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PKU Nutrition Management Guidelines
Second Edition
March 2022, v.2.4
Updated: March 2022
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Nutrition Recommendations
Question
7. For individuals with PKU whose therapy includes pegvaliase as a treatment option, what medical and nutritional considerations are associated with positive outcomes?
Conclusion Statement
Derived from evidence and consensus based clinical practice

Derived from evidence and consensus based clinical practice

Initiating a pegvaliase response trial

Pegvaliase is an enzyme (phenylalanine ammonia lyase - PAL) substitution therapy that reduces blood phenylalanine (PHE) and is approved in the U.S. for use in adults >18 years with PKU whose blood PHE >600 µmol/L on current therapy, and in Europe for adults >16 years. Pegvaliase has been used in adolescents, individuals with neurocognitive deficits (including late-treated adults), and individuals with blood PHE <600 µmol/L. Clinic protocols for initiating therapy generally follow published guidelines and/or the drug prescribing information. Setting clear expectations and understanding the individual's goals are critical to success. Initiating therapy, including dose titration and adverse event management, emphasizes individualizing treatment based on tolerance to the drug. Best practices for guiding individuals with PKU on pegvaliase therapy, including medical and nutrition management, as well as education and support strategies, continue to emerge.

Monitoring

Monitoring the clinical and nutritional status of an individual with PKU on pegvaliase therapy is necessary considering the inherent limitations of the PKU diet that can result in increased risk for nutritional deficiencies. Assessment of dietary intake (specifically protein), nutrient analysis, and evaluation of clinical signs and symptoms of nutritional insufficiencies in addition to biochemical monitoring of PHE, tyrosine (TYR) and markers of at-risk nutrients are critical to the successful unrestriction or normalization of the diet of an individual on pegvaliase therapy.

Managing pegvaliase treatment after response to therapy

After an individual's response to pegvaliase therapy the treatment goal is to establish life-long control of blood PHE concentrations (<360 µmol/L and >30 µmol/L) that lead to cognitive, psychosocial, and nutritional benefit. Contributing to these improvements is the ability to unrestrict or normalize diet while maintaining blood PHE control. Intact protein is added incrementally (10-20g), while medical food protein is decreased by similar amounts, until the DRI for dietary protein is met or exceeded. Hypophenylalaninemia (hypoPHE) and deficiency of blood TYR must be prevented. A positive outcome takes into account an individual's preferences and goals. It may include any beneficial reduction in blood PHE (as determined by the clinic), and any degree of diet liberalization and/or continuation of medical food that balances toleration of pegvaliase dosage (number of injections) required to control blood PHE.

Education and counseling to support normal nutrition with pegvaliase therapy

Education and counseling for individuals maintained on pegvaliase therapy is needed to optimize nutritional status. Because PKU dietary therapy is very restrictive, individuals (those who have accomplished adherence, as well as those who have not) must be educated in how to eat a nutritionally optimal diet (including protein quantity and quality, healthy energy intake, and micronutrient sufficiency). Individuals may have difficulty accepting high protein foods that were previously not allowed. Counseling and education should address appropriate food choices as well as food purchasing and preparation, and weight management.

Pegvaliase in special populations:

There is limited evidence on pegvaliase use in pregnant and lactating women as they were excluded from the drug clinical trials. However, subsequent case studies indicate that pegvaliase has been used successfully in pregnancy and is likely to be safe during lactation. Pegvaliase was studied in a small number of children aged 16 years and older in the early phases of the clinical trials, and it is approved in this age group in Europe. No experience of pegvaliase therapy in children under 16 has yet been published.

Recommendation 7.1

Initiating a pegvaliase response trial

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Topic 7.1.1  Link to Topic 7.1.1
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Evidence

A multidiscipinary team experienced in the treatment of PKU is needed for appropriate management of an individual starting pegvaliase therapy, including at a minimum, a metabolic dietitian and physician. European guidelines also recommend including a nurse practitioner or a nurse, and a psychiatrist or psychologist for evaluation of neurological health (F.4495, F.4500). Two centers have reported their experiences since pegvaliase became commercially available; both clinics had multidisciplinary teams made up of metabolic geneticists, a nurse or nurse practitioner, and metabolic dietitians and one clinic team also included a psychologist (F.4502, F.4475).

The gray literature reviewed included pegvaliase clinic protocols in which teams consisted of metabolic physicians (MD) and dietitians (RD), as well as nurse practitioners (NP), psychologists, and clinic coordinators (CC) (G.164, G.168).

Consensus based on clinical practice

When asked to rate the importance of the various clinicians to an effective team managing individuals treated with pegvaliase, the percent of respondents to the Delphi 1 survey giving a "very important" rating was: Metabolic RD: 92%, Metabolic Physician: 76%, Nurse Practitioner: 52%, Nurse: 52%, Clinic Coordinator: 44%, Psychologist:12%, Social Worker: 8%, Genetic Counselor: 4%.

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Evidence

Pegvaliase is approved in the US for adults with PKU with blood PHE >600 µmol/L who have not been able to achieve good metabolic control with current therapies. Published guidance also suggests considering pegvaliase for adults with good therapy adherence (F.4459), understanding that a blood PHE of 600 µmol/L is above the recommended treatment goal of <360 µmol/L, and that individuals who follow treatment recommendations should also have the option of consuming an unrestricted or normalized diet without the need for medical food.

Concurrent use of sapropterin and pegvaliase is not contraindicated and depends on clinical judgement and an individual's preference (F.4459). Only one clinical protocol reviewed addressed sapropterin use and recommended that individuals stay on sapropterin until they respond to pegvaliase, then it should be discontinued (G.160).

Individuals with high blood PHE have neurocognitive deficits that may interfere with their ability to follow a pegvaliase treatment regimen. However, pegvaliase should be considered for all adults with PKU as long as they are able to give informed consent to treatment and adhere to treatment recommendations including the requirements for monitoring adverse events (AE) (F.4459). Two European guidelines recommend consideration of pegvaliase to achieve life-long maintenance of blood PHE close to normal concentrations while normalizing intact protein intake (F.4495, F.4500).

Pegvaliase may not be ideal for women planning a pregnancy in the near future (F.4459). This was also stated in one clinic protocol (G.160). See also Recommendations for 7.5.

Consensus based on clinical practice

Adults: In the Delphi 1 survey there was 88% agreement that pegvaliase is an appropriate treatment option for adults with blood PHE >600 µmol/L, including women who are not planning pregnancy in the next year, and adults with blood PHE <600 µmol/L who want to normalize or achieve an unrestricted diet.

Sapropterin use: There was 88% overall agreement: to continue individuals on sapropterin until there is a response to pegvaliase.

Late treated: 88% of Delphi 2 respondents agreed with the statement to "consider pegvaliase for late-treated adults who can recognize adverse events (AE) associated with pegvaliase, have assistance with injections, and are able to assent or consent to treatment." Comments included that the individual must be able to recognize and verbalize AEs, recognize signs and symptoms of anaphylaxis and be able to use an EpiPen. They should also be supervised by people prepared to respond in case of anaphylactic reaction.

