Development of a practical dietitian road map for the nutritional management of phenylketonuria (PKU) patients on pegvaliase

Funding Information: Outside the submitted work, the authors disclose the following. Bausell H received personal fees from BioMarin, Ultragenyx, Horizon and Vitaflo. Bélanger-Quintana A reports personal fees from BioMarin, Nutricia, Vitaflo, Orphan Europe, Takeda and Genzyme. Rocha JC received research grants from BioMarin, Glutamine and Cambrooke, as well as personal fees from BioMarin, Applied Pharma Research, Nutricia, Merck Serono, Vitaflo, Cambrooke, PIAM and Lifediet. MacDonald A reports research funding from BioMarin, Nutricia, Applied Pharma Research, Vitaflo, Galen, Metax, Mevalia and Arla, as well as lecture fees from BioMarin, Applied Pharma Research, Nutricia and Vitaflo, and consultancy fees from BioMarin, Applied Pharma Research, Arla, Nutricia and Vitaflo. Met Ed reports grant funding from BioMarin, Nutricia, Vitaflo and Horizon Pharmaceuticals. Bernstein L and Rohr F report lecture fees from Vitaflo. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.Background: The metabolic dietitian/nutritionist (hereafter ‘dietitian’) plays an essential role in the nutritional management of patients with phenylketonuria (PKU), including those on pegvaliase. Currently, more educational support and clinical experience is needed to ensure that dietitians are prepared to provide optimal nutritional management and counselling of pegvaliase-treated patients. Methods: Via a face-to-face data-review meeting, followed by a virtual consolidation meeting, a group of expert dietitians and one paediatrician discussed and developed a series of recommendations on the nutritional evaluation and management of patients receiving pegvaliase. The consensus group consisted of 10 PKU experts: six dietitians and one paediatrician from Europe and three dietitians from the US. One European and three US dietitians had experience with pegvaliase-treated patients. Results: The consensus group recommended that a physician, dietitian and nurse are part of the pegvaliase treatment team. Additionally, a psychologist/counsellor should be included if available. Practical proposals for the nutritional evaluation of pegvaliase-treated patients at baseline, during the induction and titration phases and for long-term maintenance were developed. The consensus group suggested assessment of blood Phe at least monthly or every 2 weeks in the event of low blood Phe (i.e., blood Phe <30 μmol/L). It may be appropriate to increase blood Phe monitoring when adjusting protein intake and/or pegvaliase dose. It was recommended that natural protein intake is increased by 10–20 g increments if blood Phe concentrations decrease to <240 μmol/L in patients who are not meeting the dietary reference intake for natural protein of 0.8 g/kg. It was proposed that with pegvaliase treatment blood Phe levels could be maintained <240 μmol/L but more evidence on the safety of achieving physiological blood Phe levels is necessary before any recommendation on the lower blood Phe target can be given. Finally, both patients and dietitians should have access to educational resources to optimally support patients receiving pegvaliase. Conclusion: This practical road map aims to provide initial recommendations for dietitians monitoring patients with PKU prescribed pegvaliase. Given that practical experience with pegvaliase is still limited, nutritional recommendations will require regular updating once more evidence is available and clinical experience evolves.publishersversionpublishe

Use of pegvaliase in the management of phenylketonuria: Case series of early experience in US clinics

Objective: To present a case series that illustrates real-world use of pegvaliase based on the initial experiences of US healthcare providers. Methods: Sixteen healthcare providers from 14 centers across the US with substantial clinical experience in treating patients with phenylketonuria (PKU) with pegvaliase in the two-plus years since FDA approval (May 2018) provided cases that exemplified important lessons from their initial experiences treating patients with pegvaliase. Key lessons from each case and takeaway points were discussed in both live and virtual meetings. Results: Fifteen cases of adults with PKU (eight males, seven females), representing a spectrum of age (18 to 53 years), previous PKU care, comorbidities, and socioeconomic situations were reviewed and discussed. Full extended case reports are included in the Supplement. The cases showed that treating patients with a daily injectable can be challenging due to a patient's financial problems, treatment challenges, and neuropsychological and psychiatric comorbidities, which can be identified before starting pegvaliase, but do not prohibit successful treatment. The authors agreed that patient education on adverse events (AEs), time to efficacy, dietary changes, and food preparation is an ongoing process that should start prior to initiating pegvaliase treatment. Treatment goals and planned dietary changes once efficacy is reached should be defined prior to treatment initiation and re-evaluated throughout the course of therapy. Each patient's titration schedule and dietary adjustments are unique, depending on occurrence of AEs and individual goals of treatment. Despite the AE profile of pegvaliase, all but two patients remained motivated to continue treatment and achieved efficacy (except one patient in whom titration was still ongoing). AEs occurring early in the treatment pathway may require prolongation of the titration phase and/or concomitant medication use, but do not seem indicative of future tolerability or eventual efficacy. Close follow-up of patients during titration and maintenance to help with dietary changes is important. Conclusion: This case series provides real-world experience on the use of pegvaliase. Until data from registries and independent research become available, the data presented herein can support appropriate management of patients receiving pegvaliase in clinical practice

