PracticeUpdate Conference Series - SSIEM 2018

Sapropterin+Diet inChildrenWithPhenylketonuria Raises andMaintains Phenylalanine Tolerance Long-term treatment with sapropterin + diet in children ≤4 years of age maintains increased dietary phenylalanine tolerance.

T his outcome of the Safety Paediatric efficAcy phaRmacokinetics with Kuvan® (SPARK) exten- sion study was reported at SSIEM 2018. Frank Rutsch, MD, of Muenster University Children’s Hospital in Muenster, Germany, and colleagues eval- uated sapropterin for an additional 36 months after SPARK had ended. Subjects treated previously with a phenylalanine-re- stricted diet only were initiated with sapropterin therapy at 20 mg per kilogram of body weight daily (sapropterin extension). Those treated initially with sapropterin + diet remained on this regimen (sapropterin continuation). Key differences vs the 26-week study period were that dietary phenylalanine intake adjustments fol- lowed clinical practice standards of participating centers vs algorithm-driven stands and phenylala- nine and sapropterin dose were adjusted every 3 months versus every 2 weeks. Analyses were performed in the intent-to-treat extension population (randomized subjects who continued into the extension period). Phenylalanine tolerance increased significantly vs baseline (start of sapropterin in the 26-week study) in the saprop- terin continuation group (n=25). Significant increases were maintained throughout the study (P < .001). Dietary phenylalanine tolerance at the end of the study increased by 38.74 mg/kg daily versus base- line (P < .0001). In the sapropterin extension group (n=26), signifi- cant differences vs baseline (start of sapropterin in the extension study) were observed only between months 9 and 21 (P ≤ .0264). Dietary phenylalanine tolerance at the end of the study had increased by 5.48 mg/kg daily vs baseline (difference not signifi- cant). Blood phenylalanine levels in the sapropterin continuation group remained stable over time. In the sapropterin extension group, decreases in blood phenylalanine levels vs baseline were observed at all visits (significant at months 21, 30, and 33). No subjects withdrew due to adverse events. Dr. Rutsch explained that the SPARK extension study followed the 26-week SPARK study period in children with tetrahydrobiopterin-responsive phe- nylketonuria or mild hyperphenylalaninemia who began sapropterin therapy younger than 4 years of age. The SPARK extension study evaluated long-term safety, dietary phenylalanine tolerance (amount of dietary phenylalanine ingested while maintaining blood phenylalanine levels 120–360 µmoL/L), and phenylalanine levels over an additional 36 months of sapropterin treatment.

Dr. Rutsch concluded that the data demonstrate that long-term treatment with sapropterin + diet in children with tetrahydrobiopterin- responsive phenylketonuria who begin therapy younger than age 4 years maintains increased dietary phenylalanine tolerance over 3.5 years and supports a favorable risk/benefit profile. In a related presentation on sapropterin, Ania Carolina Muntau, MD, of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, and colleagues reviewed the outcome of two consensus meetings on the optimized protocols dosing for tests designed to assess responsiveness to sapropterin. Dr. Muntau explained that international guidelines recommend lifelong control of blood phenylalanine in patients with phenylketonuria to prevent detri- mental effects on the brain. Protocols to establish sapropterin responsiveness vary widely. The two meetings focused on regional similarities/ differences in testing practices based on discussions and on online evaluation forms sent to participants for consensus evaluation and further fine-tuning. Resulting recommendations were that patients with blood phenylalanine 360–2000 µmoL/L undergo a sapropterin trial (20 mg/kg daily), except in those with two null mutations. For neonates, a 24-h load- ing test is recommended and a ≥30% decrease from baseline blood phenylalanine indicates a response. For the majority of older infants, children, adolescents, and adults, a test duration of 48 h to 7 days is recommended, with a decrease in blood phenylalanine as the main outcome. This may be extended to approximately 4 weeks, with improved phenylalanine tolerance as the main outcome, to identify additional responders. This duration may not be possible in some countries due to restrictions or limited access to sapropterin. A 48-h sapropterin test should be considered for women with phenylke- tonuria who cannot achieve blood phenylalanine ≤360 µmoL/L with diet. Relevant medical, nutritional, and social history data and baseline information should be collected for all patients before sapropterin testing, and long-term durability of response and clinical benefits of treatment should be assessed. Dr. Muntau concluded that harmonization of sapropterin response testing protocols may improve the determination of sapropterin responders and comparison of test results worldwide. Such harmo- nization may help ensure optimal prescriptions that will lead to the greatest benefit.

Frank Rutsch, MD

Ania Carolina Muntau, MD

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PRACTICEUPDATE CONFERENCE SERIES • SSIEM 2018 20