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Evidence

The safety profile of pegvaliase has been well documented. In the Phase 3 clinical trials, the most commonly reported AEs in subjects enrolled in the two Phase 3 clinical trials (N=261) were arthralgia (70.5%), injection site reaction (62.1%), injection site erythema (47.9%) and headaches (47%) (F.4471). Almost all (99%) reactions were mild or moderate in severity and 96% resolved without dose interruption or reduction. In the clinical trials extension study including 68 subjects, a similar AE profile was seen; all reported at least one AE, including injection site reactions (72.5%), injection site erythema (67.5%), headache (67.5%), and arthralgia (65%). AE severity was noted as: mild (12.5%), moderate (76.3%), severe (11.3%), and there were no deaths. One subject had anaphylaxis, and later resumed pegvaliase (F.4460). A similar set of AEs has been seen in individuals studied post-marketing, with fatigue (46%), chills (23%), and hair loss (19%) also reported relatively frequently (F.4475). Another post-marketing study of 37 patients on pegvaliase reported the AEs seen in the majority of individuals were skin reactions (100%) and arthralgia (75%). Anaphalaxis using Brown criteria was noted in 21% of patients, with no deaths or serious sequalae. (F.4502)

The occurrence of AEs is related to immune response to pegvaliase (F.4441). Individuals develop IgG and IgM antibodies to both pegylation (PEG) and phenylalanine ammonia lyase (PAL), and antibody titers are associated with more AEs (F.4462 F.4486). Antibody response in the first 6 months is composed of anti-PEG IgM and anti-PEG IgG, whereas the response in late treatment (> 6 months) is composed of anti-PAL IgM and anti-PAL IgG (F.4442). Individuals with higher pegvaliase doses experienced more AEs in the shorter-term. However, the number of AEs decreased in the longer-term (120 weeks). AEs gradually subsided despite increased drug dose over time (F.4503, F.4467, F.4442, F.4463 F.4441).

Pegvaliase neutralizing antibodies (NAb) also developed in the majority of individuals in the clinical trials. A study that grouped individuals according to NAb titers found that the group with the highest NAb titers took a longer time to achieve blood PHE <600 µmol/L and they had lower blood concentrations of pegvaliase, whereas the group with the lowest NAb titers had a more rapid response and higher concentrations of the drug in their blood (F.4497). However, NAb titers stabilize over time once the immune response is mature, do not rise with dose increases, and do not correlate with occurrence of hypersensitivity reactions (F.4497).

While the possibility of AEs is greatest during initiation and titration, it can occur at any time (F.4471). Pegvaliase most likely induces a Type III immune-complex mediated reaction, causing hypersensitivity AEs that are different in clinical presentation and nature than IgE-mediated Type I events (F.4442), such as a severe bee sting allergy. During the clinical trials, there were 17 incidents that met the criteria for anaphylaxis that occurred in 12 individuals; all events resolved without sequalae, and 6 of these individuals remained on treatment (F.4471).

Education prior to initiating therapy necessarily focuses on prevention and management of AEs, especially the possibility of anaphylaxis (F.4445, G.168, G.164, G.172, G.165, G.160, G.167). The FDA's black box warning and the manufacturer's protocol for prescribing pegvaliase mandate that individuals and providers be enrolled in the REMS program, and that individuals are prescribed auto injectable epinephrine (e.g. EpiPen) and trained to use and always carry it with them. A wallet card describing use of pegvaliase and potential reactions is provided by the manufacturer.

Clinic protocols often state that the first pegvaliase dose is administered under medical supervision, and in some protocols subsequent dose increases are also done within the clinic via telehealth, or with the observation/guidance of an industry-based nurse (G.153, G.171, G.160).

It is critical that individuals understand signs and symptoms of hypersensitivity reactions (G.172). Education about all possible hypersensitivity reactions, mild to severe, and their management is also necessary (see Recommendation 7.1.5). One clinic protocol describes most individuals as having mild reactions, about 50% having more extensive transient reactions, and 10% having severe reactions (G.166). Each clinic protocol describes a system for the individual to call to report AEs (G.168, G.164, G.172., G.165, G.160, G.167). Especially during the drug initiation and titration, close contact with the clinic or industry-based nurse is recommended.

Consensus based on clinical practice

The Delphi 1 survey showed 100% agreement that the following information should be discussed with individuals considering pegvaliase treatment: REMS program, AE occurrence at any time during the treatment, and AE management strategies. There was 92% agreement that the individual should be observed after the first injection, 84% agreement that this should occur for the first few injections, and 76% whenever the dose is increased.

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Evidence

Suggested counseling prior to initiating pegvaliase therapy focuses on ensuring that the individual understands the risks associated with the medication but also addresses other topics that are crucial to cover, including injection training, expected time to response, clinic protocol for blood monitoring, and expectations regarding diet during titration and maintenance phases (F.4459, F.4475, F.4493, F.4502).

While not common, the possibility of having to discontinue the drug is addressed. Longo et al suggested considering discontinuation if no efficacy was achieved within 52 weeks of drug initiation, but the guidance was written prior to the FDA approval of a 60 mg/day dose (F.4459). Evidence from clinical trials indicated that several individuals required a higher dose or longer period to respond (F.4467). According to one clinic protocol reviewed, the drug may be discontinued if there is no response after 16 weeks on a dose of 60 mg/d (G.160 ). A European guideline states that if an individual does not reach a clinically relevant blood PHE reduction after 18 months discontinuation should be considered, but also states that the clinician and individual together may decide to continue pegvaliase when there are other beneficial effects (e.g. increased intact protein tolerance, improvement of neurocognitive symptoms) (F.4495).

Clinic protocols reviewed also focused on the AE education required before the first injection (including REMS, EpiPen use, and benefit of having an observer after injections), but also emphasized the need for individuals to understand what the course of therapy may entail, including a long time to respond, frequent dose adjustments, and the need to adhere to blood monitoring and clinic visit protocols (G.168, G.164, G.172, G.163, G.165, G.153, G.154, G.171, G.160. G.167, G.166, G.162). One protocol requires a contract to be signed before commencing therapy (G.172).

Consensus based on clinical practice

In Delphi 1, 92% of respondents agreed the individual should be informed that it may take 6 months or more to see a reduction in blood PHE

In Delphi 2, there was 100% agreement that the metabolic team should: a) discuss the goals of pegvaliase therapy with the individual and adjust education to their needs, b) discuss the initiation and titration process with the individual including adverse event monitoring, dose adjustments, and time to response and c) explore the individual's ability and motivation to commit to the pegvaliase treatment regimen including: maintaining their current diet unless instructed to change it, injecting the drug as prescribed, needle phobia, collecting blood samples and diet records as directed, and maintaining regular contact with the clinic.

There was no consensus that a contract should be signed prior to starting pegvaliase and only 42% of respondents in Delphi 1 agreed with this policy.

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Evidence

Pre-medications, a longer titration period after a hyper-sensitivity reaction, training and education of individuals and/or caregivers, and availability of auto-injectable adrenaline (e.g. epinephrine) at all times, can improve safety of home treatment with pegvaliase (F.4442). Although the dietitian does not prescribe medications, it important to know the types of medications used in managing AEs to be able to communicate effectively with the individual and the metabolic clinical team.

Below is a list of medications clinic protocols recommend for the prevention or treatment of AEs (F.4502, G.168, G.164, G.161, G.172, G.163, G.165, G.153, G.171, G.160).

  • Auto-injectable epinephrine (Epi-Pen) for anaphylactic reactions

  • H1 receptor antagonists [e.g.cetirizine (Zyrtec)] and H2 receptor antagonists [e.g. famotidine (Pepcid)] for hypersensitivity reactions such as rashes, injection site erythema, arthralgia

  • Antipyretic (e.g., Ibuprofen) for fever, chills

  • NSAID (e.g., naproxen sodium) for arthralgia, other pain

  • 1% Hydrocortisone or Benadryl cream for rashes

  • Prednisone for arthralgia

Published guidance recommends that H1 and H2 receptor antagonists and antipyretics be given the day before the first injection and then daily during the titration phase and discontinued based on clinical judgement once a stable pegvaliase dose is reached (F.4459, F.4495). However, if and when medications are recommended varies by clinic. Some clinics only prescribe medications if an individual experiences an AE. Others suggest the H1 and H2 receptor antagonists be taken before the first dose. Guidance in clinical protocols about how far before the first dose the medications are to be taken ranges from 1-2 hours (G.163, G.153) to 1 day (G.166) to several days (G.165), to a week prior to the first injection (G.160).

