To improve outcome for individuals with PKU who must adhere to a complex diet, alternative or adjunctive therapies have been developed. Sapropterin dihydrochoride (sapropterin or Kuvan™) is the pharmaceutical derivative of tetrahydobiopterin (BH4), which is the co-factor for phenylalanine hydroxylase. Sapropterin has been shown to be safe and effective in improving blood PHE in 20-50% of those tested. It has also been shown to reduce fluctuation in blood PHE, which has been positively correlated with improved outcomes. US protocols for testing responsiveness, dosing, and monitoring have been published. Recommendations for modifying dietary therapy after response to sapropterin, and monitoring nutritional status have been made. European protocols generally have more stringent criteria for responsiveness and some describe using sapropterin as a monotherapy with discontinuation of diet restrictions and medical food. Further studies and reports of clinical use describe a broadening criteria (beyond FDA labeling restrictions) for patient selection, dosing, response indicators, and therapy modifications. However, inconsistencies in study design, cohort characteristics, methods, and outcome measures make comparative conclusions complex. When sapropterin response allows increased tolerance of intact PRO, nutritional status and quality of life may be improved. Sapropterin therapy in special populations is not yet well documented but there is consensus that individualized use may provide nutritional, cognitive, and quality of life benefit in young children and untreated or late-treated adults, especially when blood PHE cannot be adequately controlled by diet alone. Sapropterin therapy that results in lowered maternal blood PHE during pregnancy may safely reduce the risk of MPKU syndrome effects in the fetus.
Large neutral amino acids (LNAA) are known to inhibit the passage of blood PHE into the brain through competition for carrier sites at the blood brain barrier. Supplementation with LNAA has been described as effective in improving neurocognition in individuals with PKU, but does not significantly lower blood PHE. Research on the use of LNAA in PKU is limited, and consists primarily of studies with small sample sizes or case studies with varying treatment protocols, and different measures of neurocognition and quality of life outcomes. A single clinical trial demonstrated benefit when LNAA were added to ongoing dietary management, but correlations with LNAA-treated individuals on a “relaxed” PHE diet cannot be drawn.
When treatment with sapropterin is appropriate, combine with diet therapy to improve blood PHE and/or clinical status, and develop individualized therapy plans to provide best outcome.
Sapropterin has been found (in clinical trials and subsequent clinical use) to be a safe and effective adjunctive therapy for PKU (F.1429, F.1479). 25-50% (varying with trial criteria used) of individuals given sapropterin are found to respond with lowered blood PHE (F.2626, F.2629, F.1421, F.1429). Individuals with residual enzyme activity (“mild" or "moderate" PKU) are more likely to benefit, but response is also seen in those with classical PKU. Genotype/phenotype correlation is not currently a single reliable predictor of responsiveness, but is an area of active research (F.2626, F.2627, F.1421, F.1521, F.2629). The ACMG guideline considers it appropriate to offer sapropterin to every individual with PKU who may benefit (F.2626, F.1412, F.1429). Response is commonly determined by a trial period of up to 4 weeks with a daily dose of 20 mg/kg, which provides best efficacy, and blood PHE monitoring at regular intervals (at 24 hours, then weekly) (F.2626, F.2627, F.2532, F.2629). Diet, medical food intake, and other lifestyle characteristics (level of exercise, etc.) should remain unchanged during the trial. A decrease of blood PHE >20-30% from baseline is most commonly cited as indicating response, but clinical judgment is an important factor when determining beneficial response (F.2626, F.1412, F.2629). Rapidity of blood PHE decrease varies from within 24 hours to a slower response seen only after 2-4 weeks (F.2626, F.2629). It may be more difficult to determine beneficial response to sapropterin when baseline blood PHE is already at the lower end of treatment range. A PHE challenge is recommended to clarify response in these individuals (F.673, F.1517, F.2629). Benefits of sapropterin therapy may include: decreased blood PHE in individuals unable to attain this with diet therapy alone, increased PHE intake tolerance, nutritional advantages of increased intact PRO tolerance, reduction in blood PHE variability, improvement in clinical and neurocognitive status, and improvement in quality of life resulting from relaxation of diet restriction (F.2626, F.2627, F.2629). Studies of longer term use of sapropterin show continuance of efficacy and safety, but also note some individuals fail to sustain lower blood PHE concentrations because of poor adherence to liberalized diet restrictions and to drug treatment regime (F.1176). There is a continued need for individual monitoring, education, and modification of dietary therapy or sapropterin dosage (F.1176).
