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van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Beblo S, Blau N, Bosch AM, Burlina A, Campistol J, Coşkun T, Feillet F, Giżewska M, Huijbregts SC, Leuzzi V, Maillot F, Muntau AC, Rocha JC, Romani C, Trefz F, van Spronsen FJ. European guidelines on diagnosis and treatment of phenylketonuria: First revision. Mol Genet Metab 2025; 145:109125. [PMID: 40378670 DOI: 10.1016/j.ymgme.2025.109125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 04/24/2025] [Accepted: 04/24/2025] [Indexed: 05/19/2025]
Abstract
Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine metabolism caused by deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. Untreated, PKU results in elevated phenylalanine levels in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. For this first revision of the European PKU Guidelines previous recommendations were re-evaluated and updated according to new research findings. Twenty-one professionals were divided across four working groups and supported by a coordinator and chair. In addition to an update of the previous 70 recommendations, 20 new topics were included, resulting in a total of 87 statements in this first revision of the guidelines. Research publications were reviewed up until September 2022. Evidence was graded as high, moderate, low, very low or expert opinion and the recommendations were graded conditional or strong according to GRADE methodology. All recommendations were discussed during 14 plenary online or in person meetings. Recommendations were accepted if more than 75 % of the professionals were in agreement. When recommendations were not amended, the text reported in the European guidelines of 2017 remains valid.
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Affiliation(s)
- A M J van Wegberg
- Division of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, the Netherlands.
| | - A MacDonald
- Dietetic Department, Birmingham Children's Hospital, Birmingham, UK.
| | - K Ahring
- PKU clinic, Center for Inherited Metabolic Diseases, Copenhagen University Hospital, Denmark.
| | - A Bélanger-Quintana
- Metabolic Diseases Unit, Department of Paediatrics, Hospital Ramon y Cajal Madrid, Madrid, Spain.
| | - S Beblo
- Department of Women and Child Health, Center for Rare Diseases, Leipzig University Medical Center, Leipzig, Germany.
| | - N Blau
- Divisions of Metabolism, University Children's Hospital, Zürich, Switzerland.
| | - A M Bosch
- Amsterdam UMC, location University of Amsterdam, Emma Childrens' Hospital, Department of Pediatrics, Division of Metabolic Diseases, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam, the Netherlands.
| | - A Burlina
- Division of Inherited Metabolic Diseases, Reference Centre Expanded Newborn Screening, University Hospital Padova, Italy.
| | - J Campistol
- Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain.
| | - T Coşkun
- Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
| | - F Feillet
- Pediatric Unit, Reference Center for Inborn Errors of Metabolism, University Hospital of Nancy, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, University of Lorraine, Nancy, France.
| | - M Giżewska
- Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, Szczecin, Poland.
| | - S C Huijbregts
- Department of Clinical Child and Adolescent Studies-Neurodevelopmental Disorders, Faculty of Social Sciences, Leiden University, Leiden, the Netherlands.
| | - V Leuzzi
- Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
| | - F Maillot
- CHRU De Tours, Internal Medicine department, Reference center for inherited metabolic diseases, INSERM U1253 "iBraiN", University of Tours, Tours, France.
| | - A C Muntau
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, and German Center of Child and Adolescent Health (DZKJ), Hamburg, Germany.
| | - J C Rocha
- Nutrition and Metabolism, NOVA Medical School (NMS), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; Reference Centre of Inherited Metabolic Diseases, Unidade Local de Saúde São José, 1169-045 Lisboa, Portugal; Centro de Investigação em Tecnologias e Serviços de Saúde (CINTESIS), NOVA Medical School (NMS), Faculdade de Ciências Médicas, (FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; Comprehensive Health Research Centre (CHRC), NOVA Medical School, (NMS), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal.
| | - C Romani
- College of Health and Life Sciences, Psychology Department, Aston University, UK.
| | - F Trefz
- Center for Metabolic Diseases Tuebingen, Paul-Ehrlich-Straße 23, 72076 Tübingen, Germany.
| | - F J van Spronsen
- Division of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, the Netherlands.
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Shrestha S, Zagel AL, Pillai NR, Ahmed A, Jacobson J, Ranasinghe A, Whitley CB, Jarnes JR. Pegvaliase therapy for phenylketonuria: Real-world safety, efficacy, and medication access outcomes in a pharmacist-led pegvaliase program. Genet Med 2025; 27:101405. [PMID: 40094206 DOI: 10.1016/j.gim.2025.101405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/07/2025] [Accepted: 03/07/2025] [Indexed: 03/19/2025] Open
Abstract
PURPOSE Given the complexity and close monitoring needs of pegvaliase, we evaluated the real-life clinical outcomes of patients with phenylketonuria (PKU) managed in a pharmacist-led pegvaliase pharmacotherapy program. METHODS A review of 51 PKU patients initiated on pegvaliase at the PKU clinic of M Health Fairview, Minneapolis, MN, between May 2018 and May 2024 was conducted. Data collected included baseline characteristics, payer authorization outcomes, treatment history, phenylalanine (Phe) levels, adverse events, and management strategies. RESULTS At 12-months, 55% of patients achieved Phe goal (360 μmol/L), increasing to 77% at 24 months. Among patients on maintenance doses, 87% achieved ≥20% Phe reduction at 12 months, rising to 93.5% at 24 months. Combination therapy with sapropterin and pegvaliase was associated with faster Phe goal attainment compared with pegvaliase monotherapy (P = .0599). Anaphylaxis occurred in 31% of patients, predominantly during the maintenance phase. All patients successfully initiated therapy without access barriers, although 35% required appeals for insurance approval. Common adverse events included injection site reactions (90%) and arthralgia (69%). Special populations, including 1 adolescent and 2 pregnant women, were safely managed on pegvaliase. CONCLUSION Pegvaliase effectively reduced Phe levels in PKU patients, although it carried significant risks of anaphylaxis and other adverse events. A pharmacist-led program and interdisciplinary collaboration was crucial for prompt access and effective management.
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Affiliation(s)
- Sofia Shrestha
- M Health Fairview, Minneapolis, MN; Fairview Pharmacy Services, Minneapolis, MN; Advanced Therapies Program, University of Minnesota, Fairview, Minneapolis, MN.
| | - Alicia L Zagel
- M Health Fairview, Minneapolis, MN; Fairview Pharmacy Services, Minneapolis, MN
| | - Nishitha R Pillai
- Advanced Therapies Program, University of Minnesota, Fairview, Minneapolis, MN; Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - Alia Ahmed
- Advanced Therapies Program, University of Minnesota, Fairview, Minneapolis, MN; Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - Jenny Jacobson
- M Health Fairview, Minneapolis, MN; Advanced Therapies Program, University of Minnesota, Fairview, Minneapolis, MN
| | - Alicia Ranasinghe
- M Health Fairview, Minneapolis, MN; Fairview Pharmacy Services, Minneapolis, MN; Advanced Therapies Program, University of Minnesota, Fairview, Minneapolis, MN
| | - Chester B Whitley
- Advanced Therapies Program, University of Minnesota, Fairview, Minneapolis, MN; Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - Jeanine R Jarnes
- Advanced Therapies Program, University of Minnesota, Fairview, Minneapolis, MN; Department of Pediatrics, University of Minnesota, Minneapolis, MN
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Alfadhel M, Albarakati R. First successful outcomes of pegvaliase (PALYNZIQ) in children. BMC Med Genomics 2024; 17:76. [PMID: 38515136 PMCID: PMC10958957 DOI: 10.1186/s12920-024-01847-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 03/11/2024] [Indexed: 03/23/2024] Open
Abstract
BACKGROUND PKU is an autosomal recessive hereditary inborn error of metabolism caused by a lack of phenylalanine hydroxylase enzyme activity. Pegvaliase (PALYNZIQ®) treatment has been approved to reduce blood Phe concentrations in adult phenylketonuria patients with uncontrolled blood Phe concentrations greater than 600 micromol/L on current management. However, data regarding individuals under the age of 16 is still unavailable. CASE REPORT We report a 12-year-old Saudi girl who underwent pegvaliase therapy and was closely monitored for one year. Remarkably, a positive therapeutic response became apparent six months after commencing pegvaliase treatment. Phenylalanine (Phe) levels showed significant improvement, stabilising within the < 5 to 14 µmol/L range on a regular diet without any restriction. At her current age of 12, the patient maintains an unrestricted dietary regimen, consuming a diverse selection of foods, including poultry, meat, and protein sources, all while consistently maintaining normal Phe levels with no change in mental status after treatment. The parents gave their written, informed consent in allowing the research study to be carried out and clinical data to be published. CONCLUSIONS This report addresses the potential broader applications of Pegvaliase in children, as well as its safety and tolerability in this age group. However, larger sample sizes and robust methodologies are required to validate such findings.
