NHD Issue 148 Kuvan or Sapropterin a pharmacological treatment for PKU

IMD WATCH

KUVAN OR SAPROPTERIN: A PHARMACOLOGICAL TREATMENT FOR PKU What is it and how could it help patients currently taking a highly complex low phenylalanine (Phe) diet?

Suzanne Ford, Dietary Advisor to NSPKU Suzanne is a Metabolic Dietitian working with Adults at North Bristol NHS Trust and also for the National Society of Phenylketonuria (NSPKU).

REFERENCES Please visit the Subscriber zone at NHDmag.com

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The rare genetic metabolic disorder Phenylketonuria (PKU), affects around 1 in 10,000 people in the UK.1 It is estimated that there are around 6000 people in the UK living with PKU, with only half of these under active metabolic follow-up. PKU is a lifelong disease and it is now established that treatment is, therefore, needed lifelong,2,3 the only treatment option in the UK being a low Phe diet, administered by a caregiver during infancy and childhood and, subsequently, by the individual patient as they transition into adulthood.

Treatment is aimed at reducing Phe levels towards a safe range, using a diet that is devoid of almost all natural sources of protein (ie, meat, fish, eggs, soya, nuts cheese, bread, pasta and milk). Instead, a synthetic protein substitute, with added vitamins and minerals, is taken throughout the day.

Regular dietary review by a specialist metabolic team is necessary to avoid nutritional deficiencies and encourage dietary adherence.

A survey of patients in the UK by the National Society for Phenylketonuria (NSPKU), shows that many struggle with this treatment as it is not delivered effectively in primary care and puts an undue burden, such as emotional stress, on caregivers or the individual patient.4 Walter and White (2002)5 illustrated that metabolic control is lost in early teenage years with current treatment. The timeconsuming and socially excluding nature of the diet is difficult to manage; evidence suggests that the time needed to administer diet by caregivers of children with PKU was 19 hours per week.6

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Similarly, the metabolic control of selfcaring adults managing the PKU diet whilst in employment, was reported

by Riva et al (2017)7 and showed that full-time employment worsens control compared to part-time employment.

Neurocognitive outcomes are a concern for those with PKU, as research shows Phe levels impact on executive function, such as working memory, problem solving and flexible thinking.8 Even for patients who are effectively managing their own dietary treatment and have been treated following a positive newborn screen (early treated PKU: ETPKU), there are suboptimal outcomes reported in individuals with PKU in terms of being 5-7 IQ points lower when matched with non PKU siblings.9 To summarise, dietary treatment is restrictive, complex, burdensome and suboptimal with regards outcomes.

WHAT IS KUVAN/SAPROPTERIN, OR BH4 (TETRAHYDROBIOPTERIN)?

BH4 (Kuvan) is currently the only drug treatment licensed for PKU in Europe.

Kuvan, or sapropterin, is a synthetic form of BH4, a substance that naturally occurs within the body. BH4 stimulates the enzyme phenylalanine hydroxylase (PAH – Figure 1 overleaf), which does not function correctly in people with PKU, and restores its ability to metabolise Phe. The deficiency in people who have PKU is associated with their enzyme activity and the enzyme’s functioning is closely related to its shape (shape determines configuration and efficacy of an enzyme’s active site).

IMD WATCH BH4 (Kuvan) is a helper or chaperone molecule for PAH; it makes the enzyme into a more functional shape, thus improving PAH activity and improving Phe tolerance;10 that means a person with PKU who responds to Kuvan can eat more protein, ie, it means dietary liberalisation.

In the context of PKU, BH4 keeps blood Phe levels low and stable, (lower and stable Phe is associated with better outcomes).11 People with PKU taking Kuvan can eat more natural protein (typically two or three times more), which improves their nutrition and changes the patient’s diet from abnormal to a more normal diet, and compliance with diet improves as evidenced below.

THE EVIDENCE BASE AROUND KUVAN

There is a body of evidence about the efficacy of BH4 in reducing blood Phe levels and allowing patients to take more natural protein, take less protein substitute, use lower volumes of lowprotein foods and, in some cases, come off diet entirely.12-14 There is also long-term-use data supporting the safety aspects of BH4 use.15 From a patient perspective, the effects of a liberalised diet does impact on quality of life. Even relaxing diet by having more exchanges in a day is liberalising, as patients can access vegetarian foods that are usually unsuitable for people with PKU. The effects of dietary liberalisation upon quality of life are not well evidenced in the literature, only the more objective quantitative measures, such as Phe. There is only a small amount of evidence so far. Nevertheless, BH4 is seen to reduce the impact of poor outcomes in PKU patients. Huijbregts et al (2018),16 specifically demonstrates poor outcomes in adult patients with PKU, showing that those >16 years old have worse experiences of cognition, sleep, pain, sexuality and anger than controls, and some of these relate to metabolic control (dietary treatment may have intrinsic effects on quality of life).

