MDA 2023: Apitegromab leads to sustained gains for some patients

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by Lindsey Shapiro PhD |

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Treatment with apitegromab for two years continues to stabilize or improve measures of motor function, fatigue, and life quality in children and young adults with spinal muscular atrophy types 2 and 3 who are not able to walk.

That’s according to data from the TOPAZ clinical trial (NCT03921528) and its extension part, in which both ambulatory and non-ambulatory patients are receiving Scholar Rock‘s muscle-directed therapy in combination with Spinraza (nusinersen).

The findings were discussed in an oral presentation by Thomas Crawford, MD, professor of neurology and pediatrics at Johns Hopkins University in Baltimore, Maryland, at the recent Muscular Dystrophy Association (MDA) Clinical & Scientific Conference. His talk was titled “Apitegromab in SMA (TOPAZ trial): Covariates of Multiple Efficacy Endpoints From 24 Month Data.

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Children with SMA should be monitored for cognitive function

“This analysis of our 24-month data continues to provide insights into apitegromab’s potential effects on motor function and quality of life measures over time,” Jing L. Marantz, MD, PhD, chief medical officer of Scholar Rock, said in a press release.

By the time SMA treatment is started, some patients may have experienced some degeneration in motor neurons, the specialized nerve cells that coordinate movement, which cannot be reversed with currently available therapies.

Thus, these patients will experience some residual deficits, which “are still meaningful in the lives of patients, both … in terms of impaired motor motor function as well as in subjective experiences of impaired of quality of life and fatigue,” Crawford said in the presentation.

Apitegromab is a lab-made antibody designed to block the mature form of myostatin, a protein found in skeletal muscles that works to suppress muscle growth in order to maintain proper muscle mass.

By blocking myostatin, Scholar Rock believes the treatment may boost muscle mass and help preserve motor function in SMA patients, when used alone or in combination with other SMA therapies.

The ongoing TOPAZ trial is investigating the safety and efficacy of apitegromab, given as an into-the-vein infusion every four weeks, as an add-on to Spinraza. It enrolled 58 children and young adults, ages 2-21, with SMA types 2 or 3.

TOPAZ study design

The trial had three groups of patients. One group included 20 patients, ages 2 and older, who could not walk and had started Spinraza before age 5. The second group of 15 patients included those ages 5-21 who were non-ambulatory and started on Spinraza after age 5. Lastly, the third group involved 23 patients, ages 5-21, who could walk, 12 of whom were also using Spinraza.

All participants received monthly apitegromab at a low (2 mg/kg) or high dose (20 mg/kg) and were followed for one year in the main trial. Among the 57 who completed the one-year trial, all chose to enter the trial’s extension part and receive the high dose for another year.

Participants on Spinraza had been using it for at least 10 months, with an average of about two years in the non-ambulatory groups.

Top-line data showed that motor function was stable after a year of treatment for most patients, in contrast to expected declines when the disease is left untreated. Some patients experienced motor improvements, which were particularly notable among younger patients and at the higher 20 mg/kg dose.

Gains ‘quite remarkable’

A pooled analysis of the 16 non-ambulatory patients ages 2-12 who received the 20 mg/kg dose, indicated that the average scores on the Hammersmith Functional Motor Scale Expanded (HFMSE) increased by 4.4 points with treatment, reflecting gains in motor function that were “quite remarkable,” Crawford said.

Data from the extension part also indicated that among the two non-ambulatory groups of patients,  HMFSE scores continued to be stable or further improved after two years. Stabilizations or improvements were also observed in the Revised Upper Limb Module (RULM), an assessment of upper limb function.

Looking at HMFSE scores as a function of age, Crawford said that “if you’re younger, you do much much better.” He cautioned that older patients may still benefit from the therapy, although to a lesser extent.

Apitegromab also led to a stabilization or reduction in fatigue for non-ambulatory patients, as assessed with the Patient Reported Outcome Measurement Information System (PROMIS).

Likewise, activities of daily living and mobility, two subscales of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), reflected some improvements in both domains over the two-year treatment period.

In general, patient-reported decreases in fatigue, and increases in measures of daily living and mobility, were all consistent with the motor findings on the HMFSE scale, Crawford noted.

Side effects not surprising

Side effects were consistent with the underlying disease or Spinraza treatment, with no new safety risks identified in the second year of treatment. The most common treatment emergent side effects included headache, upper respiratory tract infection, fever, cough, and the common cold, most of which were mild to moderate in severity.

Most participants are continuing treatment for a third year.

Overall, the data indicate that the effects of apitegromab “appear to be durable,” and that “targeting muscle in SMA is important to reducing overall disease burden,” Crawford concluded.

A Phase 3 trial, called SAPPHIRE trial (NCT05156320), is now ongoing to confirm the potential benefits of apitegromab in patients with SMA types 2 or 3 who are unable to walk, but can sit independently.

The trial is recruiting up to 204 participants at dozens of sites in the U.S. and Europe, and top-line data are anticipated in 2024.

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