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Affiliation(s)
- Majid Alfadhel
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia.
- Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children Hospital (KASCH), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia.
- Medical Genomic Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia.
| | - Rayyan Albarakati
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
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Pinto A, Daly A, Rocha JC, Ashmore C, Evans S, Ilgaz F, Hickson M, MacDonald A. Natural Protein Intake in Children with Phenylketonuria: Prescription vs. Actual Intakes. Nutrients 2023; 15:4903. [PMID: 38068761 PMCID: PMC10708375 DOI: 10.3390/nu15234903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/16/2023] [Accepted: 11/19/2023] [Indexed: 12/18/2023] Open
Abstract
In phenylketonuria (PKU), an important component of the UK dietary management system is a 50 mg phenylalanine (Phe)/1 g protein exchange system used to allocate the Phe/natural protein intakes according to individual patient tolerance. Any foods containing protein ≤ 0.5 g/100 g or fruits/vegetables containing Phe ≤ 75 mg/100 g are allowed without measurement or limit. In children with PKU, we aimed to assess the difference between the prescribed natural protein intake and their actual consumed intake, and to calculate the natural protein/Phe intake from foods given without measurement or restriction. Over a 6-month duration, three one-day diet diaries were collected every month by caregivers of children with PKU at the beginning of a follow-up study. Dietary intakes of Phe, as well as natural and total protein intakes, were calculated using Nutritics® (v5.09). Weekly blood Phe spots were collected by caregivers. The target blood Phe level was ≤360 μmol/L for ages up to 12 years and ≤600 μmol/L for ages ≥12 years. Sixteen early treated children (69% females) with PKU were recruited. The median age was 11 years (range: 9-13), and most had classical PKU (n = 14/16). A median of 18 (range 12-18) one-day diaries and 22 blood spots were analysed for each subject over 6 months. The median prescribed natural protein was 6 g/day (range: 3-27), but when calculated, the actual median intake from all foods consumed was 10 g/day (range: 4-37). The median prescribed Phe was 300 mg/day (range: 150-1350), but the actual median intake was 500 mg/day (range: 200-1850). The median difference between the prescribed and actual natural protein daily intakes was +4 g/day (range: -2.5 to +11.5), with a median percentage increase of 40% for natural protein/Phe intake (p < 0.001). The median blood Phe level was 250 μmol/L (range 20-750), with 91% of blood Phe levels within the target range. Only one patient (11 years) had less than 75% of their blood Phe levels within the target range. The UK Phe exchange system provides flexibility in the dietary management of PKU. With this method, the actual natural protein intake was 167% higher than the prescribed amount. Although this led to a variable daily protein intake, the majority of children (n = 15/16) experienced no deterioration in their metabolic control.
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Affiliation(s)
- Alex Pinto
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (A.D.); (C.A.); (S.E.); (F.I.); (A.M.)
- Plymouth Institute of Health and Care Research, Faculty of Health, University of Plymouth, Plymouth PL6 8BH, UK;
| | - Anne Daly
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (A.D.); (C.A.); (S.E.); (F.I.); (A.M.)
| | - Júlio César Rocha
- Nutrition and Metabolism, NOVA Medical School (NMS), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal;
- CINTESIS@RISE, Nutrition and Metabolism, NOVA Medical School (NMS), Faculdade de Ciências Médicas, (FCM), Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal
- Reference Centre of Inherited Metabolic Diseases, Centro Hospitalar Universitario de Lisboa Central, 1169-045 Lisboa, Portugal
| | - Catherine Ashmore
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (A.D.); (C.A.); (S.E.); (F.I.); (A.M.)
| | - Sharon Evans
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (A.D.); (C.A.); (S.E.); (F.I.); (A.M.)
| | - Fatma Ilgaz
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (A.D.); (C.A.); (S.E.); (F.I.); (A.M.)
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, 06100 Ankara, Turkey
| | - Mary Hickson
- Plymouth Institute of Health and Care Research, Faculty of Health, University of Plymouth, Plymouth PL6 8BH, UK;
| | - Anita MacDonald
- Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK; (A.D.); (C.A.); (S.E.); (F.I.); (A.M.)
- Plymouth Institute of Health and Care Research, Faculty of Health, University of Plymouth, Plymouth PL6 8BH, UK;
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Ziegler SG, Kim J, Ehmsen JT, Vernon HJ. Inborn errors of amino acid metabolism - from underlying pathophysiology to therapeutic advances. Dis Model Mech 2023; 16:dmm050233. [PMID: 37994477 PMCID: PMC10690057 DOI: 10.1242/dmm.050233] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 10/19/2023] [Indexed: 11/24/2023] Open
Abstract
Amino acids are organic molecules that serve as basic substrates for protein synthesis and have additional key roles in a diverse array of cellular functions, including cell signaling, gene expression, energy production and molecular biosynthesis. Genetic defects in the synthesis, catabolism or transport of amino acids underlie a diverse class of diseases known as inborn errors of amino acid metabolism. Individually, these disorders are rare, but collectively, they represent an important group of potentially treatable disorders. In this Clinical Puzzle, we discuss the pathophysiology, clinical features and management of three disorders that showcase the diverse clinical presentations of disorders of amino acid metabolism: phenylketonuria, lysinuric protein intolerance and homocystinuria due to cystathionine β-synthase (CBS) deficiency. Understanding the biochemical perturbations caused by defects in amino acid metabolism will contribute to ongoing development of diagnostic and management strategies aimed at improving the morbidity and mortality associated with this diverse group of disorders.
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Affiliation(s)
- Shira G. Ziegler
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jiyoung Kim
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jeffrey T. Ehmsen
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Hilary J. Vernon
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Rocha JC, Ahring KK, Bausell H, Bilder DA, Harding CO, Inwood A, Longo N, Muntau AC, Pessoa ALS, Rohr F, Sivri S, Hermida Á. Expert Consensus on the Long-Term Effectiveness of Medical Nutrition Therapy and Its Impact on the Outcomes of Adults with Phenylketonuria. Nutrients 2023; 15:3940. [PMID: 37764724 PMCID: PMC10536918 DOI: 10.3390/nu15183940] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/28/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Many adults with phenylketonuria (PKU) rely on medical nutrition therapy (MNT; low phenylalanine (Phe) diet with protein substitutes/medical foods) to maintain blood Phe concentrations within recommended ranges and prevent PKU-associated comorbidities. Despite disease detection through newborn screening and introduction of MNT as early as birth, adherence to MNT often deteriorates from childhood onwards, complicating the assessment of its effectiveness in the long term. Via a modified Delphi process, consensus (≥70% agreement) was sought on 19 statements among an international, multidisciplinary 13-member expert panel. After three iterative voting rounds, the panel achieved consensus on 17 statements related to the limitations of the long-term effectiveness of MNT (7), the burden of long-term reliance on MNT (4), and its potential long-term detrimental health effects (6). According to the expert panel, the effectiveness of MNT is limited in the long term, is associated with a high treatment burden, and demonstrates that adults with PKU are often unable to achieve metabolic control through dietary management alone, creating an unmet need in the adult PKU population.