In Delphi 1, there was 80% agreement among all respondents that sapropterin should be offered to any individual >4 years of age who may benefit. Percent agreement increased (91% RD and 100% MD) regarding offering sapropterin to individuals with mild or moderate PKU. Most respondents disagreed that genotype alone can be reliably used to predict response to sapropterin.
Conduct a PHE challenge to determine maximal dietary PHE tolerance when sapropterin response brings blood PHE to within control range, or to clarify a sapropterin response when historical blood PHE is already within control range.
Sapropterin as adjunctive therapy may allow dietary liberalization, with increased tolerance of PHE/intact protein, and decreased need for medical food. Changes in PHE tolerance range from minimal increases to total dietary relaxation. Recommendations are published for conducting a systematic PHE challenge (F.673, F.2627, F.1517. F.2629). These include incremental addition of a measurable PHE source (e.g. nonfat dry milk added to medical food) followed by evaluation of blood PHE levels until maximum PHE tolerance is determined. This method can also be used to clarify sapropterin response in individuals already maintaining blood PHE levels within control range (F.673, F.1517).
This topic was not addressed in the consensus process.
Modify dietary therapy in individuals responsive to sapropterin to accomodate increased PHE tolerance. Liberalization should reflect increased PHE/intact protein intake, decreased medical food intake, and vitamin/mineral supplementation as appropriate. Monitor nutritional status and educate individuals regarding modified dietary recommendations.
Response to sapropterin may support increased PHE tolerance from minimal, to 3-4+ times baseline, to discontinuation of restrictions in some individuals (F.2566, F.1425). After determining maximum PHE tolerance, the PHE source used to trial tolerance is replaced with PHE/intact protein from food sources (F.1517). Some dietary PHE restriction must often be retained (F.2627, F.2629). If the increased intact PRO tolerated is sufficient to meet DRI recommendations, medical food may be decreased or discontinued, as long as energy needs are met (Y.12). Recommendations usually call for retaining some medical food to maintain taste acceptance and a source of PHE-free protein in case protein needs exceed tolerance of intact protein (e.g. during pregnancy, infection, and rapid growth) (F.2627, F.1152, F.1517). Regular monitoring is still required to track blood PHE control, nutrient adequacy, and normal growth. See research question 4 and TABLE #8, Monitoring Nutritional Management of PKU for further monitoring guidance. Vitamin and micronutrient supplements may be needed if medical food is decreased or discontinued, and monitoring is important to determine adequacy of intake (F.1152, F.1425). Re-education for adherence to a more liberalized PHE/intact PRO intake is necessary (F.2626, F.2627, F.1517). Counseling should be individualized and may include: appropriate natural protein sources (nutritionally sound and easily quantified), accurate portioning, counting grams of protein instead of milligrams PHE, label reading, distribution of high PRO foods through the day, vitamin and mineral supplements required, taking sapropterin appropriately, and importance of continued monitoring (F.2627, F.1517). Some studies report an increase in adherence to liberalized therapy and improvement in quality of life when sapropterin is an adjunct to treatment, although the need for a quality of life assessment tool specific for PKU is noted (F.1429, F.1152, F.2626, F.2627, F.2629, F.1515).
In Delphi 1, there was lack of consensus on whether the DRI for PRO is sufficient for individuals with PKU who receive sapropterin as adjunctive therapy (55% RD and 33% MD respondents). Responses and comments showed variation in practice or lack of experience regarding how diet therapy should be adjusted (e.g. decreasing medical food, eliminating modified low protein foods).
In Delphi 2, agreement among all respondents varied regarding continuance of medical food for individuals with PKU who respond to sapropterin: 78% approved of decreasing medical food if energy needs are met, 62-67% felt minimal intake of medical food should be continued to enhance metabolic control and maintain taste acceptance, and 62% agreed modified low protein foods could be discontinued without compromising the diet.
