1.1. Disease Prevalence and Incidence
Phenylalanine hydroxylase (PAH) deficiency, traditionally known as phenylketonuria (PKU), is an autosomal recessive inborn error of metabolism caused by mutations in the gene encoding PAH, the enzyme that converts phenylalanine (Phe) to tyrosine.1,2 More than 800 mutations that lead to PAH deficiency have been identified, which, in turn, results in a wide range of clinical phenotypes and spectrum of disease severity.1,2 The most severely affected individuals are those with the phenotype of “classical PKU,” whose untreated Phe blood levels are typically greater than 1,200 µmol/L, whereas normal mean Phe levels are 60 µmol/L.1 Patients with Phe levels of 900 to 1,200 µmol/L are considered to have moderate PKU and those with Phe levels of 600 to 900 µmol/L to have mild or atypical PKU.1 If untreated, Phe levels accumulate to toxic levels in the brain, which can lead to profound neurocognitive, neuropsychiatric, and developmental problems. Early detection through newborn screening and treatment prevents the most dramatic clinical sequelae, although over time subtle intellectual and neuropsychiatric issues may manifest even with treatment.1 In addition, patients treated from the early weeks of life with good metabolic control, but who lose control in later childhood or adulthood, may experience both reversible and irreversible neuropsychiatric consequences.1
Phenylketonuria occurs in approximately one in every 12,000 to 15,000 infants born in North America, accounting for approximately 300 new cases each year.3 It is estimated that in Canada, 26 to 32 infants were born with PKU in the past year and approximately 1,250 patients with PKU are currently being actively managed across the provinces.12 The management of PAH deficiency or PKU places a large burden on patients and their families, which can result in social isolation, reduced quality of life, and financial difficulties. Patient expectations are that sapropterin (SAP), a synthetic form of tetrahydrobiopterin (BH4), will lower Phe levels and increase Phe tolerance so that patients are able to eat a more varied diet and be less isolated from their peers.
1.2. Standards of Therapy
With the exception of SAP, no pharmacologic therapies are approved in Canada for the treatment of PKU. The mainstay of treatment is dietary manipulation based on a Phe-restricted diet and Phe medical foods, as detailed in Appendix 7. The goals of dietary therapy are to lower Phe levels, while still providing sufficient Phe for protein formation, normal growth, and health maintenance and to prevent catabolism. The Phe-restrictive diet is expensive, unpalatable, and includes three main components: medical food (synthetic Phe-free formula containing other essential amino acids, vitamins, iron, and trace elements), natural foods (strictly “vegan-vegetarian,” excluding high-protein foods such as meat, fish, chicken, bread, eggs, cheese, nuts, and certain legumes), and specially designed (and expensive) low-protein foods to give needed variety to the diet. The strict diet imposes an economic and social burden on patients and their families, which often leads to non-adherence, especially among adolescents and young adults.4 The transition to adulthood is identified as a high-risk period for individuals with PAH deficiency due to the desire for increased independence, peer pressure, rebellious behaviour, loss to follow-up, and the high cost of medical foods.1
According to the most recent clinical practice guidelines put forth by the American College of Medical Genetics and Genomics (ACMG), the primary goal of therapy is to lower Phe blood levels and any interventions, including medications or combination of therapies that help to achieve that goal in an individual without other negative consequences, should be considered appropriate therapy.1 The ACMG guidelines recommend lifelong treatment for patients with untreated Phe levels greater than 360 µmol/L, with the goal of maintaining Phe blood levels in the range of 120 to 360 µmol/L for patients of all ages.1 Many treatment centres in North America initiate treatment when the Phe blood level is 360 µmol/L or higher; however, the evidence regarding clinical outcome in untreated patients with Phe levels between 360 and 600 µmol/L is mixed, and published evidence of harm associated with these levels has been inconsistent.1 Initiation of treatment should be undertaken as early as possible, preferably within the first week of life, with a goal of normalizing Phe blood levels within the first two weeks.1 The primary treatment is dietary manipulation with frequent modification to respond to growth, life stages, concurrent illness, and comorbidities.1 The first and only pharmacologic drug currently available for treatment of PAH deficiency is SAP; however, only approximately 25% to 50% of patients are