Scholar Rock, a clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, announced an oral presentation of TOPAZ Phase 2 trial results by the lead principal investigator, Thomas Crawford, M.D. of Johns Hopkins Medicine. In the TOPAZ trial, treatment with apitegromab in conjunction with nusinersen in patients with Types 2 and 3 SMA led to meaningful motor function improvements of up to 20 points as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE). New exploratory analyses being presented further support apitegromab’s potential to improve motor function in patients with SMA.
SMA remains a devastating and debilitating disease despite the utilization of SMN upregulators that prevent further motor neuron deterioration. A muscle-directed approach such as apitegromab, a selective inhibitor of myostatin activation, has the potential to complement SMN upregulators and address motor function impairments in patients with SMA. Scholar Rock’s TOPAZ Phase 2 trial (NCT03921528) evaluated apitegromab across a broad age range (2-21 years) of patients with Type 2 and 3 SMA. Except for some ambulatory patients who received apitegromab as a monotherapy, patients enrolled in TOPAZ were receiving chronic maintenance doses of nusinersen. Both non-ambulatory cohorts had received more than 5.0 mean maintenance doses or approximately 2 years of treatment at baseline. Clinical data from the CHERISH and SHINE studies of nusinersen offer background insights into this patient population. These studies observed that nusinersen-treated patients primarily experienced stabilization or only slight increases in HFMSE scores beyond the initial 15-month treatment period. In addition, even in the initial 15-month treatment period, patients who initiated nusinersen treatment age ≥5 on average experienced declines in HFMSE and rarely attained a ≥3-point increase in HFMSE in a 12-month timeframe.
Results following 12-months of treatment with apitegromab added to background nusinersen therapy, in the TOPAZ trial, included:
- Majority (74%, 23/31) of non-ambulatory patients showed a clinical improvement (≥1-point increase) in Hammersmith Functional Motor Scale Expanded (HFMSE).
- In the non-ambulatory cohort of patients (mean age 3.8) on background nusinersen started earlier in life (<5 years of age), treatment with apitegromab 20 mg/kg led to sizeable increases in HFMSE.
- Mean increase from baseline was +7.1 points.
- 88% (7/8) of patients improved (attained a ≥1-point increase).
- 63% (5/8) of patients attained a ≥5-point increase.
- 38% (3/8) of patients attained a >10-point increase.
- Patients had received approximately two years of prior nusinersen treatment at the time of enrollment (5.4 mean maintenance doses) and were in the chronic maintenance phase of nusinersen therapy during the TOPAZ trial.
- In the non-ambulatory cohort of patients (mean age 11.7) on background nusinersen started later in life (≥5 years of age), treatment with apitegromab 20 mg/kg led to an increase in HFMSE, contrasting with declines experienced on average by this patient population without treatment.
- Mean increase from baseline was +0.6 points by intent-to-treat analysis and +1.2 points by per-protocol analysis.
- 64% (9/14) of patients improved (attained a ≥1-point increase).
- 29% (4/14) of patients attained a ≥3-point increase.
- Patients had received approximately two years of prior nusinersen treatment at the time of enrollment (5.1 mean maintenance doses) and were in the chronic maintenance phase of nusinersen therapy during the TOPAZ trial.
- A post-hoc analysis across all non-ambulatory patients showed no correlation between change in HFMSE score at 12 months and duration of prior nusinersen therapy, providing further evidence that improvements in motor function may be attributed to apitegromab.
- WHO Motor Development Milestones, a high bar assessment representing major functional achievements, were gained by seven of 35 non-ambulatory patients treated with apitegromab and nusinersen, including three patients who initiated background nusinersen therapy later in life (≥5 years of age).
- Five patients achieved one new WHO motor milestone, including one patient gaining the ability to walk independently and one patient gaining the ability to stand independently.
- One patient achieved two new WHO motor milestones (hands and knees crawling and standing with assistance).
- One patient achieved three new WHO motor milestones (hands and knees crawling, standing with assistance, and walking with assistance).
- The five most frequently reported treatment-emergent adverse events (AEs) included headache, pyrexia, upper respiratory tract infection, cough, and nasopharyngitis. Incidence and severity of AEs were consistent with the underlying patient population and background therapy.
- Data from additional exploratory endpoints are being analyzed and will be presented in the future, such as at medical and scientific conferences.
A randomized, double-blind, placebo-controlled Phase 3 trial is anticipated to initiate by the end of 2021 and is expected to evaluate apitegromab as an add-on to nusinersen or risdiplam in patients with non-ambulatory Type 2 and Type 3 SMA.