Last update 01 Nov 2024

Hyperphenylalaninemia

Last update 01 Nov 2024

Basic Info

Synonyms

Hyperphenylalaninaemia, Hyperphenylalaninemia, Hyperphenylalaninemia (disorder)

+ [8]

Introduction

any of several autosomal recessive defects in the hydroxylation of phenylalanine resulting in accumulation and excretion of dietary phenylalanine; most commonly the defect is in the enzyme phenylalanine 4-monooxygenase; the most severe manifestation of this is classic PHENYLKETONURIA, but two benign forms also occur; rarely the defect is one of tetrahydrobiopterin metabolism.

Drugs associated with Hyperphenylalaninemia

Sapropterin Dihydrochloride

Target

PAH

Mechanism

PAH agonists

Active Org.

Dipharma Francis Srl [+5]

Originator Org.

Daiichi Sankyo Co., Ltd.

Active Indication

Hyperphenylalaninemia, BH4-Deficient, B [+4]

Inactive Indication

Albuminuria [+12]

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date27 Mar 1992

L-Sepiapterin

Target

eNOS

Mechanism

eNOS modulators

Active Org.

PTC Therapeutics, Inc.

Originator Org.

Censa Pharmaceuticals, Inc.Startup

Active Indication

Phenylketonurias

Inactive Indication

Diabetic Gastroparesis [+3]

Drug Highest PhaseNDA/BLA

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Phelimin

Target-

Mechanism-

Active Org.-

Originator Org.

MipSalus ApS

Active Indication-

Inactive Indication

Hyperphenylalaninemia [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with Hyperphenylalaninemia

NCT04272736 / Not yet recruitingNot Applicable

Evaluating the Compliance, Acceptability, Safety and Tolerance of a Lower Calorie Protein Substitute for the Dietary Management of Phenylketonuria in Children and Adults - a Pilot Study

This study will evaluate the compliance, acceptability, gastrointestinal (GI) tolerance and safety of a lower calorie amino acid based liquid protein substitute for patients with Phenylketonuria (PKU) or hyperphenylalaninemia (HPA).

Start Date01 Dec 2023

Sponsor / Collaborator

Nutricia UK Ltd

DRKS00031972 / SuspendedNot ApplicableIIT

Study to evaluate the reliability and practicability of the PKU Sensor and PKU App in home settings of patients with phenylketonuria - PKU Sensor

Start Date01 Aug 2023

Sponsor / Collaborator

University Hospital Heidelberg

DRKS00030654 / RecruitingNot ApplicableIIT

Evaluation of the metabolic situation on pregnancy course and outcome in patients with phenylketonuria - Pregnancy_PKU

Start Date02 Nov 2022

Sponsor / Collaborator-

100 Clinical Results associated with Hyperphenylalaninemia

100 Translational Medicine associated with Hyperphenylalaninemia

0 Patents (Medical) associated with Hyperphenylalaninemia

1,392

Literatures (Medical) associated with Hyperphenylalaninemia

01 Dec 2024·Molecular Genetics and Metabolism Reports

Health economic impact of patients with phenylketonuria (PKU) in France – A nationwide study of health insurance claims data

Article

Author: Schneider, Kim Maren ; Jacob, Christian ; Douillard, Claire ; Charrière, Sybil ; Bouée, Stéphane ; Theil, Julia ; Maillot, Francois ; Arnoux, Jean-Baptiste

