Sialic Acid may be a potential treatment for GNE myopathy
NE myopathy is a rare, debilitating myopathy
with devastating consequences for patients,
leading to many years of severe disability and
near quadriplegia. This neuromuscular disorder
is caused by mutations in the GNE gene coding
for a bifunctional enzyme called glucosamine
(UDP-N-acetyl)-2-epimerase/N-acetylmannosamine
kinase (GNE/MNK) (Eisenberg et al., 2001; Jay
et al., 2009). The GNE/MNK enzyme is the
rate-controlling and regulated first step in
the biosynthesis of sialic acid, which is
required for the glycosylation of proteins and
lipids. There are no approved treatments for
GNE myopathy.
Studies of uptake in vitro (Oetke et al., 2001; Bardor et al., 2005; Hinderlich et al., 2001) and correction of GNE/MNK deficiency in mouse models has shown that substrate replacement using sialic acid or its precursor ManNAc can have a substantial benefit on disease biochemistry, pathophysiology and disease course (Galeano et al., 2007; Malicdan et al., 2010). In particular, a study in the HIBM mouse model has shown that when sialic acid at 20 mg/kg was provided in the water to affected mice, a profound impact on preventing muscle pathology and clinical disease over a 52 week period was observed when compared to controls (Malicdan et al., 2009).
Sialic Acid is being investigated as a treatment option for GNE myopathy patients that may prevent and reverse disease pathology and adverse clinical outcomes by countering the underlying sialic acid deficiency state. Sialic acid (SA) was chosen as the active ingredient for this program, based on the successful data on the absorption and treatment effect in the relevant mouse model (Malicdan et al., 2009). Additionally, an extended release formulation of SA was developed (SA-ER) by Ultragenyx to provide a more sustained and stable supply of SA over a 24 hour period. The extended release formulation avoids surges in CMP-sialic acid levels associated with bolus doses and high peak levels that might feedback inhibit GNE/MNK expression or activity.
The Phase 2 clinical study UX001-CL201, a Phase 2 Randomized Double-Blind Placebo-Controlled Parallel Group Study to Evaluate the Dose and Pharmacodynamic Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets in Patients with GNE Myopathy or Hereditary Inclusion Body Myopathy (HIBM), is designed to determine if treatment with SA at either of two doses (3000 and 6000 mg/day) over a 24- or 48-week period can improve or restore sialylation biochemistry in GNE myopathy patients.
Studies of uptake in vitro (Oetke et al., 2001; Bardor et al., 2005; Hinderlich et al., 2001) and correction of GNE/MNK deficiency in mouse models has shown that substrate replacement using sialic acid or its precursor ManNAc can have a substantial benefit on disease biochemistry, pathophysiology and disease course (Galeano et al., 2007; Malicdan et al., 2010). In particular, a study in the HIBM mouse model has shown that when sialic acid at 20 mg/kg was provided in the water to affected mice, a profound impact on preventing muscle pathology and clinical disease over a 52 week period was observed when compared to controls (Malicdan et al., 2009).
Sialic Acid is being investigated as a treatment option for GNE myopathy patients that may prevent and reverse disease pathology and adverse clinical outcomes by countering the underlying sialic acid deficiency state. Sialic acid (SA) was chosen as the active ingredient for this program, based on the successful data on the absorption and treatment effect in the relevant mouse model (Malicdan et al., 2009). Additionally, an extended release formulation of SA was developed (SA-ER) by Ultragenyx to provide a more sustained and stable supply of SA over a 24 hour period. The extended release formulation avoids surges in CMP-sialic acid levels associated with bolus doses and high peak levels that might feedback inhibit GNE/MNK expression or activity.
The Phase 2 clinical study UX001-CL201, a Phase 2 Randomized Double-Blind Placebo-Controlled Parallel Group Study to Evaluate the Dose and Pharmacodynamic Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets in Patients with GNE Myopathy or Hereditary Inclusion Body Myopathy (HIBM), is designed to determine if treatment with SA at either of two doses (3000 and 6000 mg/day) over a 24- or 48-week period can improve or restore sialylation biochemistry in GNE myopathy patients.