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Affiliation(s)
- Júlio César Rocha
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal
- Reference Centre of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Rua Jacinta Marto, 1169-045 Lisboa, Portugal
- CINTESIS@RISE, Nutrition and Metabolism, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal
| | - Kirsten K. Ahring
- Departments of Paediatrics and Clinical Genetics, PKU Clinic, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Heather Bausell
- Division of Genetics, Genomics, and Metabolism, Ann & Robert H Lurie Children’s Hospital of Chicago, 225 E. Chicago Ave., Chicago, IL 60611, USA
| | - Deborah A. Bilder
- Department of Psychiatry, Division of Child & Adolescent Psychiatry, University of Utah Huntsman Mental Health Institute, 501 Chipeta Way, Salt Lake City, UT 84108, USA
| | - Cary O. Harding
- Department of Molecular and Medical Genetics, Oregon Health & Science University, 3222 SW Research Drive, Portland, OR 97239, USA
| | - Anita Inwood
- Queensland Lifespan Metabolic Medicine Service, Queensland Children’s Hospital, 501 Stanley St., South Brisbane, QLD 4101, Australia
- School of Nursing and Social Work, The University of Queensland, Chamberlain Building, St. Lucia, QLD 4072, Australia
| | - Nicola Longo
- Department of Pediatrics, Division of Medical Genetics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT 84108, USA
| | - Ania C. Muntau
- Department of Pediatrics, University Children’s Hospital, University Medical Centre Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - André L. Santos Pessoa
- Albert Sabin Children’s Hospital, R. Tertuliano Sales, 544—Vila União, Fortaleza 60410-794, CE, Brazil
- Av. Dr. Silas Munguba, 1700—Itaperi, State University of Ceará (UECE), Fortaleza 60714-903, CE, Brazil
| | | | - Serap Sivri
- Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Gevher Nesibe Cd., 06230 Ankara, Turkey
| | - Álvaro Hermida
- Diagnosis and Treatment of Congenital Metabolic Diseases Unit (UDyTEMC), Department of Pediatrics, Faculty of Medicine, Clinical University Hospital of Santiago de Compostela, University of Santiago de Compostela, CIBERER, MetabERN, Institute of Clinical Research of Santiago de Compostela (IDIS), Rúa de San Francisco s/n, 15706 Santiago de Compostela, Spain
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Adams AD, Fiesco-Roa MÓ, Wong L, Jenkins GP, Malinowski J, Demarest OM, Rothberg PG, Hobert JA. Phenylalanine hydroxylase deficiency treatment and management: A systematic evidence review of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2023; 25:100358. [PMID: 37470789 DOI: 10.1016/j.gim.2022.12.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/08/2022] [Accepted: 12/08/2022] [Indexed: 07/21/2023] Open
Abstract
PURPOSE Elevated serum phenylalanine (Phe) levels due to biallelic pathogenic variants in phenylalanine hydroxylase (PAH) may cause neurodevelopmental disorders or birth defects from maternal phenylketonuria. New Phe reduction treatments have been approved in the last decade, but uncertainty on the optimal lifespan goal Phe levels for patients with PAH deficiency remains. METHODS We searched Medline and Embase for evidence of treatment concerning PAH deficiency up to September 28, 2021. Risk of bias was evaluated based on study design. Random-effects meta-analyses were performed to compare IQ, gestational outcomes, and offspring outcomes based on Phe ≤ 360 μmol/L vs > 360 μmol/L and reported as odds ratio and 95% CI. Remaining results were narratively synthesized. RESULTS A total of 350 studies were included. Risk of bias was moderate. Lower Phe was consistently associated with better outcomes. Achieving Phe ≤ 360 μmol/L before conception substantially lowered the risk of negative effect to offspring in pregnant individuals (odds ratio = 0.07, 95% CI = 0.04-0.14; P < .0001). Adverse events due to pharmacologic treatment were common, but medication reduced Phe levels, enabling dietary liberalization. CONCLUSIONS Reduction of Phe levels to ≤360 μmol/L through diet or medication represents effective interventions to treat PAH deficiency.
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Affiliation(s)
- April D Adams
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX; Division of Maternal-Fetal Medicine, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Moisés Ó Fiesco-Roa
- Programa de Maestría y Doctorado en Ciencias Médicas, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico; Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City, Mexico
| | | | | | | | | | - Paul G Rothberg
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Judith A Hobert
- University of Utah School of Medicine, Salt Lake City, UT; ARUP Laboratories, Salt Lake City, UT
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Gustafson KT, Mokhtari N, Manalo EC, Montoya Mira J, Gower A, Yeh YS, Vaidyanathan M, Esener SC, Fischer JM. Hybrid Silica-Coated PLGA Nanoparticles for Enhanced Enzyme-Based Therapeutics. Pharmaceutics 2022; 15:143. [PMID: 36678770 PMCID: PMC9866096 DOI: 10.3390/pharmaceutics15010143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/22/2022] [Accepted: 12/28/2022] [Indexed: 01/04/2023] Open
Abstract
Some cancer cells rely heavily on non-essential biomolecules for survival, growth, and proliferation. Enzyme based therapeutics can eliminate these biomolecules, thus specifically targeting neoplastic cells; however, enzyme therapeutics are susceptible to immune clearance, exhibit short half-lives, and require frequent administration. Encapsulation of therapeutic cargo within biocompatible and biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) is a strategy for controlled release. Unfortunately, PLGA NPs exhibit burst release of cargo shortly after delivery or upon introduction to aqueous environments where they decompose via hydrolysis. Here, we show the generation of hybrid silica-coated PLGA (SiLGA) NPs as viable drug delivery vehicles exhibiting sub-200 nm diameters, a metastable Zeta potential, and high loading efficiency and content. Compared to uncoated PLGA NPs, SiLGA NPs offer greater retention of enzymatic activity and slow the burst release of cargo. Thus, SiLGA encapsulation of therapeutic enzymes, such as asparaginase, could reduce frequency of administration, increase half-life, and improve efficacy for patients with a range of diseases.
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Affiliation(s)
- Kyle T. Gustafson
- Cancer Early Detection Advanced Research (CEDAR) Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
| | - Negin Mokhtari
- Cancer Early Detection Advanced Research (CEDAR) Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Electrical Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Elise C. Manalo
- Cancer Early Detection Advanced Research (CEDAR) Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Jose Montoya Mira
- Cancer Early Detection Advanced Research (CEDAR) Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
| | - Austin Gower
- Cancer Early Detection Advanced Research (CEDAR) Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Ya-San Yeh
- Cancer Early Detection Advanced Research (CEDAR) Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Mukanth Vaidyanathan
- Cancer Early Detection Advanced Research (CEDAR) Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Nano Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Sadik C. Esener
- Cancer Early Detection Advanced Research (CEDAR) Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Electrical Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA
- Department of Nano Engineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jared M. Fischer
- Cancer Early Detection Advanced Research (CEDAR) Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
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Hollander S, Viau K, Sacharow S. Pegvaliase dosing in adults with PKU: Requisite dose for efficacy decreases over time. Mol Genet Metab 2022; 137:104-106. [PMID: 35964530 DOI: 10.1016/j.ymgme.2022.08.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 11/28/2022]
Abstract
Novel pharmaceutical therapies such as pegvaliase, phenylalanine ammonia lyase (PAL), have enhanced disease control for many individuals with phenylketonuria (PKU). We present a retrospective chart review to assess pegvaliase doses over time in individuals followed at the Boston Children's Hospital PAL Clinic, including those who started pegvaliase in a clinical trial ("trial patients") and those who started after drug came to market ("post-market patients"). Trial patients were on pegvaliase an average of 4.8 years longer, and their mean current pegvaliase dose was 126 ± 92 compared to 223 ± 147 mg/week for post-market patients (p = 0.0155), suggesting that the pegvaliase dose for target efficacy may decrease over time in adults with PKU. In post-market patients, we demonstrated a significant, inverse correlation with dose change and number of weeks from response (r = -0.46, p = 0.046). The entire cohort showed significant variability in terms of time to achieve a therapeutic response, response dose, and current dose. Our data suggest that patients tolerate a reduction in pegvaliase dose over time while maintaining efficacy. This is a clinically meaningful finding as it indicates that patients may reduce number of weekly injections over time on pegvaliase.
