Nutritional Impacts of Palynziq on Patients With Phenylketonuria (PKU)

Palynziq and PKU: Treatment Impacts on Diet Quality, Neurological Health, Nutritional Status, and the Metabolome

Phenylketonuria (PKU) is an inherited metabolic disorder that impairs the metabolism of the essential amino acid phenylalanine (Phe). Without stringent dietary control, Phe accumulates in the blood and brain of PKU patients, leading to severe cognitive deficits. Achieving metabolic control, defined as blood Phe levels within the range of 120-360 μmol/L, has been a significant challenge for PKU patients using traditional diet therapy. The new FDA approved pharmacologic treatment, Palynziq, offers a new approach that could significantly reduce the burden of PKU by improving blood Phe levels and allowing for a less restrictive diet. As little is known about the global metabolic and physiologic effects of Palynziq, the present study aims to capture changes in diet quality, neurological health, nutritional status, the nutritional metabolome, and patient perceptions of mental and social health with sustained Palynziq therapy.

Study Overview

• Status: Recruiting
• Conditions: Phenylketonurias
• Intervention / Treatment: Drug: Palynziq

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 45

Contacts and Locations

• Study Contact: Name: Rani Singh, PhD, RDN, LD; Phone Number: 778-404-8519; Email: rsingh@emory.edu

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • The Emory Clinic
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University Hospital Georgia Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients who have been diagnosed with PKU

Description

Inclusion Criteria:

• 16 years of age or older
• diagnosed with PKU through newborn screening or via diagnosis later in life
• capable of providing consent for medical tests and procedures
• prescription for Palynziq and be enrolled in the Palynziq Risk Evaluation and Mitigation Strategy (REMS) program
• Substudy: Participants must have completed visit 2 of the main study

Exclusion Criteria:

• unable to provide consent
• a diagnosis of, or take medication for psychiatric, behavioral, or other inherited metabolic disorders

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Palynziq Therapy for PKU; Participants with PKU who are starting Palynziq therapy, or have recently started Palynziq therapy but have not achieved response.

