infant had achieved a range of motor milestones.
• These findings suggest that risdiplam may be useful when given in addition to another disease modifying therapy, or as a bridge between birth and another therapy.

 

Podium Presentation 6. Real-World Outcomes Following Onasemnogene Abeparvovec in Patients with Spinal Muscular Atrophy and Invasive Ventilatory Support: Findings from the RESTORE Registry

Yasemin Erbas, PhD ~ SMA Europe, Freiburg, Baden-Württemberg, Germany

Main Points:

• Some people with SMA may require a procedure to help them breath better known as a tracheostomy. People with SMA who have tracheostomies were not included in the original clinical trials testing the efficacy and safety of the disease modifying therapy, onasemnogene abeparvovec. However, since its FDA-approval in 2019, onasemnogene abeparvovec has been prescribed to people with SMA who have tracheostomies.
• To learn about the effects of onasemnogene abeparvovec treatment on individuals with SMA and tracheostomies, Dr. Erbas and her colleagues reviewed the records from the multinational SMA registry, RESTORE. They found that of 31 patients who had tracheostomies and received onasemnogene abeparvovec, many had achieved or maintained motor milestones, and almost all had experienced improved motor function.
• These findings support the idea that people with tracheostomies can benefit from treatment with onasemnogene abeparvovec.

 

Podium Presentation 7. Increased Muscle Specific Force in Mouse Models of SMA and Aging via Administration of the 15-PGDH inhibitor, MF-300

Micah Webster, PhD ~ Empirium Bio, California, United States

Main Points:

• Although disease modifying therapies have made it possible for many individuals with SMA to gain and/or retain motor function abilities, muscle weakness remains an unmet need.
• Webster and his fellow researchers found that in an SMA mouse model, treatment with a molecule known as MF-300 for four weeks leads to improved muscle force and positive effects on gene expression within muscle cells. MF-300 acts by binding to and inhibiting another molecule that has been associated with muscle weakness.
• Discoveries such as these may lead to new ways to address unmet needs like muscle weakness in people with SMA.

 

Podium Presentation 1. Safety and Tolerability of Onasemnogene Abeparvovec for Patients with Spinal Muscular Atrophy Weighing ≤17 kg and ≤24 Months Old: Phase 4 OFELIA Study

Nayla Mumneh, MD ~ Novartis Gene Therapies, Illinois, United States

Main Points:

• The OFELIA study was a Phase 4, open label, multicenter study conducted in Latin American to test the safety and efficacy of onasemnogene abeparvovec in infants and young children who weighed more and were older than those who participated in previous trials.
• Mumneh’s group found that among the 12 infants and children who received onasemnogene abeparvovec in the OFELIA study, most improved or maintained motor function for 18 months after treatment. The safety profile of onasemnogene abeparvovec in this group was similar to that found in other studies.
• These results broaden the understanding of the range of infants and children who may benefit from onasemnogene abeparvovec treatment in Latin America.

 

 

Podium Presentation 2. Safety and Efficacy of Intravenous Onasemnogene Abeparvovec in Pediatric Patients with Spinal Muscular Atrophy: Findings from the Phase 3b SMART Study

Hugh McMillan MD, MSc, FRCPC, FAAN ~ Children’s Hospital of Eastern Ontario, Canada

Main Points:

• The SMART study was a multinational Phase 3b clinical trial designed to evaluate the safety and efficacy of onasemnogene abeparvovec in infants and young children weighing between 8.5 kg and 21 kg.
• McMillan and his fellow researchers found that during the 52 weeks following treatment, most of the 24 participants in the SMART study gained or maintained motor function abilities. The safety profile of onasemnogene abeparvovec in this group was similar to that found in other studies.
• As clinical trials for disease modifying therapies for SMA expand their eligibility criteria for participants, more is learned about who can benefit from treatment.

 

Podium Presentation 3. Interim Clinical, Neurofilament, and Safety Results from the Open-Label Phase 4 RESPOND Study Evaluating Nusinersen in Children with Spinal Muscular Atrophy Previously Treated with Onasemnogene Abeparvovec

Crystal Proud, MD ~ Children's Hospital of The King's Daughters, Virginia, United States

Main Points:

• The aim of the multinational RESPOND study is to test the safety and efficacy of nusinersen in infants and young children who have been treated with onasemnogene abeparvovec but still have unmet treatment needs.
• Proud and her colleagues found that 183 days after treatment with nusinersen, most of the participants experienced increased motor function. In addition, mean levels of a biomarker of axonal damage decreased. The safety profile of nusinersen was similar to that found in previous studies.
• Studies like this help researchers and clinicians understand whether using more than one disease modifying therapy for SMA can improve patient outcomes.

 

Podium Presentation 4. FIREFISH Parts 1 and 2: 5-Year Efficacy and Safety of Risdiplam in Type 1 SMA

Maria Mazurkiewicz-Bełdzińska, MD, PhD ~ Medical University of Gdańsk, Pomerania Province, Poland

Main Points:

• FIREFISH is a multicenter, open label study to determine the dosage, efficacy, and safety of risdiplam in children who have SMA Type 1 and two copies of the SMN2
• Mazurkiewicz-Bełdzińska’s group determined that after four years of risdiplam treatment, 91% of children were living, and 81% of those living did not require permanent support to breath. Furthermore, the researchers found that participants either maintained or gained motor skills and function. Safety findings were similar to those identified in previous studies.
• These results provide information about the long-term safety and efficacy of risdiplam treatment in children who have SMA Type 1 and two copies of the SMN2

 

Podium Presentation 5. Study Design and Status Update on the SYNAPSE-SMA Phase 2 Trial of NMD670 in Ambulatory Adults with Spinal Muscular Atrophy Type 3.

Vera Kiyasova, MD, PhD ~ NMD Pharma, Denmark

Main Points:

• Although disease modifying therapies for SMA have shown success in halting disease progression, unmet needs in muscle strength and function remain in some people with SMA.
• A molecule called “NMD670” has shown promise in increasing neuromuscular communication and muscle function in SMA mice. SYNAPSE-SMA is proof-of-concept, Phase 2 study in which Dr. Kiyasova and her colleagues will evaluate the tolerability, safety, and efficacy of NMD670 in ambulatory adults with SMA Type 3. The study has thus far enrolled 33 participants from four countries, with a goal of 55 patients.
• Compounds like NMD670 may be developed as add-on treatments to disease modifying therapies to achieve the best possible outcomes for people with SMA.

 

Podium Presentation 6. Taldefgrobep Alfa: Preclinical and Clinical Data Supporting the Phase 3 RESILIENT Study in Spinal Muscular Atrophy

Lindsey Lair, MD ~ Biohaven Pharmaceuticals, Inc., CT, United States and SMA Foundation, WY, Unites States

Main Points:

• Taldefgrobep alfa is a molecule that stimulates muscle growth by binding preventing other molecules from inhibiting the process. In research studies in which human participants had neuromuscular diseases other than SMA, taldefgrobep alfa has been shown to be safe.
• Lair and her fellow researchers used SMA mice to study the combined effect of taldefgrobep alfa plus a molecule that increases SMN protein levels on muscle structure and function. They found that when the two compounds were given to SMA mice together, muscle structure and function improved more than it did when mice were only given the SMN protein upregulator.
• Compounds like taldefgrobep alfa may be developed for use alongside disease modifying therapies to support muscle structure and function in individuals with SMA.