Improved attention linked to sustained phenylalanine reduction in adults with early-treated phenylketonuria.

Pegvaliase is approved to reduce phenylalanine (Phe) levels for people with phenylketonuria (PKU). PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) data were analyzed to evaluate the relationship between Phe and inattention in adult participants with PKU. In the modified-intent-to-treat population (N = 156), baseline mean (SE) plasma Phe was 1263 (29) µmol/L and the Attention Deficit Hyperactivity Disorder Rating Scale-IV Inattentive (IA) symptoms score was 9.8 (0.5). Mean (SE) IA scores fell 9.0 (1.1) in Quartile 1 (Phe reduction between 1166 and 2229 µmol/L) versus 4.3 (0.7) in Quartile 4 (Phe reduction of 139 µmol/L to increase of 934 µmol/L), p = 0.004. Least squares mean (SE) change from baseline IA score was -7.9 (0.7) for participants with final Phe ≤ 360 µmol/L and -4.5 (0.7) for final Phe > 360 µmol/L, p < 0.001. In the inattention subgroup, IA scores fell 13.3 (1.5) in Quartile 1 (Phe reduction between 1288 and 2229 µmol/L) versus 6.2 (1.3) in Quartile 4 (Phe reduction of 247 to increase of 934 µmol/L), p = 0.009. Inattention symptoms improved among those whose Phe levels decreased, particularly those with high baseline IA scores. IA improvements were larger among participants with the greatest plasma Phe reductions, supporting this value as a therapeutic goal.

Pharmacokinetic, pharmacodynamic, and immunogenic rationale for optimal dosing of pegvaliase, a PEGylated bacterial enzyme, in adult patients with phenylketonuria.

Phenylketonuria (PKU), a deficiency in the activity of the enzyme phenylalanine hydroxylase, leads to toxic levels of phenylalanine (Phe) in the blood and brain. Pegvaliase (recombinant Anabaena variabilis phenylalanine ammonia lyase conjugated with polyethylene glycol) is approved to manage PKU in patients aged greater than or equal to 18 years in the United States and in patients aged greater than or equal to 16 years in the European Union. Pharmacokinetic, pharmacodynamic, and immunogenicity results from five open-label pegvaliase trials were assessed. Studies with induction/titration/maintenance (I/T/M) dosing regimens demonstrated pharmacokinetic stabilization and sustained efficacy associated with maintenance doses (20, 40, or 60 mg/day). Immune-mediated pegvaliase clearance was high during induction/titration phases when the early immune response was peaking. The combination of low drug dosage and high drug clearance led to low drug exposure and minimal decreases in blood Phe levels during induction/titration. Higher drug exposure and substantial reductions in blood Phe levels were observed later in treatment as drug clearance was reduced due to the maturation of the immune response, which allowed for increased dosing to target levels. The incidence of hypersensitivity reactions was temporally associated with the peaking of the early antidrug immune response and decreased with time as immune response matured after the first 6 months of treatment. These results support an I/T/M dosing regimen and suggest a strategy for administration of other nonhuman biologics to achieve efficacy and improve tolerability.

Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial.

INTRODUCTION: Pegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU. METHODS: PRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study). The RDT, Part 2 of PRISM-2, was an 8-week trial that evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes in PRISM-2 participants who had achieved at least a 20% blood Phe reduction from pre-treatment baseline with pegvaliase treatment. Participants were randomized 2:1 to either continue pegvaliase (20 mg/day or 40 mg/day) or switch to matching placebo. RESULTS: The pooled pegvaliase group enrolled 66 participants and each placebo group enrolled 14 participants. The primary endpoint of change in blood Phe concentration from RDT entry to RDT Week 8 was met with clinically meaningful and statistically significant differences between the pegvaliase and placebo groups. Mean (SD) blood Phe at the beginning of the RDT when all participants were receiving pegvaliase was 563.9 µM (504.6) in the group assigned to the 20 mg/day placebo group (n = 14), 508.2 µM (363.7) in those assigned to the 40 mg/day placebo group (n = 14), and 503.9 µM (520.3) in those assigned to continue pegvaliase treatment (n = 58). At Week 8 of the RDT, the least squares mean change (95% confidence interval) in blood Phe was 949.8 µM (760.4 to 1139.1) for the 20 mg/day placebo group and 664.8 µM (465.5 to 864.1) for the 40 mg/day placebo group in comparison to 26.5 µM (-68.3 to 121.3) for the pooled (20 mg/day and 40 mg/day) pegvaliase group (P < 0.0001 for pooled pegvaliase group vs each placebo group). Adverse events (AEs) were usually lower in the pooled placebo group when compared to the pooled pegvaliase group. The most common AEs for the pooled pegvaliase and pooled placebo groups were arthralgia (13.6% and 10.3%, respectively), headache (12.1% and 24.1%), anxiety (10.6% and 6.9%), fatigue (10.6% and 10.3%), and upper respiratory tract infection (1.5% and 17.2%). CONCLUSION: Mean blood Phe reduction was sustained in the pegvaliase group, while placebo groups had mean blood Phe concentration increase toward pre-treatment baseline levels. Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants.

Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM).

BACKGROUND: Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU. METHODS: Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600 µmol/L were randomized 1:1 to a maintenance dose of 20 mg/day or 40 mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5 mg/day to 60 mg/day. RESULTS: Of 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12 months and ≥ 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) µmol/L at baseline, 564.5 (531.2) µmol/L at 12 months, and 311.4 (427) µmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24 months, 68.4% of participants achieved blood Phe ≤600 µmol/L, 60.7% of participants achieved blood Phe ≤360 µmol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120 µmol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6 months of exposure (early treatment phase) than after 6 months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae. CONCLUSION: Results from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment.

Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria.

This systematic review and meta-analysis (MA) investigates the impact of elevated blood phenylalanine (Phe) on neuropsychiatric symptoms in adults with phenylketonuria (PKU). The meta-analysis of PKU is challenging because high-quality evidence is lacking due to the limited number of affected individuals and few placebo-controlled, double-blind studies of adults with high and low blood Phe. Neuropsychiatric symptoms associated with PKU exceed general population estimates for inattention, hyperactivity, depression, and anxiety. High Phe is associated with an increased prevalence of neuropsychiatric symptoms and executive functioning deficits whereas low Phe is associated with improved neurological performance. Findings support lifelong maintenance of low blood Phe.

An Adaptation of the Profile of Mood States for Use in Adults With Phenylketonuria

Abstract Adults with phenylketonuria (PKU) experience disturbances in mood. This study used qualitative and quantitative techniques to adapt the 65-item Profile of Mood States (POMS) for the assessment of key mood domains in adults with PKU. First, cognitive interviews on 58 POMS items (excluding 7 Friendliness domain items) among 15 adults and adolescents (age ≥16 years) with PKU were conducted to eliminate items poorly understood or considered irrelevant to PKU; 17 items were removed. Next, the remaining POMS items were quantitatively examined (Mokken scaling and Rasch analysis) in 115 adult patients with PKU. An additional 21 items were removed iteratively, resulting in the 20-item draft PKU-POMS. Finally, the psychometric properties of the draft PKU-POMS were examined. The instrument displayed strong psychometric properties (reliability, validity, and responsiveness) over 6 domains (Anxiety, Depression, Anger, Activity, Tiredness, and Confusion) and all items were well understood in the final cognitive interviews with 10 adults with PKU.

Assessing the Content Validity of the Investigator-Rated ADHD Rating Scale Version IV Instrument Inattention Subscale for Use in Adults With Phenylketonuria

Abstract Content validity of the 18-item Investigator-Rated Attention-Deficit Hyperactivity Disorder (ADHD) Rating Scale IV (I-ADHD RS-IV) with adult prompts was investigated using qualitative interviews of US clinicians who had prior experience rating adults with phenylketonuria (PKU) using the I-ADHD RS-IV. Fourteen qualitative interviews were conducted to obtain key symptom experiences of adults with PKU and assessed the relevance, clarity, and administration of the I-ADHD RS-IV. Participants (n = 13, 92.9%) endorsed the inattention symptoms as key experiences by adults with PKU and endorsed the instrument as fit for purpose for adults with PKU. Participants generally reported low frequencies of occurrence for the 9 I-ADHD RS-IV hyperactivity/impulsivity items. Despite some clinicians' concerns for the lack of patient self-awareness, the participants reported no difficulty selecting a rating on these items. This in-depth study of the content validity of the I-ADHD RS-IV provides evidence that this clinician-reported instrument captures the severity of important inattention symptoms in adults with PKU.

Evaluation of Neuropsychiatric Function in Phenylketonuria: Psychometric Properties of the ADHD Rating Scale-IV and Adult ADHD Self-Report Scale Inattention Subscale in Phenylketonuria.

