Search

Objective: To evaluate effects of sapropterin dihydrochloride on blood phenylalanine (Phe) and symptoms of neuropsychiatric impairment in children and adolescents with phenylketonuria (PKU)., Study Design: PKU subjects 8-17 years of age (n = 86) were randomized to double-blind treatment with sapropterin (n = 43) or placebo (n = 43) for 13 weeks, then all received open-label sapropterin therapy for an additional 13 weeks. Blood Phe and symptoms of inattention, hyperactivity/impulsivity (Attention-Deficit/Hyperactivity Disorder Rating Scale IV [ADHD RS-IV]), executive functioning (Behavior Rating Inventory of Executive Function), depression (Hamilton Rating Scale for Depression), and anxiety (Hamilton Rating Scale for Anxiety) were assessed., Results: Following the 13-week randomization phase, the sapropterin and placebo groups had mean changes in blood Phe of -20.9% and +2.9%, respectively. Corresponding least square mean differences in ADHD RS-IV scores were significantly greater for the sapropterin vs the placebo group: Total (-3.2 points, P = .02), Inattention subscale (-1.8 points, P = .04), and Hyperactivity/Impulsivity subscale (-1.6 points, P = .02). Forest plots favored sapropterin treatment over placebo for all ADHD RS-IV and Behavior Rating Inventory of Executive Function indices. There were no significant differences in reported problems with attention or executive function between the 2 groups at baseline or at week 26 following the 13-week open-label treatment period. Anxiety and depression scores did not differ significantly between cohorts at any time. Sapropterin was well tolerated, with a favorable safety profile., Conclusions: Sapropterin reduced blood Phe and was associated with significant improvement in parent-reported symptoms of inattention, hyperactivity/impulsivity, and executive functioning in children and adolescents with PKU., Trial Registration: ClinicalTrials.gov, NCT01114737. Registered 27 April 2010, https://clinicaltrials.gov/ct2/show/NCT01114737., Competing Interests: Declaration of Competing Interest Funding source: BioMarin Pharmaceutical Inc. This manuscript was prepared with assistance from John Mahoney with funding from BioMarin Pharmaceutical Inc. M.L.G. has received consulting fees from and participated as a clinical trial investigator for BioMarin and Encoded Therapeutics. E.R.J. was an employee and stockholder of BioMarin at the time of the study. S.E.M. has received consulting fees from Levo Therapeutics and has participated as a clinical trial investigator for Aardvark Therapeutics, Harmony Biosciences, Levo Therapeutics, and Ultragenyx. S.M.S. has received consulting fees from Acadia, Adamas, Alkermes, Allergan, Abbvie, Arbor Pharmaceuticals, AstraZeneca, Avanir, Axovant, Axsome, Biogen, BioMarin, Biopharma, Celgene, Concert, ClearView, DepoMed, EMD Serono, Eisai Pharmaceuticals, Eurolink, Ferring, Forest, Genomind, Innovative Science Solutions, Impel, Karuna, NeuroPharma, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Jazz, Karuna, Lilly, Lundbeck, Merck, Neos, Neurocrine, Novartis, Noveida, Otsuka, Perrigo, Pfizer, Pierre Fabre, Proxymm, Relmada, Reviva, Sage Therapeutics, Servier, Shire, Sprout, Sunovion, TMS NeuroHealth, Takeda, Taliaz, Teva, Tonix, Tris Pharma, Trius, Vanda, Vertex, and Viforpharma; holds options in Genomind, Lipidio, and Delix; has been a board member of RCT Logic and Genomind; has served on speaker bureaus for Acadia, Genentech, Janssen, Lundbeck, Merck, Otsuka, Servier, Sunovion, Takeda, and Teva; and has received research and/or grant support from Acadia, Alkermes, Allergan/AbbVie, AssureX, Astra Zeneca, Arbor Pharmaceuticals, Avanir, Axovant, Biogen, Braeburn Pharmaceuticals, BristolMyer Squibb, Celgene, CeNeRx, Cephalon, Dey, Eisai, Eli Lilly, Forest, GenOmind, Glaxo Smith Kline, Harmony Biosciences, Indivior, Intra-Cellular Therapies, Ironshore, ISSWSH, Janssen, JayMac, Jazz, Lundbeck, Merck, Neurocrine, Neuronetics, Novartis, Otsuka, Pear Therapeutics, Pfizer, Reviva, Roche, Sage, Servier, Shire, Sprout, Sunovion, Supernus, TMS NeuroHealth Centers, Takeda, Teva, Tonix, Torrent, and Vanda. D.A.B. has received consulting fees from BioMarin, Encoded Therapeutics, Synlogic Therapeutics, and Taysha Gene Therapies, and travel support from BioMarin. A.S.