To prevent injection site reactions, individuals should be encouraged to rotate injection sites between doses. Injection site reactions can be treated with an H1-receptor antagonist, topical steroids, or cold compresses (F.4442).

Recommended treatments for arthralgia are NSAIDs (if the individual has no renal dysfunction or other contraindications to NSAIDs), acetaminophen/paracetamol, or low dose steroids for a maximum of 6 weeks (F.4442).

Consensus based on clinical practice

In Delphi 1 when asked about AE management during the induction and titration phase, 76% of respondents indicated that H1 antagonists should be used routinely prior to injection, and 80% that H2 antagonists should be used routinely prior to injection. In contrast, steroids and antipyretics are used for symptomatic individuals but not routinely prior to injection. A consensus (96%) of all respondents agreed that steroid use should be considered if an individual is symptomatic, but 0% agreed with routine use. Similarly, 88% agreed that antipyretics be considered if an individual is symptomatic and 16% agreed that they should be used routinely.

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Evidence

Pegvaliase initiation and titration is recommended based on the FDA approved prescribing information (F.4445, F.4459, F.4463, Y.32). RECOMMENDATION TABLE #10, Recommended Dosing Regimen for Pegvaliase

Typical induction is 2.5 mg weekly for 4 weeks then the dose is titrated based on toleration over at least 5 weeks to 20 mg/day. If there is no response after 24 weeks, the dose can be increased to 40 mg/day. Formerly, discontinuation of pegvaliase was recommended if there was no response after 16 weeks (F.4445), but updated prescribing information is to increase to 60 mg/day (Y.32) and current practice indicates higher doses are used off-label.

Titration is based on how well the individual tolerates dose increases. Many individuals require slower titration, especially in cases where AEs are severe or difficult to manage. In some individuals, a response is seen at a dose lower than 20 mg/day, and yet others may require increase to 40 mg/day before 24 weeks on the 20 mg/day dose (F.4459). In one report of 37 individuals starting pegvaliase therapy, 35 were able to follow the standard dosing recommendation, and two slowed down titration because of AE's (F.4502).

In reports from the clinical trials, one paper describes starting at 2.5 mg/week for 4 weeks then titrating to 20 or 40 mg/d (F.4471). In another publication, low-dose induction therapy of 2.5 mg/week was given for 4-8 weeks, after which the dose or frequency was increased over a minimum of 4 weeks until reaching blood PHE ≤600 μmol/L. The "maintenance dose" was defined as a dose resulting in blood PHE ≤600 μmol/L that was sustained for at least 4 weeks without dose modification (F.4486).

Gray literature references recommend titration as described in the prescribing information, recognizing that some individuals may need a subsequent decrease to the last dose tolerated for more severe AEs, a slower dose escalation, holding the dose for a longer time for a mild AE such as a rash, or continuing the usual schedule but increasing H1 antihistamine prior to a dose increase. (G.160)

Consensus based on clinical practice

Over all, 88% of Delphi 1 respondents agreed that the suggested dose titration regimen in the pegvaliase prescribing information is appropriate for most individuals. In MD/NP respondents, 100% disagreed that the titration in the prescribing information is too slow.

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Evidence

Published guidance suggests monitoring blood PHE every 1-4 weeks (F.4459), suggesting that contact with the clinic should occur with at least this frequency. However, guidance for how often to see an individual varies from weekly to quarterly, with more visits needed during the titration phase (F.4502, G.164, G.172, G.167, G.160). Visit frequency also depends on geography (distance from the clinic), use of telehealth, and clinic personnel available. Of the pegvaliase clinic protocols examined, most suggested seeing the individual for a medical and/or nutrition visit every month but having weekly check-ins with the clinical team. In addition, many clinics work with industry-based Clinic Coordinators who do home or telehealth visits weekly during titration (F.4502, G.160, G.153, G.165). These visits are to reinforce injection training and often continue until an individual is comfortable injecting, at each dose increase, and as needed for support and education.

Consensus based on clinical practice

The Delphi 1 survey showed that 76% of RDs and 50% of MD/NPs (68% overall agreement) agreed that visits every 2-4 months were optimal, while 63% of MD/NPs and 41% of RDs (48% overall agreement) agreed that once per month was optimal.

When asked about the frequency of additional contacts for education and support (phone, in person, telehealth), weekly contacts reached consensus (80% overall agreement), while every 2 weeks and as needed both achieved 76% agreement.

Recommendation 7.2

Assessing and monitoring nutritional status during all phases of pegvaliase therapy: laboratory markers, nutritional intake, clinical evaluation and optimal frequency of monitoring.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Topic 7.2.1  Link to Topic 7.2.1
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Evidence

In a European guideline consensus report, assessment of nutritional intake, using food frequency questionnaires (FFQ), 24-hour recall, or 3-day food records was proposed for minimal nutritional status assessments with a frequency of up to once per month during the titration and dosing optimization phase and every 6 months during the maintenance and diet normalization phase. The authors recommended use of FFQs as the preferred method to collect dietary intake information with a Food Neophobia Scale (FNS) as an optional method. (F.4495)

Dietary assessment using a three-day food record and FFQ in addition to FNS and Epicurean Eating Tendencies (EET) scale were used in a study to establish nutritional quality of the diet of individuals who responded to pegvaliase and to identify potential explanations for reluctance of the individuals to introduce high protein foods after responding to pegvaliase (F.4475).

Clinic protocols reviewed emphasized evaluating current dietary intake data using diet records, FFQ, or typical eating pattern of the individual (including medical foods used) during the initiation visit to assess adequacy of the diet (G.160, G.163, G.165, G.167, G.171). Reviewing diet records with every adjustment based on dose/PHE levels was also recommended (G.160, G.163). These assessments were also used to adjust diet therapy when blood PHE levels began to drop (G.160, G.163, G.165, G.167, G.171).

Consensus based on clinical practice

In Delphi 1 survey, there was 100% overall agreement that food and nutrition history (diet intake, FFQ, or typical eating pattern) should be monitored during initiation/titration and maintenance phase. The RDs specifically noted the importance of using these tools in recognizing potential areas of nutritional deficiency. There was 96% agreement to perform nutrient analysis of dietary intake information collected during initiation with 100% overall agreement during the maintenance phase.

As to nutritional intake during the initiation and titration phase, the Delphi 1 survey showed 88% overall agreement that protein intake should be tracked and 96% overall agreement that the diet (assuming that it is nutritionally adequate) should stay consistent, including medical food, unless otherwise instructed.

For individuals who are not consuming medical food and are eating freely at baseline , there was 100% overall agreement that obtaining food records to track protein intake should only be collected as the clinic considers it necessary with 68% agreement to collect protein intake data three days prior to a blood PHE monitoring sample. For individuals who are consuming medical food and/or are restricting protein/PHE at baseline , there was 100% overall agreement that obtaining food records to track protein intake should only be collected as the clinic considers it necessary with 72% agreement to collect protein intake data three days prior to a blood PHE monitoring sample. However, 94% of the RDs and 88% of the MD/NPs agreed that food records to track protein intake in either group are necessary.

The Delphi 1 survey showed there was 100% overall agreement to look at food behaviors and attitudes and RDs specifically noted this was critical to their counseling with 60% agreement to specifically look at food neophobia.

