Index of sustained Phe response and improvements in PKU clinical outcome assessments in patients receiving pegvaliase
Biochemical/Metabolic and Therapeutics
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Secondary Categories:
Introduction:
Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of the enzyme phenylalanine hydroxylase, which results in phenylalanine (Phe) accumulation in the blood and brain leading to neurocognitive deficits and executive function impairment. Pegvaliase is approved as an enzyme-substitution therapy for adults (US), or patients aged ≥16 years (EU) with PKU and uncontrolled blood Phe >600 μmol/L on existing management. Longitudinal blood Phe measures and temporal patterns of response to pegvaliase are variable, complicating the evaluation and interpretation of the relationship of Phe response to pegvaliase with clinical outcomes. However, patient-level Phe responses to pegvaliase can be expressed in terms of achieving and remaining below threshold values representing a sustained Phe response (SPR). This secondary analysis of data from the PRISM phase 3 clinical trials examined the relationship between SPR and symptoms of impaired attention and mood disturbance, as assessed using the Attention Deficit Hyperactivity Disorder Rating Scale-IV Inattention (ADHD RS-IV IA) subscale and the PKU Profile of Mood States Total Mood Disturbance (PKU-POMS TMD) self-reported score.
Methods:
The longitudinal pattern of serial Phe measures for each patient, expressed as the expected value of Phe at time t (Phet; days since baseline), was estimated with a generalized additive model smoother function. A 95% confidence interval (CI) for Phet reflects the range of plausible values for estimated Phet given the number of temporally proximal Phe measures and their variability. SPR was defined as when the upper 95% CI of the longitudinally modeled pattern in estimated mean Phet remains below specific Phe thresholds: ≤600 µmol/L (SPR600), ≤360 µmol/L (SPR360), or ≤120 µmol/L (SPR120). A Bayesian multilevel ordinal regression model, conditioning on patient with varying intercepts and varying effects, estimated the monotonic effects of SPR, fitted as a 4-level ordinal predictor (No SPR vs. SPR600, SPR360, and SPR120), on estimated ADHD RS-IV IA and PKU-POMS TMD scores.
Results:
Patients with baseline ADHD RS-IV IA score >9 (n=91), indicating the presence of inattention likely to impede daily functioning in adults with PKU, were included in a regression model with the ordinal predictor for SPR to estimate conditional outcomes. Estimated ADHD RS-IV IA score showed consistent improvement with lower SPR thresholds (Bayesian posterior probability (BPPr)> 0 = 0.99). Estimated ADHD RS-IV IA score (95% Bayesian credibility intervals) when SPR was not achieved was 9.6 (8.6, 10.8) compared with 7.3 (6.4, 8.4) for SPR600, 6.9 (6.0, 8.0) for SPR360, and 5.5 (4.5, 6.6) for SPR120. Similar patterns were observed in models including the overall population without restriction on baseline score and for ADHD RS-IV total score. Models for PKU-POMS TMD score included patients with baseline scores greater than the median (>14; n=69) and similarly showed a consistent improvement with lower SPR thresholds (BPPr >0.99): Estimated PKU-POMS TMD score when SPR was not achieved was 28.3 (25.8, 30.9) compared with 25.2 (22.6, 28.1) for SPR600, 24.6 (22.1, 27.5) for SPR360, and 22.1 (19.2, 25.3) for SPR120.
Conclusion:
ADHD RS-IV IA and PKU-POMS TMD scores improved with the achievement of lower blood Phe levels, expressed as an index of sustained Phe response. ADHD RS-IV IA and PKU-POMS TMD scores at sustained Phe levels ≤120 µmol/L were significantly better than those at sustained Phe levels of ≤600 µmol/L or ≤360 µmol/L, adding to the body of evidence that current recommended blood Phe targets of 120-360 µmol/L may not be sufficient for optimal patient outcomes and that patients may benefit from normalizing Phe levels.
Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of the enzyme phenylalanine hydroxylase, which results in phenylalanine (Phe) accumulation in the blood and brain leading to neurocognitive deficits and executive function impairment. Pegvaliase is approved as an enzyme-substitution therapy for adults (US), or patients aged ≥16 years (EU) with PKU and uncontrolled blood Phe >600 μmol/L on existing management. Longitudinal blood Phe measures and temporal patterns of response to pegvaliase are variable, complicating the evaluation and interpretation of the relationship of Phe response to pegvaliase with clinical outcomes. However, patient-level Phe responses to pegvaliase can be expressed in terms of achieving and remaining below threshold values representing a sustained Phe response (SPR). This secondary analysis of data from the PRISM phase 3 clinical trials examined the relationship between SPR and symptoms of impaired attention and mood disturbance, as assessed using the Attention Deficit Hyperactivity Disorder Rating Scale-IV Inattention (ADHD RS-IV IA) subscale and the PKU Profile of Mood States Total Mood Disturbance (PKU-POMS TMD) self-reported score.
Methods:
The longitudinal pattern of serial Phe measures for each patient, expressed as the expected value of Phe at time t (Phet; days since baseline), was estimated with a generalized additive model smoother function. A 95% confidence interval (CI) for Phet reflects the range of plausible values for estimated Phet given the number of temporally proximal Phe measures and their variability. SPR was defined as when the upper 95% CI of the longitudinally modeled pattern in estimated mean Phet remains below specific Phe thresholds: ≤600 µmol/L (SPR600), ≤360 µmol/L (SPR360), or ≤120 µmol/L (SPR120). A Bayesian multilevel ordinal regression model, conditioning on patient with varying intercepts and varying effects, estimated the monotonic effects of SPR, fitted as a 4-level ordinal predictor (No SPR vs. SPR600, SPR360, and SPR120), on estimated ADHD RS-IV IA and PKU-POMS TMD scores.
Results:
Patients with baseline ADHD RS-IV IA score >9 (n=91), indicating the presence of inattention likely to impede daily functioning in adults with PKU, were included in a regression model with the ordinal predictor for SPR to estimate conditional outcomes. Estimated ADHD RS-IV IA score showed consistent improvement with lower SPR thresholds (Bayesian posterior probability (BPPr)> 0 = 0.99). Estimated ADHD RS-IV IA score (95% Bayesian credibility intervals) when SPR was not achieved was 9.6 (8.6, 10.8) compared with 7.3 (6.4, 8.4) for SPR600, 6.9 (6.0, 8.0) for SPR360, and 5.5 (4.5, 6.6) for SPR120. Similar patterns were observed in models including the overall population without restriction on baseline score and for ADHD RS-IV total score. Models for PKU-POMS TMD score included patients with baseline scores greater than the median (>14; n=69) and similarly showed a consistent improvement with lower SPR thresholds (BPPr >0.99): Estimated PKU-POMS TMD score when SPR was not achieved was 28.3 (25.8, 30.9) compared with 25.2 (22.6, 28.1) for SPR600, 24.6 (22.1, 27.5) for SPR360, and 22.1 (19.2, 25.3) for SPR120.
Conclusion:
ADHD RS-IV IA and PKU-POMS TMD scores improved with the achievement of lower blood Phe levels, expressed as an index of sustained Phe response. ADHD RS-IV IA and PKU-POMS TMD scores at sustained Phe levels ≤120 µmol/L were significantly better than those at sustained Phe levels of ≤600 µmol/L or ≤360 µmol/L, adding to the body of evidence that current recommended blood Phe targets of 120-360 µmol/L may not be sufficient for optimal patient outcomes and that patients may benefit from normalizing Phe levels.