New Phase 2 TOPAZ Trial Data Indicate Positive Trends in Quality-of-Life Measures Over 24 Months with Apitegromab for Nonambulatory Patients with Types 2 and 3 SMA
- Tertiary endpoint data show trends of continuous improvement in activities of daily living, fatigue, and endurance over 24 months
- These data indicate the potential for sustained improvement in quality-of-life measures for patients with symptomatic SMA and offer further evidence of possible durable effects of apitegromab
“SMA can have a significant impact on the ability to perform daily activities but there is limited research on potential interventions to improve quality-of-life measures, such as increasing muscle endurance and reducing fatigue.1,2 These positive TOPAZ data indicate sustained improvements of quality-of-life measures over 24 months in the patient population studied,” said
The TOPAZ trial assessed activities of daily living (ADL), fatigue, and muscle endurance by three tertiary endpoint measures:
- The Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) measures pediatric abilities through three functional domains, daily activities, mobility, and social cognition;3
- Patient Reported Outcome Measurement Information System (PROMIS) measures mild subjective feelings of tiredness to debilitating and sustained feelings of exhaustion, with lower scores reflecting less fatigue;4,5 and
Endurance Shuttle Box and
Block Test(ESBBT), a muscle endurance measurement tool, evaluates how fast a patient fatigues with the added measure of endurance6 and may be complementary to outcome measures that focus on arm motor function, such as the Revised Upper Limb Module (RULM) assessment.
The tertiary endpoint data from these measures show trends of continuous improvement over 24 months. These data are relevant for informing the therapeutic hypotheses being evaluated in the Phase 3 SAPPHIRE trial. Limitations of these exploratory quality-of-life data analyses include small patient sample sizes in an open-label study, and further exploration is warranted. Specifically, the data found:
- Nonambulatory Type 2 patients (aged two or older who began receiving nusinersen maintenance therapy before age five) reported stabilization or continuous improvements in ADL up to a mean change from baseline of 3 points (n=14) in PEDI-CAT scores and fatigue up to a mean change from baseline of 5 points (n=10) in PROMIS scores over 24 months of apitegromab.
- Nonambulatory Types 2 and 3 patients (aged five to 21 who began receiving nusinersen maintenance therapy at or after age five) reported stabilization or increases in ADL up to a mean change from baseline of 0.7 points (n=8) in PEDI-CAT scores, and less fatigue up to a mean change from baseline of 3.5 points (n=2) in PROMIS scores over 24 months of apitegromab. Additionally, these patients also experienced trends in improvements in fatigability and endurance measures based on mean change in ESBBT activities. The trends of improvement with ESBBT are consistent with the previously reported increases in RULM scores observed in the TOPAZ trial at 24 months.
These findings complement previously reported data from the TOPAZ trial 24-month extension period that demonstrated sustained and durable improvements in motor function as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE) and RULM in patients with nonambulatory Types 2 and 3 SMA.
No safety risks were identified over 24 months of treatment. The incidence and severity of adverse events were consistent with the underlying patient population and nusinersen therapy. The five most common treatment-emergent adverse events (TEAEs) were headache, pyrexia, upper respiratory tract infection, cough, and nasopharyngitis. No deaths or serious adverse reactions have been observed with apitegromab. A total of 14 serious TEAEs have been reported over the 24-month treatment period, all assessed by the respective trial investigator as unrelated to apitegromab.
Of the 55 patients who completed the 24-month TOPAZ extension period, 54 have opted to continue treatment in the 36-month extension period.
About the Phase 2 TOPAZ Trial
The TOPAZ trial is an ongoing proof-of-concept, open-label Phase 2 trial evaluating the safety and efficacy of apitegromab in patients with Types 2 and 3 SMA. In the main treatment period, patients were dosed intravenously every four weeks as monotherapy or with nusinersen, an approved SMN therapy. The trial enrolled 58 patients in the
Apitegromab is a selective inhibitor of the activation of myostatin and is an investigational product candidate for the treatment of patients with spinal muscular atrophy (SMA). Myostatin, a member of the TGFβ superfamily of growth factors, is expressed primarily by skeletal muscle cells, and the absence of its gene is associated with an increase in muscle mass and strength in multiple animal species, including humans.
Spinal muscular atrophy (SMA) is a rare, and often fatal, genetic disorder that typically manifests in young children. An estimated 30,000 to 35,000 patients are afflicted with SMA in
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2 Yang M. et al.
5 Belter L, et al.
6 Cure SMA. Best Practices for Physical Therapists and Clinical Evaluators in Spinal Muscular Atrophy (SMA). 2021. Available at: https://www.curesma.org/wp-content/uploads/2021/09/Clinical-Evaluators-Best-Practices-13-August-2021.pdf.