Positive Phase 2 Topaz Trial Extension Data Demonstrate Sizable and Sustained Motor Function Improvement at 24 Months with Apitegromab for Non-Ambulatory Patients with Types 2 and 3 Spinal Muscular Atrophy (SMA)
- Sizable and sustained improvement in Hammersmith Functional Motor Scale-Expanded (HFMSE) scores observed at 24 months
- Substantial increase in Revised Upper Limb Module (RULM) scores observed at 24 months
- No serious safety risks identified over 24 months
- Enrollment progressing in pivotal Phase 3 SAPPHIRE registrational trial
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"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,” said
“These data support apitegromab’s potential to meaningfully improve the lives of non-ambulatory patients with Types 2 and 3 SMA,” said
TOPAZ evaluated apitegromab across a broad age range (2-21 years) of patients with Types 2 and 3 SMA. All 35 non-ambulatory patients (Cohorts 2 and 3) and 12 of 23 ambulatory patients (Cohort 1) were receiving nusinersen maintenance therapy. The primary efficacy endpoint for the non-ambulatory population was mean change from baseline in HFMSE. Additional endpoints included mean change from baseline in RULM, an assessment specifically designed for upper limb function in patients with SMA. The HFMSE is a validated measure for the assessment of gross motor function in SMA, while the RULM is validated to evaluate upper limb motor performance by evaluating tasks which correspond to the ability to perform various everyday activities with their hands and arms.
For this 24-month evaluation, an observed case analysis was conducted, which pooled all the non-ambulatory patients (Cohorts 2 and 3) and was based upon the available data for given timepoints. This analysis population included patients receiving either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab (inclusive of patients in Cohort 3 who switched from 2 mg/kg to 20 mg/kg in Year 2) and did not exclude any patients who had missed apitegromab doses due to study site access restrictions from COVID-19.
Non-ambulatory patients (age range of 2 to 21 years old) with valid HFMSE assessments had sizable, sustained gains in HFMSE scores at 24 months from baseline (prior to first dose of apitegromab), while RULM scores continued to increase at 24 months. The mean change from baseline results for non-ambulatory patients showed:
Pooled non-ambulatory pts
*excluding pts w/scoliosis surgery
Mean Change from Baseline in
HFMSE (95% CI)
(95% CI: 1.2, 6.0)
(95% CI: 1.5, 6.5)
(95% CI: 2.0, 6.9)
Mean Change from Baseline in
RULM (95% CI)
(95% CI: 0.2, 2.3)
(95% CI: 0.8, 3.0)
(95% CI: 1.2, 3.4)
*Three patients in the non-ambulatory group underwent scoliosis surgery in year 2, which has been reported to negatively impact HFMSE scores for a considerable period afterwards1. This analysis excluded post-surgery data of these patients.
Dose response continued to be observed across the 24 months of apitegromab administration based upon HFMSE scores and pharmacodynamic data (target engagement as measured by serum latent myostatin concentrations), with signs that there may be further HFMSE increases as non-ambulatory patients originally receiving the low dose switched to the high dose treatment.
Data at 24-months for ambulatory patients with Type 3 SMA (Cohort 1) suggest stability of Revised Hammersmith Scale (RHS) scores in patients receiving 20 mg/kg of apitegromab and nusinersen. The mean RHS change from baseline at 24-months was ‑0.7 points (95% CI: -3.1, 1.7) for the apitegromab and nusinersen subgroup (n=10) and ‑2.8 points (95% CI: -8.4, 2.8) for the apitegromab monotherapy subgroup (n=11). A subset of individuals in Cohort 1(n=21) had RHS improvements, as reflected by 42.9% (9/21) and 23.8% (5/21) of patients having ≥1-point and ≥3-point RHS increases from baseline at 24 months respectively.
Of the 55 patients who completed the 24-month TOPAZ extension period, 54 have opted to continue treatment in the 36-month extension period.
Consistent with the 12-month safety data, no serious safety risks were identified as part of the analysis of the cumulative 24-month data. The incidence and severity of adverse events were consistent with the underlying patient population and background therapy. The five most common treatment-emergent adverse events (TEAEs) were headache, pyrexia, upper respiratory tract infection, cough, and nasopharyngitis. No deaths or serious adverse reactions have been observed with apitegromab. A total of 14 serious TEAEs have been reported over the 24-month treatment period, all assessed by the respective trial investigator as unrelated to apitegromab.
Details of the podium presentation at
Title: TOPAZ Extension: 24-Month Efficacy and Safety of Apitegromab in Patients with Later-Onset Spinal Muscular Atrophy (Type 2 and Type 3 SMA)
Clinical Drug Development Session:
About the Phase 2 TOPAZ Trial
The TOPAZ trial is an ongoing proof-of-concept, open-label phase 2 trial evaluating the safety and efficacy of apitegromab in patients with Types 2 and 3 SMA. In the main treatment period, patients were dosed intravenously every four weeks as monotherapy or with nusinersen, an approved SMN therapy. The trial enrolled 58 patients in the
About the Phase 3 SAPPHIRE Trial
SAPPHIRE is an ongoing randomized, double-blind, placebo-controlled, phase 3 clinical trial evaluating the safety and efficacy of apitegromab in non-ambulatory patients with Types 2 and 3 SMA who are receiving SMN therapy (either nusinersen or risdiplam). Approximately 156 patients aged 2-12 years old are anticipated to be enrolled in the main efficacy population. These 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. An exploratory population of approximately 48 patients aged 13-21 years old will also separately be evaluated. These patients will be randomized 2:1 to receive either apitegromab 20 mg/kg or placebo. 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. SAPPHIRE is expected to enroll 55 sites in the
Apitegromab is a selective inhibitor of the activation of myostatin and is an investigational product candidate for the treatment of patients with spinal muscular atrophy (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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