Search

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

Consumer and community engagement (CCE) in the implementation of genomics into health services and associated research is needed to ensure that changes benefit the affected patients. Queensland Genomics was a program to implement genomics into a public health service. We describe its Community Advisory Group’s (CAG) structure and function and provide recommendations based on the CAG members’ perspectives. The CAG provided advice to the Queensland Genomics program and its projects in an advisory capacity. The CAG was also resourced to develop and lead community-focused activities. Key enablers for CAG included; diversity of CAG members’ skills and experience, adequate resourcing, and the CAG’s ability to self-determine their direction. The CAG experienced limitations due to a lack of mechanisms to implement CCE in the Program’s projects. Here, we provide insights and commentary on this CAG, which will be useful for other initiatives seeking to undertake CCE in genomic research and health care.

Health Interpreters enable effective communication between health practitioners and patients with limited knowledge of the predominant language. This study developed and evaluated a training session introducing Health Interpreters to genetics. The online training was delivered multiple times as a single 2-h session comprising lectures and activities. Participants completed questionnaires (pre-, post-, and 6-months follow-up) to assess the impact of training on knowledge, attitude, self-efficacy, and self-reported practice behaviour. Questionnaires were analysed using descriptive statistics, Fisher’s Exact, or independent t-test. In total, 118 interpreters participated in the training sessions. Respondent knowledge improved, with gains maintained at 6-months (p < 0.01). There were no changes in self-efficacy, and attitudes. Training did not change self-reported practice behaviour, but there was notable pre-existing variability in participants’ methods of managing unknown genetic words. Most respondents agreed that training was useful (93%) and relevant (79%) to their work. More respondents reported learning more from the case study activity (86%) than the group activity (58%). Health Interpreters found the training acceptable and demonstrated sustained improvement in knowledge of genetic concepts. Increased delivery of this training and associated research is needed to assess findings in a larger cohort and to measure the impact on patients.