In Delphi 2 survey, 94% of respondents (MDs and RDs) agreed that a comprehensive nutrition assessment is needed at baseline and should be repeated when the individual enters the diet adjustment and maintenance phases of the pegvaliase therapy. There was 100% agreement as to the importance of monitoring and evaluating dietary intake at each diet adjustment including: protein quantity, quality, and source (plant, animal, synthetic), transition from medical food, and food variety and acceptance. In addition, 94% of respondents agreed that standard repeatable methods for nutrition assessment and documentation including dietary intake (especially protein) should be established at the clinic level.

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Evidence

Dietary assessment using a three-day food record and FFQ in addition to FNS and EET scales were used in a recently published study to establish diet quality of individuals who responded to pegvaliase and to identify potential explanations for reluctance of the individuals to introduce high protein foods after responding to pegvaliase (F.4475).

Consensus based on clinical practice

In Delphi 2 survey, 100% of respondents (MDs and RDs) agreed it is important to assess the individual's food knowledge, attitudes, and beliefs, especially knowledge of what constitutes an unrestricted healthy diet, taste or texture aversions, fears and phobias of previously forbidden foods, and preferences for new foods to include as the diet is normalized. A consensus (100%) of respondents agreed it is important to periodically discuss, document, and update the individual's personal diet goals, expectations, fears, and preferences. Additionally, 88% of respondents agreed with the importance of exploring methods or assessing and documenting food attitudes, aversions and fears related to liberalizing/normalizing a PHE-restricted diet.

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Evidence

Improvements in neurocognition and neuropsychological outcomes, quality of life (QoL) and emotional well-being of individuals with PKU are treatment goals of pegvaliase therapy (F.4495). QoL impacts therapy adherence, and social and neurocognitive profiles, but published systematic research related to these outcomes is limited. One European guideline recommends full IQ assessment, with neurocognition and psychiatric follow-up tailored to an individual's clinical and life conditions. Validated assessment tools focused on self-report of QoL, neurocognition, and neuropsychological issues specific to individuals with PKU are available (L.363, L.364) and are recommended as part of clinical follow-up and are useful in overall management of PKU management. (F.4495, F.4500)

Consensus based on clinical practice

In Delphi 2 survey, 88% of respondents (MDs and RDs) agreed with the importance of establishing at the clinic level standard repeatable methods for assessing QoL and neurocognitive assessment.

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Evidence

Blood PHE is the primary biomarker for optimizing treatment and monitoring is considered a reliable predictor of response to treatment. ACMG and GMDI guidelines recommend maintenance of plasma PHE concentrations in the range of 120-360 µmol/L (F.2626, F.2627). Blood PHE and TYR measurements were frequently monitored during the clinical trials with pegvaliase (F.4459, F.4486).

Post-marketing studies indicate blood PHE and TYR is monitored every 2 weeks in one metabolic clinic (F.4502). In another clinic monitoring is every month until the diet is changed, and then is increased to weekly (F.4475).

Clinic protocols emphasized monitoring of blood PHE and TYR or plasma amino acids (G.159, G.160, G.163, G.171).

Consensus based on clinical practice

As to optimal frequency of testing or blood PHE monitoring, the Delphi 1 survey showed there was 100% overall agreement that blood PHE should be monitored with frequency determined per clinic protocol.

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Evidence

In a report looking at the first 1.5 years of experience with pegvaliase therapy in a clinic setting, baseline labs obtained were plasma amino acids, blood chemistry, and nutritional labs including 25-OH vitamin D, vitamin B12, prealbumin, iron studies, and zinc, in addition to inflammatory markers such as ESR and C-reactive protein (F.4475). The study timeline was extended, and the same group specifically examined the nutritional status of these pegvaliase treated adults by looking at markers for protein and EFA status, lipid profile, Hgb A1c, vitamins A and E, and 25-hydroxy vitamin D, RBC folate, iron status, Mg, Se, Zn and MMA (F.4496).

See GMDI Nutrition Management for PKU Guideline for nutritional status monitoring recommendations in individuals with PKU. TABLE #8, Monitoring Nutritional Management of PKU

In addition to monitoring of blood PHE and TYR or plasma amino acids, clinic protocols also suggested additional laboratory testing to monitor other nutritional indices, blood chemistry, and inflammatory markers (G.159).

European guidelines for dietitians suggest that the following nutrition assessments be performed for individuals receiving pegvaliase (F.4495):

At a minimum - anthropometrics and food intake

Strongly recommended - plasma amino acids, prealbumin, CBC, ferritin, total

homocysteine or MMA, folic acid, vitamin B12, vitamin D, iron, calcium, zinc, selenium

Recommended - body composition (fat free body mass, phase angle obtained from

bioelectrical impedance analysis), bone mineral density (DXA scan)

Consensus based on clinical practice

The Delphi 1 survey showed there was 92% overall agreement during initiation and 83% overall agreement during maintenance to monitor plasma amino acid levels. As to monitoring other laboratory markers that measure nutrients at risk for insufficiency such as: prealbumin, vitamin D, vitamin B12, folate, EFA, lipid profile, Fe, Zn, Se, MMA, and inflammatory markers, there was 16-80% overall agreement during initiation and 4-75% overall agreement during maintenance. The highest level of agreement was for monitoring 25-OH vitamin D at baseline for initiation and titration (80% overall) and during the diet adjustment period (75% overall).

In Delphi 2 survey, 73% of respondents (MDs and RDs) agreed with monitoring plasma amino acids, prealbumin, ferritin, vitamin D and CBC every 6-12 months, and 94% of the respondents agreed with monitoring additional biomarkers including but not limited to vitamin B12, MMA, RBC folate, Fe, Zn, Se, lipid profile and HgbA1c if dietary intake is suboptimal, or other indications are present. Nominal Group discussion reached 100% agreement that baseline assessment should include a full set of biochemical indicators of nutritional status as best practice.

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Evidence

Clinical assessment has focused on signs and symptoms of hypersensitivity and adverse reactions to pegvaliase as described in section 7.1. Current (2018) evidence- and consensus-based recommendations indicate that individuals should be assessed (in person or by telephone/telemedicine) for signs and symptoms of hypersensitivity reactions every 2-4 weeks during introduction and initial titration and during dose changes (F.4459). Vital signs and safety measures should be evaluated at screening, then weekly, then every 4 weeks thereafter when response is noted (F.4486). Clinic protocols recommended monitoring vital signs (BP, HR, Temp, O2%) prior to the injection and one-hour post injection (G.160, G.171).

Anthropometric evaluation including weight, height, body mass index (BMI), and waist circumference was proposed as a recommendation for minimal nutritional status assessments with up to once per month during the titration and dosing optimization phase and every 6 months during the maintenance and diet normalization phase (F.4495).

Attention to nutrition-related clinical assessment was raised in a study looking at nutrition status of pegvaliase responders, in which a nutrition focused questionnaire revealed 5 of 11 females had experienced hair loss before and during treatment (F.4475). The researchers were not able to correlate this finding with other clinical factors such as blood PHE, protein intake, or pegvaliase dosing.

Consensus based on clinical practice

As to nutrition assessment, the Delphi 1 survey showed 100% overall agreement that anthropometrics including weight, height and BMI should be monitored during both initiation and maintenance phase.

In Delphi 2 survey, 94% of respondents agreed that an assessment of physical signs of nutritional status is needed.

