Phase 3 trial of apitegromab in SMA type 2 and 3 patients underway

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by Margarida Maia PhD |

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Scholar Rock announced that a Phase 3 clinical trial of its experimental muscle-targeting therapy apitegromab has finished enrolling children and young adults with spinal muscular atrophy (SMA) types 2 or 3, who are unable to walk but can sit independently.

“Completing SAPPHIRE enrollment is a critical step on the path to bringing apitegromab, a potentially transformative therapy, to individuals living with SMA,” Jay Backstrom, MD, president and CEO of Scholar Rock, said in a company press release.

The company anticipates releasing top-line study results in late 2024.

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Apitegromab aims to increase muscle mass to improve motor abilities

In SMA, a lack of SMN protein causes motor neurons — the nerve cells that control muscle movement — to become damaged and die over time. This results in muscle weakness and wasting, leading to problems with breathing, eating, and walking.

By the time doctors begin treating SMA, damage may have occurred to motor neurons that cannot be reversed with available disease-modifying therapies. As a result, some patients continue to experience impairments in motor function.

Myostatin is a naturally occurring protein mainly found in skeletal muscles, the muscles used for movement. It normally limits muscle growth, which under normal circumstances helps to maintain a healthy muscle mass.

Apitegromab is an antibody designed to block the precursor (inactive) form of myostatin, preventing its conversion into a mature (active) form. By reducing myostatin levels, apitegromab is expected to increase muscle mass and improve motor function.

The Phase 3 SAPPHIRE trial (NCT05156320) aimed to recruit up to 204 patients with SMA type 2 or 3, who are on stable treatment with Spinraza (nusinersen) or Evrysdi (risdiplam) at over 50 sites across the U.S. and Europe.

Its main goal is to evaluate the effectiveness of one year of apitegromab treatment versus a placebo, using a standardized measure of motor function called the Hammersmith Functional Motor Scale Expanded (HFMSE).

The main analysis will test two doses of apitegromab — given by intravenous (into-the-vein) infusion once every four weeks at 10 or 20 mg/kg — against a placebo in up to 156 children, ages 2-12 years.

Up to 48 adolescents and young adults, ages 13-21, were recruited for a separate exploratory analysis, and randomly assigned to either the higher dose of apitegromab or a placebo, also infused once every four weeks.

Findings in Phase 2 TOPAZ trial helped to guide SAPPHIRE’s design

This study’s design made use of results from TOPAZ (NCT03921528), a Phase 2 proof-of-concept trial that tested the safety and efficacy of two doses of apitegromab (2 and 20 mg/kg) in 58 children and young adults, ages 2–21, with SMA type 2 or 3.

After one year of treatment, apitegromab — given alone or as an add-on to Spinraza — led to improvements in motor function, as measured by the HFMSE. Greater gains were observed with the higher dose (20 mg/kg) and among patients who were unable to walk.

Patients who completed TOPAZ had the option of rolling into an extension study, where all are receiving apitegromab at 20 mg/kg for up to three years. Those initially using Spinraza, an SMN-boosting treatment, continued to take it.

Two-year and three-year data were consistent and showed that apitegromab continues to be associated with sustained gains in motor function for patients who entered the study unable to walk.

“The 36-month [three-year] data from TOPAZ, which reinforced long-term sustained and clinically meaningful improvement in motor function on top of SMN therapy, gives us strong conviction that apitegromab could provide substantial benefit beyond SMN therapy alone,” Backstrom said.

Thomas Crawford, MD, principal investigator of the TOPAZ study, will present these findings in two poster presentations at the 28th Annual Congress of the World Muscle Society, taking place Oct. 3 to 7 in South Carolina.

Crawford, who is a professor of neurology and pediatrics at Johns Hopkins University, also will share patient-reported outcome measures of fatigue, mobility, and activities of daily living.

The posters are titled “Effect of apitegromab on PEDI-CAT and PROMIS-fatigue questionnaire at 36 months in patients with spinal muscular atrophy” and “Effect of apitegromab on motor function at 36 months in patients with nonambulatory spinal muscular atrophy aged 2–12 years old.”

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