Ammonia control in children with urea cycle disorders (UCDs); Phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate

Abstract

Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). Study Design Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored. Results Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198–476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range = 192–449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24 h with occasional values >100 μmol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p ≥ 0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p = 0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN. Conclusions These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring.

Endoplasmic reticulum stress inhibition reduces hypertension through the preservation of resistance blood vessel structure and function

“…4-PBA is a low molecular weight chemical chaperone that is currently approved for clinical use in urea cycle disorders [50] and has been shown to inhibit endoplasmic reticulum stress [22,23]. The precise action of 4-PBA to dampen UPR marker expression, as shown in these reports, appears to be due to its ability to prevent protein aggregation and aid in the folding of proteins.…”

Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells

“…These data raise the possibility that small molecule chemical chaperones, such as those approved for treatment of urea cycle disorders, may be useful to prevent disease in patients with 16p13.1 duplications and possibly for other disease-causing genomic duplications in which increased expression of a gene leads to increased ER stress (60,61). Duplication of 16p13.1 is the most common genetic alteration associated with acute aortic dissections, and a specific therapy to prevent these deadly dissections would be beneficial for this at risk population.…”

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

“…Recently, the possible uses for 4-PBA as a therapeutic molecule have expanded significantly. Current findings suggest it has up to three pharmacological modes of action: it acts as an ammonia scavenger (Lichter-Konecki et al, 2011), a weak histone deacetylase inhibitor (HDACi) (Miller et al, 2011), and an endoplasmic reticulum (ER) stress inhibitor (Basseri et al, 2009a;Xiao et al, 2011;Yam et al, 2007) (Fig. 2).…”