Pharmacodynamics, safety, tolerability and pharmacokinetics of a single oral dose of an engineered phenylalanine ammonia-lyase in patients with phenylketonuria

• DOI: 10.1016/j.ymgmr.2023.101012
• Publication Date: 2023-09-26T21:58:23Z
• Authors: Timothy Nicholas ...; Louise Healy; Tim Heise; Anita Inwood; Catherine Manolikos; Yusof Rahman; Hans-Juergen Woerle; Christian J. Hend...
• Keywords: Phenylalanine ammonia-lyase; Tolerability; Hyperphenylalaninemia; Pharmacodynamics; Phenylketonurias

The cornerstone treatment of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) is a lifelong low-protein diet with phenylalanine (Phe) free L-amino acid supplements. However, the PKU has significant shortcomings, there clinically unmet need for new therapeutics to improve patient outcomes. CDX-6114 modified ammonia-lyase (PAL) enzyme obtained by mutation in Anabaena variabilis PAL sequence. CodeEvolver® protein engineering technology been applied degradation resistance enzyme. In our first phase I trial, 19 patients were given single oral dose at 7.5 g, 2.5 0.7 or placebo cross-over design. After an overnight fast, received standardised breakfast 20 g protein, thus exceeding dietary recommendations meal PKU. Plasma levels Phe cinnamic (CA) measured over 5-h period following dosing. During development CDX-6114, stability assessment using reverse-phase high-performance liquid chromatography (HPLC) assay revealed two peaks. second peak was identified as CA. It not previously known that part mechanism action, CA remained associated conversion Phe. Thus, recalculating historical amounts bulk substance necessary. An updated extinction coefficient achieved applying correction factor 0.771 reported doses. Postprandial plasma increased all cohorts time between 10% 30% from baseline, although actual within observation. When accounting interquartile ranges, these concentrations similar placebo. As no longer reliable marker pharmacodynamics, consistently detectable amount seen who provided proof enzymatic activity metabolising gastrointestinal Peak shortly after intake, rapid decline, low compared levels. This pattern indicates short half-life, possibly due formulation inability withstand lower pH human stomach animal models earlier studies. trial establish safety tolerability CDX-6114. A safe well tolerated, serious adverse events presence anti-drug antibodies detected. Efficacy will be explored future trials optimised formulation.