Recommendation 7.3

Managing pegvaliase therapy after response : blood PHE and TYR monitoring, pegvaliase dosage adjustment, modification of dietary protein and medical food, supplementation of deficient nutrients.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Topic 7.3.1  Link to Topic 7.3.1
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Evidence

ACMG guidelines recommend optimal blood PHE concentrations as those maintained ≤360 µmol/L. In clinical trials for pegvaliase therapy (PRISM-1 and PRISM-2) 44% of participants achieved blood PHE concentrations ≤360 μmol/L by 12 months, 61% of participants by 24 months, and 51% achieved blood PHE levels ≤120 μmol/L by 24 months of treatment (F.4471).

Evidence- and consensus-based recommendations developed in 2018 by expert health-care professionals experienced in the use of pegvaliase recommended that efficacy and benefit of pegvaliase therapy should primarily be determined by a significant reduction of blood PHE concentration from baseline, or maintenance of blood PHE concentration within an acceptable range, and with progress in normalizing diet which was defined as ability to consume more intact protein with reduced requirement for medical foods (F.4459). One research article suggested that improvements in specific neurotransmitters may be more likely in individuals who achieve blood PHE concentrations <360 µmol/L as compared with individuals with PHE concentrations >900 µmol/L. The report stated that blood PHE concentrations between 31 and 120 µmol/L should not be regarded as too low. (F.4430)

A poster reporting data from the pegvaliase clinical trials addressed outcomes of individuals who had hypophenylalaninemia (hypoPHE) as defined by two or more blood PHE results < 30 µmol/L. They found that overall, a state of hypoPHE occurred at all levels of pegvaliase doses, and appeared to be well tolerated, manageable, and allowed for greater dietary intake of intact protein and PHE. Individuals with hypoPHE tended to respond to pegvaliase earlier, discontinued the study less often, and did not have more AEs, except for a higher incidence of alopecia (G.158).

The 2018 evidence- and consensus-based recommendations noted hair loss and/or skin abnormalities in some individuals with hypoPHE but there was disagreement as to whether this was caused by the hypoPHE. The recommendations included, as a precaution, that extended periods of hypoPHE (<30 µmol/L for >3 months) should be avoided and addressed with diet or pegvaliase dosage adjustments. (F.4459)

There was little information in the gray literature about optimal blood PHE concentrations, but one clinical protocol suggested that clinicians should aim for a minimum 20% reduction in blood PHE concentrations (G.168).

Consensus based on clinical practice

In the Nominal Group 89% agreed that blood PHE of 30 µmol/L was an appropriate lower limit for good treatment, noting that this should be accompanied by normal blood TYR and a nutritionally adequate diet. In Delphi 2 survey results there was 94% overall agreement that an appropriate target blood PHE concentration for individuals treated with pegvaliase should be <360 µmol/L and >30 µmol/L.

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Evidence

The 2018 evidence- and consensus-based recommendations stated that a definition of clinically meaningful efficacy should be determined by the clinician and also be based on an individual's goals. They recommended consideration of any clinically meaningful reduction in blood PHE concentration (as determined by the clinic) to be a positive outcome. Additional benefits to consider when determining efficacy included an observed reduction in disease burden, an improvement in QoL, and an improvement of psychosocial well-being and/or cognitive function. (F.4459) This is supported in a recommendation statement in a European guideline (F.4500).

Consensus based on clinical practice

There was 88% overall agreement from the Delphi 2 survey that any clinically meaningful reduction in blood PHE concentration in an individual on pegvaliase therapy is a positive outcome.

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Evidence

There is little published data about the use of pegvaliase concurrently with sapropterin therapy. One study reported it is unclear whether concurrent use is more beneficial (F.4445). The 2018 evidence- and consensus-based recommendations stated that the decision to discontinue sapropterin therapy and administer pegvaliase should be at the discretion of the treating clinician and include individual preference (F.4459).

One clinic reported that 54% (20/37) of individuals who started on pegvalise had concomitant sapropterin use. One individual was denied insurance coverage when using both sapropterin and pegvaliase, and several reported not taking sapropterin once they started pegvaliase injections (F.4502). This study and one clinical protocol reviewed recommended that individuals stay on sapropterin until they respond to pegvaliase (blood PHE<120 µmol/L on two occasions) then it is discontinued (F.4502, G.160).

Consensus based on clinical practice

In the Delphi 1 survey there was 88% overall agreement that individuals should remain on sapropterin therapy until blood PHE reaches the treatment range (as defined by the clinician) but there was poor agreement that sapropterin should continue until diet is normalized.

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Evidence

The 2018 evidence- and consensus-based recommendations stated that blood PHE concentrations should be controlled by balancing adjustments in diet and pegvaliase dose, with a goal of maintaining blood PHE concentration as low as possible while "normalizing diet" (defined as receiving the DRI for protein and discontinuing medical food). The report suggests that individuals on a restricted diet.

Normal protein intake for adults is variable. An analysis of trends from the 2001-2014 National Health and Nutrition Examination Survey (NHANES) indicated that adults in the US averaged a higher consumption of protein than the DRI (0.8 g/kg ideal body weight/day), ranging from 1.15 g protein/kg ideal body weight to 1.45 g protein/kg ideal body weight daily (L.362). The Acceptable Macronutrient Distribution Range for protein is 10-35% of total energy intake (L.362); and the range of protein intake reflected in the USDA My Plate guidance for Americans consuming a healthy eating pattern is 1.48-1.86 g/kg/day (L.365). European guidance defines normal protein intake as at least 0.8 g protein/kg/day from a mix of animal and plant sources and without any medical food (F.4495).

A recent study investigating the nutritional status of adults on pegvaliase therapy showed that the PKU cohort was comparable to US adults in nutritional quality of dietary intake, as described by the NHANES 2015-2016 Survey's Healthy Eating Index. However, when looking specifically at protein status, mean intake of intact protein foods (e.g., meat, poultry, seafood, eggs, soy, nuts, seeds and legumes) was significantly lower than the US sample. This indicates that adults with PKU on pegvaliase therapy, even though they meet the DRI for amount of protein intake, may still have a lower overall consumption of protein than the US average (F.4496). Another study looking at long-term effectiveness of pegvaliase therapy alone as compared to dietary plus sapropterin therapy concluded that (in adults with blood PHE > 600 µmol/L) pegvaliase is the first treatment for PKU that reduces blood PHE to target range, while allowing a diet with intact protein intake approaching the DRI (F.4485).

There was relatively little guidance in the gray literature about diet modification for individuals receiving pegvaliase. Two clinical protocols suggested that dietary protein could be increased after a 20% reduction in blood PHE concentrations over 3-4 measurements (G.168, G.160). One clinical protocol recommended increasing intact protein after blood PHE concentrations dropped but did not recommend a specific amount of protein or of blood PHE reduction (G.167). None of the clinical protocols addressed decreasing medical food.

Consensus based on clinical practice

In the Delphi 2 survey there was 100% overall agreement that intact protein should be added when blood PHE concentration falls to 120 µmol/L on two or more consecutive measurements and could be added earlier if blood PHE levels drop rapidly. Additionally, there was 100% overall agreement that if blood PHE concentration is maintained in the target range, intact protein should be added incrementally until the individual meets or exceeds the DRI by up to 1.5-2.0 times the DRI, depending on individual status.

The Nominal Group discussion included whether it is appropriate, if the diet is inadequate in protein.

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Evidence

Evidence- and consensus-based recommendations from 2018 suggested that if blood PHE concentrations are <30 µmol/L on 2 consecutive results, intact protein should be increased to the DRI or greater. If blood PHE remains below 30 µmol/L after this increase in protein intake, the recommendation was to decrease total weekly pegvaliase dose by 10-20% with the overall goal of minimizing extended periods of hypoPHE (F.4459). This guidance was mirrored in European guidelines for nutrition management in individuals receiving pegvaliase (F.4495).