-V. has received consulting fees from Acer, Applied Therapeutics, BioMarin, Horizon, and Ultragenyx; has participated as a clinical trial investigator for Acadia, Alexion, Amicus, BioMarin, Cerecor, Genzyme, Homology, Horizon, Kaleido, Mallenkrodt, and Ultragenyx; and has received travel support from BioMarin and Ultragenyx. D.D. is an employee of Creyon Bio and has received consulting fees from Taysha Gene Therapies., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate effects of holding parenteral nutrition (PN) for 3 hours prior to newborn screening (NBS) on false-positive NBS rate for amino acids (AAs) in very low birth weight (VLBW) infants (birth weight <1500 g)., Study Design: We analyzed data from 12 567 consecutive births in 1 hospital between May 2010 and June 2013. VLBW infants were stratified into 3 groups: (1) infants without PN before NBS (no-PN group); (2) infants with early PN running at the time of NBS (early-PN group); and (3) infants with early-PN that were temporarily replaced by dextrose-containing intravenous fluid 3 hours prior to NBS (stop-PN group). We compared the false-positive rate for AA and cost effectiveness between the groups., Results: The false-positive rate for AA among 413 VLBW infants was significantly higher than infants with birth weight >1500 g (7.62% vs 0.05%; P < .001). There were no false-positive results for AA in the no-PN group. The false-positive rate for AA in the stop-PN group (2/65) was significantly lower than the early-PN group (29/245) (3.1% vs 11.8%; P = .037). The stop-PN group was more cost effective than early-PN group, saving $17.27 per infant screened ($5.53 vs $22.80) or $192.54 for each false-positive result for AA averted. Further reductions in inconclusive samples were also noted., Conclusions: VLBW and early-PN are significant factors for false-positive results for AA. Holding PN containing AAs for 3 hours before NBS collection is a practical and cost-effective method to significantly reduce the false-positive rate for AA in VLBW infants., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To examine ammonia levels, pharmacokinetics, and safety of glycerol phenylbutyrate (GPB; also referred to as HPN-100) and sodium phenylbutyrate (NaPBA) in young children with urea cycle disorders (UCDs)., Study Design: This open label switch-over study enrolled patients ages 29 days to under 6 years taking NaPBA. Patients underwent 24-hour blood and urine sampling on NaPBA and again on a phenylbutyric acid-equimolar dose of GPB and completed questionnaires regarding signs and symptoms associated with NaPBA and/or their UCD., Results: Fifteen patients (8 argininosuccinate lyase deficiency, 3 argininosuccinic acid synthetase deficiency, 3 ornithine transcarbamylase deficiency, 1 arginase deficiency) ages 2 months through 5 years enrolled in and completed the study. Daily ammonia exposure (24-hour area under the curve) was lower on GPB and met predefined noninferiority criteria (ratio of means 0.79; 95% CI 0.593-1.055; P=.03 Wilcoxon; 0.07 t test). Six patients experienced mild adverse events on GPB; there were no serious adverse events or significant laboratory changes. Liver tests and argininosuccinic acid levels among patients with argininosuccinate lyase deficiency were unchanged or improved on GPB. Eleven of 15 patients reported 35 symptoms on day 1; 23 of these 35 symptoms improved or resolved on GPB. Mean systemic exposure to phenylbutyric acid, phenylacetic acid, and phenylacetylglutamine (PAGN) were similar and phenylacetic acid exposure tended to be higher in the youngest children on both drugs. Urinary PAGN concentration was greater on morning voids and varied less over 24 hours on GPB versus NaPBA., Conclusions: GPB results in more evenly distributed urinary output of PAGN over 24 hours were associated with fewer symptoms and offers ammonia control comparable with that observed with NaPBA in young children with UCDs., (Copyright © 2013 Mosby, Inc. All rights reserved.)