BackgroundPhenylketonuria (PKU) is an inherited metabolic disease. If left untreated, it can lead to severe irreversible intellectual disability and can cause seizures, behavior disturbance, and white matter disease. This study aimed at evaluating the health economic impact of patients with PKU in France.MethodsThis retrospective observational study used health insurance claims data from the French SNDS (Système National des Données de Santé) database, which contains data from over 66 million French inhabitants. Patients with PKU were identified by ICD-10 diagnosis codes E70.0 (PKU) and E70.1 (Other hyperphenylalaninemia) documented as a chronic condition (affection de longue durée - ALD) or in the inpatient setting in the SNDS database between 2006 and 2018. Patients with PKU were matched to controls without PKU by age, sex, and region. Patients with early- and late-diagnosed PKU were defined as patients born after and before the implementation of nationwide newborn screening in France in 1972, respectively. Outcomes were analyzed for the year 2018.ResultsOverall, 3549 patients with PKU were identified in the database on January 1st, 2018. Of those, 3158 patients versus 15,703 controls with at least one healthcare consumption in 2018 were available for outcome analyses. Patients with PKU had 7.7 times higher healthcare costs than non-PKU controls in 2018 (€11,144 versus 1456 mean costs; p < 0.0001). Pharmaceutical costs including dietary amino acid supplements were the cost driver and contributed 80.0% of the overall mean difference (MD) between patients with PKU and matched non-PKU controls. More than half (52.4%) of the mean pharmaceutical costs per patient with PKU was attributable to medical foods including dietary amino acid supplements.Of the 3158 patients with PKU, 2548 (80.7%) were classified as early-diagnosed and 610 (19.7%) as late-diagnosed. Increased healthcare costs, in comparison to non-PKU controls, were more evident in early-diagnosed patients (€11,263 versus €855 mean costs; 13.2-fold increase; p < 0.0001). For patients with late-diagnosed PKU, healthcare costs were 2.7-fold higher compared to matched non-PKU controls (€10,644 versus €3951 mean costs; p < 0.0001). Outpatient pharmaceutical costs accounted for 89.1% of the MD between early-diagnosed patients and controls. Among late-diagnosed patients, 55.5% of the MD were attributable to costs for inpatient care, followed by costs for outpatient care (23.9%) and outpatient pharmaceutical costs (20.6%).ConclusionThe results indicate that PKU is associated with substantially increased health care costs compared to non-PKU controls in France. The health economic impact was most evident in patients with early-diagnosed PKU due to increased outpatient pharmaceutical costs, especially for medical foods including dietary amino acid supplements. For late-diagnosed and by definition older patients with PKU, the excess costs compared with matched controls were mostly driven by costs for inpatient care.

01 Dec 2024·Genetics in Medicine

Mapping the genetic landscape of treatable inherited metabolic disorders in a large Middle Eastern biobank

Article

Author: Afifi, Nahla ; Akil, Ammira ; Abdi, Mona ; Al-Maraghi, Aljazi ; Alvi, Muhammad ; Fakhro, Khalid A. ; Ismail, Said I. ; Badii, Ramin ; Aliyev, Elbay ; Puthen, Jithesh V. ; Saad, Chadi ; Fethnou, Eleni ; Althani, Asmaa ; Tatari, Zohreh ; Krishnamoorthy, Navaneethakrishnan ; Ben-Omran, Tawfeg ; Alshafai, Mashael ; Poolat, Shafeeq ; Liu, Wei ; Temanni, Ramzi ; Ennaifar, Maryem ; Abdellatif, Rania ; Yasin, Heba ; Alkhayat, Eiman ; Chouchane, Lotfi ; Khatib, Mohammedhusen ; El Khouly, Ahmed ; Devadoss Gandhi, Geethanjali ; Lorenz, Stephan ; Albagha, Omar ; Alkuwari, Fatima ; Mbarek, Hamdi ; Al-Ali, Rashid ; Darwish, Dima ; Fadl, Tasnim ; Zaid, Tariq Abu ; Saqri, Tariq Abu ; Al-Sarraj, Yasser ; Syed, Najeeb ; Qafoud, Fatima ; Badji, Radja ; Almabrazi, Hakeem ; Al-Khodor, Souhaila ; Hamza, Mehshad ; Vempalli, Fazulur Rehaman ; Pathare, Tushar ; Mokrab, Younes ; Al-Saei, Omayma ; Tomei, Sara ; Suhre, Karsten ; Al-Muftah, Wadha ; Estivill, Xavier ; Akil, Ammira A.

PURPOSETo date, approximately 1400 inherited metabolic disorders (IMDs) have been described, some of which are treatable. It is estimated that 2% to 3% of live births worldwide are affected by treatable IMDs. Roughly 80% of IMDs are autosomal recessive, leading to a potentially higher incidence in regions with high consanguinity.METHODOLOGYThe study utilized genome sequencing data from 14,060 adult Qatari participants who were recruited by the Qatar Biobank and sequenced by the Qatar Genome Program. The genome sequencing data were analyzed for 125 nuclear genes known to be associated with 115 treatable IMDs.RESULTSOur study identified 253 pathogenic/likely pathogenic single-nucleotide variations associated with 69 treatable IMDs, including 211 known and 42 novel predicted loss-of-function variants. We estimated that approximately 1 in 13 unrelated individuals (8%) carry a heterozygous pathogenic variant for at least 1 of 46 treatable IMDs. Notably, phenylketonuria/hyperphenylalaninemia and homocystinuria had among the highest carrier frequencies (1 in 68 and 1 in 85, respectively).CONCLUSIONPopulation-based studies of treatable IMDs, particularly in globally under-studied populations, can identify high-frequency alleles segregating in the community and inform public health policies, including carrier and newborn screening.