In one post-marketing study, 5 of 13 individuals responding to pegvaliase needed less than daily dosing to maintain blood PHE in the target range, with some only needing as low as 20 mg/week (F.4502).

Consensus based on clinical practice

In the Delphi 1 survey there was good consensus that amounts of protein exceeding the DRI can be added to the diet if blood PHE concentrations are maintained in the treatment range. Additionally, if the diet provides at least the DRI from intact protein, reducing pegvaliase dose is appropriate when blood PHE concentrations fall too low to prevent hypoPHE.

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Evidence

For individuals on a restricted diet and/or receiving medical food, the 2018 evidence- and consensus-based report recommended incrementally increasing intact protein by 10-20 g while decreasing protein from medical food by 10-20 grams until diet is normalized (F.4459). European guidance also recommends reduction of medical food as possible (F.4495)

Consensus based on clinical practice

There was little consensus in the Delphi 1 survey regarding how to appropriately adjust medical food intake for an individual on pegvaliase therapy, but there was agreement that there should be a goal of eliminating medical food incrementally as intake of intact protein meets or exceeds the DRI.

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Evidence

The 2018 evidence- and consensus-based recommendations suggested that maintenance of physiologic TYR blood concentrations is important and TYR supplementation should be considered if post-prandial blood TYR is repeatedly <30 µmol/L (F.4459). In the pegvaliase clinical trials, all study participants were instructed to take 500 mg supplemental TYR three times a day with meals, making reports non-informative regarding any evidence of hypotyrosinemia or need for TYR supplementation during pegvaliase administration (F.4471).

In one study, all 37 individuals had blood TYR concentrations in the normal range (monitored every 2 weeks) and none required supplementation (F4502). One clinical protocol addressed TYR supplementation and recommended a <30 µmol/L blood TYR concentration threshold for starting TYR supplements. The protocol further recommended titrating TYR dose to keep blood TYR in the normal range and dividing the TYR supplement into 3 doses per day. (G.160)

Consensus based on clinical practice

In the Delphi 1 survey there was overall consensus that if post-prandial blood TYR concentrations repeatedly fall <30 µmol/L, intact protein should be increased, or TYR should be supplemented.

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Evidence

The stated goal of pegvaliase treatment is to provide life-long maintenance of blood PHE concentrations while "normalizing diet", which is defined as not requiring medical food and containing at least the DRI for protein. However, there is recognition that an individual's goals and preferences should be included in a pegvaliase treatment plan (F.4459).

One study reporting pegvaliase therapy outcomes after 1.5 years of post-trial clinical experience noted 50% of individuals who responded to therapy were able to tolerate a normal protein intake (>0.8 g/kg/day) with no medical food. Those individuals who continued diet restriction, tolerated a median 50% increase of intact protein and a 25% decrease in medical food protein. (F.4475)

A summary of case studies of individuals receiving pegvaliase reported some individuals wished to liberalize but not totally normalize diet rather than take multiple injections per day to achieve blood PHE control (F.4493).

Consensus based on clinical practice

In the Delphi 2 survey there was 94% overall agreement with the stated goal of pegvaliase therapy: maintaining blood PHE within treatment range with an unrestricted diet and discontinuation of medical food. There was also agreement that individual preferences for balancing degree of diet liberalization and some continuation of medical food with number of pegvaliase injections required to achieve blood PHE control should be taken into account, and that a positive treatment outcome should be determined in the context of an individual's preferences and goals.

Recommendation 7.4

Educating and counseling regarding appropriate food choices to support normal nutrition requirements: increased intact protein, healthy energy intake, and micronutrient sufficiency.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Topic 7.4.1  Link to Topic 7.4.1
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Evidence

The 2018 evidence- and consensus-based recommendations for using pegvaliase recognized the potential for pegvaliase therapy to reduce disease burden and improve quality of life (QoL), psychosocial well-being, and cognitive function. Monitoring the impact of pegvaliase on these outcomes and managing individualized patient expectations regarding the benefit of pegvaliase therapy was recommended. (F.4459)

One study looked at a subgroup of subjects participating in the Phase 3 pegvaliase clinical trials. Because impaired attention has been designated as the most common ADHD domain in early-treated adults with PKU, the relationship between an extended period of plasma PHE reduction and sustained improvements in symptoms of inattention was examined. Findings suggested a direct and dose responsive relationship between improvements in inattention symptoms and metabolic control, and greater symptom improvement was associated with greater blood PHE reductions. This was especially robust when blood PHE concentrations fell below 360 µmol/L. The authors conclude that in PKU adults receiving pegvaliase therapy, better blood PHE control, possibly combined with increased dietary protein intake, can improve attention difficulties and benefit QoL. They also postulate support for the benefit of maintaining blood PHE levels within normal range if diet is normalized (F.4499).

In a cross-sectional study, individuals who were naïve to pegvaliase reported the minimum benefits they believed therapy should provide to make the possible adverse effects of therapy acceptable. These benefits included lessening disease burden and social challenges and limiting barriers to adherence enough to expect improvement in QoL. Only 28.8% reported satisfaction with their current treatment (treatment modalities included diet restriction, medical food, sapropterin, and no therapy), and a large proportion (84.4%) indicated difficulty following a PKU diet. Over 50% reported making careless mistakes, difficulty paying attention, avoiding, or delaying tasks requiring thought, being distracted by proximity of noise or action, and misplacing things. Subjects reported barriers to the PKU diet as feeling burdened with weighing/measuring/estimating protein content of foods (60%), feeling less able to lead a normal social life (49%), and believing the PKU diet prevented sufficient nutrient intake (73%). Non-adherence to therapy during the previous week was reported by 76%. The authors concluded that individuals with PKU were willing to tolerate risk for AEs associated with pegvaliase in exchange for improvement in blood PHE levels that beneficially impacted QoL. In this study those unwilling to receive pegvaliase cited fear of injections (needles), concern about hypersensitivity reactions, and cost of the therapy. (F.4478)

In one study describing clinical experience, individuals receiving pegvaliase therapy reported subjective outcomes that included improvement in QoL, verbal communication, and daily living functioning (F.4475).

In a summary of case studies of individuals receiving pegvaliase, investigators stated that treatment goals and individual expectations vary and should be clearly defined and re-evaluated throughout the course of therapy as goals may change. Reported expectations included ability to eat a more normal diet, control of blood PHE concentrations that resulted in more clarity of thinking without a restrictive diet and decrease or discontinuation of medical food. Clinical providers were described as more effective if they understood the challenges associated with changing life-long dietary habits. Ongoing communication and guidance were considered essential. (F.4493)

A European guideline suggested food neophobia questionnaires as useful in assessing an individual's readiness to change eating habits. Because pegvaliase therapy changes an individual's dietary intake the authors recommended periodic assessment of nutritional (especially protein) intake and biochemical status (especially plasma amino acids). (F.4495)

Consensus based on clinical practice

This topic was not addressed in consensus collection.

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Evidence

Disordered or atypical eating behavior is reported to be common in individuals who have always been required to follow a restricted diet, with many reporting guilt when consuming high-protein foods. Change in these dietary restrictions as allowed by successful pegvaliase therapy should include recognition that individuals may need help to adjust their emotional response to these previously "forbidden" foods (F.4459).

