Italian national consensus statement on management and pharmacological treatment of phenylketonuria

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.

Newborn Screening and Treatment of Phenylketonuria: Projected Health Outcomes and Cost-Effectiveness

The objective of this study was to evaluate the cost-effectiveness of newborn screening and treatment for phenylketonuria (PKU) in the context of new data on adherence to recommended diet treatment and a newly available drug treatment (sapropterin dihydrochloride). A computer simulation model was developed to project outcomes for a hypothetical cohort of newborns with PKU. Four strategies were compared: (1) clinical identification (CI) with diet treatment; (2) newborn screening (NBS) with diet treatment; (3) CI with diet and medication (sapropterin dihydrochloride); and (4) NBS with diet and medication. Data sources included published literature, primary data, and expert opinion. From a societal perspective, newborn screening with diet treatment had an incremental cost-effectiveness ratio of $6400/QALY compared to clinical identification with diet treatment. Adding medication to NBS with diet treatment resulted in an incremental cost-effectiveness ratio of more than $16,000,000/QALY. Uncertainty analyses did not substantially alter the cost-effectiveness results. Newborn screening for PKU with diet treatment yields a cost-effectiveness ratio lower than many other recommended childhood prevention programs even if adherence is lower than previously assumed. Adding medication yields cost-effectiveness results unlikely to be considered favorable. Future research should consider conditions under which sapropterin dihydrochloride would be more economically attractive.

Response to sapropterin hydrochloride (Kuvan®) in children with phenylketonuria (PKU): a clinical trial

BackgroundPhenylketonuria (PKU) is one of the most common types of inborn error of metabolism. The mainstay of therapy for PKU has been dietary phenylalanine (Phe) restriction. Sapropterin dihydrochloride has been shown to be effective in reducing Phe levels in PKU patients.MethodsThis study was a clinical trial performed in the pediatric endocrine clinic of Imam Reza Hospital, Mashhad, Iran.ResultsAll children between 1 and 10 years of age with a diagnosis of PKU whose serum Phe levels were between 120 and 360 μmol/L, in Khorasan Razavi province in the north-east of Iran, were enrolled. Twenty-four patients were enrolled in the study.Intervention: A free diet for 72 h was allowed and then a 20-mg/kg/day dose of Kuvan®was administered. More than 30% reduction in blood Phe levels was described as responsive. Eight patients responded to the loading test and were eligible for the second stage of the study. In this stage, Phe powder in combination with Kuvan was provided. Patients’ serum Phe was measured weekly for 3 months. All eight patients showed Phe tolerance in 3 months, and their serum Phe levels remained within the range.ConclusionsTreatment with Kuvan can help reduce blood Phe levels in our pediatric PKU population and allows patients to follow a more liberal diet.

PP14 Budget Impact Of Sapropterin Dihydrochloride For Phenylketonuria

IntroductionThe National Committee for Health Technology Incorporation (CONITEC) evaluates health technologies to recommend their inclusion or exclusion within the Brazilian Public Health System (SUS), and uses the budget impact assessment to estimate costs to the system. The Ministry of Health (MS) guideline recommends treatment of phenylketonuria (PKU) with restricted phenylalanine diet and phenylalanine-free amino acid formula (PFAAf) supplementation. CONITEC evaluated the inclusion of sapropterin dihydrochloride for PKU in the SUS.MethodsThe population eligible for treatment was evaluated by the number of patients receiving PFAAf between 2014 and 2017 registered in the SUS. Patients were stratified by age/weight and a simple linear regression was performed to estimate the future population. The costs of treatment and testing the responsiveness of sapropterin dihydrochloride were estimated according to the recommended dosage guideline of the MS, leaflet and public purchasing prices. A univariate deterministic sensitivity analysis was performed to evaluate different prices, responsiveness test methods and variations in the reduction of formula use.ResultsThe incorporation of sapropterin dihydrochloride would generate an incremental budget impact in the SUS of around BRL 79 million (USD 21.7 million) in 2019 and BRL 300 million (USD 82.1 million) in five years (2019-2023). The univariate sensitivity analysis estimated that the incremental budget impact could be between BRL 66 and BRL 103 million (USD 18 and USD 28 million) in the first year and between BRL 251 and BRL 388 million (USD 69 and USD 106 million) in five years. Sensitivity analysis showed that the price of sapropterin dihydrochloride was the most sensitive variable in the model.ConclusionsThe incorporation of sapropterin dihydrochloride in the SUS represents a significant budgetary impact and covers a small number of patients. Sapropterin dihydrochloride was recommended by CONITEC for the treatment of women with PKU, with a positive drug responsiveness test, and who are in the preconception period or in the gestational period.