Policy & Regulation
Scholar Rock Touts 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
6 April 2021 - - US-based biopharmaceutical company Scholar Rock (NASDAQ: SRRK) has released positive top-line data from the TOPAZ Phase 2 clinical trial evaluating apitegromab (SRK-015) in patients with Type 2 and Type 3 spinal muscular atrophy.

The TOPAZ Phase 2 proof-of-concept trial enrolled 58 patients with Type 2 and Type 3 SMA across 16 study sites in the United States and Europe.

The trial evaluated the safety and efficacy of intravenous apitegromab dosed every four weeks over a 12-month treatment period. Four patients (one in Cohort 2 and three in Cohort 3) each missed three consecutive doses of apitegromab over the course of the 12-month treatment period due to COVID-19-related site access restrictions and are excluded from the prespecified intent-to-treat primary analysis.

Cohort 1: This open-label, single-arm cohort enrolled 23 patients with ambulatory Type 3 SMA. Patients were treated with 20 mg/kg of apitegromab either as a monotherapy or in conjunction with an approved SMN upregulator therapy (nusinersen). 

The primary objectives of Cohort 1 were to assess safety and the mean change from baseline in RHS following 12 months of treatment.

In Cohort 1 (pooled population), the mean change from baseline in RHS score was a 0.3-point decline. The Cohort 1 efficacy data suggest a potential clinical effect of apitegromab in certain patients in this population, as 57% of patients observed a maintenance or improvement in RHS score (>0-point change from baseline) and 22% of patients achieved at least a 3-point increase in RHS score from baseline.

Cohort 2: This open-label, single-arm cohort enrolled 15 patients with Type 2 or non-ambulatory Type 3 SMA and who were already receiving treatment with an approved SMN upregulator (nusinersen) initiated at age five years or older. 

One patient missed three consecutive doses of apitegromab due to COVID-19-related site access restrictions and was excluded from the prespecified intent-to-treat primary analysis. The primary objectives of the cohort were to assess safety and the mean change from baseline in HFMSE following 12 months of treatment.

Cohort 2 efficacy data demonstrate improvement of motor function from baseline. The mean change from baseline in HFMSE score was a 0.6-point increase.

The majority of patients achieved at least a 1-point increase in HFMSE and 29% of patients achieved at least a 3-point increase in HFMSE from baseline. Potential durability of effect was observed up to 12 months of treatment.

One patient in Cohort 2 was identified as having received concomitant treatment with an acetylcholinesterase inhibitor before and during the study, which was not permitted by the trial protocol.

This patient experienced a seven-point decline in HFMSE score at the 12-month timepoint.

In the per protocol analysis conducted in accordance with the prespecified approach, which excludes this patient as well as the patient who missed three consecutive doses due to COVID-19-related site access restrictions, the mean change from baseline in HFMSE score for Cohort 2 was a 1.2-point improvement.

Cohort 3: This randomized, double-blind, parallel arm portion of the trial enrolled patients with Type 2 SMA who had initiated treatment with an approved SMN upregulator (nusinersen) before five years of age. Twenty patients were randomized in a 1: 1 ratio to receive the low dose (apitegromab 2 mg /kg Q4W) or high dose (apitegromab 20 mg/kg Q4W); both treatment arms were in conjunction with an approved SMN upregulator therapy (nusinersen). 

Three patients (two in high-dose arm and one in low-dose arm) each missed three consecutive doses of apitegromab due to COVID-19-related site access restrictions and were excluded from the prespecified intent-to-treat primary analysis.

The primary objectives of the cohort were to assess safety and the mean change from baseline in HFMSE following 12 months of treatment.

Cohort 3 efficacy data demonstrate further improvements in motor function relative to what was observed at the six-month interim analysis. The mean change from baseline in HFMSE score was a 7.1-point and a 5.3-point improvement for the 20 mg/kg and 2 mg/kg dose arms, respectively.

The majority of patients in Cohort 3 achieved at least a 5-point increase in HFMSE and 35% of patients achieved greater than a 10-point increase in HFMSE over baseline.

Dose response was observed; the 20 mg/kg dose achieved numerically greater mean improvements from baseline in HFMSE scores than the 2 mg/kg dose across all assessed timepoints in the 12-month treatment period.

The clinically observed dose response was consistent with the pharmacodynamic (target engagement) results. Both the 20 mg/kg and 2 mg/kg doses yielded high levels of target engagement (>100-fold increase from baseline), but the 20 mg/kg dose led to a relatively higher absolute level of target engagement.

Spinal muscular atrophy 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 the United States(1) and Europe(2). It is characterized by the loss of motor neurons, atrophy of the voluntary muscles of the limbs and trunk and progressive muscle weakness.

The underlying pathology of SMA is caused by insufficient production of the SMN (survival of motor neuron) protein, essential for the survival of motor neurons, and is encoded by two genes, SMN1 and SMN2(3).

While there has been progress in the development of therapeutics that address the underlying SMA genetic defect, there continues to be a high unmet need for therapeutics that directly address muscle atrophy.

Apitegromab (SRK-015) is a selective inhibitor of the activation of latent myostatin and is an investigational product candidate for the treatment of patients with spinal muscular atrophy.

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.

Scholar Rock said it believes the inhibition of the activation of latent myostatin with apitegromab may promote a clinically meaningful improvement in motor function.
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