01 Oct 2024·The Lancet

Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial

Article

Author: Opladen, Thomas ; Sacharow, Stephanie ; Lah, Melissa ; Campistol Plana, Jaume ; Tchan, Michel ; Cabrales Guerra, Ixiu Del Carmen ; Chakrapani, Anupam ; Gao, Lan ; Mungan, Halise Neslihan ; Northrup, Hope ; Bratkovic, Drago ; Kiykim, Ertugrul ; Zhao, Zhenming ; Guimas, Arlindo ; Rutsch, Frank ; Ingalls, Kimberly ; Larkin, Alexandra ; Oliveira, Anabela ; Lund, Allan ; Guilder, Laura ; Cabrales Guerra, Ixiu del Carmen ; Bélanger-Quintana, Amaya ; Muntau, Ania C ; Khan, Aneal ; Agladze, Dodo ; Zori, Roberto ; Margvelashvili, Lali ; Minami, Maria Avanise Yumi ; MacDonald, Anita ; Milner, Sarah ; Schwartz, Ida Vanessa D ; Ezgu, Fatih ; Peters, Heidi ; Greenbaum, Rochelle ; Hughes, Catalina ; Smith, Neil ; Longo, Nicola ; Vijay, Suresh ; Feillet, François

BACKGROUNDPhenylketonuria is an inherited condition characterised by neurotoxic accumulation of phenylalanine (Phe). APHENITY assessed the efficacy and safety of orally administered synthetic sepiapterin in children and adults with phenylketonuria.METHODSAPHENITY was a phase 3, randomised, double-blind, placebo-controlled study performed at 34 clinics, hospitals, and university sites in 13 countries. Individuals of all ages with a clinical diagnosis of phenylketonuria were eligible for inclusion if they had a blood Phe concentration of 360 μmol/L or higher at study entry, whereas individuals with hyperphenylalaninaemia due to pathogenic variants in GCH1, PTS, QDPR, SPR, and PCBD1, consistent with a diagnosis of primary BH₄ deficiency, were excluded. Part 1 was a 14-day open-label assessment of blood Phe concentration response to sepiapterin. In part 2, sepiapterin-responsive participants were randomly assigned (1:1) by a web-response system based on a block randomisation schedule (permuted block size of 2 and 4) to 6 weeks of sepiapterin (forced-dose escalation: 20, 40, and 60 mg/kg per day per consecutive 2-week period) or placebo. The investigational drug and placebo were identical in their appearance and delivery. Dried blood samples were collected for analysis of Phe concentration on days -1, 1 (before dose was administered), 5, 10, 14, 19, 24, 28, 33, 38, and 42 in part 2, either in-clinic or at home. The primary endpoint for part 2, mean change from baseline in blood Phe after 6 weeks, was assessed in the primary analysis set of participants with at least a 30% reduction in blood Phe concentration in part 1, who took at least one dose in part 2. Safety was evaluated in all participants receiving at least one dose of treatment. The completed study is registered at EudraCT (2021-000474-29) and ClinicalTrials.gov (NCT05099640).FINDINGSAPHENITY was conducted between Sept 30, 2021, and April 3, 2023. 187 people were assessed for eligibility, of whom 157 were enrolled. In part 1, 156 participants were assessed or evaluated, of whom 114 (73%) were sepiapterin-responsive (ie, ≥15% reduction in blood Phe from baseline). In part 2, 98 participants (49 in the placebo group and 49 in the sepiapterin group) were in the primary analysis set. There was a significant reduction of blood Phe concentration after 6 weeks of sepiapterin (-63%, SD 20) compared with placebo (1%, 29; least squares mean change -395·9 μmol/L, SE 33·8; p<0·0001). Treatment-emergent adverse events were reported in 33 (59%) of 56 participants who received sepiapterin and 18 (33%) of 54 participants who received placebo. Most treatment-emergent adverse events were mild gastrointestinal events (11 [20%] of 56 participants who received sepiapterin and ten [19%] of 54 participants who received placebo) that resolved quickly. There were no deaths and no serious or severe adverse events.INTERPRETATIONSepiapterin is a promising oral therapy for individuals with phenylketonuria, was well tolerated, and resulted in significant and clinically meaningful reductions in blood Phe concentration in participants with varying disease severity.FUNDINGPTC Therapeutics.

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Hyperphenylalaninemia

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