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Affiliation(s)
- Suzanne Hollander
- Division of Genetics and Genomics, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA; Department of Clinical Nutrition, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA.
| | - Krista Viau
- Division of Genetics and Genomics, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Stephanie Sacharow
- Division of Genetics and Genomics, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA
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10
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Olofsson S, Gralén K, Hoxer C, Okhuoya P, Persson U. The impact on quality of life of diet restrictions and disease symptoms associated with phenylketonuria: a time trade-off and discrete choice experiment study. THE EUROPEAN JOURNAL OF HEALTH ECONOMICS : HEPAC : HEALTH ECONOMICS IN PREVENTION AND CARE 2022; 23:993-1005. [PMID: 34842989 DOI: 10.1007/s10198-021-01415-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 11/11/2021] [Indexed: 06/13/2023]
Abstract
Phenylketonuria (PKU) is a metabolic disorder leading to a deficiency in the metabolism of phenylalanine (Phe). Elevated Phe levels in the blood, tissue and brain may lead to emotional, cognitive, and physical symptoms in adults. To control blood Phe levels, most individuals with PKU need to follow a strict, life-long Phe-restricted diet. The main objective of this study was to estimate the impact of PKU-related disease symptoms and dietary restrictions on health-related quality of life (HRQoL). This study was designed as a web-based survey using the methods of Time Trade-Off (TTO) and Discrete Choice Experiment with duration (DCETTO) in a survey of the Swedish general population and population with PKU. Data were collected using questionnaires for TTO diet (n = 509), TTO symptoms (n = 507), and DCETTO (n = 1117). The disutility of diet restrictions ranged from 0.050 for a partially restricted diet without medical food to 0.193 for a fully restricted diet with medical food in the TTO (DCE: 0.043-0.108). The disutility of experiencing symptoms (emotional, cognitive and physical) ranged from 0.148 for mild symptoms to 0.593 for severe symptoms in the TTO (DCE: 0.122-1.522). The study shows that both diet and symptoms have a significant negative impact on HRQoL in PKU and that utility estimates are largely consistent across methods and samples.
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Affiliation(s)
- Sara Olofsson
- The Swedish Institute for Health Economics, IHE, Lund, Sweden.
| | - Katarina Gralén
- The Swedish Institute for Health Economics, IHE, Lund, Sweden
| | | | | | - Ulf Persson
- The Swedish Institute for Health Economics, IHE, Lund, Sweden
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11
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Burlina A, Biasucci G, Carbone MT, Cazzorla C, Paci S, Pochiero F, Spada M, Tummolo A, Zuvadelli J, Leuzzi V. Italian national consensus statement on management and pharmacological treatment of phenylketonuria. Orphanet J Rare Dis 2021; 16:476. [PMID: 34784942 PMCID: PMC8594187 DOI: 10.1186/s13023-021-02086-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/13/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by defects in the phenylalanine-hydroxylase gene (PAH), the enzyme catalyzing the conversion of phenylalanine to tyrosine. PAH impairment causes phenylalanine accumulation in the blood and brain, with a broad spectrum of pathophysiological and neurological consequences for patients. Prevalence of disease varies, with peaks in some regions and countries, including Italy. A recent expert survey described the real-life of clinical practice for PKU in Italy, revealing inhomogeneities in disease management, particularly concerning approach to pharmacotherapy with sapropterin hydrochloride, analogous of the natural PAH co-factor, allowing disease control in a subset of patients. Therefore, the purpose of this paper is to continue the work initiated with the expert survey paper, to provide national guidances aiming to harmonize and optimize patient care at a national level. PARTICIPANTS The Consensus Group, convened by 10 Steering Committee members, consisted of a multidisciplinary crowd of 46 experts in the management of PKU in Italy. CONSENSUS PROCESS The Steering Committee met in a series of virtual meeting in order to discuss on clinical focuses to be developed and analyzed in guidance statements, on the basis of expert practice based evidence, large systematic literature review previously performed in the expert survey paper, and evidence based consensus published. Statements were re-discussed and refined during consensus conferences in the widest audience of experts, and finally submitted to the whole consensus group for a modified-Delphi voting. RESULTS Seventy three statements, divided in two main clinical areas, PKU management and Pharmacotherapy, achieved large consensus in a multidisciplinary group of expert in different aspects of disease. Importantly, these statements involve guidances for the use of sapropterin dihydrochloride, still not sufficiently implemented in Italy, and a set of good practice to approach the use of novel enzyme replacement treatment pegvaliase. CONCLUSIONS This evidence-based consensus provides a minimum set of guidances for disease management to be implemented in all PKU centers. Moreover, these guidances represent the first statement for sapropterin dihydrochloride use, implementation and standardization in Italy, and a guide for approaching pegvaliase treatment at a national level on a consistent basis.
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Affiliation(s)
- Alberto Burlina
- Division of Inherited Metabolic Diseases, Reference Center for Expanded Newborn Screening, DIDAS Servizi Di Diagnostica Integrata, University Hospital Padova, 35128, Padua, Italy
| | - Giacomo Biasucci
- Maternal and Child Health Department, Pediatrics and Neonatology Unit, Guglielmo da Saliceto Hospital, 29121, Piacenza, Italy.
| | - Maria Teresa Carbone
- Pediatric Division, Metabolic and Rare Diseases, Santobono Pausilipon Hospital, 80122, Naples, Italy
| | - Chiara Cazzorla
- Division of Inherited Metabolic Diseases, Reference Center for Expanded Newborn Screening, DIDAS Servizi Di Diagnostica Integrata, University Hospital Padova, 35128, Padua, Italy
| | - Sabrina Paci
- Paediatric Department, ASST Santi Paolo E Carlo, San Paolo Hospital, University of Milan, 20142, Milan, Italy
| | - Francesca Pochiero
- Metabolic and Muscular Unit, A. Meyer Children's Hospital, Florence, Italy
| | - Marco Spada
- Department of Pediatrics, Regina Margherita Children's Hospital, University of Torino, 10126, Turin, Italy
| | - Albina Tummolo
- Metabolic Diseases Department, Clinical Genetics and Diabetology, Giovanni XXIII Children's Hospital, 70126, Bari, Italy
| | - Juri Zuvadelli
- Paediatric Department, ASST Santi Paolo E Carlo, San Paolo Hospital, University of Milan, 20142, Milan, Italy
| | - Vincenzo Leuzzi
- Department of Human Neuroscience, Unit of Child Neurology and Psychiatry, University La Sapienza, 00185, Rome, Italy
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12
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Vimalesvaran S, Dhawan A. Liver transplantation for pediatric inherited metabolic liver diseases. World J Hepatol 2021; 13:1351-1366. [PMID: 34786171 PMCID: PMC8568579 DOI: 10.4254/wjh.v13.i10.1351] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/23/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) remains the gold standard treatment for end stage liver disease in the pediatric population. For liver based metabolic disorders (LBMDs), the decision for LT is predicated on a different set of paradigms. With improved outcomes post-transplantation, LT is no longer merely life saving, but has the potential to also significantly improve quality of life. This review summarizes the clinical presentation, medical treatment and indications for LT for some of the common LBMDs. We also provide a practical update on the dilemmas and controversies surrounding the indications for transplantation, surgical considerations and prognosis and long terms outcomes for pediatric LT in LBMDs. Important progress has been made in understanding these diseases in recent years and with that we outline some of the new therapies that have emerged.
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Affiliation(s)
- Sunitha Vimalesvaran
- Paediatric Liver GI and Nutrition Center, King's College Hospital, London SE5 9RS, United Kingdom
| | - Anil Dhawan
- Paediatric Liver GI and Nutrition Center, King's College Hospital, London SE5 9RS, United Kingdom
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13
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Differences of Phenylalanine Concentrations in Dried Blood Spots and in Plasma: Erythrocytes as a Neglected Component for This Observation. Metabolites 2021; 11:metabo11100680. [PMID: 34677395 PMCID: PMC8537883 DOI: 10.3390/metabo11100680] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 11/17/2022] Open
Abstract
Monitoring phenylalanine (Phe) concentrations is critical for the management of phenylketonuria (PKU). This can be done in dried blood spots (DBS) or in EDTA plasma derived from capillary or venous blood. Different techniques are used to measure Phe, the most common being flow-injection analysis tandem mass spectrometry (FIA-MS-MS) and ion exchange chromatography (IEC). Significant differences have been reported between Phe concentrations in various sample types measured by different techniques, the cause of which is not yet understood. We measured Phe concentrations in 240 venous blood samples from 199 patients with hyperphenylalaninemia in dried blood spots, EDTA plasma and erythrocytes by FIA-MS-MS and IEC. Phe concentrations were significantly lower in erythrocytes than in plasma leading to about 19% lower Phe DBS concentrations compared with plasma independent from the method used for quantification. As most therapy recommendations for PKU patients are based on plasma concentrations reliable conversion of DBS into plasma concentrations is necessary. Variances of Phe concentrations in plasma and DBS are not linear but increases with higher concentrations indicating heteroscedasticity. We therefore suggest the slope of the 75th percentile from quantile regression as a correction factor.
