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Scholar Rock Reports Positive Trends in Phase 2 Study of Therapy for Non-ambulatory SMA2 and SMA3 Patients

October 24, 2022

Scholar Rock reported new quality-of-life data from its phase 2 TOPAZ trial extension period evaluating patient outcomes after 24 months of treatment that indicate stabilization or continued improvement with apitegromab for non-ambulatory patients with types 2 and 3 spinal muscular atrophy receiving an SMN-targeted therapy.

Photo: Jay Backstrom, CEO of Scholar Rock

The data were featured in a podium presentation at the 3rd International Scientific Congress on SMA in Barcelona, Spain.

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 the United States and Europe. It is characterized by the loss of motor neurons, atrophy of the voluntary muscles of the limbs and trunk and progressive muscle weakness. The underlying pathology of SMA is caused by insufficient production of the SMN protein, essential for the survival of motor neurons, and is encoded by two genes, SMN1 and SMN2. While there has been progress in the development of therapeutics that address the underlying SMA genetic defect, via SMN-dependent pathways, there continues to be a high unmet need for therapeutics that directly address muscle function.

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. 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. Scholar Rock believes that inhibiting myostatin activation with apitegromab may promote a clinically meaningful improvement in motor function in patients with SMA.

The TOPAZ trial is an ongoing proof-of-concept, open-label phase 2 trial evaluating the safety and efficacy of apitegromab in patients with SMA type 2 and type 3. 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 U.S. and Europe. The primary efficacy endpoints were mean change from baseline in Revised Hammersmith Scale (RHS) score at 12 months for the ambulatory population (Cohort 1), and mean change from baseline in HFMSE score at 12 months for the non-ambulatory population (Cohorts 2 and 3). The trial also includes multiple 12-month extension periods designed to evaluate longer-term patient outcomes.

The 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), which measures pediatric abilities through three functional domains, daily activities, mobility, and social cognition; the Patient Reported Outcome Measurement Information System (PROMIS), which measures mild subjective feelings of tiredness to debilitating and sustained feelings of exhaustion, with lower scores reflecting less fatigue; and the Endurance Shuttle Box and Block Test (ESBBT), a muscle endurance measurement tool that evaluates how fast a patient fatigues with the added measure of endurance 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.

Non-ambulatory 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 in PEDI-CAT scores and fatigue up to a mean change from baseline of 5 points in PROMIS scores over 24 months of apitegromab; non-ambulatory 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 in PEDI-CAT scores, and less fatigue up to a mean change from baseline of 3.5 points 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.

The 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 non-ambulatory 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.

“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. These positive TOPAZ data indicate sustained improvements of quality-of-life measures over 24 months in the patient population studied,” said Jay Backstrom, CEO of Scholar Rock. “As the phase 3 SAPPHIRE trial advances, these additional TOPAZ trial analyses coupled with the previously reported measures of motor function, such as HFMSE and RULM, continue to yield positive, consistent results, building the case for apitegromab as a promising new treatment option for patients with SMA.”

The U.S. Food and Drug Administration has granted Fast Track, Orphan Drug, and Rare Pediatric Disease designations, and the European Medicines Agency has granted Priority Medicines (PRIME) and Orphan Medicinal Product designations, to apitegromab for the treatment of SMA.

Author: Rare Daily Staff

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