In a summary of case studies describing pegvaliase therapy, individuals were shown to have limited understanding of what constitutes a healthy diet because they had never been allowed unrestricted food choices. One case study recommended that dietary changes be made slowly and with specific recommendations. This summary stated that education for a healthy diet should continue throughout maintenance, with assessment of dietary intake and eating behavior during follow-up clinic visits. (F.4493)

Addition of high protein foods: The 2018 evidence- and consensus-based recommendations for the use of pegvaliase included education for meeting and maintaining normal nutrition requirements, and individualized guidance for transitioning to a normalized diet (defined as the ability to consume at least the DRI for protein and reduced or discontinued medical food). The authors recommended that the metabolic dietitian evaluate nutrient intake and adequacy, especially quality of protein, and counsel individuals on how to introduce high protein foods into their diet, including: correct portioning, food safety, and cooking methods. (F.4459)

One cross-sectional study indicated individuals treated with pegvaliase for approximately 5 years were able to consume a normal amount of protein. Mean protein intake was 73.2 gm, with 62% coming from animal protein (F.4475).

Weight management and healthy energy intake: The risk for overweight/obesity is increased with unhealthy dietary patterns. In a paper reporting nutritional status of individuals treated with pegvaliase, adults with PKU were more likely to be overweight compared to non-PKU controls. Individuals participating in the pegvaliase clinical trials often consumed more calories and experienced a weight gain from baseline. The authors suggested that relaxing of dietary restrictions with pegvaliase therapy can enable a healthier diet but may also allow overindulgence of previously restricted foods. (F.4496)

In a summary of case studies, proactive attention to weight control was recommended. One case study described an individual, whose discontinuation of dietary protein restrictions resulted in significant weight gain (F.4493). After a year on pegvaliase, individuals followed in one clinic experienced weight changes that represented improvements in BMI (F.4475). However, a study of individuals following an unrestricted diet for over 4 years on pegvaliase maintenance therapy found 50% were overweight and 39% were obese. The authors recommended that successful transition to a normal diet requires ongoing education for healthy food choices and cooking methods to achieve a well-balanced diet and healthy weight (F.4475).

European guidelines recommend prevention of onset or increase of overweight or obesity, with focus on quality of nutrient intake (especially protein) representing an opportunity to optimize body composition, especially as this is often unbalanced in individuals treated with PKU diet therapy. (F.4495)

Micronutrient insufficiency:

An individual's nutrient adequacy should be evaluated by a metabolic dietitian, and supplementation recommended if appropriate. Use of a multivitamin and/or individual calcium, iron, vitamin B12, and biotin supplements for individuals with inadequate nutrient intake should be considered (F.4459). A cross-sectional study of the nutritional status of 18 individuals examined vitamin/mineral status with laboratory monitoring of vitamins A, E, and 25-hydroxy vitamin D, red blood cell count, folate, serum iron, ferritin, transferrin saturation, magnesium, methylmalonic acid, selenium, and zinc. Generally, individuals studied had normal nutritional status, but some exhibited low 25-hydroxyvitamin D (<30 ng/mL) and/or low ferritin (F.4475).

Gray literature sources emphasized the importance of education for a healthy diet that begins with initiation of pegvaliase and continues after response is established and throughout therapy maintenance (G.158, G.149, G.150). Several clinical protocols described education for individuals receiving pegvaliase maintenance therapy. One protocol recommended food choices, micronutrient sufficiency, and the need for adequate dietary protein be discussed with individuals at each phase of therapy (G.158). Counseling for how to meet intact protein goals and balance a diet to provide essential nutrients was recommended, and food lists of protein content (0.5-5.0g/portion) of foods were provided (G.158, G.150, G.149). High protein food choices were noted as often high in fat content, and unlimited snack foods as contributory to weight gain (G.157). Education was recommended for food choices that promote healthy weight control, and for low fat cooking methods (G.149, G.150). One protocol provided a handout of lean vs. fatty meats, low fat cooking methods, and low-fat dairy choices (G.149).

Consensus based on clinical practice

Delphi 1 survey results indicated strong consensus for a metabolic dietitian's role after an individual has responded to pegvaliase to include: maintaining a relationship with the individual, support of long-term treatment adherence, counseling regarding healthy eating, and monitoring nutritional status and adequacy of protein intake. Overall consensus was consistently strong for ongoing nutrition counseling and support regarding: high protein food options and serving size (87%), tracking increased protein intake in liberalized but not normalized diets (83%), incorporating more protein into a healthy diet (96%), weight management (91%), cooking and recipe help (91%), and budgeting and grocery shopping (91%).

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Evidence

The 2018 evidence- and consensus-based recommendations noted that individuals who choose to follow a predominantly vegetarian diet should be educated on how to incorporate high-quality protein into their diet, and those who choose to follow a vegan diet should be educated to consume 10-15% more protein than the DRI due to reduced bioavailability of plant protein These individuals were considered at risk for micronutrient deficiencies and should be monitored and educated regarding the use of supplements. (F.4459) European guidelines recommend an increase of 20% more protein, or 1 g protein/kg/day for these individuals (F.4495).

Consensus based on clinical practice

Consensus was not sought for this topic.

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Evidence

Individuals receiving pegvaliase therapy may need counseling to transition to inclusion of unfamiliar higher protein foods in their diet. It is recommended that any emotional response, or neophobia, resulting from recommendation of previously forbidden foods, and a possible loss of identity, should be recognized and counseling provided. (F.4459)

In one study, the Food Neophobia Scale (FNS), adapted for PKU, was administered to 18 individuals who had received pegvaliase therapy for about 5 years. Percentage of individuals was noted as: 47% with low, 35% with moderate, and 18% with a high degree of food neophobia. Those having a low degree of food neophobia were less fearful of trying new foods and experienced increased enjoyment of food as assessed by an Epicurean Eating Tendency (EAT) questionnaire. (F.4475)

Consensus based on clinical practice

The Delphi 1 survey showed strong support for counseling regarding consuming previously forbidden high protein foods (91%) and acceptance of new food tastes and textures (96%).

The Delphi 2 survey reported 100% agreement that care givers should recognize and provide counseling for individuals who have difficulty accepting foods previously contraindicated, and these individuals should be referred to a psychologist or other professional if indicated.

Recommendation 7.5

Pegvaliase therapy in special populations

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Topic 7.5.1  Link to Topic 7.5.1
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Evidence

Evidence is limited to animal studies (which were outside the scope of this review) and one case report of a woman continuing pegvaliase during pregnancy (see recommendation 7.5.2). Pegvaliase prescribing information states that use in pregnancy may cause fetal harm based on studies in rabbits and rats. Rabbits who were given 7.5 times the maximum recommended daily dose based on body weight during the period of organogenesis had increased embryo resorption, marked reduction in fetal weight and fetal malformations, and 8% of fetuses were aborted; whereas pregnant rabbits treated with 3 times the maximum dose had no adverse effects on embryo or fetal development. Rats given 4.2 times the maximum dose during a 28-day premating period through mating and organogenesis showed skeletal abnormalities, and pregnant rats given 19.4 times the maximum daily dose showed reduction in litter sizes and fetal weights associated with maternal toxicity. Rats given less than the maximum dose had no adverse effects on embryo-fetal development. (Y.32)

Clinic protocols include counseling women with PKU of childbearing age about the need to use birth control and, in some centers, a contract must be signed acknowledging this (G.170. G.167). Several metabolic clinics have pegvaliase protocols that call for counseling women who are considering pregnancy about the risks associated with maternal PKU (MPKU) and the lack of experience with pegvaliase during pregnancy (G.170, G.160). Pregnancy testing before initiating pegvaliase therapy is also included in some clinic protocols (G.160, G.171).

Consensus based on clinical practice

This recommendation was not specifically addressed in the Delphi process.

