Urea cycle disorders (UCDs) are a group of rare inherited
metabolic diseases caused by a deficiency of one of the
enzymes or transporters that constitute the
urea cycle. Defects in these
enzymes lead to acute accumulation (hyperammonemic crises, HAC) or chronically elevated levels (
hyperammonemia) of
ammonia in the blood and/or various tissues including the brain, which can cause persistent neurological deficits, irreversible brain damage,
coma, and death. Ongoing treatment of UCDs include the use of
nitrogen-scavenging agents, such as
sodium phenylbutyrate (
salt of 4-phenylbutyric
acid; NaPBA) or
glycerol phenylbutyrate (GPB). These treatments provide an alternative pathway for
nitrogen disposal through the urinary excretion of
phenylacetylglutamine. ACER-001 is a novel formulation of NaPBA with
polymer coated pellets in
suspension, which is designed to briefly mask the unpleasant bitter taste of NaPBA and is being developed as a treatment option for patients with UCDs. Four Phase 1 studies were conducted to characterize the bioavailability (BA) and/or bioequivalence (BE) of ACER-001 (in healthy volunteers) and taste assessment relative to NaPBA
powder (in taste panelists). ACER-001 was shown to be bioequivalent to NaPBA
powder under both fed and fasting conditions. Lower systemic exposure of
phenylacetate (PAA) and phenylbutyrate (PBA) was observed when ACER-001 was administered with a high-fat meal relative to a fasting state suggesting that the lower doses of PBA administered under fasting conditions may yield similar efficacy with potentially fewer dose dependent adverse effects relative to higher doses with a meal. ACER-001 appeared to be adequately taste-masked, staying below the aversive taste threshold for the first 3 min after the formulation was prepared and remaining palatable when taken within 5 min.