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Molecular Genetics and Metabolism Reports 28 (2021) 100771
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism Reports
journal homepage: www.elsevier.com/locate/ymgmr
Development of a practical dietitian road map for the nutritional
management of phenylketonuria (PKU) patients on pegvaliase
Júlio César Rocha a, b, c, *, Heather Bausell d, Amaya Bélanger-Quintana e, Laurie Bernstein f,
Hülya Gökmen-Özel g, Alexandra Jung h, Anita MacDonald i, Fran Rohr j, Esther van Dam k,
Margret Heddrich-Ellerbrok l
a
Nutrition & Metabolism, NOVA Medical School, Faculty of Medical Sciences, University of Lisbon, Lisbon, Portugal
b
Reference Centre of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
c
Center for Health Technology and Services Research (CINTESIS), Porto, Portugal
d
Division of Clinical Nutrition & Genetics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
e
Metabolic Disease Unit, Hospital Ramon y Cajal, Madrid, Spain
f
Department of Pediatrics Section of Clinical Genetics and Metabolism, Aurora, Children's Hospital Colorado, University of Colorado, Anschutz Medical Campus, Aurora,
CO, USA
g
Nutrition and Dietetics Department, Faculty of Health Sciences, Hacettepe University, Ankara, Turkey
h
Competence Center for Rare Metabolic Diseases, Charité – University Hospital Berlin, Berlin, Germany
i
Department of Dietetics, Birmingham Women's and Children's Hospital, Birmingham, UK
j
Met Ed, Boulder, CO, USA
k
Department of Dietetics, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands
l
University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
A R T I C L E I N F O A B S T R A C T
Keywords: Background: The metabolic dietitian/nutritionist (hereafter ‘dietitian’) plays an essential role in the nutritional
Phenylketonuria management of patients with phenylketonuria (PKU), including those on pegvaliase. Currently, more educational
PKU support and clinical experience is needed to ensure that dietitians are prepared to provide optimal nutritional
Phenylalanine
management and counselling of pegvaliase-treated patients.
Pegvaliase
Nutrition
Methods: Via a face-to-face data-review meeting, followed by a virtual consolidation meeting, a group of expert
Dietitian dietitians and one paediatrician discussed and developed a series of recommendations on the nutritional eval
Nutritionist uation 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 di
etitians 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
J.C. Rocha et al. Molecular Genetics and Metabolism Reports 28 (2021) 100771
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.
1. Introduction meeting. Both meetings aimed to use insights from these EU and US PKU
experts to develop consensus on the nutritional evaluation before initi
Phenylketonuria (PKU) is a rare autosomal recessive disorder caused ation of pegvaliase and to develop recommendations for dietary ad
by deficiency in activity of the hepatic enzyme, phenylalanine hydrox justments during treatment with pegvaliase.
ylase (PAH) [1]. Without treatment, it results in elevated blood and
brain phenylalanine (Phe) concentrations, leading to neurocognitive 2.1. Face-to-face dietitian meeting
and neuropsychological complications [1,2]. American and European
guidelines recommend lifelong treatment and follow-up although their In November 2019, eight dietitians (six EU and two US dietitians)
upper blood Phe targets vary (in patients aged ≥12 years ≤360 and 600 attended the face-to-face meeting. During the meeting, the pegvaliase
μmol/L, respectively) [2,3]. Dietary restriction of Phe, maintaining clinical trial data and prescription labels were reviewed and topics
blood Phe within treatment range, can prevent severe complications concerning the nutritional management of PKU patients in the context of
when initiated immediately after diagnosis, usually soon after birth as pegvaliase were discussed. Discussion was structured and guided by
PKU is identified via newborn screening programmes [2,3]. However, presentations with questions formulated by three of the expert di
dietary management poses a significant burden to patients with PKU, etitians. Detailed minutes of the meeting were taken and 17 draft rec
resulting in a progressive deterioration in dietary adherence and a ommendations were formulated.
