SRK-015 Shows Positive Proof-of-Concept in Spinal Muscular Atrophy


The 12-month results from the phase 2 TOPAZ clinical trial are anticipated by the second quarter of 2021, according to Scholar Rock.

Thomas Crawford, MD, professor of neurology, Johns Hopkins University School of Medicine

Thomas Crawford, MD

Scholar Rock has announced that its phase 2 TOPAZ clinical trial (NCT03921528) of SRK-015, an investigational agent for the treatment of patients with type 2 and type 3 spinal muscular atrophy (SMA), has achieved positive 6-month interim results across all 3 cohorts assessed.1

In addition to the primary end point of the study, measured as change in Hammersmith scale scores (Hammersmith Functional Motor Scale-Expanded [HFMSE] in non-ambulatory patients and the Revised Hammersmith Scale [RHS] in ambulatory patients), reporting improvement in all 3 groups, a dose-response was observed at all time points evaluated during the double-blind, randomized portion of the trial.

The top-line data from the 12-month treatment period are anticipated in the second quarter of 2021. As of October 23, 2020, 100% of patients (n = 39) who had completed the 12-month treatment period opted into the extension period.

“These interim results are important because they demonstrate the potential of this muscle-directed approach to improve motor function of individuals with Type 2 and Type 3 SMA,” said lead investigator Thomas Crawford, MD, professor of neurology, Johns Hopkins University School of Medicine, in a statement. “In the last few years, we’ve celebrated the remarkable success in treating SMA with SMN-upregulating approaches that stabilize against neurodegeneration. These findings highlight the potential for a whole new approach to SMA therapy, used in conjunction with the SMN-enhancing therapies, to address the persistent and significant unmet needs of individuals weakened by SMA.”

SRK-015 is a highly selective inhibitor of the activation of latent myostatin. TOPAZ included 58 patients with types 2 and 3 SMA across 16 sites in the United States and Europe, with patients split into 3 cohorts. This interim analysis was pre-planned for all 3 cohorts, though 3 patients (Cohort 2, n = 1; Cohort 3, n = 2) missed 3 doses and the 6-month timepoint due to COVID-19 site access restrictions and thus were not included in the analysis.

READ MORE: Why an Inclusive Patient Population Is Important for the Future of DMD Treatment

Cohort 1 was an open-label, single-arm group and included 23 patients with ambulatory type 3 SMA treated with 20 mg/kg dose every 4 weeks as either monotherapy or with nusinersen (Spinraza; Biogen). Cohort 2 was also open-label and single arm and included 15 patients with either type 2 or nonambulatory type 3 SMA who were already receiving SMA therapy and were treated with 20 mg/kg dose every 4 weeks. Cohort 3—the randomized, double-blind portion of the trial—included 20 patients with type 2 SMA who had begun treatment with nusinersen prior to age 5 years. They were randomized to either the high dose (20 mg/kg) or low dose (2 mg/kg) every 4 weeks.

The high-dose arm (n = 9; mean age at baseline, 3.8 years) of Cohort 3 achieved a mean 5.6-point (95% CI, 2.5–8.7) improvement from baseline in the HFMSE, while the low-dose arm (n = 9; mean age at baseline, 4.1 years) attained a mean 2.4-point (95% CI, –0.9 to 5.8) improvement at the 6-month interim analysis time point. At baseline, the high-dose arm had a mean HFMSE score of 23.5 (range, 14–42) and the low-dose arm had a mean HFMSE score of 26.1 (range, 12–44).

The proportion of patients in the high-dose and low-dose Cohort 3 arms to achieve a ≥1-point increase in HFMSE score was 100% (n = 9) and 67% (n = 6), respectively. The proportion of patients in the high-dose arm to achieve a ≥3-point and ≥5-point improvement was 67% (n = 6) and 56% (n = 5), respectively, with the low-dose arm reporting proportions of 44% (n = 4) and 33% (n = 3), respectively.

“This is an exciting and important step towards establishing SRK-015 as the potential first muscle-directed therapy for patients with SMA, while also providing important validation of our scientific approach of targeting the latent forms of growth factors,” said Yung Chyung, MD, Chief Medical Officer, Scholar Rock, in a statement. “These interim data support the continuation of the TOPAZ trial and we look forward to engaging with regulatory authorities regarding our registrational trial plans.”

There were no safety signals noted from this interim analysis, with the incidence and severity of adverse events (AEs) remaining consistent with the underlying patient population and background therapy. There were no severe AEs reported, and only 1 patient in Cohort 1 reported a serious AE (grade 2 viral upper respiratory infection), though it resolved and was unrelated to SRK-015. Another patient in Cohort 1 discontinued due to muscle fatigue which was also deemed unrelated to the study drug. The most frequently reported AEs were headache, upper respiratory tract infection, pyrexia, nasopharyngitis, and cough.

Previously, early-phase data suggest that the investigational agent has sustained and robust target engagement. Pharmacokinetic data revealed that drug exposure was dose-proportional and SRK-015’s serum half-life was 23 to 33 days across the different dose cohorts. The pharmacokinetic profile displayed by SRK-015 was consistent with what is regularly observed for monoclonal antibodies.2

1. Scholar Rock Announces Positive Proof-of-Concept Data from TOPAZ Phase 2 Trial Interim Analysis of SRK-015 in Patients with Type 2 and Type 3 Spinal Muscular Atrophy. News release. Scholar Rock. October 27, 2020. Accessed November 2, 2020.
2. Scholar Rock Announces Positive Final Results from Phase 1 Clinical Trial of SRK-015 in Healthy Volunteers. News release. Scholar Rock. June 5, 2019. Accessed November 2, 2020.
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