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 (SMA)
– Phase 3 trial is a randomized, double-blind, placebo-controlled trial of apitegromab as add-on to background SMN therapy in non-ambulatory Type 2/3 SMA
– Trial design is informed by the positive results from the prior TOPAZ trial, including a new exploratory analysis of patients 2-12 years old with non-ambulatory Type 2/3 SMA
“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,” said
SAPPHIRE Trial Design
SAPPHIRE is a randomized, double-blind, placebo-controlled, phase 3 clinical trial. Approximately 156 patients aged 2-12 years old with non-ambulatory Type 2/3 SMA are anticipated to be enrolled in the main efficacy population. Patients will be randomized 1:1:1 to receive for 12 months either apitegromab 10 mg/kg, apitegromab 20 mg/kg, or placebo by intravenous (IV) infusion every 4 weeks added on top of background SMN treatment. Patients receiving the background SMN treatment of nusinersen as well as patients receiving background SMN treatment of risdiplam will both be eligible for enrollment.
Additional key elements of the study design include the following:
- At baseline, all patients will be required to be in the chronic maintenance phase of SMN treatment, corresponding to > 6 months of prior treatment in the case of risdiplam or > 10 months of prior treatment in the case of nusinersen.
- 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).
- The primary efficacy endpoint will evaluate the mean change from baseline in the Expanded Hammersmith Functional Motor Scale (HFMSE) total score after 12 months of treatment.
Additional endpoints will evaluate safety, proportion of patients with >3-point HFMSE increase, Revised Upper Limb Module (RULM), and
World Health Organization( WHO) motor developmental milestones, pharmacokinetics, pharmacodynamics, anti-drug antibody, and other outcome measures.
In addition, the trial provides the opportunity for an interim analysis when at least 50% of patients in the main efficacy population (age 2-12 years) have completed 12 months of treatment.
Separately from the main efficacy population, an exploratory population of 48 patients aged 13-21 years old with non-ambulatory Type 2/3 SMA will be evaluated. 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. In this subpopulation of older individuals with SMA, the safety and tolerability of apitegromab will be characterized, and efficacy will also be evaluated in an exploratory, nonpowered manner.
To further characterize apitegromab in SMA, upon completion of the 12-month treatment period, all patients will be offered the option of enrolling in an open-label extension study. In this open-label extension, the safety and tolerability of apitegromab will be evaluated, along with an exploratory characterization of longer-term efficacy. In addition, the TOPAZ extension continues to follow patients from TOPAZ and evaluate the longer-term efficacy and safety of apitegromab. Among the 57 patients
SAPPHIRE is planned to enroll across 55 sites globally, including in the
“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,” said
TOPAZ Insights Inform Key Elements of the SAPPHIRE Design
The SAPPHIRE design was informed by results from the TOPAZ phase 2 proof of concept trial of apitegromab in patients with Type 2 and Type 3 SMA. Key features of the SAPPHIRE design include the following:
- SAPPHIRE enrolls patients with non-ambulatory Type 2/3 SMA, which was the population of individuals observed to have the largest HFMSE increases from baseline in TOPAZ.
- Selection of the age 2-12 population in SAPPHIRE was informed by the positive efficacy results of an exploratory post hoc analysis from TOPAZ, as described in further detail below.
- SAPPHIRE will use the same primary efficacy endpoint (mean HFMSE change from baseline) as had been used in TOPAZ.
- SAPPHIRE will use the same treatment duration (12 months) as had been used in TOPAZ.
- SAPPHIRE will evaluate apitegromab at 20 mg/kg, which was observed in TOPAZ to have a greater effect than the 2 mg/kg dose both in terms of efficacy and pharmacodynamics. As it is possible that an intermediate dose of apitegromab between 2 and 20 mg/kg may offer comparable effects as the 20 mg/kg dose, SAPPHIRE will include an apitegromab 10 mg/kg arm. To control type I error caused by multiple comparisons, the efficacy analysis will first compare the apitegromab 20 mg/kg arm against placebo before any testing of apitegromab 10 mg/kg against placebo.
Exploratory Analysis of Age 2-12 Non-Ambulatory Patients from TOPAZ
This exploratory post hoc analysis from TOPAZ pooled together patients from both non-ambulatory cohorts (patients
The 12-month apitegromab results from this age 2-12 years old exploratory analysis of the pooled non-ambulatory cohorts in TOPAZ include the following:
- N= 16 total, with 50% of these patients being from the cohort of background nusinersen initiated at age < 5 years and 50% of these patients being from the cohort of background nusinersen initiated at age > 5 years
- All patients were in the chronic maintenance phase of nusinersen treatment. Data from the SHINE study suggest that the effects of nusinersen upon HFMSE generally plateau after initial increases.1
- Mean HFMSE change from baseline was 4.4-point increase (95% CI of 1.3, 7.4)
- 81% (13/16) of patients had > 1-point increase in HFMSE
- 56% (9/16) of patients had > 3-point increase in HFMSE
Among the older subset of patients (individuals
whohad started their background nusinersen at the age of > 5 years) in this analysis, 75% (6/8) of patients had > 1-point increase in HFMSE and 50% (4/8) of patients had > 3-point increase in HFMSE
Apitegromab is a selective inhibitor of the activation of myostatin and is an investigational product candidate for the treatment of patients with SMA. Myostatin, a member of the TGFβ superfamily of growth factors, is expressed primarily by skeletal muscle cells, and the absence of its gene is associated with an increase in muscle mass and strength in multiple animal species, including humans.
Spinal muscular atrophy (SMA) is a rare, and often fatal, genetic disorder that typically manifests in young children. An estimated 30,000 to 35,000 patients are afflicted with SMA in
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1 This information from a third-party study is provided for background purposes only and is not intended to convey or imply a comparison to the TOPAZ clinical trial results.
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