SRK-015, Scholar Rock’s muscle-targeted therapy, safely and effectively improved motor function in children and young adults with spinal muscular atrophy (SMA) types 2 and 3, six-month interim data from a Phase 2 trial show.

These benefits were more pronounced with higher doses of SRK-015 and, not surprisingly, in those treated earlier in life. Top-line one-year data from the trial, which is expected between April and June 2021, will help assess the durability and extent of these motor function gains.

“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,” Thomas Crawford, MD, the trial’s lead investigator and a professor of neurology at the Johns Hopkins University School of Medicine, said in a press release.

“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 of Scholar Rock.

“We look forward to engaging with regulatory authorities regarding our registrational trial plans,” Chyung added.

SRK-015 is a monoclonal antibody that works by preventing the conversion of the precursor, or latent form, of myostatin — a growth factor mainly produced in skeletal muscle cells to suppress muscle growth — into its active form. By preventing the formation of myostatin’s active form instead of directly blocking its activity, SRK-015 is expected to cause fewer side effects than such conventional myostatin suppressors while still working to improve patients’ muscle strength and motor function.

As a muscle-directed therapy, SRK-015 is based on a different approach than the thus-far approved disease-modifying therapies for SMA. Those therapies — Biogen’s Spinraza, Novartis’ gene therapy Zolgensma, and Roche’s oral therapy Evrysdi — aim to restore the production of SMN, the protein missing in SMA patients, while SRK-015’s focus is on improving muscle strength.

“In the last few years, we’ve celebrated the remarkable success in treating SMA with SMN-upregulating approaches that stabilize against neurodegeneration,” Crawford said.

“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,” he said.

The ongoing, proof-of-concept Phase 2 trial (NCT03921528), known as TOPAZ, is evaluating SRK-015’s safety and effectiveness in 58 children and young adults, ages 2 to 21, with SMA types 2 and 3.

The participants, enrolled at multiple sites across the U.S. and Europe, were divided into three groups, in which all are receiving intravenous (into-the-vein) injections of SRK-015 every four weeks, for up to one year. Depending on the group, the participants receive a high or low dose of the medication.

Group one comprises 23 patients with SMA type 3 (mean age of 12.6 years; range 7–21 years) who are ambulatory, or able to walk unaided. Patients in this group are receiving SRK-015’s higher dose (20 mg/kg) either alone (11 patients), or in combination (12 patients) with Spinraza, the first disease-modifying therapy approved for SMA.

The second group includes 15 patients with SMA type 2 or type 3; the type 3 participants are unable to walk unaided. The individuals in this group — who have a mean age of 11.7 years, and a range of 8–19 years — also are being treated with the high dose of SRK-015, in addition to Spinraza. Spinraza was started after age 5 for each patient.

The 20 children in group three (mean age of about 4 years; range 2–6 years) have SMA type 2. These children were randomly assigned to receive either the therapy’s high or low (2 mg/kg) dose, in addition to Spinraza, initiated before age 5.

TOPAZ’s main goal is to determine if treatment with SRK-015 leads to clinically meaningful improvements in the participants’ motor function.

Such function will be assessed with the Revised Hammersmith Scale (RHS) in ambulatory patients and using the Hammersmith Functional Motor Scale Expanded (HFMSE) among those who are unable to walk unaided.  Higher scores in both scales indicate greater motor function. Increases of at least three points in Hammersmith scores are typically considered clinically meaningful.

Additional goals included assessing SRK-015’s safety and pharmacological properties.

Due to COVID-19-related site access restrictions, three patients — one in group two and two in group three — had missed three doses each of SRK-015 at the six-month mark, in addition to their six-month assessment. Their six-month timepoints were therefore not included in the pre-planned interim six-month analysis.

The interim data showed that treatment with SRK-015 increased Hammersmith scores in all three groups, with 67% of the total participants seeing their scores increase by at least one point, and 35% having their scores rise by three or more points.

An SRK-015 dose response was observed in group three across all evaluated timepoints, with SMA type 2 children given the high dose attaining a 5.6-point mean increase in the HFMSE score, compared with the 2.4-point mean improvement in the low-dose group. The therapy’s pharmacological properties also supported the observed dose response.

Notably, a substantial proportion of participants in each group achieved clinically meaningful motor function improvements: 17–36% of ambulatory SMA type 3 patients in group one; 21% of type 2 or non-ambulatory type 3 patients in group two; and 44–67% of children with type 2 disease who initiated Spinraza before age 5, who were in group three.

Similarly, a greater proportion of younger patients achieved a five-point or more increase in the Hammersmith scores than those of older age. Specifically, 33–56% of SMA type 2 children, up to age 6, had a five-point or greater score increase versus 9–14% of type 2 and 3 patients (older than 6 and up to 21 years).

In addition, HFMSE scores progressively increased over the six-month treatment period, suggesting that a plateau in motor function improvements had not yet been reached in the ongoing trial.

Interestingly, greater responses — both in terms of mean RHS change and in the proportion of patients responding — were seen among ambulatory SMA type 3 patients treated with SRK-015 alone, compared with those receiving SRK-015 in addition to Spinraza.

SRK-015 was generally well-tolerated, with no safety concerns identified and no severe or life-threatening adverse events reported. The most frequently reported adverse events were headache, upper respiratory tract infection, fever, common cold, and cough.

A serious adverse event (a viral upper respiratory infection) in one patient and trial discontinuation of another participant were both considered as unrelated to SRK-015 by the trial investigator.

The TOPAZ trial is expected to continue until early 2021.

SRK-015 has received orphan drug designation in the U.S. and in Europe, as well as rare pediatric disease designation in the U.S. These designations are meant to speed the therapy’s development and review by providing regulatory support and financial benefits, and also ensure marketing exclusivity for a period of time upon regulatory approval (seven years in the U.S. and 10 years in Europe), if granted.