BACKGROUND: Previous qualitative research among adults and parents of children with phenylketonuria (PKU) has identified inattention as an important psychiatric aspect of this condition. The parent-reported ADHD Rating Scale-IV (ADHD RS-IV) and the Adult ADHD Self-Report Scale (ASRS) have been validated for measuring inattention symptoms in persons with attention-deficit/hyperactivity disorder (ADHD); however, their psychometric attributes for measuring PKU-related inattention have not been established. OBJECTIVE: The primary objective of this investigation was to demonstrate the reliability, validity, and responsiveness of the ADHD RS-IV and ASRS inattention symptoms subscales in a randomized controlled trial of patients with PKU aged 8 years or older. METHODS: A post hoc analysis investigated the psychometric properties (Rasch model fit, reliability, construct validity, and responsiveness) of the ADHD RS-IV and ASRS inattention subscales using data from a phase 3b, double-blind, placebo-controlled clinical trial in those with PKU aged 8 years or older. RESULTS: The Rasch results revealed good model fit, and reliability analyses revealed strong internal consistency reliability (α ≥ 0.87) and reproducibility (intraclass correlation coefficient ≥ 0.87) for both measures. Both inattention measures demonstrated the ability to discriminate between known groups (P < 0.001) created by the Clinical Global Impression-Severity scale. Correlations between the ADHD RS-IV and the ASRS with the Clinical Global Impression-Severity scale and the age-appropriate Behavior Rating Inventory of Executive Function Working Memory subscale were consistently moderate to strong (r ≥ 0.56). Similarly, results of the change score correlations were of moderate magnitude (r ≥ 0.43) for both measures when compared with changes over time in Behavior Rating Inventory of Executive Function Working Memory subscales. CONCLUSIONS: These findings of reliability, validity, and responsiveness of both the ADHD RS-IV and the ASRS inattention scales, in addition to content validation results, support their use for the assessment of inattention symptoms among persons with PKU aged 8 years or older in both clinical and research settings.

A prospective population pharmacokinetic analysis of sapropterin dihydrochloride in infants and young children with phenylketonuria.

BACKGROUND AND OBJECTIVES: Untreated phenylketonuria (PKU), a hereditary metabolic disorder caused by a genetic mutation in phenylalanine hydroxylase (PAH), is characterized by elevated blood phenylalanine (Phe) and severe neurologic disease. Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance. The objective of this study was to determine the appropriate dose of sapropterin in pediatric patients (0-6 years). The study design used D-optimization and was prospectively powered to achieve precise estimates of clearance and volume of distribution. METHODS: Oral sapropterin (5 or 20 mg/kg) was administered once daily. Sapropterin plasma concentrations were measured by a validated method. Population pharmacokinetic analysis was performed with NONMEM(®) version 7.2 on pooled data from 156 pediatric and adult PKU patients in two phase III clinical studies. RESULTS: The best pharmacokinetic model was a one-compartment model with an absorption lag, first-order input, and linear elimination, with a factor describing endogenous BH4 levels. Body weight was the only covariate significantly affecting sapropterin pharmacokinetics. Based on recommended dosing, exposure across age groups was comparable. The absorption rate and terminal half-life suggest flip-flop pharmacokinetic behavior where absorption is rate limiting. CONCLUSION: The effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate. The doses selected for pediatric patients provided similar exposure as in adults. Given the slow absorption and elimination half-life, once-daily dosing is justified.

Safety and efficacy of insulin detemir basal-bolus therapy in type 1 diabetes patients: 14-week data from the European cohort of the PREDICTIVE study.

OBJECTIVE: PREDICTIVE is a multi-national, prospective, observational study, assessing the safety and efficacy of insulin detemir in patients with diabetes. RESEARCH DESIGN AND METHODS: The European cohort includes 20,531 patients with diabetes (7420 type 1) from 11 countries. A subgroup of 4782 type 1 patients were transferred from a basal-bolus regimen with NPH insulin (n = 3117) or insulin glargine (n = 1665) to insulin detemir basal-bolus therapy; or from a human insulin basal-bolus regimen (n = 570) to insulin detemir/insulin aspart (part of the pre-study NPH group). Mean follow-up was 14.4 weeks. The primary endpoint was serious adverse drug reactions (SADRs), including major hypoglycaemia. Secondary endpoints were: incidence of overall and nocturnal hypoglycaemia; haemoglobin A(1c) (HbA(1c)); fasting glucose; within-patient fasting glucose variability; and change in body weight. RESULTS: SADRs were reported by 62 (2.0%) patients previously receiving NPH insulin, 45 (2.7%) patients previously receiving insulin glargine and seven (1.2%) patients previously receiving human basal-bolus insulins. Major hypoglycaemia was significantly reduced in NPH insulin (55%), insulin glargine (51%), and human basal-bolus insulin groups (54%; p < 0.0001 for all). Total and nocturnal hypoglycaemic episodes were also significantly reduced in all groups (p < 0.0001 for all). HbA(1c) was reduced in patients previously receiving NPH insulin (0.5%), insulin glargine (0.4%), and human basal-bolus insulins (0.6%; p < 0.0001 for all). Mean fasting glucose and within-patient fasting glucose variability significantly decreased in all patients (p < 0.0001 for all). Body weight remained stable. CONCLUSIONS: In this open-label, prospective, observational study, insulin detemir basal-bolus therapy improved glycaemic control and reduced hypoglycaemia with weight neutrality in type 1 patients in actual clinical practice.