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14
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Li Y, Tan Z, Zhang Y, Zhang Z, Hu Q, Liang K, Jun Y, Ye Y, Li YC, Li C, Liao L, Xu J, Xing Z, Pan Y, Chatterjee SS, Nguyen TK, Hsiao H, Egranov SD, Putluri N, Coarfa C, Hawke DH, Gunaratne PH, Tsai KL, Han L, Hung MC, Calin GA, Namour F, Guéant JL, Muntau AC, Blau N, Sutton VR, Schiff M, Feillet F, Zhang S, Lin C, Yang L. A noncoding RNA modulator potentiates phenylalanine metabolism in mice. Science 2021; 373:662-673. [PMID: 34353949 PMCID: PMC9714245 DOI: 10.1126/science.aba4991] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 08/31/2020] [Accepted: 06/25/2021] [Indexed: 12/13/2022]
Abstract
The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair -/- and Pah R408W/R408W mice and improved the Phe tolerance of these mice.
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Affiliation(s)
- Yajuan Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhi Tan
- Intelligent Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Yaohua Zhang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhao Zhang
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA
| | - Qingsong Hu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ke Liang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yao Jun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Youqiong Ye
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA
| | - Yi-Chuan Li
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA
| | - Chunlai Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lan Liao
- Genetically Engineered Mouse Core, Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jianming Xu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhen Xing
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yinghong Pan
- Department of Biochemistry and Biology, University of Houston, Houston, TX 77030, USA
| | - Sujash S Chatterjee
- Department of Biochemistry and Biology, University of Houston, Houston, TX 77030, USA
| | - Tina K Nguyen
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Heidi Hsiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sergey D Egranov
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - David H Hawke
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Preethi H Gunaratne
- Department of Biochemistry and Biology, University of Houston, Houston, TX 77030, USA
| | - Kuang-Lei Tsai
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA
| | - Leng Han
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA
| | - Mien-Chie Hung
- Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan
- Department of Biotechnology, Asia University, Taichung 413, Taiwan
| | - George A Calin
- Department of Translational Molecular Pathology, Division of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Fares Namour
- Department of Molecular Medicine and Reference Center for Inborn Errors of Metabolism, University Hospital of Nancy, Nancy F-54000, France
- INSERM, U1256, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France
| | - Jean-Louis Guéant
- Department of Molecular Medicine and Reference Center for Inborn Errors of Metabolism, University Hospital of Nancy, Nancy F-54000, France
- INSERM, U1256, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France
| | - Ania C Muntau
- University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany
| | - Nenad Blau
- Division of Metabolism, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland
| | - V Reid Sutton
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Manuel Schiff
- Necker Hospital, APHP, Reference Center for Inborn Error of Metabolism and Filière G2M, Pediatrics Department, University of Paris, Paris 75007, France
- Inserm UMR_S1163, Institut Imagine, Paris 75015, France
| | - François Feillet
- INSERM, U1256, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France.
- Pediatric Department Reference Center for Inborn Errors of Metabolism Children University Hospital Nancy, Nancy F-54000, France
| | - Shuxing Zhang
- Intelligent Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
- The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Chunru Lin
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Liuqing Yang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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15
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Viau K, Wessel A, Martell L, Sacharow S, Rohr F. Nutrition status of adults with phenylketonuria treated with pegvaliase. Mol Genet Metab 2021; 133:345-351. [PMID: 34116943 DOI: 10.1016/j.ymgme.2021.06.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/02/2021] [Accepted: 06/04/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Pegvaliase is an enzyme substitution therapy that reduces blood phenylalanine (Phe) in adults with phenylketonuria (PKU), and often allows normalization of protein intake (≥0.8 g protein/kg). Here we examine the nutrition status of adults with PKU consuming a normal protein intake without medical food after being treated with pegvaliase for ≥1 year. METHODS A cross-sectional study evaluating nutritional intake (3-day food record and food frequency questionnaire), anthropometrics, laboratory indices of protein, micronutrient, and essential fatty acid (EFA) status, and questionnaires evaluating food neophobia and Epicurean eating pleasure. RESULTS Participants (n = 18, 61% female) started pegvaliase 4.9 ± 2.1 years prior to enrollment and were aged 38.2 ± 8.8 years with a mean BMI of 29.2 ± 4.1 kg/m2. Participants consumed a mean of 73.2 ± 17.6 g protein/d (1.0 ± 0.3 g/kg/d). Eleven participants had low blood Phe (<30 μmol/L) with adequate protein intake and normal indices of protein status. Micronutrient and EFA concentrations were normal except for mildly low vitamin D (<30 ng/mL, n = 12). Intakes of sodium, saturated fat, and added sugars exceeded recommendations for healthy adults, though mean diet quality was comparable to a US adult reference population. Lower food neophobia scores correlated with an increased aesthetic appreciation of food. However, 53% of participants self-reported having moderate (n = 6) to high (n = 3) food neophobia. DISCUSSION Participants treated with pegvaliase consumed an unrestricted diet with adequate dietary protein and, overall, had normal protein, micronutrient, and fatty acid status. Despite low blood Phe, protein nutriture was not compromised. While nutritional deficiencies were not identified, diet quality was suboptimal and some participants reported food neophobia. Nutrition education remains an important component of care as patients adapt to a normal diet.
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Affiliation(s)
- Krista Viau
- Division of Genetics and Genomics, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, United States.
| | - Ann Wessel
- Division of Genetics and Genomics, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, United States
| | - Leslie Martell
- Division of Genetics and Genomics, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, United States
| | - Stephanie Sacharow
- Division of Genetics and Genomics, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, United States; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, United States
| | - Fran Rohr
- Met Ed, Boulder, CO 80302, United States
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16
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Lah M, McPheron M. Palynziq clinic: One year and 43 patients later. Mol Genet Metab 2021; 133:250-256. [PMID: 34074593 DOI: 10.1016/j.ymgme.2021.05.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/19/2021] [Accepted: 05/16/2021] [Indexed: 01/31/2023]
Abstract
Pegvaliase-pqpz (Palynziq) is an enzyme substitution therapy FDA approved May 2018 to treat phenylketonuria in adults with blood phenylalanine levels greater than 600 μmol/L (10 mg/dL). Pegvaliase is administered via subcutaneous injection and carries a high risk of side effects including anaphylaxis. A consensus statement on its use recommends careful education and monitoring of patients. We established a dedicated Palynziq Clinic in October 2018 with detailed protocols to minimize these risks. In the first year, we evaluated 43 patients, initiated Palynziq in 37 and transitioned two trial patients to commercial drug. 13/37 patients (35.1%) have sustained blood phenylalanine levels <360 μmol/L (6 mg/dL) without adjunct sapropterin dihydrochloride treatment or medical food. The timing and dosage needed to achieve a response did not correlate with patient weight, starting phenylalanine level, starting diet, or co-treatment with sapropterin dihydrochloride. Some patients had consistently low phenylalanine levels <30 μmol/L (0.5 mg/dL) and required doses as low as 20 mg weekly. Anaphylactic episodes were reported by 21.6% (8/37 patients) versus 10% seen in the clinical trial. Rates of other side effects were similar to or less than those in the trial. Adverse reactions commonly occurred shortly after dosage increases. We provide a model for safely introducing and managing pegvaliase in adult patients with PKU.
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Affiliation(s)
- Melissa Lah
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America.
| | - Molly McPheron
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America
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17
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Qi Y, Patel G, Henshaw J, Gupta S, Olbertz J, Larimore K, Harding CO, Merilainen M, Zori R, Longo N, Burton BK, Li M, Gu Z, Zoog SJ, Weng HH, Schweighardt B. Pharmacokinetic, pharmacodynamic, and immunogenic rationale for optimal dosing of pegvaliase, a PEGylated bacterial enzyme, in adult patients with phenylketonuria. Clin Transl Sci 2021; 14:1894-1905. [PMID: 34057292 PMCID: PMC8504851 DOI: 10.1111/cts.13043] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 12/03/2022] Open
Abstract
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 Anabaenavariabilis 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.
