#CureSMA2021 – Apitegromab Safely Increases Motor Abilities in SMA Types 2, 3

Meaningful further improvements in motor skills were evident with apitegromab treatment in later-onset spinal muscular atrophy (SMA) patients on maintenance doses of Spinraza (nusinersen), updated Phase 2 TOPAZ trial findings show.

“The TOPAZ results show that apitegromab has promising potential to benefit the large portion of individuals with SMA who still manifest muscle weakness,” Thomas Crawford, MD, the trial’s lead investigator, said in a press release.

These data were presented by Crawford at the recent 2021 Virtual SMA Research & Clinical Care Meeting, and expand on top-line trial results reported earlier this year.

Apitegromab (SRK-015) prevents the conversion of a latent, or idle, form of myostatin — a protein that suppresses muscle growth — into its active form. Scholar Rock, apitegromab’s developer, expects the investigational medicine to improve patients’ muscle mass, strength, and motor function, while causing fewer side effects than other active myostatin suppressors.

The ongoing trial (NCT03921528) is evaluating apitegromab’s safety and effectiveness in 58 patients between the ages of 2 and 21, with SMA types 2 and 3.

Participants received either a low dose (2 mg/kg) or a high dose (20 mg/kg) of apitegromab once every four weeks intravenously (into-the-vein) for up to one year. Most (83%) were treated at high dose, excepting some ambulatory (able to walk) patients given apitegromab alone, and the majority (81%) received it alongside Spinraza.

After one year of treatment, nearly three-quarters (74%) of non-ambulatory participants showed clinical improvement, as measured by a gain of at least one point on the Hammersmith Functional Motor Scale Expanded (HFMSE).

Gains were especially pronounced among the eight non-ambulatory participants (mean age of 3.8) on high-dose apitegromab, who had also started Spinraza before they were 5 years old.

Patients in this group increased their HFMSE scores by a mean of 7.1 points. Seven gained at least one point, five gained at least five points, and scores for three children increased by over 10 points. Of note, increases of at least three points in Hammersmith scores are typically considered clinically meaningful.

Gains in HFMSE scores were also reported among 14 non-ambulatory patients (mean age, 11.7) on high-dose apitegromab who started Spinraza at age 5 or older, contrasting with declines experienced — on average — by this patient population without treatment.

Scores increased by a mean of 0.6 or 1.2 points, depending on the analysis used. Nine of these patients gained at least one point, and four gained at least three points.

Children in both groups had been using Spinraza  for about two years at the time of their enrollment in TOPAZ and continued its use as a maintenance therapy during the trial. TOPAZ is due to conclude in April 2023.

Because both Spinraza and apitegromab are expected to aid patients’ motor skills, there was some question as to how much each therapy contributed to the observed improvements.

Investigators determined that apitegromab treatment was likely behind the motor gains observed in this trial, as participants using Spinraza had reached a “plateau” in terms of improvement before entering the study.  A later, post-hoc TOPAZ analysis also showed no correlation between HFMSE changes after one year of treatment and the length of prior Spinraza use across all non-ambulatory participants, the researchers reported.

Seven of the 35 non-ambulatory patients treated with both medications — including three who began Spinraza after age 5 —made between one and three major functional achievements, as measured by the World Health Organization Motor Development Milestones.

Five patients gained one new WHO motor milestone, including one who began to walk independently and one who could stand independently. One patient gained two of these milestones: an ability to crawl on hands and knees, and to stand with assistance. Another gained three WHO motor milestones: an ability to crawl on hands and knees, and standing and walking with assistance.

The most frequently reported treatment-related adverse side effects were headache, fever, upper respiratory tract infection, cough, and cold symptoms.

Scholar Rock is analyzing data from other exploratory TOPAZ endpoints, and plans to present them at a later date.

The company also hopes to initiate a Phase 3 trial of apitegromab as an add-on therapy to Spinraza among SMA types 2 and 3 patients by year’s end.

“In recent years, there have been some really remarkable advances in therapy for SMA that increase the low levels of SMN protein in motor neurons,” Crawford said. “But these findings suggest the fortunate streak for SMA therapeutics can potentially continue, this time targeting the persistent weakness in a complementary fashion at the level of muscle.”