Individualize and closely monitor sapropterin therapy when used in special populations, such as: infants and young children, pregnancy, and late- or untreated adults.
US labeling for sapropterin does not restrict use for any age, and recent studies show safety and efficacy in young children and infants (F.2629). European protocols include BH4 loading tests in infants with subsequent sapropterin therapy in responsive individuals regardless of age (F.2629). US clinics commonly recommend establishing the caregiver's proficiency in diet management and the infant or young child's acceptance of medical food before offering sapropterin therapy. However, determining response to sapropterin in 2-4 year olds and adjusting therapy accordingly may have the benefit of improved metabolic control along with possible nutritional benefit of more natural PRO during rapid growth and development (F.2626, F.2629).
In Delphi 1, there was little agreement regarding offering sapropterin to children <2 years of age.
In Delphi 2, 53% of respondents agreed that individualized sapropterin therapy is appropriate for children <2 years of age, but 62% also felt there was value in waiting to start therapy until care-takers were accomplished at dietary management and children developed acceptance of diet restrictions and medical food. 43% of respondents agreed that BH4 loading to ascertain responsiveness in the newborn would useful, but only 29% thought this test would be feasible in their practice.
In the Nominal Group, 75% of all participants saw benefit in testing infants for sapropterin response after stabilization of blood PHE through dietary treatment, especially if response allows an increase of natural PRO in the diet. 50% felt delaying testing somewhat could allow for care-takers to become more adept at dietary management. 12% of participants felt offering sapropterin should be delayed until 4-5 years of age.
Sapropterin use in pregnancy has not been evaluated in controlled trials, but there is no evidence of teratogenicity in pregnancy. Case reports document successful outcomes with sapropterin therapy that is initiated both before and after conception (F.2626, F.2627, F.2629, F.1517). Designated a Category C drug for pregnancy, sapropterin use can be justified when response allows the known risk of high maternal blood PHE concentrations in the fetus to be reduced. A patient registry for sapropterin in pregnancy is currently in place and will provide future longitudinal data. See also Question 6 regarding PKU and pregnancy.
In Delphi 2, 81% of all respondents agreed that individualized sapropterin therapy is appropriate for use during pregnancy when diet alone is not successful in controlling maternal blood PHE.
Late- or untreated adults with PKU or adults taken off diet as children may also benefit from sapropterin, as these individuals often have difficulty with re-initiation of and adherence to diet restriction and medical food intake. Suggested protocol for trialing sapropterin in adults who exhibit cognitive and behavior deficits is to begin with small doses (5 mg/kg/day) and slowly increase dosage while monitoring clinical neurocogitive status and/or behavior (F.1517). Caution is recommended when concurrent medications include psychotropic drugs (F.1517). Improved behavior is sometimes correlated with sapropterin response, but controlled studies are lacking (F.1517). Sapropterin therapy in this population should be individualized and practical within the limitations of the individual. See also Question 6.
In Delphi 1, there was strong agreement (91% RD and 100% MD) for first attempting to initiate dietary therapy in individuals who were late- or untreated, or taken off diet as children. There was also strong agreement (80% of all respondents) for offering sapropterin to these individuals.
In Delphi 2, there was 95% agreement of all respondents for use of sapropterin as a treatment in late- or untreated adults. 77% of respondents did not feel it essential to try to initiate diet therapy before testing for sapropterin response. Comments included a statement that sapropterin therapy is easier than initiating diet and should be considered first.
In the Nominal Group, 63% of participants agreed that sapropterin is a viable treatment option for late- or untreated adults with PKU.
Consider LNAA supplementation in adults with PKU who are unable to achieve metabolic control with diet or other adjunctive therapy. LNAA therapy is not recommended for use in infants, young children, or women who are pregnant or may become pregnant.