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Affiliation(s)
- Yulan Qi
- BioMarin Pharmaceutical Inc, Novato, CA, USA
| | - Gina Patel
- BioMarin Pharmaceutical Inc, Novato, CA, USA
| | | | - Soumi Gupta
- BioMarin Pharmaceutical Inc, Novato, CA, USA
| | - Joy Olbertz
- BioMarin Pharmaceutical Inc, Novato, CA, USA
| | | | - Cary O Harding
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
| | | | - Roberto Zori
- Division of Genetics and Metabolism, University of Florida, Gainesville, FL, USA
| | - Nicola Longo
- Division of Medical Genetics, University of Utah, Salt Lake City, UT, USA
| | - Barbara K Burton
- Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital, Chicago and Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Mingjin Li
- BioMarin Pharmaceutical Inc, Novato, CA, USA
| | - Zhonghua Gu
- BioMarin Pharmaceutical Inc, Novato, CA, USA
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18
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Burton BK, Longo N, Vockley J, Grange DK, Harding CO, Decker C, Li M, Lau K, Rosen O, Larimore K, Thomas J. Pegvaliase for the treatment of phenylketonuria: Results of the phase 2 dose-finding studies with long-term follow-up. Mol Genet Metab 2020; 130:239-246. [PMID: 32593547 DOI: 10.1016/j.ymgme.2020.06.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/08/2020] [Accepted: 06/11/2020] [Indexed: 01/28/2023]
Abstract
BACKGROUND Phenylketonuria (PKU) is characterized by a deficiency in phenylalanine hydroxylase (PAH) that may lead to elevated blood phenylalanine (Phe) and significant neurocognitive and neuropsychological comorbidities. Pegvaliase (PALYNZIQ®, BioMarin Pharmaceutical Inc.) is a PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), which converts Phe to trans-cinnamic acid and ammonia, and was approved in May 2018 in the United States and in May 2019 in the European Union for decreasing blood Phe levels in adults with PKU with blood Phe levels >600 μmol/L. The efficacy and safety of pegvaliase was assessed in two phase 2 dose-finding studies in adults with PKU (PAL-002, NCT00925054, and PAL-004, NCT01212744). Participants completing these studies could enroll in a long-term extension study (PAL-003, NCT00924703). METHODS Participants in PAL-002 received pegvaliase 0.001, 0.003, 0.01, 0.03, or 0.1 mg/kg weekly for 8 weeks, then continued treatment for a further 8 weeks with dose and/or frequency adjusted to achieve blood Phe concentrations of 60 to 600 μmol/L. Participants in PAL-004 received pegvaliase 0.001 to 0.4 mg/kg 5 days/week for 13 weeks, with modifications made to the starting dose in response to safety and/or efficacy, followed by 3 additional weeks of follow-up assessments. The maximum allowable daily dose in both studies was 1.0 mg/kg/day (5.0 mg/kg/week). Participants who completed any of the phase 2 studies (PAL-002; PAL-004; or a third phase 2 study, 165-205) were eligible to enroll in an open-label, multicenter, long-term extension study (PAL-003, NCT00924703). RESULTS Thirty-seven of the 40 enrolled participants completed PAL-002 and 15 of the 16 enrolled participants completed PAL-004. Mean blood Phe at baseline was 1311.0 (standard deviation [SD] 354) μmol/L in PAL-002 and 1482.1 (SD 363.5) μmol/L in PAL-004. Mean blood Phe did not substantially decrease with pegvaliase treatment in PAL-002 (-206.3 [SD 287.1] μmol/L at Week 16) or PAL-004 (-410.8 [SD 653.7] μmol/L at Week 13). In PAL-004, mean blood Phe dropped from baseline by 929.1 μmol/L (SD 691.1) by Week 2; subsequent to dose modifications and interruptions, this early decrease in mean Phe level was not sustained. With increased pegvaliase dose and duration in PAL-003, mean blood Phe levels steadily decreased from baseline, with mean reductions by Week 120 of 68.8% (SD 44.2%) in PAL-002 participants and 75.9% (SD 32.4%) in PAL-004 participants. All participants in PAL-002 and PAL-004 reported ≥1 adverse event (AE), with higher exposure-adjusted event rates in PAL-004. The majority of AEs were mild (87.2% in PAL-002, 86.7% in PAL-004) or moderate (12.4% in PAL-002, 13.3% in PAL-004). The most commonly reported AEs in PAL-002 were injection site reaction (50.0% of participants), headache (42.1%), injection site erythema (36.8%), nausea (34.2%), and arthralgia (29.0%), and in PAL-004 were arthralgia (75.0%), headache (62.5%), dizziness (56.3%), injection site erythema (56.3%), and injection site reaction (50.0%). CONCLUSIONS In two phase 2 dose-finding studies, pegvaliase did not lead to substantial blood Phe reductions. Higher and more frequent pegvaliase dosing in PAL-004 led to a substantial initial drop in blood Phe, but an increase in the number of hypersensitivity AEs and dose reductions or interruptions. With increased dose and duration of treatment in PAL-003, mean blood Phe reduction was substantial and sustained, and the frequency of hypersensitivity AEs decreased and stabilized. Together, these studies led to the development of an induction-titration-maintenance regimen that has been approved for pegvaliase, with patients starting at a low weekly dose that gradually increases in dose and frequency until they achieve a standard non-weight-based daily maintenance dose. This regimen has been tested in a third phase 2 study, as well as in two successful phase 3 studies of pegvaliase.
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Affiliation(s)
- Barbara K Burton
- Department of Pediatrics, Division of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E Chicago Ave, Chicago, IL 60611, United States of America.
| | - Nicola Longo
- Department of Pediatrics, Division of Medical Genetics, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, United States of America.
| | - Jerry Vockley
- Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh and Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, United States of America.
| | - Dorothy K Grange
- Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University, 660 S Euclid Ave, St. Louis, MO 63110, United States of America.
| | - Cary O Harding
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States of America.
| | - Celeste Decker
- Research and Development, BioMarin Pharmaceutical Inc., 105 Digital Dr, Novato, CA 94949, United States of America
| | - Mingjin Li
- Research and Development, BioMarin Pharmaceutical Inc., 105 Digital Dr, Novato, CA 94949, United States of America.
| | - Kelly Lau
- Research and Development, BioMarin Pharmaceutical Inc., 105 Digital Dr, Novato, CA 94949, United States of America.
| | - Orli Rosen
- Research and Development, BioMarin Pharmaceutical Inc., 105 Digital Dr, Novato, CA 94949, United States of America.
| | - Kevin Larimore
- Research and Development, BioMarin Pharmaceutical Inc., 105 Digital Dr, Novato, CA 94949, United States of America.
| | - Janet Thomas
- Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, 12605 E 16th St, Aurora, CO 80045, United States of America.
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Krämer J. Sustaining benefits of nutritional therapy in young adults with phenylketonuria - A 2 year prospective study. Mol Genet Metab Rep 2020; 22:100573. [PMID: 32099818 PMCID: PMC7026618 DOI: 10.1016/j.ymgmr.2020.100573] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 01/31/2020] [Indexed: 01/09/2023] Open
Abstract
Introduction Phenylketonuria (PKU) is an inborn error of metabolism, which is caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH). Life-long Phe-free diet impairs quality of life, especially in adolescents and young adults which take responsibility over their diet and therapy from their parents, but expect freedom in daily routine. Methods and results 105 patients with PKU were screened for eligibility for participating in this study. Data of 21 patients with genetic predictive value (GPV) ≤5 and age between 14 and 30 years were included in the analysis. Mean age of the study population was 22.6 ± 7.5 years, 8 patients (38%) were female. At baseline, structured counselling by a professional nutrionist was performed. Mean Phe-level at baseline was 926 ± 432 μmol/l, after six months Phe-levels were significantly reduced to 709 ± 314 μmol/l (p = .039), in total 4 additional patients (38% of the population) reached values within the therapeutic goal. After 12, 18 and 24 months, mean Phe-level elevated significantly to initial level (869 ± 427 μmol/l; p = .311). Mean daily intake of natural protein at baseline was 32.3 ± 24.3 g per day. There was a significant decrease after 6 months (26.9 ± 18.8 g/day; p = .049) and 12 months (25.9 ± 16.2 g/day; p = .30) compared to baseline. Values at 18 months (27.5 ± 9.2 g/day; p = .26) and 24 months (35.0 ± 22.3 g/day; p = .87) did not differ. Mean daily supplementation of Phe-free amino acids was 26.2 ± 19.2 g per day. In all follow-up examinations a significant increase compared to baseline values was calculated (42.4 ± 17.6 g/day after 6 moths (p = .028), 52.1 ± 29.9 g/day after 12 months (p ≤.01), 38.7 ± 20.3 g/day after 18 months (p < .01) and 39.3 ± 21.9 g/day after 24 months (p = .014)). At baseline, mean total protein intake (natural protein plus supplements) was 0.97 ± 0.42 g per kg body weight (g/kgBW). After 24 months the protein intake was within recommended levels. (1.23 ± 0.33 g/kgKB; p = .013). After 24 months, plasma Vitamin B12 increased to 424.8 ± 176.9 pg/ml (baseline 368.6 ± 205.6 pg/ml; p = .049) and Vitamin D increased to 30.4 ± 9.9 ng/ml (baseline 24.5 ± 10.1 ng/ml; p = .06). Conclusion Counselling by a professional nutrionist in young adults with PKU has clear short-term effects on plasma Phe-levels. Easy applicable therapeutic recommendations, as additional intake of amino acid supplement, are well tolerated and result in strict therapy adherence up to 24 months. Apart from that, the effects on Phe-levels seem only to sustain for about 6 months. More frequent nutritional counselling, i.e. at least two times per year, is recommended to preserve positive effects on Phe-levels. Lack of Vitamin B12 and Vitamin D still are common in PKU patients, but not necessarily need to be substituted. They can effectively be equalized by a well-balanced diet within 24 months.