subsequent increase in blood Phe concentrations [4,5]. Sapropterin
dihydrochloride (sapropterin) was the first non-dietary pharmacological 2.2. Virtual consolidation meeting
therapy for PKU [6,7]. Although effective in lowering blood Phe con
centrations and increasing Phe tolerance, it is mainly used in conjunc Recommendations were developed in five areas of pegvaliase treat
tion with a Phe-restricted diet and in patients with residual PAH activity ment: the multidisciplinary team (2 statements), nutritional status
[8–10]. The treatment landscape of PKU has further expanded with the evaluation and follow-up (4 statements), diet and protein intake (7
approval of pegvaliase, an enzyme substitute therapy consisting of a statements), blood Phe target range (2 statements) and education (2
PEGylated recombinant phenylalanine ammonia lyase (PAL) isolated statements).
from the cyanobacterium Anabaena variabilis that converts Phe to In March 2020, a secure online-platform was set up using the virtual
ammonia and trans-cinnamic acid [11]. In May 2018, the Food and Drug engagement tool, Within3 (https://www.within3.com/), aiming to work
Administration (FDA) approved the use of pegvaliase for the treatment towards consensus recommendations for the nutritional management of
of adult patients with PKU with blood Phe >600 μmol/L [12]. In May pegvaliase-treated patients. On the platform, the PKU experts could
2019, the European Medicines Agency (EMA) approved pegvaliase for share their opinion on each statement and respond to each other's
the treatment of PKU patients aged ≥16 years with blood Phe >600 comments. Participants could log in as often as desired at any time
μmol/L [13]. Consensus recommendations for pegvaliase were devel during a 4-week commenting period. Except for two EU dietitians, all
oped in 2018 by US healthcare professionals who were involved in the attendees of the face-to-face meeting participated in the virtual meeting.
clinical development programme [14]. These consensus recommenda Additionally, one EU paediatrician and one US dietitian who were not
tions defined that the treatment goal of pegvaliase is to provide lifelong present at the face-to-face meeting participated in the virtual platform
reduction of blood Phe and to normalise diet while maintaining blood discussion.
Phe below guideline recommended thresholds [14]. Given the central
role of metabolic dietitians/nutritionists (hereafter ‘dietitian’) in the 2.3. Practice recommendations
management of patients with PKU, this paper aims to develop a practical
road map for dietitians who are managing patients with PKU treated The practice recommendations and outcomes of the discussions from
with pegvaliase. These dietary recommendations are based on expert both meetings are described. Practice recommendations on the clinical
opinion and should have regular review when real-world evidence ac approach for treating patients with pegvaliase were initiated by the
cumulates with evolving clinical pegvaliase experience. Therefore, these dietitians with pegvaliase experience (three US and one EU dietitian)
dietary recommendations are intended as a starting point for dietitians while the other experts considered each of these using their experience
who are caring for patients with PKU on pegvaliase. working with PKU within the EU to ensure good applicability in Euro
pean centres. Although the statements are based on expert opinion and
2. Methods available literature only, they aim to give practical guidance to di
etitians. These practice recommendations are minimum care re
A group of experienced dietitians and one paediatrician (hereafter quirements and consider different hospital resources and infrastructure
‘consensus group’) working with PKU attended a face-to-face data-re within the same or different countries.
view meeting, followed by a virtual consolidation meeting, to discuss
the nutritional management of PKU patients before and during treat 3. Results
ment with pegvaliase.
At the time, the only European country which had experience with 3.1. A multidisciplinary team to support patients with PKU on pegvaliase
pegvaliase was Germany. Therefore, one German dietitian who was
experienced in treating and managing patients on pegvaliase was It is important to establish key members of the multidisciplinary
included to bring the EU perspective on treatment with pegvaliase. The team supporting patients on pegvaliase and to systematically collect
other six EU PKU experts, who did not have experience with pegvaliase, data to measure the full impact of introducing pegvaliase as a treatment.
are internationally recognised for their experience in PKU and most of The consensus group agreed that the core pegvaliase treatment team
them are part of the European Nutritionist Group on PKU. Additionally, should consist of a physician, a dietitian and a nurse (either a registered
three US dietitians with proven long-term experience in PKU and in nurse or a nurse practitioner). It also strongly recommended that a
treating and managing diet for patients on pegvaliase joined the psychologist/counsellor should be an integral part of the core pegvaliase
2J.C. Rocha et al.
