Nutritional Impacts of Palynziq on Patients With Phenylketonuria (PKU)

Phenylketonuria (PKU) is an autosomal recessive disorder caused by more than 500 pathogenic variants in the phenylalanine hydroxylase (PAH) gene. Due to these mutations, affected individuals have reduced activity or complete deficiency of the enzyme phenylalanine hydroxylase, which metabolizes the essential amino acid phenylalanine (Phe) to tyrosine. Consequently, Phe and its byproducts accumulate in the blood and brain of PKU patients, which can have irreparable physical and neurocognitive effects. These may include intellectual disabilities, seizures, eczema, psychosis, and hypopigmentation. To prevent these adverse conditions, early diagnosis and meticulous control of blood Phe levels are required. For optimal metabolic control, the American College of Medical Genetics (ACMG) recommends lifelong maintenance of Phe concentrations within the range of 120-360 μmol/L.

Diet therapy has dramatically improved metabolic control and nutritional status in PKU patients and when adherent to dietary treatment, numerous patients have been able to achieve normal growth and prevent severe cognitive deficits. This, however, is not an easy task given a steep restriction of intact protein is required to keep blood Phe levels within the therapeutic range. To meet nutritional needs in the absence of dietary protein, patients consume large volumes of Phe-free amino acid formulas (medical food) and specialized low-protein modified foods. While this regimen may improve overall diet quality, due to the fortification of formula with vitamins and minerals, the poor palatability and high cost medical food makes diet therapy a significant burden for patients and their families.

Pharmacologic therapies now provide an innovative approach to improve patient health and quality of life by liberalizing the traditional protein-restricted diet. Palynziq is a PEGylated recombinant of phenylalanine lyase, which can lower blood Phe concentrations. Given increasing numbers of PKU patients will be initiating Palynziq therapy, it is essential to prospectively evaluate the impact of this novel treatment on the neurological health, diet quality, and nutritional metabolome of patients when administered in a clinical setting. This knowledge will not only improve the efficacy of the treatment, but will be essential for expanding the current dietary guidelines to meet the unique needs of patients treated with Palynziq.

The objectives of this proposal are to obtain information on the diet quality, neurological health, and nutritional metabolome of patients with PKU at baseline and after intervention with Palynziq. This is a three-year observational study that includes non-pregnant adults who have PKU and have obtained a physician's prescription to initiate Palynziq treatment. Patients who complete the three year study are now eligible to participate in a sub-study which extends the main protocol for up to five years.

• Change in Average Intact Protein Intake [Time frame: Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)]
• Days From Palynziq Initiation to Response [Time frame: Baseline up to Response (up to 60 days)]
• Days From Palynziq Initiation to Consumption of Dietary Reference Intake for Intact Protein [Time frame: Baseline up to 12 Months Post-Response (up to 14 months after baseline)]
• Change in Neuro-QOL - Cognitive Function - Short Form Score [Time frame: Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)]
• Change in Neuro-QOL Sleep Disturbance - Short Form Score [Time frame: Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)]
• Change in The Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Score [Time frame: Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)]
• Change in PROMIS-29 Anxiety and Depression Score [Time frame: Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)]
• Change in PROMIS Emotional Support Score [Time frame: Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)]
• Change in Plasma Neurotransmitters [Time frame: Baseline through 12 Months Post-Response (up to 14 months after baseline)]
• Change in Plasma Amino Acids [Time frame: Baseline through 12 Months Post-Response (up to 14 months after baseline)]
• Change in Essential Fatty Acids [Time frame: Baseline through 12 Months Post-Response (up to 14 months after baseline)]
• Intra-subject Change in Bone Mineral Density [Time frame: Baseline through 12 Months Post-Response (up to 14 months after baseline)]