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Affiliation(s)
- Johannes Krämer
- Corresponding author at: University of Ulm, Division of Pediatric Neurology and Inborn Errors of Metabolism, Eythstr. 24, 89075 Ulm, Germany.
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Krämer J. Case-control study about the acceptance of Pegvaliase in Phenylketonuria. Mol Genet Metab Rep 2020; 22:100557. [PMID: 31956507 PMCID: PMC6957785 DOI: 10.1016/j.ymgmr.2019.100557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 12/21/2019] [Indexed: 10/25/2022] Open
Abstract
Introduction Pegvaliase is a novel enzyme substitution therapy approved by the European Drug Administration (EDA) in May 2019 for the treatment of Phenylketonuria (PKU) in adults and children ≥16 years of age. The pegylated phenylalanine ammonia lyase is isolated from bacteria and therefore provokes multifarious immunogenic reactions. Thus, the selection of the right patient for a potential harmful treatment is essential for patient's contentedness and long-term therapy compliance. Methods and results 101 patients with PKU were screened for eligibility for an additional treatment with Pegvaliase. 51 patients were included in the study, 26 received a structural information about the new treatment for in mean 43 ± 12 min and clinical data and plasma Phe-levels were assessed. After 4 weeks of consideration the willing of treatment initiation as well as reasons for denial are registered. 7 patients (27%) concluded in beginning of treatment. Phe-level in this (acceptance) group were higher (1180 ± 231 μmol/l) compared to the denial group (930 ± 278 μmol/l, p = .01). After 4 weeks Phe-levels in the acceptance group remained stable (1264 ± 311 μmol/l, p = .26) while Phe-levels in the denial group decreased (779 ± 226 μmol/l, p < .01). Main reasons for denial of therapy were fear of adverse effects (47%), no need for additional treatment (26%) and the subcutaneous way of application (21%). Conclusion PKU patients have reservations against an invasive subcutaneous treatment for their disease. This is mainly caused by the form of application by syringe and the potential harmful side effects. Only less than one-third of the patients in our cohort are willing to start treatment. Besides that, most PKU patients seem to have untapped potential for self-contained reduction of Phe-levels only by being focused on their diet.
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Affiliation(s)
- Johannes Krämer
- Division of Inborn Errors of Metabolism, Children's Hospital, University of Ulm, Ulm, Germany.,Division of Pediatric Neurology, Children's Hospital, University of Ulm, Ulm, Germany
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Harding CO. Prospects for Cell-Directed Curative Therapy of Phenylketonuria (PKU). MOLECULAR FRONTIERS JOURNAL 2019; 3:110-121. [PMID: 32524084 PMCID: PMC7286632 DOI: 10.1142/s2529732519400145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Phenylketonuria (PKU) due to recessively inherited phenylalanine hydroxylase (PAH) deficiency is among the most common inborn errors of metabolism. Dietary therapy begun early in infancy prevents the major manifestations of the disease but shortcomings to treatment continue to exist including lifelong commitment to a complicated and unpalatable diet, poor adherence to diet in adolescence and adulthood, and consequently a range of unsatisfactory outcomes, including neuropsychiatric disorders, frequently develop. Novel treatments that do not strictly depend upon dietary protein restriction are actively sought. This review discusses the potential for and the limitations of permanently curative cell-directed treatment of PKU, including liver-directed gene therapy and gene editing, if initiated during early infancy. A fictional but realistic vignette of a family with a new baby girl recently diagnosed with PKU is presented. What is needed to permanently cure her?
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Affiliation(s)
- Cary O Harding
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Mailstop L-103, 3181 Sam Jackson Park Rd., Portland, OR 97239, USA
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Abstract
Phenylalanine hydroxylase (PAH) deficiency is an inborn error of metabolism that results in elevated phenylalanine levels in blood. The classical form of the disease with phenylalanine level > 1200 µmol/L in blood is called phenylketonuria (PKU) and is associated with severe intellectual disability when untreated. In addition, phenylalanine levels above the therapeutic range in pregnant female patients lead to adverse fetal effects. Lowering the plasma phenylalanine level prevents intellectual disability, maintaining the level in the therapeutic range of 120-360 µmol/L is associated with good outcome for patients as well as their pregnancies. Patient phenotypes are on a continuous spectrum from mild hyperphenylalaninemia to mild PKU, moderate PKU, and severe classic PKU. There is a good correlation between the biochemical phenotype and the patient's genotype. For over four decades the only available treatment was a very restrictive low phenylalanine diet. This changed in 2007 with the approval of cofactor therapy which is effective in up to 55% of patients depending on the population. Cofactor therapy typically is more effective in patients with milder forms of the disease and less effective in classical PKU. A new therapy has just been approved that can be effective in all patients with PAH deficiency regardless of their degree of enzyme deficiency or the severity of their phenotype. This article reviews the mainstay therapy, adjunct enzyme cofactor therapy, and the newly available enzyme substitution therapy for hyperphenylalaninemia. It also provides an outlook on emerging approaches for hyperphenylalaninemia treatment such as recruiting the microbiome into the therapeutic endeavor as well as therapies under development such as gene therapy.
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Affiliation(s)
- Uta Lichter-Konecki
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, School of Medicine, Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
| | - Jerry Vockley
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, School of Medicine, Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
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Zori R, Ahring K, Burton B, Pastores GM, Rutsch F, Jha A, Jurecki E, Rowell R, Harding C. Long-term comparative effectiveness of pegvaliase versus standard of care comparators in adults with phenylketonuria. Mol Genet Metab 2019; 128:92-101. [PMID: 31439512 PMCID: PMC9013411 DOI: 10.1016/j.ymgme.2019.07.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/30/2019] [Accepted: 07/30/2019] [Indexed: 12/20/2022]
Abstract
Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency, resulting in high blood and brain Phenylalanine (Phe) concentrations that can lead to impaired brain development and function. Standard treatment involves a Phe-restricted diet alone or in conjunction with sapropterin dihydrochloride in responsive patients. The Food and Drug Administration approved pegvaliase enzyme substitution therapy for adults with blood Phe >600 μmol/L in the US. Recently, the European Commission also approved pegvaliase for treatment of PKU patients aged 16 years or older with blood Phe >600 μmol/L. The analyses presented below were conducted to provide comparative evidence on long-term treatment effectiveness of pegvaliase versus standard of care in adults with PKU. Adult patients (≥18 years) with baseline blood Phe >600 μmol/L who had enrolled in the pegvaliase phase 2 and phase 3 clinical trials were propensity score-matched to historical cohorts of patients treated with "sapropterin + diet" or with "diet alone". These cohorts were derived from the PKU Demographics, Outcome and Safety (PKUDOS) registry and compared for clinical outcomes including blood Phe concentration and natural intact protein intake after 1 and 2 years. Propensity scores were estimated using logistic regression with probability of treatment as outcome (i.e. pegvaliase, "sapropterin + diet", or "diet alone") and patient demographic and disease severity covariates as predictors. An additional analysis in adult PKU patients with baseline blood Phe ≤600 μmol/L comparing non-matched patient groups "sapropterin + diet" to "diet alone" using PKUDOS registry data only was also conducted. The analyses in patients with baseline blood Phe >600 μmol comparing pegvaliase with "sapropterin + diet" (N = 64 matched pairs) showed lower mean blood Phe concentrations after 1 and 2 years with pegvaliase (505 and 427 μmol/L) versus "sapropterin + diet" (807 and 891 μmol/L); mean natural intact protein intake after 1 and 2 years was 49 and 57 g/day respectively with pegvaliase versus 23 and 28 g/day with "sapropterin + diet". The analysis comparing pegvaliase with "diet alone" (N = 120 matched pairs) showed lower mean blood Phe at 1 and 2 years with pegvaliase (473 and 302 μmol/L) versus "diet alone" (1022 and 965 μmol/L); mean natural intact protein intake after 1 and 2 years was 47 and 57 g/day with pegvaliase and 27 and 22 g/day with "diet alone". Considerably more patients achieved blood Phe ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe after 1 and 2 years of pegvaliase versus standard treatments. The analysis in patients with baseline blood Phe ≤600 μmol/L showed lower blood Phe after 1 and 2 years with "sapropterin + diet" (240 and 324 μmol/L) versus "diet alone" (580 and 549 μmol/L) and greater percentages of patients achieving blood Phe targets ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe. These results support pegvaliase as the more effective treatment option to lower Phe levels in adults with PKU who have difficulty keeping blood Phe ≤600 μmol/L with "diet alone". For patients with blood Phe ≤600 μmol/L, adding sapropterin to dietary management is an appropriate treatment option, for those responsive to the treatment.