Table 1
Proposed composition of the multidisciplinary team at centres treating PKU patients with pegvaliase.
Specialty Responsibilities
Consensus group recommendations about the composition of the multidisciplinary teams at centres treating PKU patients with pegvaliase
Physician - Diagnosis and decisions on appropriate therapeutic approach, considering potential adverse events
- Pegvaliase prescription
- Patient assessment prior to receiving pegvaliase
- Titration of pegvaliase dose and assessment of patient progress during follow-up clinic visits
- Management of adverse reactions
Dietitian/nutritionist - Key role in monitoring and assuring adequate nutritional status of patients
- Detailed food pattern analysis pre- and post-pegvaliase
- Nutrition re-education as a strategy to reduce the risk of lifestyle-related comorbidities
- Assessment of nutritional intake
- Interpretation of blood Phe results in conjunction with dietary evaluation
- Assessment of patient progress during follow-up clinic visits
- Contribute to decisions on appropriate therapeutic approach, based on individual (dietetic) patient status/needs
- Point of contact for the patient in terms of blood Phe reporting and diet education
3
Nurse - Education and practical support of patients on pegvaliase injections
- Point of contact for the patient in terms of managing drug titration and side effects
- In some countries, nurse practitioners can also prescribe medication and assess patient's progress during follow-up clinic visits
- Underline the global advice given by the physician and dietitian regarding treatment adherence, administration and dietary management
If resources are available, the following specialties should be included in the multidisciplinary team:
Psychologist/counsellor (highly recommended) - Surveillance and follow-up on any neurocognitive/psychological deficits
- Perform neurocognitive testing and quality of life assessments
- Patient counselling and support
- Monitor patient's fears and help manage their expectations
Molecular Genetics and Metabolism Reports 28 (2021) 100771
Social worker - Assessing individual patients' socioeconomical needs and support system, and providing assistance in finding solutions in these areas
- Advising and supporting patients in contacting the necessary service providers/agencies
Home support worker - Home support with blood sampling, treatment, social challenges and pregnancy management
- Can be any profession depending on availability, although a nurse would be able to provide education and support regarding injections and potential adverse events
Coordinator - Administrative assistant as central point of contact for e.g., organising appointments
- Especially valuable at treatment initiation to coordinate appointments with the multidisciplinary team
Phe: phenylalanine, PKU: phenylketonuria.J.C. Rocha et al. Molecular Genetics and Metabolism Reports 28 (2021) 100771
Table 2 Table 2 (continued )
Proposed assessments for nutritional status. Frequency of all assessments may be Assessment Details Frequency during Frequency during
increased if there is a clinical reason for concern or according to the centre's titration and maintenance and
current follow-up protocol. dosing diet
Assessment Details Frequency during Frequency during optimisation normalisation
titration and maintenance and risk, but not
dosing diet essential in routine
optimisation normalisation follow-up [2]
Consensus group recommendations for minimal nutritional status assessments BMI: body mass index; DXA: dual-energy x-ray absorptiometry; LBP: low blood
Phe, Phe: phenylalanine, PKU: phenylketonuria.
