Nonambulatory SMA Patients Show Gains With 2 Years of Apitegromab

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by Steve Bryson, PhD |

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Two years of treatment with the investigational therapy apitegromab continued to improve motor function in Spinraza-treated children and young adults with later-onset spinal muscular atrophy (SMA) who cannot walk, according to new extension data of the Phase 2 TOPAZ trial.

The therapy’s developer, Scholar Rock, is also running SAPPHIRE (NCT05156320), a Phase 3 trial to evaluate apitegromab as an add-on treatment to either Spinraza or Evrysdi (risdiplam) in nonambulatory children and young adults with SMA type 2 and 3. The study is enrolling at multiple sites in the U.S., with up to 55 sites expected across the country and in Europe.

“These data support apitegromab’s potential to meaningfully improve the lives of nonambulatory patients with Types 2 and 3 SMA,” Nagesh Mahanthappa, PhD, founding CEO and president of Scholar Rock, said in a press release. “As a company, we are dedicated to the SMA community and are urgently enrolling patients in our ongoing pivotal Phase 3 SAPPHIRE trial.”

Two-year data were recently presented at the Cure SMA Research & Clinical Care Meeting by TOPAZ lead investigator Thomas Crawford, MD, of Johns Hopkins Medicine.

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Early Work Supports Apitegromab’s Safety as SMA Muscle Therapy

Apitegromab is a lab-made antibody that selectively binds to myostatin, a protein mainly found in muscles used for movement (skeletal muscles) that limits muscle growth to maintain healthy muscle mass.

By reducing myostatin, the therapy, which is infused into the bloodstream, aims to increase muscle mass and improve motor function in SMA, an inherited condition marked by muscle weakness and wasting.

The Phase 2 TOPAZ trial (NCT03921528) evaluated apitegromab in 58 people with type 2 and 3 SMA (later onset), ages 2–21, including those who could walk (ambulatory) and those who couldn’t (nonambulatory).

The 23 ambulatory participants (cohort 1), aged 5 to 21, were treated with apitegromab only (monotherapy) or in combination with Spinraza (nusinersen).

The nonambulatory participants were divided into two groups (cohorts 2 and 3). Cohort 2 included 15 patients, ages 5 to 21, who started on Spinraza after age 5 and received 20 mg/kg of apitegromab with Spinraza. Cohort 3 included 20 patients ages 2 and up who started Spinraza before age 5 and received 2 or 20 mg/kg of apitegromab with Spinraza.

Among the 57 who completed the one-year primary treatment phase, apitegromab improved motor function for many trial participants, with all choosing to enter the trial’s extension phase for an additional year of treatment.

The presentation, titled “TOPAZ Extension: 24-Month Efficacy and Safety of Apitegromab in Patients with Later-Onset Spinal Muscular Atrophy (Type 2 and Type 3 SMA),” provided a pooled analysis of nonambulatory patients in the extension phase.

This analysis encompassed patients at both dose levels, including all of the low-dose patients who switched to the high dose, plus those who missed doses due to study site restrictions from COVID-19.

After two years of apitegromab, the combined nonambulatory group, ages 2 to 21, showed additional gains in motor function, as assessed by the Hammersmith Functional Motor Scale Expanded (HFMSE). Scores rose from a mean of 3.5 points after one year to 4.0 points after two years compared to before apitegromab.

Upper limb motor performance, as measured by the Revised Upper Limb Module (RULM), also improved, with mean scores rising from 1.3 points after one year to 1.9 at two years.

During the second year, three nonambulatory patients underwent surgery to correct scoliosis, a curvature of the spine, which can negatively impact motor scores. The revised mean HFMSE score that excluded data from these patients was now 4.4, while the mean RULM score increased to 2.3.

Although there was no relationship between HFMSE and RULM scores after one year, after two years of treatment, there was a significant correlation between these two measures.

Pharmacological data from cohort 3 showed higher apitegromab in the bloodstream and increased myostatin engagement when low-dose patients switched to a higher dose. There were also signs of further HFMSE increases with the higher dose, all suggesting a dose response, according to Scholar Rock.

“The 24-month results provide long-term data and evidence, underscoring the findings of the 12-month primary treatment period of the TOPAZ trial in which patients receiving apitegromab experienced sizable motor function gains,” George Nomikos, MD, PhD, senior vice president at Scholar Rock, said. “This durability and continued increase in motor function support the transformative potential of apitegromab for patients suffering with SMA.”

The company also provided a two-year update on ambulatory patients, which suggested motor function stability based on the Revised Hammersmith Scale (RHS). Overall, the mean RHS score dropped 2.8 points in the apitegromab monotherapy group and 0.7 points in the apitegromab/Spinraza group after two years. Still, 42.9% showed an increase of one or more points, while 23.8% improved by three or more points after two years.

Consistent with safety data after one year, no serious safety issues were reported as part of the two-year analysis. The five most common treatment-emergent adverse events (TEAEs) included headache, fever, upper respiratory tract infection, cough, and inflamed nasal passages.

Of the 55 TOPAZ participants who completed the two-year extension period, 54 have opted to continue a third year of treatment.