However, happiness, anger and social functioning scores improve with use of BH4/sapropterin independent of metabolic control, illustrating the social exclusion and negative effects of dietary treatment. This work supports other quality of life studies in the population of PKU patients taking diet and compared to those taking Kuvan.17,18 IS KUVAN SAFE AND DOES IT HAVE SIDE EFFECTS?

Long-term safety data has been collected on

Figure 1: Tetrameric structure of the enzyme PAH

sapropterin for long-term use – in reality it has been in use by patients for well over 10 years now. The summary of product characteristics19 for sapropterin reports headache and rhinorrhea as very common adverse reactions, occurring in ≥1/10 of people treated with sapropterin.

Common adverse reactions (occurring in ≥1/100 to <1/10 people treated with sapropterin) include hypophenylalaninaemia, pharyngolaryngeal pain, nasal congestion, cough, diarrhea, vomiting, abdominal pain, dyspepsia and nausea.

BACKGROUND, CONTROVERSY AND RECENT NEWS ABOUT KUVAN

Patients in the UK who are having Kuvan are very small in number at the time of writing, and most are prescribed on compassionate grounds. The Declaration of Helsinki, developed for the medical community by the World Medical Association, is widely regarded as the cornerstone document on human research ethics.20 Thus, there is a small number of children and adults taking Kuvan in the UK who have assisted in research and in return, in the absence of commissioning of the drug, receive long-term compassionate use of the drug.

Earlier this year the PKU Association Ireland (PKUAI) announced they had been made aware that KUVAN® (sapropterin dihydrochloride) had been approved by the Irish Health and Safety Executive Senior Leadership team and would be available in specific circumstances to our patient group for reimbursement from 1st July 2019.21 NSPKU, KUVAN, PATIENT POWER

The required standard for the volume, quality and power of an evidence base to support commissioning is very high, but difficult to meet in a small patient population, as the www.NHDmag.com October 2019 - Issue 148

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IMD WATCH Figure 2: PKU diagram of inheritance

A patient can undergo responsiveness testing by maximising their Phe tolerance before starting any BH4/Kuvan and then starting a calculated dose of BH4, undertaking twice weekly bloodspots whilst keeping Phe intake at baseline.23 If the patient responds, the bloodspot results will fall and subsequently the diet can be liberalised once response has been demonstrated.

USE OF KUVAN IN THE UK

England A possible interim policy by NHS England (England only) could lead to commissioning, as, in December 2018, NHS England published a draft interim policy for Kuvan, but did not fund the treatment for cost reasons. It was accepted that there was sufficient evidence to support the use of Kuvan, but it was then not prioritised for funding in July. NHS England has said this will be reconsidered in November 2019. comparatively lower resources and patient numbers limit the ability to conduct high powered randomised controlled trials. NSPKU has campaigned to all parties involved with the commissioning of Kuvan in the UK, including NICE, who evaluate evidence during the treatment commissioning process.

PRACTICAL USE: HOW IS KUVAN RESPONSIVENESS TESTED AND, IF A PATIENT IS RESPONSIVE, HOW IS THE DOSE DECIDED?

DNA analysis can be used to predict if a person with PKU will respond to Kuvan as described

by Trefz.22 In some countries, DNA testing is routinely done so that the patient’s PAH mutation is known soon after diagnosis. There are certain mutations associated with responsiveness and some with null responsiveness (a ‘null’ mutation). For each gene, there are two ‘alleles’ and one allele is inherited from each parent (see Figure 2). If a patient has two ‘null’ alleles in their PAH gene, then they will not be a responder.

We can only estimate the proportion of the UK population of people with PKU who would respond, thought to be about 30% of the patient group. This estimate is based on what is thought about certain PAH mutations being prevalent in the UK PKU community, compared with other European countries.

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Scotland In August 2018, the Scottish Medicines Consortium (SMC) stated that after careful consideration of all the evidence, the SMC Committee has been unable to recommend this medicine for use by NHS Scotland.

Wales and Northern Ireland There are no separate arrangements in place for commissioning Kuvan.

Kuvan is used in: Austria; Belgium; Bulgaria; Czech Republic; Denmark; Estonia; France; Germany; Hungary; Italy; Ireland; Latvia; Lithuania; Luxembourg; Netherlands; Norway; Portugal; Romania; Russia; Slovakia; Slovenia; Spain; Switzerland and Turkey.

CONCLUSION

Kuvan is a safe and effective treatment for PKU. Thousands of people with PKU use Kuvan (BH4) outside the UK, as it is provided by most European health systems. It has been available since 2008 in the EU but, as mentioned above, has never been commissioned by the NHS except for pregnant women with PKU. Kuvan is safe and clinically effective, as well as being cost effective compared with potential costs of maternal PKU syndrome, and is deemed safe in pregnancy.24