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Evidence

Phenylalanine is a known fetal teratogen. The Maternal Phenylketonuria Collaborative Study reported outcomes of 468 pregnancies and 331 live births in pregnant women with PKU and demonstrated that uncontrolled blood PHE concentrations above 600 µmol/L were associated with an increased risk for miscarriage, major birth defects (including microcephaly and major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ. (L.35, Y.32)

In one recent case-study, a 22-year-old woman with PKU was in the 28th week of pegvaliase treatment and on a dose of 10 mg/day when her pregnancy was identified. She discontinued pegvaliase for one week until a discussion with the metabolic team resulted in the decision to resume pegvaliase therapy (at 10 mg/day) because of her history of high blood PHE on diet therapy alone. Subsequently, she had several dose adjustments based on low blood PHE and/or concern about hypophenylalaninemia (hypoPHE). While the birth outcome of the pregnancy was normal, her pregnancy management had challenges: anxiety due to a psychological aversion to high protein foods, and logistical issues, including timely blood PHE monitoring, and time lags between the medical team's decision to adjust the dose and availability of the new dose. (F.4487)

Three pregnancies in two women on pegvaliase were reported in one metabolic clinic. The first pregnancy came to attention 6 weeks after initiating pegvaliase therapy when the woman presented to the emergency department with abdominal pain and was found to be having a miscarriage. She continued pegvaliase therapy and at 19 weeks of therapy had a second pregnancy. She elected to discontinue pegvaliase and afterwards miscarried this pregnancy late in the first trimester. The second woman became pregnant while on pegvaliase and decided to remain on therapy since her blood PHE was in good control. She had an early pregnancy loss at 7 weeks gestation during her 50th week of pegvaliase therapy. (F.4502)

Considering the known risk of MPKU, and in accordance with published guidance on pegvlaliase use (F.4459), pegvaliase use during pregnancy should be considered on a case-by-case basis (G.162). If pregnancy occurs, the clinic is to be contacted immediately (G.167) and enrollment into the maternal pegvaliase surveillance program is recommended (Y.32).

Consensus based on clinical practice

88% of Delphi 2 survey respondents (MDs and RDs) agreed with this recommendation.

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Evidence

There is currently insufficient experience in pregnant women treated with pegvaliase to recommend a blood PHE treatment range (120-360 µmol/L) that is different from published guidelines for MPKU (Cunningham, Nutrition Management Guideline for PKU). While some clinics advocate for tighter blood PHE control during pregnancy, there is a concern about low blood PHE in pregnancy impacting fetal growth, and pegvaliase therapy may increase the possibility of hypoPHE. In one reported case study of pegvaliase therapy continued during pregnancy, low blood PHE was concerning and challenging to manage (F.4487).

Consensus based on clinical practice

Consensus concerning optimal blood PHE during pregnancy was not reached in Delphi 2; respondents commented about the concern of low blood PHE as well as the "safe" upper limit for blood PHE in MPKU being <240 µmol/L.

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Evidence

The 2018 evidence- and consensus-based recommendations suggested that pegvaliase not be recommended for women of childbearing age who plan to become pregnant in the near future. When pegvaliase is discontinued, a 4-week washout period is needed to clear the drug (F.4459).

In one poster presentation, the researchers suggested that being of childbearing age should not be a deterrent for the medical team to offer pegvaliase because it is possible for women to successfully return to a PHE-restricted diet before conception. They reported successful transition from pegvaliase to the PHE-restricted diet in 2 women, describing 4 pregnancies resulting in 3 live births without complications and one stillbirth. The authors observed that improved blood PHE control while receiving pegvaliase therapy may help women achieve better adherence when returning to a PHE-restricted diet because of improved executive function. One of the women in this summary was off pegvaliase for 7 months prior to her first pregnancy and remained off for 5 years (with 3 pregnancies during this time) while the other discontinued pegvaliase at nearly 6 weeks gestation. Both women were able to maintain good blood PHE control during pregnancy with diet alone and both successfully resumed pegvaliase therapy, reaching efficacy and consuming a normal protein intake without medical food. (G.173)

Consensus based on clinical practice

This question was not addressed in the consensus process.

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Evidence

Returning to a PHE-restricted diet for pregnancy can be successful. In one report the transition occurred over 8-10 weeks and required close nutrition counseling and support to maintain blood PHE between 120 and 360 µmol/L (F.4474).

Consensus based on clinical practice

This question was not addressed in Delphi 2, however there was discussion in the Nominal Group about the difficulty in transitioning from pegvaliase therapy to a PHE-restricted diet and the need for support.

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Evidence

There are no studies in humans regarding pegvaliase use during lactation. In a study in rats, pegvaliase was detected in rat milk but not in the pups, and pegvaliase administration at high doses during lactation resulted in decreased pup weight and survival. The prescribing information for pegvaliase states that it may cause low PHE content of human milk, but no data is available (Y.32).

Pegvaliase is unlikely to be absorbed by the infant because it is a polypeptide that is probably destroyed in the infant's gastrointestinal tract by proteases (F.4428). In addition, pegvaliase is active against only free PHE and the PHE intake in a breastfed infant is bound in intact protein, mainly lactalbumin. Therefore, any trace amount of undetected phenylalanine ammonia lyase (PAL) activity in breast milk will not alter infant nutrition (F.4474). The pegvaliase prescribing information recommends careful monitoring of blood PHE concentrations in breast-feeding women to prevent hypoPHE (Y.32).

There was one case report of a woman with PKU who discontinued pegvaliase during pregnancy and lactation. The case highlighted the difficulty of maintaining a PHE-restricted diet after childbirth. The individual, though well-educated and motivated, was unable to sustain the diet restrictions and monitoring of blood PHE during this period. This report also included the analysis of one sample of pumped breast milk taken after the woman resumed pegvaliase and was receiving a dose of 20 mg/day. Comparisons with a control breast milk sample from a woman without PKU and a laboratory standard showed that the activity of phenylalanine ammonia lyase (PAL) in the woman's sample was indistinguishable from the comparison samples. The authors concluded that resuming pegvaliase during lactation would be considered in future pregnancies. (F.4474) In the only reported case study of a woman on pegvaliase during pregnancy, the individual chose not to breast-feed her infant (F.4487).

Consensus based on clinical practice

In Delphi 2, 81% of respondents agreed with considering pegvaliase use during lactation.

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Evidence

No data is available in individuals under age 16. There is limited evidence about the use of pegvaliase in adolescence from the early phases of the clinical trials where individuals over age 16 years were enrolled (F.4486). In subsequent trials participants were age 18 years or older. Of the 261 individuals in Study 301, 11 were aged between 16 and 18 years at enrollment. All 11 individuals had inadequate blood PHE control (blood PHE levels above 600 µmol/L) at baseline. These individuals received the same induction/titration/maintenance regimen (with maximum dose of 40 mg/day) as those aged 18 years and older in this study. Of the 11 individuals initially enrolled in Study 301, 3 patients reached blood PHE levels ≤ 600 µmol/L by 12 months, 7 reached this threshold by 24 months, and 8 reached this threshold by 36 months. Adverse reactions were similar in type and frequency to the adult study population. (Y.33) In Europe, pegvaliase is approved in doses up to 60 mg/d for individuals aged 16 years or older who have inadequate blood PHE control on prior management (F.4495, Y.33).

A recent case series that reported on several individuals who were on pegvaliase therapy while in college has implications for adolescents. Authors noted that it is important to consider the individual's life events when initiating the drug, as too much flux can make it difficult to manage induction and titration and may lead to treatment discontinuation. One individual discontinued pegvaliase when she started college as she feared significant side effects while away from home. (F.4493)

Consensus based on clinical practice

There was unanimous agreement (100% of respondents) in Delphi 1 that adolescents age 16 years and older should be offered pegvaliase if blood PHE is >600 µmol/L.

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