RARE Daily

Scholar Rock Reports New Positive Data from 3-Year Extension Study in Spinal Muscular Atrophy

July 5, 2023

Rare Daily Staff

Scholar Rock reported new data from the phase 2 TOPAZ trial extension period evaluating spinal muscular atrophy patient outcomes at 36 months of treatment with apitegromab.

These data showed that continued treatment with apitegromab over the extended treatment period was associated with substantial and sustained improvement in motor function, as well as improvements in patient-reported outcome measures in patients with nonambulatory Types 2 and 3 spinal muscular atrophy (SMA) receiving survival motor neuron (SMN)-targeted therapy.

Detailed results were presented at the Cure SMA Research & Clinical Care Meeting in Orlando, Florida.

“These promising long-term data highlight the therapeutic potential of muscle-targeted therapies, such as apitegromab, to help those with SMA address persistent weakness,” said Thomas Crawford, of Johns Hopkins Medicine, and the lead principal investigator of the TOPAZ trial. “Incorporating a muscle-targeted therapy with apitegromab’s clinical profile into the treatment paradigm could allow patients to sustain or potentially achieve new gains in motor functioning.”

Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disease that afflicts an estimated 30,000 to 35,000 people in the United States and Europe. The disease is characterized by the loss of motor neurons, atrophy of the voluntary muscles of the limbs and trunk, and progressive muscle weakness. While there has been progress in the development of therapeutics that address the loss of motor neurons, there continues to be a high unmet need for therapies that directly address the progressive muscle weakness that leads to loss of motor function in SMA.

Apitegromab is an investigational fully human monoclonal antibody inhibiting myostatin activation by selectively binding the pro- and latent forms of myostatin in the skeletal muscle. It is the first muscle-targeted treatment candidate to demonstrate clinical proof of concept in 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. The U.S. Food and Drug Administration (FDA) has granted Fast Track, Orphan Drug and Rare Pediatric Disease designations, and the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) and Orphan Medicinal Product designations, to apitegromab for the treatment of 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 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-targeted 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 nonambulatory population (Cohorts 2 and 3). The trial also includes multiple 12-month extension periods designed to evaluate longer-term patient outcomes.

Over the 36-month extended treatment period, nonambulatory patients (ages 2-21) experienced substantial and sustained gains in Hammersmith Functional Motor Scale-Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores from baseline.

For the 36-month data, an observed case analysis was conducted, which pooled data for all nonambulatory patients (including those patients on 20 mg/kg of apitegromab for the full duration of the trial, and those who switched from 2 mg/kg to 20 mg/kg at various time intervals in year 2) and was based upon the available data. These analyses exclude data for patients post scoliosis surgery.

Nonambulatory patients (ages 2-21) had improvements in PEDI-CAT (measure of activities of daily living) and PROMIS-Fatigue (a patient-reported outcome tool measuring fatigue) that were consistent and sustained at 36 months. The mean change in PEDI-CAT daily activity domain from baseline at 36 months was 2.2, indicating an improvement in the ability to perform daily activities. The mean change in PROMIS-Fatigue from baseline at 36 months was –4.6, indicating a decline in fatigue. These improvements in PEDI-CAT and PROMIS-Fatigue were generally consistent with improvements in motor function across the 36 months of the study period.

Treatment-emergent adverse events (TEAEs) at 36 months were consistent with previous reports at 12 and 24 months, with no new findings after an aggregate of 198 patient-years of exposure. TEAEs were mostly mild-to-moderate in severity, and generally consistent with the underlying patient population and background therapy. No deaths or suspected unexpected serious adverse reactions or hypersensitivity reactions were observed with apitegromab at 36 months. A total of 21 serious TEAEs were reported over the 36-month treatment period. No patients displayed positive titers for apitegromab antibodies (ADA).

More than 90 percent of nonambulatory patients remained on treatment in the extension study.

“The results further strengthen our confidence in apitegromab’s therapeutic potential for patients with SMA, as well as validate Scholar Rock’s approach to selectively inhibiting the pro and latent forms of myostatin,” said Jay Backstrom, president and CEO of Scholar Rock. “In addition to the sustained benefit observed with consistent HFMSE scores, we saw continued improvement in RULM scores, and reductions in fatigue as reported by patients—all of which can be important factors in performing activities of daily living. We remain committed to advancing the standard of care for people with SMA, and we look forward to sharing updates on our pivotal phase 3 SAPPHIRE trial, which we anticipate will complete enrollment in the third quarter of 2023.”

Photo: Jay Backstrom, president and CEO of Scholar Rock

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