LNAA therapy is reported to improve neurocognitive functioning in some adults (F.2441, F.2451), with the description of the benefit found primarily in small studies and case reports using differing protocols. In most reports, decrease in blood PHE is not seen (F.2441). A single clinical trial reports an effect on blood and brain PHE and neuropsychological performance in early treated individuals who retained usual diet restriction. Participants consumed medical food plus LNAA supplements, medical food alone, LNAA alone, or neither medical food nor LNAA. Blood PHE was lowest in individuals who received medical food plus LNAA, followed by medical food alone, and then LNAA alone. This study also reports that improved executive functioning correlated with LNAA, but notes wide cohort and individual variation (F.2451). The mode of action for LNAA supplementation is thought to be through competitive inhibition for the LAT1 carrier at the blood/brain barrier when blood PHE is elevated, and in some products (containing lysine) at the gut mucosa (F.2441). Findings of improved neurocognitive function are believed to result from decrease in brain PHE, and normalization of neurotransmitter production and myelinization (F.2441, F.1149). One study reports long term use of LNAA with a liberalized diet (75% protein allowance from intact protein, 25% from LNAA) in children and adults, and notes improvement in quality of life. Neurocognitive results are not reported. Acceptable blood PHE control was <1500 µmol/L, which is significantly above US recommended treatment ranges (F.1175).
LNAA should be avoided in pregnancy, as blood PHE is not lowered sufficiently to prevent fetal PHE toxicity, and effects on fetal growth and neural system development are unknown (F.2626, F.2627, F.2441, F.2629). LNAA are not recommended for use in infants and young children as effect on growth has not been studied (F.2626). LNAA should be given only with caution to patients who are prescribed psychotropic drugs affecting neurotransmitter levels, as combined effects are unknown (F.2451). Treatment with LNAA should be limited to adolescents and adults who are unsuccessful in maintaining blood PHE control, and has been found ineffective in patients already compliant with diet. LNAA therapy benefit has been reported in a population of adults who were late diagnosed or previously untreated, although no positive correlation to neurocognition was seen when blood PHE was <1200 µmol/L (F.2451). Larger, well-controlled studies are needed to quantify and substantiate LNAA efficacy and safety, especially when used as a monotherapy (F.2626, F.2627, F.2176, F.2441, F.2629).
In Delphi 1, there was limited support for LNAA therapy in general. 100% of respondents disagreed with use of LNAA in infants or growing children. 80% of all respondents agreed that LNAA therapy could be used in adults who were unable to achieve good metabolic control with diet therapy alone.
When LNAA therapy is chosen, provide 20-30% of total protein intake from LNAA supplements, and the remaining 70-80% from intact dietary protein. Total protein intake should meet DRI requirements (0.8 g/kg/day). Monitor adequacy of protein intake and plasma amino acids to prevent essential amino acid deficiencies.
Clinical use of LNAA therapy varies widely and there is insufficient experience to describe best prescriptive protocol. Most reports recommend providing 20-30% of total PRO requirements (0.8-1.0 g/kg/day) from LNAA, and the remaining 70-80% from intact PRO food sources to accomplish a minimal PHE restriction (F.2627, F.1149, G.86). LNAA products differ significantly in formulation (specific LNAA included and proportional amounts, vitamin and minerals) so must be evaluated for individual patient needs. See TABLE #6, Classification of Medical Foods for PKU for product classifications. One source recommends a therapy goal of blood PHE <1200 µmol/L, which requires some dietary protein restriction and medical food intake (G.86). Plasma amino acids should be monitored monthly to ensure nutritional adequacy, and vitamin and mineral supplements may be needed (G.86). Efficacy of LNAA therapy is difficult to assess, as blood PHE concentrations are not a useful marker. Changes in white matter on MRI have been reported as indicators of LNAA efficacy (F.2503). Although monitoring PHE concentration in the brain would be best to show efficacy, this is impractical in a clinical setting. Monitoring melatonin as a surrogate marker for serotonin levels (deficient in individuals with PKU who demonstrate poor executive functioning) has been suggested, but this method requires further validation (F.2627).
In Delphi 1, there was a lack of consensus regarding specifics of how to incorporate LNAA into therapy management.
In Delphi 2, 52% of respondents agreed that 20-25% of PRO requirements should be provided by the LNAA product and 75-80% by intact PRO. Comments suggest a lack of experience with use of LNAA and a lack of evidence for positive outcomes. 86% of respondents agree that inclusion of medical food along with LNAA therapy results in best outcome