Blood Phe - Primary - Monthly regular - Monthly regular
concentrations biomarker of blood follow-up follow-up
Phe control - Every 2 weeks in - Every 2 weeks in treatment team emphasising the importance of assessing the neuro
case of LBP case of LBP cognitive and psychological status of pegvaliase-treated patients,
(blood PheJ.C. Rocha et al. Molecular Genetics and Metabolism Reports 28 (2021) 100771
the risk of cardiovascular disease and hyperlipidaemia [19–21]. Due to EU prescription label [13]. Blood Phe may be assessed more frequently
pegvaliase being a treatment for late adolescent and adult patients with upon the metabolic team's discretion, e.g., during periods when protein
PKU monitoring of blood pressure, insulin resistance and lipid profile is intake and/or pegvaliase dose are adjusted. The frequency of nutritional
recommended [22]. In addition, lifestyle and quality of life (QoL) intake assessments may be decreased to once every 6 months together
questionnaires, such as the PKU-QoL [23,24], may be valuable to with the assessment of anthropometric parameters. If resources are
examine healthy or unhealthy changes in lifestyle and the overall impact available, micronutrient, amino acid and body composition analyses can
of pegvaliase on the physical, emotional and social aspects of PKU be performed annually or on a more regular basis if necessary, partic
patients. ularly when managing comorbidities [20,21]. In general, all nutritional
status assessments should be performed more often if there are any
3.2.2. Titration and dose optimisation phase clinical concerns or if the treatment centre already follows a stricter
As indicated by the US and EU pegvaliase prescription labels, blood protocol, assuming this will not cause an excessive burden for the
Phe should be assessed monthly during titration and dosing optimisation patient.
phases [12,13]. However, the consensus group suggests more frequent
blood Phe monitoring upon the metabolic team's discretion. Centres
with a more frequent follow-up protocol in place before adoption of 3.3. Treatment goals of pegvaliase
pegvaliase, may either reconsider or continue their blood Phe moni
toring frequency when offering pegvaliase, reflecting the patients' in 3.3.1. Blood Phe target range
dividual needs and support required. According to the EU pegvaliase Longo et al., described that it is feasible for patients on pegvaliase to
prescription label, it is recommended to monitor blood Phe levels every maintain blood Phe concentrations below the usual lower target range of
two weeks in the event of low blood Phe (LBP; i.e.,J.C. Rocha et al. Molecular Genetics and Metabolism Reports 28 (2021) 100771
pegvaliase. As a consequence, we have made no recommendation on the pegvaliase, protein adjustments will be dependent on the baseline
lower blood Phe target. Nevertheless, future guidance will be provided nutritional status of the individual patient and usual protein intake. If
when additional studies and real-world experience address the amino the patient does not meet the recommended protein intake (i.e., 0.8 g of
acid profile, bone mineral density and growth outcomes of pegvaliase- protein/kg/day from a mix of animal and plant sources, excluding
treated patients achieving long-term blood Phe concentrations be protein substitute supplementation), natural protein intake can be
tween 31 and 120 μmol/L while being on a normal diet. For the upper increased. Patients should be encouraged to eat high-quality protein to
blood Phe target, the majority of the experts recommended targeting ensure balanced nutrition. When the nutritional needs are met and blood
concentrations below 240–360 μmol/L. Although there is no published Phe remains within the treatment target range, no adjustments to the
evidence in adults, recent data suggest that blood Phe concentrations dietary protein intake should be made in the first phase of pegvaliase
below 240 μmol/L may improve neurocognition in children/adolescents treatment (Fig. 1). In case natural protein intake is above the DRI for
with PKU [25,26]. protein, dose reduction can be considered if the patient is well-
controlled on pegvaliase (Fig. 1). In the event of LBP, patients should
3.3.2. Normalisation of diet be advised to increase natural protein intake. When diet is normalised,
3.3.2.1. Recommended protein intake. The consensus group defined a Table 3
normal protein intake as at least 0.8 g of protein/kg/day from a mix of Summary of the dietitian road map recommendations developed by the
animal and plant sources, without any supplementation from protein consensus group.
