Those findings were shared in two poster presentations during the SMA Europe 2nd International Scientific Congress in Paris-Evry, France.
SRK-015 is an investigational treatment designed to improve muscle strength and motor function in people with SMA. The therapy works by specifically inhibiting the precursor, or latent, form of myostatin, a growth factor produced primarily in skeletal muscle cells that suppresses muscle growth.
“We are pleased to be presenting preclinical and clinical data for SRK-015 at the SMA Europe Congress as we continue to advance the development of SRK-015 towards a goal of improving motor function in patients with SMA,” said Yung Chyung, MD, chief medical officer of Scholar Rock.
Since SRK-015 targets the latent, or pre-active, form of myostatin and not its active form, researchers believe it has fewer undesirable side effects than conventional, non-selective inhibitors.
The Phase 2 TOPAZ trial (NCT03921528) involves 58 patients, ages 2 to 21, taking part at 19 sites in the U.S. and Europe.
The company, in “A Phase 2 Study to Evaluate the Efficacy and Safety of SRK-015 in Patients with Later-Onset Spinal Muscular Atrophy (TOPAZ): An Introduction,” presented proof-of-concept trial details as well as preliminary pharmacokinetic (PK) — essentially how the body works with a medicine — and pharmacodynamic (PD) – the interactions between the body and a compound — data.
Participants were divided into three groups: Individuals with SMA type 3 who are ambulatory, or able to walk (23 patients with a mean age of 12.7), some of whom are receiving an approved SMA treatment and some of whom are not; patients with SMA type 2 or those with SMA type 3 who are not able to walk (15 patients with a mean age of 11.8) who started receiving treatment after turning 5; and patients with SMA type 2 (20 patients, with a mean age of 4 years) who started receiving treatment before age 5.
The main goal of the study was to determine if treatment with SRK-015 leads to clinically meaningful outcomes in patients’ motor function, as measured by the functional scales Revised Hammersmith Scale (RHS) and the Hammersmith Functional Motor Scale Expanded (HFMSE). The HFMSE assesses 13 clinically relevant items from the Gross Motor Function Measure (GMFM) related to lying/rolling, crawling, crawling/kneeling, standing, and walking/running/jumping. Scores range from 0 to 66, with lower scores indicating poorer motor function.
Researchers also assessed changes in the six- minute walk test (6MWT), which measures exercise capacity and is used to assess motor function in SMA.
At the time of enrollment, the mean HFMSE score of the second group — those with type 2 or non-ambulatory type 3 SMA — was 22.5 (assessed in 12 patients), and for the third group — those with type 2 SMA and a mean age of 4 — the score was 24.8 (assessed in 16 patients). In the group with ambulatory type 3 SMA, the RHS score was 47.4 (10 patients).
All participants will receive treatment for up to one year. The treatment period will be followed by an extension period of 52 weeks and a follow-up period of 12 weeks.
Preliminary analysis for SRK-015’s PK and PD profile included data from 29 participants from all three groups.
As of the data cut-off (November 2019), each of the 29 participants had received one dose of the medication, followed by a monitoring period of four weeks.
Preliminary PD data show SRK-015 interacts with its target, the latent form myostatin, increasing its levels in a dose-dependent manner in participants’ blood up to 100 times.
Preliminary PK data show that the increase in the levels of latent myostatin in the first four weeks following the administration of SRK-015 were comparable between SMA patients in the trial and healthy adult volunteers participating in a previous Phase 1 trial.
No new safety concerns were identified or reported during the preliminary PK/PD analysis period.
“An early look” at SRK-015’s potential is likely in the middle of this year, when TOPAZ Phase 2 interim safety and efficacy results are expected, Chyung said.
Scholar Rock also presented preclinical data on muSRK-015P, the mouse version of SRK-015, in a study, “Clinical Development of SRK-015, a Fully Human Anti-proMyostatin Monoclonal Antibody, for the Treatment of Later-Onset Spinal Muscular Atrophy.
Treatment with muSRK-015P improved muscle strength and increased the force applied by foot and leg muscles (plantar flexors) by 20%–51%. Treatment also led to a greater proportion of muscle fibers, compared with placebo, in mouse models of early and late restoration of survival motor neuron (SMN), the missing protein in those with SMA.
This was accompanied by a rise in blood levels of latent myostatin following treatment, which was also observed in different animal models, including rats and cynomolgus monkeys following administration of SRK-015. No differences were seen with placebo.
The treatment’s favorable pharmacological profile was also maintained across the different animal models.
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