Drug: Palynziq; Participants will take Palynziq as prescribed by their genetics doctor. In accordance with the Palynziq Risk Evaluation and Mitigation Strategy (REMS) protocol, patients will have their first injection of Palynziq at the Emory Genetics Clinic under the supervision of a physician. After initiating therapy, patients will continue to mail in blood spot filter papers and 3-day dietary records to their clinic providers as standard components of clinical care.; Other Names: Pegvaliase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intra-subject Change in Intact Protein Intake	Intra-subject change in intact protein intake will be assessed by participant-reported 3-day dietary records.	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Intra-subject Change in Medical Food Protein Intake	Intra-subject change in medical food protein intake will be assessed by participant-reported 3-day dietary records.	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Sub study: Intra-subject change in intact protein and medical food protein intake.	Intra-subject change in medical food protein intake will be assessed by participant-reported 3-day dietary records.	12 Months Post-Response through additional five years (6 years post-response)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Average Intact Protein Intake	Average intact protein intake will be determined by participant-reported 3-day dietary records.	Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)
Days From Palynziq Initiation to Response	The average length of time (in days) from Palynziq initiation until response, as defined by three consecutive plasma Phe levels lower than the upper limit of the recommended treatment range (<360 μmol/L) and a significant increase in intact protein intake (at least 60 percent of the dietary reference intake (DRI) or a two-fold increase from baseline diet prescription), will be determined.	Baseline up to Response (up to 60 days)
Days From Palynziq Initiation to Consumption of Dietary Reference Intake for Intact Protein	The average length of time (in days) from Palynziq initiation it takes for participants to consume the dietary reference intake for intact protein (46g females, 56g males).	Baseline up to 12 Months Post-Response (up to 14 months after baseline)
Change in Neuro-QOL - Cognitive Function - Short Form Score	The Neuro-QOL Cognitive Function Short Form includes 8 items asking participants about their cognition during the past 7 days. Responses to statements of if cognition problems are occurring are given on a scale from 1 to 5 where 1 = very often and 5 = never. The amount of difficulty experienced from daily life tasks are responded to on a scale from 1 to 5 as 1 = cannot do task and 5 = no difficulty. Scores are scaled to a T-score with a mean of 50 and a standard deviation of 10. Scores higher than 50 indicate that the respondent in experiencing more cognition problems than the average person.	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	The Neuro-QOL Sleep Disturbance Short Form includes 8 items asking participants about their sleep during the past 7 days. Responses to statements of if sleep problems are occurring are given on a scale from 1 to 5 where 1 = never and 5 = always. Scores are scaled to a T-score with a mean of 50 and a standard deviation of 10. Scores higher than 50 indicate that the respondent in experiencing more sleep problems than the average person.	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	The PROMIS Global Health instrument includes 10 items asking participants about their health and quality of life. Responses to items are given on a scale from 1 to 5 where 1 = poor and 5 = excellent. Scores are scaled to a T-score with a mean of 50 and a standard deviation of 10. Scores higher than 50 indicate that the respondent in experiencing greater quality of life than the average person.	Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)
Change in PROMIS-29 Anxiety and Depression Score	The PROMIS-29 instrument includes 8 items asking participants about anxiety and depression. Responses to are given on a scale from 1 to 5 where 1 = never and 5 = always. The total summed score from these items ranges from 8 to 40 and higher scores indicate greater anxiety and depression.	Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)
Change in PROMIS Emotional Support Score	The PROMIS Emotional Support instrument includes 16 items asking participants about forms of emotional support they have available. Responses to items are given on a scale from 1 to 5 where 1 = never and 5 = always. Raw scores are scaled to a T-score with a mean of 50 and a standard deviation of 10. Scores higher than 50 indicate that the respondent has greater emotional support than the average person.	Baseline, Response (up to 60 days) 12 Months Post-Response (up to 14 months after baseline)
Change in Plasma Neurotransmitters	Intra-subject change in neurotransmitter analysis will be assessed using fasting blood samples.	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Change in Plasma Amino Acids	Intra-subject change in plasma amino acids will be assessed using fasting blood samples.	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Change in Essential Fatty Acids	Intra-subject change in essential acids will be assessed using fasting blood samples.	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Intra-subject Change in Bone Mineral Density	Bone mineral density will be assessed with dual-energy x-ray absorptiometry (DEXA)	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Intra-subject Change in Percent Fat Body Mass	Percent fat body mass will be assessed with DEXA.	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Intra-subject Change in Percent Lean Body Mass	Percent lean body mass will be assessed with DEXA.	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Intra-subject Change in Resting Energy Expenditure	Resting energy expenditure (kilocalories/day) from Palynziq initiation through 12 months post-response will be assessed using indirect calorimetry and self-reported activity level.	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Intra-subject Change in Grip Strength	Muscle strength will be assessed using a dynamometer, which will measure grip strength on each hand.	Baseline through 12 Months Post-Response (up to 14 months after baseline)
Sub-Study: Change in Plasma Neurotransmitters	Intra-subject change in neurotransmitter analysis will be assessed using fasting blood samples.	12 Months Post-Response through additional five years (6 years post-response)
Sub-Study: Change in Neuro-QOL - Cognitive Function - Short Form Score	The Neuro-QOL Cognitive Function Short Form includes 8 items asking participants about their cognition during the past 7 days. Responses to statements of if cognition problems are occurring are given on a scale from 1 to 5 where 1 = very often and 5 = never. The amount of difficulty experienced from daily life tasks are responded to on a scale from 1 to 5 as 1 = cannot do task and 5 = no difficulty. Scores are scaled to a T-score with a mean of 50 and a standard deviation of 10. Scores higher than 50 indicate that the respondent in experiencing more cognition problems than the average person.	12 Months Post-Response through additional five years (6 years post-response)
Sub-Study: Change in Neuro-QOL Sleep Disturbance - Short Form Score	The Neuro-QOL Sleep Disturbance Short Form includes 8 items asking participants about their sleep during the past 7 days. Responses to statements of if sleep problems are occurring are given on a scale from 1 to 5 where 1 = never and 5 = always. Scores are scaled to a T-score with a mean of 50 and a standard deviation of 10. Scores higher than 50 indicate that the respondent in experiencing more sleep problems than the average person.	12 Months Post-Response through additional five years (6 years post-response)
Sub-Study: Change in The Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Score	The PROMIS Global Health instrument includes 10 items asking participants about their health and quality of life. Responses to items are given on a scale from 1 to 5 where 1 = poor and 5 = excellent. Scores are scaled to a T-score with a mean of 50 and a standard deviation of 10. Scores higher than 50 indicate that the respondent in experiencing greater quality of life than the average person.	12 Months Post-Response through additional five years (6 years post-response)
Sub-Study: Change in PROMIS-29 Anxiety and Depression Score	The PROMIS-29 instrument includes 8 items asking participants about anxiety and depression. Responses to are given on a scale from 1 to 5 where 1 = never and 5 = always. The total summed score from these items ranges from 8 to 40 and higher scores indicate greater anxiety and depression.	12 Months Post-Response through additional five years (6 years post-response)
Sub-Study: Change in PROMIS Emotional Support Score	The PROMIS Emotional Support instrument includes 16 items asking participants about forms of emotional support they have available. Responses to items are given on a scale from 1 to 5 where 1 = never and 5 = always. Raw scores are scaled to a T-score with a mean of 50 and a standard deviation of 10. Scores higher than 50 indicate that the respondent has greater emotional support than the average person.	12 Months Post-Response through additional five years (6 years post-response)

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: BioMarin Pharmaceutical
• Investigators: Principal Investigator: Rani Singh, PhD, RDN, LD, Emory University

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2019
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: May 21, 2020
• First Submitted That Met QC Criteria: May 26, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 3, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: IRB00111450

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO