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

Deborah A Bilder, Georgianne L Arnold, David Dimmock, Mitzie L Grant, Darren Janzen, Nicola Longo, Mina Nguyen-Driver, Elaina Jurecki, Markus Merilainen, Gianni Amato, Susan Waisbren, Deborah A Bilder, Georgianne L Arnold, David Dimmock, Mitzie L Grant, Darren Janzen, Nicola Longo, Mina Nguyen-Driver, Elaina Jurecki, Markus Merilainen, Gianni Amato, Susan Waisbren

Abstract

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.

Keywords: PEGylated ammonia lyase; inattention; pegvaliase; phenylalanine; phenylketonuria.

Conflict of interest statement

Deborah A. Bilder has received consulting fees as a Phase 3 Clinical Trials Steering Committee member for pegvaliase from BioMarin Pharmaceutical and consulting fees from Audentes Therapeutics, Encoded Therapeutics, Synlogic Therapeutics, and Taysha GTx. Georgianne L. Arnold has received funding for clinical trial activities involving pegvaliase from BioMarin Pharmaceutical. David Dimmock has received consulting fees from Audentes Therapeutics, Ichorion Therapeutics, BioMarin Pharmaceutical, Complete Genomics, Taysha GTx, and Flagship Pioneering. Mitzie L. Grant has received consulting fees, speaker fees and travel support and has participated as a clinical trial investigator for BioMarin Pharmaceutical. Darren Janzen and Mina Nguyen‐Driver have received speaker fees and travel support from BioMarin Pharmaceutical. Nicola Longo has received consulting fees as a Phase 3 Clinical Trials Steering Committee member and funds for clinical trial activities involving pegvaliase from BioMarin Pharmaceutical. Elaina Jurecki and Markus Merilainen are employees and shareholders of BioMarin Pharmaceutical. Gianni Amato was an employee of BioMarin Pharmaceutical at the time of manuscript initiation. Susan Waisbren has received consulting fees from BioMarin Pharmaceutical.

© 2021 BioMarin Pharmaceutical Inc. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.

Figures

FIGURE 1
FIGURE 1
Mean (SE) plasma phenylalanine (Phe) concentrations and Attention Deficit Hyperactivity Disorder Rating Scale‐IV (ADHD RS‐IV) inattention subscale (IA) scores over time. (a) Modified intention‐to‐treat total population (N = 156). (b) Participants with baseline ADHD RS‐IV IA score ≥ 10 (IA subgroup; N = 71). (c) Participants with baseline ADHD RS‐IV IA score ≤ 9 (N = 85). Note that number of patients accounted for differs between efficacy parameters per time‐point. *Number of patients contributing to Phe evaluation. **Number of patients contributing to ADHD RS‐IV IA score evaluation
FIGURE 2
FIGURE 2
Change from baseline in Attention Deficit Hyperactivity Disorder Rating Scale‐IV (ADHD RS‐IV) inattention subscale (IA) score by change from baseline in plasma phenylalanine (Phe) quartiles. (a) Modified intention‐to‐treat population (N = 156). (b) IA subgroup (N = 71)
FIGURE 3
FIGURE 3
Change from baseline to last observation in Attention Deficit Hyperactivity Disorder Rating Scale‐IV (ADHD RS‐IV) inattention subscale (IA) score by final plasma phenylalanine (Phe) cut off value of 360 μmol/L and 600 μmol/L in modified intention‐to‐treat population (N = 156). These analyses are not reported for the IA subgroup because of the small number of participants available for analysis at last observation. *p‐value: 0.005 for LS mean (SE) change from baseline in IA score with final plasma Phe ≤ 600 μmol/L versus >600 μmol/L. **p‐value: 0.001 for LS mean (SE) change from baseline in IA score with final plasma Phe ≤ 360 μmol/L versus >360 μmol/L

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