SAP-responsive.1 The mechanism by which residual PAH activity is enhanced by SAP is unclear, but it is speculated that BH4 or SAP acts to improve folding and increases stability of the mutant protein; therefore, patients with mild deficiency are most likely to respond because some stable protein is required for SAP to function.1 Nonetheless, responsive patients are identified even among those with compete PAH deficiency, so the ACMG guidelines recommend that every PAH-deficient patient be offered a trial of SAP.1 Responsiveness is commonly assessed by starting the patient on 20 mg/kg/day of SAP and obtaining Phe blood levels at regular intervals (e.g., at 24 hours and weekly up to four weeks) with the assumption that the diet remains stable during the testing period.1 In responders, a decline in Phe blood levels is expected although the ACMG guidelines do not specify an expected range of decline.1 The ACMG guidelines do state that clinical judgment is required to determine what constitutes a significant or beneficial decline in Phe blood levels from baseline in an individual, but 30% is often cited as evidence of effective Phe reduction.1 Ongoing treatment in SAP responders is typically 5 to 20 mg/kg/day of SAP in conjunction with a Phe-restricted diet.1
1.3. Drug
Sapropterin is a synthetic formulation of BH4, a necessary co-factor for the PAH enzyme, which hydroxylates Phe through an oxidative reaction to form tyrosine.5 In patients with PKU, treatment with BH4 can activate residual PAH enzyme, improve the oxidative metabolism of Phe, and decrease Phe blood levels in some patients.5 In patients with PKU who are responsive to BH4, Phe blood levels decrease within 24 hours after a single administration of SAP, although the maximal effect on Phe blood levels may take a month or longer, depending upon the patient.13
Kuvan (sapropterin dihydrochloride) is available as 100 mg oral tablets. Kuvan is indicated, in conjunction with a Phe-restricted diet, to reduce Phe blood levels in patients with hyperphenylalaninemia (HPA) due to BH4-responsive PKU.5 The recommended starting dose is 10 mg/kg/day and response to therapy is determined by change in blood Phe following treatment with 10 mg/kg/day for a period of up to one month.5 Blood Phe levels should be checked after one week of initiating treatment and periodically for up to a month. If blood Phe does not decrease from baseline, the dose may be increased weekly to a maximum of 20 mg/kg/day, with frequent monitoring of blood Phe levels over a one-month period. Patients whose blood Phe levels do not decrease after one month of treatment at 20 mg/kg/day are considered non-responders, and treatment should be discontinued in these patients. Once responsiveness to Kuvan has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg/day according to response to therapy. As recommended for clinical management of PKU, blood Phe levels in patients receiving SAP should be tested one or two weeks after each dose adjustment and monitored frequently thereafter. Patients treated with SAP must continue on a Phe-restricted diet.
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| Indication under review |
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| In conjunction with a Phe-restricted diet to reduce blood Phe levels in patients with hyperphenylalaninemia (HPA) due to BH4-responsive PKU. |
| Reimbursement criteria requested by sponsor |
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Ongoing funding of sapropterin (Kuvan) for non-pregnant patients and patients actively planning pregnancy who have a diagnosis of PKU and who have demonstrated a response to the initial 6 month trial of sapropterin and who meet ALL of the following criteria:
Compliance with low protein diet, formulas, and treatment with sapropterin; AND Has achieved - a)
normal sustained blood Phe levels [Greater than 120 µmol/L and less than 360 µmol/L] (At least 2 levels measured at least 1 month apart); OR - b)
sustained blood Phe reduction of at least 30% (At least 2 levels measured at least 1 month apart) compared to baseline if the Phe baseline level is less than 1200 µmol/L; OR - c)
sustained blood Phe reduction of at least 50% (At least 2 levels measured at least 1 month apart) compared to baseline if the Phe baseline level is greater than 1200 µmol/L; AND
Demonstrated increase of dietary protein tolerance based on targets set between the clinician and patient; OR Clinically meaningful age-appropriate improvement in: - a)
neurobehavioural or neurocognitive function or impairment for patients with such impairments as determined by peer reviewed clinically validated scales; OR - b)
demonstrated improvement in Quality of Life using peer reviewed validated scales; AND
Managed by a physician specialized in metabolic/biochemical diseases
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