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Affiliation(s)
- Roberto Zori
- University of Florida Health, Gainesville, FL, USA.
| | - Kirsten Ahring
- Copenhagen University Hospital, Department of Paediatrics, PKU Clinic, Copenhagen, Denmark.
| | | | - Gregory M Pastores
- Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland.
| | - Frank Rutsch
- Münster University Children's Hospital, Department of General Pediatrics, Münster, Germany.
| | | | | | | | - Cary Harding
- Oregon Health & Science University, Portland, OR, USA.
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Hausmann O, Daha M, Longo N, Knol E, Müller I, Northrup H, Brockow K. Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy. Mol Genet Metab 2019; 128:84-91. [PMID: 31375398 DOI: 10.1016/j.ymgme.2019.05.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/13/2019] [Accepted: 05/13/2019] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To provide recommendations for managing hypersensitivity adverse events (HAEs) to an injectable enzyme substitution therapy (pegvaliase, a PEGylated phenylalanine ammonia lyase enzyme) in adult patients with phenylketonuria (PKU). METHODS Eight European academic immunology experts with a broad range of experience in hypersensitivity, anaphylaxis, and/or drug reactions, and two geneticists from the USA with pegvaliase experience convened for two advisory board meetings. Efficacy, safety, and immunological profile of pegvaliase were discussed with the objective of developing recommendations for the clinical management of HAEs associated with pegvaliase treatment. RESULTS Based on available immunogenicity data, it was concluded that pegvaliase induces a Type III hypersensitivity reaction, causing HAEs with peak event rates during induction/titration and a decline over time during maintenance therapy. The decline in HAEs with longer duration of therapy was considered to likely be driven by anti-drug antibody affinity maturation, reduced immune complex formation, and decreased complement activation over time. Immunology and PKU experts unanimously supported that the use of an induction, titration, and maintenance dosing regimen and implementation of several risk mitigation strategies contributed to the improvement of tolerability over time. Key risk mitigation strategies utilized in the Phase 3 clinical trials such as premedication with H1-receptor antagonists, allowance for a longer titration period after an HAE, patient education, and requirement to carry auto-injectable adrenaline (epinephrine) should be continued in clinical practice. A tool for administration of auto-injectable adrenaline in patients using pegvaliase was suggested. It was added that after the occurrence of a severe HAE a temporary dose reduction is more likely to improve tolerability than treatment interruption. CONCLUSIONS Overall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable adrenaline is recommended. Because pegvaliase offers the possibility to normalize diet, while maintaining blood phenylalanine within the recommended therapeutic range, safe use of this medication in the clinical setting is important. Ongoing monitoring of long-term clinical safety of patients on pegvaliase treatment in the commercial setting was recommended.
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Affiliation(s)
- Oliver Hausmann
- Adverse Drug Reactions, Analysis & Consulting (ADR-AC) GmbH, Bern, and Research Affiliate, Department of Rheumatology, Immunology and Allergology Inselspital, University of Bern, Switzerland
| | - Mohamed Daha
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - Nicola Longo
- Department of Pediatrics, University of Utah, Salt Lake City, UT, USA
| | - Edward Knol
- Department of Immunology and Dermatology, Department of Allergology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Ingo Müller
- Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hope Northrup
- Department of Pediatrics, The McGovern Medical School, Houston, TX, USA
| | - Knut Brockow
- Department of Dermatology and Allergy, School of Medicine Technical University of Munich, Munich, Germany.
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Depletion of interfering IgG and IgM is critical to determine the role of IgE in pegvaliase-associated hypersensitivity. J Immunol Methods 2019; 468:20-28. [DOI: 10.1016/j.jim.2019.03.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 10/23/2018] [Accepted: 03/13/2019] [Indexed: 01/06/2023]
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Longo N, Dimmock D, Levy H, Viau K, Bausell H, Bilder DA, Burton B, Gross C, Northrup H, Rohr F, Sacharow S, Sanchez-Valle A, Stuy M, Thomas J, Vockley J, Zori R, Harding CO. Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria. Genet Med 2018; 21:1851-1867. [PMID: 30546086 PMCID: PMC6752676 DOI: 10.1038/s41436-018-0403-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 11/29/2018] [Indexed: 11/23/2022] Open
Abstract
Purpose Phenylketonuria (PKU) is a rare metabolic disorder that requires
life-long management to reduce phenylalanine (Phe) concentrations within the
recommended range. The availability of pegvaliase (PALYNZIQ™, an enzyme that can
metabolize Phe) as a new therapy necessitates the provision of guidance for its
use. Methods A Steering Committee comprising 17 health-care professionals with
experience in using pegvaliase through the clinical development program drafted
guidance statements during a series of face-to-face meetings. A modified Delphi
methodology was used to demonstrate consensus among a wider group of health-care
professionals with experience in using pegvaliase. Results Guidance statements were developed for four categories: (1)
treatment goals and considerations prior to initiating therapy, (2) dosing
considerations, (3) considerations for dietary management, and (4) best
approaches to optimize medical management. A total of 34 guidance statements
were included in the modified Delphi voting and consensus was reached on all
after two rounds of voting. Conclusion Here we describe evidence- and consensus-based recommendations for
the use of pegvaliase in adults with PKU. The manuscript was evaluated against
the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument
and is intended for use by health-care professionals who will prescribe
pegvaliase and those who will treat patients receiving pegvaliase.
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Affiliation(s)
- Nicola Longo
- Division of Medical Genetics, University of Utah, Salt Lake City, UT, USA.
| | - David Dimmock
- Rady Children's Institute for Genomic Medicine, San Diego, CA, USA
| | - Harvey Levy
- Division of Genetics and Genomics, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Krista Viau
- Division of Genetics and Genomics, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Heather Bausell
- Division of Clinical Nutrition & Genetics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Deborah A Bilder
- Department of Psychiatry, University of Utah, Salt Lake City, UT, USA
| | - Barbara Burton
- Department of Medical Genetics, Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Christel Gross
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Hope Northrup
- Division of Medical Genetics, Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Fran Rohr
- Nutrition Center, Boston Children's Hospital, Boston, MA, USA
| | - Stephanie Sacharow
- Division of Genetics and Genomics, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | | | - Mary Stuy
- Department of Medical and Molecular Genetics, IU School of Medicine, Indianapolis, IN, USA
| | - Janet Thomas
- Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA
| | - Jerry Vockley
- Department of Pediatrics University of Pittsburgh School of Medicine, Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
| | - Roberto Zori
- Division of Genetics and Metabolism, University of Florida, Gainesville, FL, USA
| | - Cary O Harding
- Departments of Molecular and Medical Genetics and Pediatrics, Oregon Health & Science University, Portland, OR, USA
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