substitutes, while ensuring that all nutrient requirements are met. This Topic Recommendation(s) by the consensus group
protein intake provides the recommended intake of protein defined by
Multidisciplinary team The core treatment team should comprise a physician,
the World Health Organization [27] and should be sustained over time dietitian/nutritionist and a nurse. If resources are
with the maintenance of adequate clinical and biochemical nutritional available, also a psychologist/counsellor (highly
status. The dietitian is essential to ensure that these recommendations recommended), social worker, home support worker
are met. Additionally, the dietitian should advise patients to eat high- and coordinator should be part of the
multidisciplinary team
quality biological protein, which may be challenging for patients who
have not been used to eating these foods prior to treatment with peg Nutritional status - Blood Phe concentrations, anthropometrics and
evaluation nutritional intake were identified as minimally
valiase. For patients with PKU on a vegan diet, the protein intake should
required for follow-up
be, in general, 20% more (1 g of protein/kg/day), due to the intake of - Blood Phe concentrations should be assessed
potentially lower quality protein. Currently, there is insufficient monthly (or every 2 weeks in case of low blood Phe,
knowledge to make a recommendation on the upper limit for proteinJ.C. Rocha et al. Molecular Genetics and Metabolism Reports 28 (2021) 100771
dose reduction should be considered. Regardless of the dietary or dose Funding
adjustments, blood Phe concentrations should be monitored closely to
evaluate the impact of changes in natural protein intake or dose on the The face-to-face and virtual meeting leading up to this dietitian road
outcomes of pegvaliase. map, as well as assistance in development of the current manuscript,
were funded by BioMarin International, Ltd.
3.3.3. Additional treatment goals
Additional treatment goals of pegvaliase are improvements in neu
rocognition and (neuro)psychological outcomes, QoL and emotional Declaration of Competing Interest
well-being, together with the minimisation of comorbidities, such as
obesity and metabolic syndrome [19]. These additional goals emphasise All authors received financial reimbursement from BioMarin at fair
the importance of a multidisciplinary team (Table 1), including a psy market value for their participation in the face-to-face and/or virtual
chologist/counsellor, in the management of patients with PKU on meeting. The manuscript was developed by the authors and reviewed by
pegvaliase. BioMarin.
Outside the submitted work, the authors disclose the following.
Bausell H received personal fees from BioMarin, Ultragenyx, Horizon
3.4. Education and Vitaflo. Bélanger-Quintana A reports personal fees from BioMarin,
Nutricia, Vitaflo, Orphan Europe, Takeda and Genzyme. Rocha JC
Education of patients before treatment with pegvaliase and during received research grants from BioMarin, Glutamine and Cambrooke, as
the transition to a normalised diet is crucial to ensure correct use of well as personal fees from BioMarin, Applied Pharma Research, Nutri
pegvaliase and appropriate dietary management. One-on-one counsel cia, Merck Serono, Vitaflo, Cambrooke, PIAM and Lifediet. MacDonald A
ling should continue to be the mainstay but can be complemented with reports research funding from BioMarin, Nutricia, Applied Pharma
additional educational tools to inform and support patients with PKU Research, Vitaflo, Galen, Metax, Mevalia and Arla, as well as lecture fees
before and during treatment with pegvaliase. Printed educational ma from BioMarin, Applied Pharma Research, Nutricia and Vitaflo, and
terials, such as information leaflets/handouts, remain important but consultancy fees from BioMarin, Applied Pharma Research, Arla,
may not be sufficient to convey the message, as patients are not always Nutricia and Vitaflo. Met Ed reports grant funding from BioMarin,
reading or understanding these. Other tools enabling patient education Nutricia, Vitaflo and Horizon Pharmaceuticals. Bernstein L and Rohr F
may include instructional videos, workshops and mobile applications for report lecture fees from Vitaflo.
(self-)monitoring diet and pegvaliase injections [30].
Dietitians should be educated on the nutritional challenges of pa
Acknowledgments
tients treated with pegvaliase. Although the interaction between dieti
tian and patient may be reduced after diet normalisation from once
The authors are grateful to Ismar Healthcare NV who provided
monthly to semi-annually, it remains important to maintain this central
medical writing assistance on behalf of BioMarin Pharmaceutical Inc.
point of contact for follow-up of comorbidities and long-term diet
ensuring patients continue to eat an adequate diet meeting the nutri
tional needs of each patient and for re-education of pegvaliase-treated References
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