Sapropterin for treating hyperphenylalaninaemia in phenylketonuria

1.1 Sapropterin is recommended as an option for treating hyperphenylalaninaemia that responds to sapropterin (response as defined in the summary of product characteristics) in people with phenylketonuria (PKU), only if they are:

1.2 This recommendation is not intended to affect treatment with sapropterin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.

Why the committee made these recommendations

PKU is an inherited condition that causes raised levels of phenylalanine in the blood. Without treatment, this causes irreversible brain damage in babies and children and can affect brain function in adults. The only treatment for PKU is a diet to manage phenylalanine and overall protein intake (protein-restricted diet) and prescribed supplements. The diet is challenging and time-consuming, so it is difficult for some people to maintain. Sapropterin, plus a protein-restricted diet, is used for people whose PKU has been shown to respond to it. The aim of treatment is to maintain satisfactory blood phenylalanine levels to reduce PKU symptoms and complications, and potentially allow a less restricted diet.

Clinical trial evidence compares sapropterin plus a protein-restricted diet with diet alone. It shows that sapropterin effectively reduces blood phenylalanine levels in the short term for people whose PKU has been shown to respond to it, but it is uncertain how well it works in the long term. There is no clinical trial or registry evidence to show how much sapropterin reduces the need for a protein-restricted diet, or how it affects quality of life or brain development.

In people under 18, treatment for PKU is particularly important because of the higher risk of irreversible brain damage to the developing brain. This risk is highest in younger children, particularly up to age 12. Sapropterin may reduce the risk of brain damage for these children, but there is no clinical evidence to confirm this, and this potential benefit is not captured in the cost-effectiveness estimates. Taking uncaptured benefits and the clinical evidence into account, cost-effectiveness estimates are acceptable at the upper limit of what NICE considers an acceptable use of NHS resources. Sapropterin is therefore recommended for people under 18. The dose for children can be increased above the starting dose of 10 mg/kg, only if target blood phenylalanine levels are not achieved at a dose of 10 mg/kg. So, it is recommended for treating PKU in people under 18, normally at a dose of 10 mg/kg.

Stopping treatment and relying on diet alone at 18 years old is not clinically ideal. It would benefit young adults if treatment with sapropterin could be continued for as long as possible during final brain development and transition into adulthood. Taking this into account the maximum age at which sapropterin can be considered a cost‑effective use of NHS resources is 21. However, for this use to be cost effective people would need to continue the dose they were having when they were under 18. In practice this may mean that some young adults may need more dietary control alongside sapropterin between the ages of 18 and 21 (inclusive) than they would with a higher dose. Sapropterin is recommended for people aged 18 to 21, continuing the dose they were having before turning 18. People who have not had sapropterin before turning 18 can still have it until they turn 22. But the purpose of recommending sapropterin for this age group is to allow more control of phenylalanine levels while transitioning from sapropterin to dietary control alone by age 22, when the brain is nearly fully developed.

The risk of irreversible brain damage reduces with age, particularly after brain development is complete. So the adverse effects of being unable to follow the protein-restricted diet are considerably reduced in adults compared with the risks in childhood. Adults may still gain considerable benefit from sapropterin because of fewer symptoms related to raised phenylalanine levels, without having to follow the protein-restricted diet as strictly. However, these benefits are included in the economic modelling. Also, in adults the weight-based dose together with the higher average mg per kg dose results in costs that are considerably higher than in children, but the benefits are not correspondingly higher for adults. Even taking into account any uncaptured benefits in adults, the cost-effectiveness estimates are substantially higher than what NICE considers an acceptable use of NHS resources. So, it is not recommended for adults after they reach the age of 22.

Raised phenylalanine levels in pregnant women with PKU can cause severe birth defects in their unborn children. This could increase maternal anxiety, with the additional burden of the even more restrictive diet that is needed during pregnancy to maintain the stricter recommended phenylalanine levels. There is not enough evidence to predict how much sapropterin might prevent harm to the unborn child. If the risk of major harm is reduced, which is possible, then there are likely to be major lifelong benefits for the unborn child. The benefits for the pregnant woman with PKU who has the treatment are included in the cost-effectiveness analysis, but benefits for the unborn child have not been included. Taking the benefits for both these individuals into account, the cost-effectiveness estimates are likely to be within what NICE considers acceptable. So, sapropterin is recommended during pregnancy until birth.