SRK-015 Increases Myostatin Growth Factor Levels Up to 100-fold in SMA Patients, Early Trial Data Shows

SRK-015, an investigational treatment designed to improve muscle strength and motor function in people with spinal muscular atrophy (SMA), interacts with its intended target in a dose-dependent manner, increasing by up to 100-fold the levels of latent myostatin in the blood, according to preliminary data from a Phase 2 trial.

Developed by Scholar Rock, SRK-015 is a highly selective inhibitor of the precursor, or latent form, of myostatin, a growth factor produced primarily in skeletal muscle cells to suppress muscle growth.

Since the therapy targets the latent, or pre-active form of myostatin and not its active form, researchers expect SRK-015 to cause fewer undesirable side effects than conventional, non-selective inhibitors.

The efficacy and safety of this experimental treatment is currently being tested in a proof-of-concept, Phase 2 trial called TOPAZ (NCT03921528).

The study is currently ongoing and is still recruiting patients at several sites across the U.S. and Europe. Scholar Rock is planning to enroll up to 55 children and adults with SMA type 2 and 3. The trial is expected to conclude in April 2021.

Once enrolled, participants are divided into three groups: individuals with SMA type 3; patients with SMA type 2 and those with SMA type 3 who are not able to walk without assistance; and patients with SMA type 2.

Participants placed in the first two groups will receive intravenous (through the vein) infusions of SRK-015 at a dose of 20 mg/kg every four weeks. Meanwhile, those in the third group will receive intravenous infusions of the medication at a dose of 20 mg/kg or 2 mg/kg every four weeks. All participants will receive treatment for up to one year.

The study’s main goal is to determine if treatment with SRK-015 leads to clinically meaningful improvements in patients’ motor function. This will be assessed by several functional scales, including the Revised Hammersmith Scale (RHS) and the Hammersmith Functional Motor Scale Expanded (HFMSE).

Additional study goals include evaluating the treatment’s safety and the pharmacokinetic (PK) and pharmacodynamic (PD) properties of SRK-015. PK and PD essentially refer to the interactions between the body and a specific compound. These interactions are analyzed to understand how a medication is absorbed, distributed, metabolized, and then eliminated from the body.

Scholar Rock now has announced preliminary data from a planned analysis of TOPAZ that focused on evaluating the PK/PD properties of SRK-015 in a sub-group of 29 participants from all three groups. These participants included 12 from group 1, eight from group 2, and nine from group 3.

As of the data cut-off, all 29 participants had already received one dose of the medication, followed by a monitoring period of four weeks.

The findings confirmed that SRK-015 interacted with its intended target, the latent form myostatin, increasing its levels in participants’ serum up to 100-times.

This increase in the levels of latent myostatin — in the four weeks following the administration of SRK-015 — was similar to that seen in a group of healthy volunteers participating in a previous Phase 1 trial.

When administered to people with SMA, SRK-015 showed dose-proportional drug exposure, meaning that the medication was eliminated from the body at a constant pace. This also was consistent with data from healthy adults.

No new safety concerns were identified or reported during this preliminary PK/PD analysis.

“We are pleased with the progress we have made to date towards our goal of developing SRK-015 as a muscle-directed therapy to address the functional deficits that remain a significant unmet need for patients with SMA despite advancements with SMN upregulators,” Yung Chyung, MD, Scholar Rock’s chief medical officer, said in a press release.

“These preliminary PK/PD results positively address two important questions for the program by both confirming the presence of latent myostatin in patients with SMA and further corroborating the ability of SRK-015 to engage this drug target, including in pediatric patients with SMA,” Chyung added.

“These results represent a key milestone for Scholar Rock by showing that we can indeed bring together cutting-edge monoclonal antibody technology with deep structural biology insights to target latent forms of growth factors in the context of human disease,” said Nagesh Mahanthappa, PhD, president and CEO of Scholar Rock.

“We look forward to building upon these insights as we advance a growing portfolio of product candidates,” Mahanthappa said.

Scholar Rock is planning to announce new findings during the first half of 2020 from another interim analysis. That will include data from patients who have been exposed to SRK-015 for at least six months. Top-line data from the full 12-month treatment period should be available by late 2020 and the beginning of 2021.