Phase 3 SAPPHIRE Trial of Apitegromab in SMA Types 2, 3 Announced


After previously showing proof-of-concept in a phase 2 setting, investigators will continue to evaluate efficacy and safety of apitegromab, potentially the first muscle-directed therapy for patients with SMA.

Nagesh Mahanthappa, PhD

Nagesh Mahanthappa, PhD

A newly announced placebo-controlled phase 3 clinical trial, dubbed SAPPHIRE, will evaluate the efficacy and safety of apitegromab (Scholar Rock), a selective inhibitor of the activation of latent myostatin, in a cohort of 156 patients aged 2-12 years old with nonambulatory spinal muscular atrophy (SMA) types 2 and 3.1

Patients included in the pivotal study will be randomized 1:1:1 to receive apitegromab 10 mg/kg or 20 mg/kg, or placebo by intravenous infusion every 4 weeks for a 12-month period. Apitegromab will be evaluated in conjunction with SMN-targetedtreatment nusinersen (Spinraza; Biogen), similar to the phase 2 TOPAZ study (NCT03921528). Patients receiving background SMN treatment with risdiplam (Evrysdi; PTC Therapeutics) will also be eligible for the study. Once 50% of the main efficacy population completes their 12 months of treatment, Scholar Rock will provide an interim analysis update.

Investigators will use change from baseline on the Expanded Hammersmith Functional Motor Scale (HFMSE) total score as the primary end point, and several other additional end points including safety, the proportion of patients with at least a 3-point HFMSE increase, Revised Upper Limb Module (RULM) scores, and World Health Organization motor developmental milestones. The trial will also assess pharmacodynamics, pharmacokinetics, and antidrug antibodies.

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"Despite the important progress in SMA treatment offered by SMN therapies, there continues to be significant unmet medical need, and we believe that apitegromab has the potential to improve motor function as add-on to background SMN therapy and transform the lives of patients with SMA," Nagesh Mahanthappa, PhD, interim chief executive officer, Scholar Rock, said in a statement.1 "We are excited to advance to the pivotal trial phase of apitegromab development through SAPPHIRE."

All patients will undergo a chronic maintenance phase of their SMN treatment, corresponding to at least 6 months of prior treatment with risdiplam and at least 10 months of prior treatment with nusinersen. Notably, randomization will be stratified by both the background SMN treatment (nusinersen vs risdiplam) as well as the age at which SMN treatment had been initiated (<5 years vs >5 years).

Results from TOPAZ provided proof-of-concept of apitegromab’s abilities in SMA types 2 and 3. A majority of the 23 patients (57%; n = 13) with ambulatory SMA type 3 who received a 20-mg/kg dose monotherapy across cohort 1 maintained or improved their motor function, as reflected by a greater than 0-point change from baseline in Revised Hammersmith Scale (RHS). The investigators also documented that 22% of patients (n = 5) in cohort 1 attained a greater than 3-point increase from baseline in RHS. Additionally, there was a 0.3-point decline in mean change from baseline in RHS across the entire cohort.2

Cohort 2, which included 14 patients with type 2 and nonambulatory SMA type 3 treated with 20-mg/kg apitegromab, observed a mean change from baseline in HFMSE of a 0.6-point improvement. The majority (64%; n = 9) of patients achieved at least a 1-point increase in HFMSE and 29% (n = 4) of patients achieved at least a 3-point increase in HFMSE from baseline. These patients, who were already receiving treatment with nusinersen initiated at age 5 years or older, also observed the potential durability of effect with apitegromab for up to 12 months of treatment.

Seventeen patients included in cohort 3 were randomized 1:1 to receive the low dose (apitegromab 2 mg/kg) or high dose (apitegromab 20 mg/kg) and further demonstrated improvements in motor function relative to what was observed at the 6-month interim analysis. All told, there was a 7.1-point and 5.3-point mean improvements for the 20 mg/kg and 2 mg/kg dose arms, respectively, from baseline in HFMSE score.

"We are encouraged and motivated by the positive results of the TOPAZ phase 2 proof-of-concept trial, which informed the design of SAPPHIRE to evaluate the therapeutic potential of apitegromab in SMA," Yung Chyung, MD, chief medical officer, Scholar Rock, said in a statement.1 "Building on the solid foundation of TOPAZ, our phase 3 trial and the broader program are aimed at advancing the development of apitegromab towards our aspiration of transforming the lives of patients with SMA.”

SAPPHIRE will also include an exploratory population that includes 48 patients aged 13-21 years old with non-ambulatory SMA type 2/3. These patients will be randomized 2:1 to receive either apitegromab 20 mg/kg or placebo added to background SMN treatment with nusinersen or risdiplam.

At the conclusion of the 12-month treatment period in SAPPHIRE, patients will have the choice to enroll in an open-label extension, which will continue to evaluate the safety and tolerability of the drug, as well as an exploratory characterization of longer-term efficacy.

In July, NeurologyLive® caught up with Chyung to discuss the results of TOPAZ in detail. Watch his commentary below as he provides reasoning for the palpable buzz surrounding apitegromab and its clinical pathway.

1. Scholar Rock announces design of phase 3 SAPPHIRE clinical trial evaluating apitegromab in non-ambulatory patients with type 2 and type 3 spinal muscular atrophy. News release. Scholar Rock. November 30, 2021. Accessed December 2, 2021.
2. Scholar Rock announces positive 12-month top-line results from the TOPAZ phase 2 clinical trial evaluating apitegromab in patients with type 2 and type 3 spinal muscular atrophy (SMA). News release. April 6, 2021. Accessed December 2, 2021.
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