Scholar Rock Announces Publication of Preclinical Data on the Therapeutic Benefit of Inhibiting Myostatin Activation in Models of Spinal Muscular Atrophy

December 3, 2018

CAMBRIDGE, Mass., Nov. 27, 2018 (GLOBE NEWSWIRE) — Scholar Rock Holding Corporation (NASDAQ: SRRK), a clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, today announced the publication, “Specific Inhibition of Myostatin Activation is Beneficial in Mouse Models of SMA Therapy” in the peer-reviewed journal Human Molecular Genetics. The publication details preclinical studies demonstrating that a highly specific inhibitor of myostatin activation effectively increased muscle mass and function in mouse models of Spinal Muscular Atrophy (SMA).  In addition, despite baseline serum levels of inactive latent myostatin being lower in the SMA mice than in mice without disease, successful target engagement was observed as evidenced by increased levels of latent myostatin in serum following treatment.  Together, the results support the potential for myostatin blockade as a therapeutic strategy to address motor functional deficits in SMA.

“Despite recent advances with the advent of SMN upregulator therapy, there remains significant unmet medical need to improve muscle function in patients with SMA,” said Nagesh Mahanthappa, Ph.D, President and CEO of Scholar Rock.  “These preclinical results highlight the therapeutic opportunity of inhibiting myostatin activation to address the muscle atrophy and weakness in SMA. We believe that SRK-015, currently in a Phase 1 trial of healthy volunteers, has the potential to be the first muscle-directed therapy for patients with SMA.”

The preclinical results published today in Human Molecular Genetics demonstrated that specific blockade of myostatin activation, in conjunction with SMN upregulator treatment, improved muscle mass and function in SMNΔ7 mouse models of SMA. Highlights from the study include:

  • In SMNΔ7 mouse models of SMA, dosage and timing of intervention with a small molecule SMN2 splice modulator were varied to modulate disease severity.

 

    • In the model with a relatively more severe SMA phenotype, mice received four weeks of treatment with muSRK-015P (the mouse analog of SRK-015) as well as optimal doses of the SMN upregulator that mimic the use of therapy to more fully restore SMN expression.  This led to a significant increase in muscle strength, as demonstrated by a 44%-51% increase in maximal torque of the plantarflexor muscle group, compared to control animals treated only with optimal doses of the SMN upregulator over the same treatment period.

 

    • In the model with a relatively less severe SMA phenotype, mice received four weeks of treatment with muSRK-015P, together with background therapy with optimal dosing of the SMN upregulator that was started shortly after birth.  This resulted in a 20%-30% increase in maximal torque of the plantarflexor muscle group, compared to control animals not treated with muSRK-015P.
  • Treatment of SMNΔ7 mice with muSRK-015P resulted in a multi-fold increase in serum levels of latent myostatin, which confirms the presence of the target in these models and successful target engagement from systemic administration of the antibody.

 

  • In addition, while the absolute level of serum latent myostatin was lower in the more severe SMA mouse group than in the normal control group, the levels were comparable when normalized to body weight or gastrocnemius muscle weight.  This finding suggests that the lower serum latent myostatin levels in the SMA group do not reflect reduced production or concentration of myostatin target in diseased skeletal muscle but may instead be attributable to reduced overall muscle mass.  This interpretation is supported by the observation that treatment with muSRK-015P resulted in an accumulation of latent myostatin to equivalent levels in both the earlier and later SMN intervention severity models.  Importantly, the relevance of myostatin as a target in this SMA preclinical model is demonstrated by the effects of muSRK-015 upon muscle mass and function.

The publication can be accessed at:  http://www.scholarrock.com/platform/publications/

Long, K., O’Shea, K., Khairallah, R., et al. Specific Inhibition of Myostatin Activation is Beneficial in Mouse Models of SMA Therapy. 2018. Human Molecular Genetics, ddy382