Recommendations for the use of sapropterin in phenylketonuria

Phenylketonuria (PKU) is an inherited disorder of phenylalanine (Phe) metabolism. Until recently, the only treatment for PKU was a Phe-restricted diet. Increasing evidence of suboptimal outcomes in diet-treated individuals, inconsistent PKU management practices, and the recent availability of tetrahydrobiopterin (BH(4)) therapy have fueled the need for new management and treatment recommendations for this metabolic disorder. BH(4), now available as sapropterin dihydrochloride (sapropterin), may offer the potential for improved metabolic control as well as enhanced dietary Phe tolerance in some PKU patients. A group of metabolic dietitians from North America convened in June 2011 to draft recommendations for the use of sapropterin therapy in PKU. Physicians with extensive experience in PKU management were invited at a later date to contribute to the development of these recommendations. Based on extensive clinical experience and current evidence, the present recommendations provide guidance from patient selection and determination of sapropterin response to the long-term management of patients on sapropterin therapy. Target Phe levels, nutritional adequacy, neurocognitive screening and adherence to treatment are addressed to optimize patient outcomes

Nutrition management of PKU with pegvaliase therapy: update of the web-based PKU nutrition management guideline recommendations

Abstract Background The web-based GMDI/SERN PKU Nutrition Management Guideline, published before approval of pegvaliase pharmacotherapy, offers guidance for nutrition management of individuals with phenylketonuria (PKU) treated with dietary therapy and/or sapropterin. An update of this guideline aims to provide recommendations that improve clinical outcomes and promote consistency and best practice in the nutrition management of individuals with PKU receiving pegvaliase therapy. Methodology includes: formulation of a research question; review, critical appraisal, and abstraction of peer-reviewed studies and unpublished practice literature; expert input through Delphi surveys and a Nominal Group process; and external review by metabolic experts. Results Recommendations, summary statements, and strength of evidence are included for each of the following topics: (1) initiating a pegvaliase response trial, (2) monitoring therapy response and nutritional status, (3) managing pegvaliase treatment after response to therapy, (4) education and support for optimal nutrition with pegvaliase therapy, and (5) pegvaliase therapy during pregnancy, lactation, and adolescence. Findings, supported by evidence and consensus, provide guidance for nutrition management of individuals receiving pegvaliase therapy for PKU. Recommendations focus on nutrition management by clinicians, as well as the challenges for individuals with PKU as a result of therapy changes. Conclusions Successful pegvaliase therapy allows the possibility for individuals with PKU to consume an unrestricted diet while still maintaining the benefits of blood phenylalanine control. This necessitates a perspective change in education and support provided to individuals in order to achieve healthy nutrient intake that supports optimal nutritional status. The updated guideline, and companion Toolkit for practical implementation of recommendations, is web-based, allowing for utilization by health care providers, researchers, and collaborators who advocate and care for individuals with PKU. These guidelines are meant to be followed always taking into account the provider’s clinical judgement and considering the individual’s specific circumstances. Open access is available at the Genetic Metabolic Dietitians International ( https://GMDI.org ) and Southeast Regional Genetics Network ( https://managementguidelines.net ) websites

Strategies for Successful Long-Term Engagement of Adults With Phenylalanine Hydroxylase Deficiency Returning to the Clinic

Nearly half of all patients diagnosed with phenylalanine hydroxylase (PAH) deficiency, also known as phenylketonuria, are lost to follow-up (LTFU); most are adults who stopped attending clinic after the age of 18 years. To understand why adult patients with PAH deficiency disengage from their clinic, a focus group of 8 adults with PAH deficiency who had been LTFU for 2 or more years was held in March 2016. Ten clinicians observed the focus group and discussed strategies for successfully reengaging adult patients and encouraging lifelong management of PAH deficiency. Four strategies were proposed: (1) create a safe, supportive environment, (2) acknowledge patients as partners in their care, (3) develop individualized management plans, and (4) provide patients with additional resources. These strategies provide a framework to motivate change in clinical practice to meet the unique needs of adults with PAH deficiency

Expert Consensus on the Long-Term Effectiveness of Medical Nutrition Therapy and Its Impact on the Outcomes of Adults with Phenylketonuria

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