Review for NHS Surrey Area Prescribing Committee. Date: February 2011

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1 Review for NHS Surrey Area Prescribing Committee Treatment: Sapropterin for Phenylketonuria (PKU) Prepared by: NHS Surrey Pharmaceutical Commissioning Team Topic Submitted by: SEC Specialised Commissioning Group Date: February Purpose of the Review SEC SCG has requested that a funding position be taken by all PCTs regarding this drug as there have been some requests to use it. 2. Appropriateness 2.1 The patient: patients with phenylketonuria. Sapropterin (Kuvan ) is licensed for the treatment of hyperphenylalaninaemia in patients aged 4 years with PKU who have demonstrated a response to treatment. 2.2 The condition: Phenylketonuria (PKU) is a rare metabolic disease resulting in raised blood phenylalanine levels which can reach neurotoxic concentrations. The condition is characterised by poor neurocognitive and neuromotor development with subsequent impairment of intelligence and social functioning. For a detailed description of the condition, refer to pages 3-4 of the North East Treatment Advisory Group (NETAG) review (attached) The Intervention: Sapropterin is the first drug treatment available for PKU. It is an epimer of an endogenous enzyme substrate. 1 It is available as soluble tablets with dosage based on weight and titrated according to blood phenylalanine levels. Care setting: Prescribing would be initiated and continued by specialist centres due to its cost, it would not be included within payment by results tariff. 2.4 Alternative treatments: PKU is currently treated by dietary restriction of phenylalanine. This requires almost complete elimination of protein rich foods from diets with the substitution of specially prepared dietary supplements resulting in a low-phe diet. However compliance with the special diet is often suboptimal. A number of reasons has been put forward to explain the poor compliance including psychological and social causes. It is widely acknowledged that the dietary supplements required to maintain a low-phe diet are considered by patients to be of low palatability. 1 A systematic review published by the Cochrane collaboration in 2009 looked at dietary interventions for PKU. 2 This concluded that Phe levels are significantly lower in patients on a low-phe diet compared to a less restricted diet with a mean

2 difference at three months of 700 micromol/l (n = 251). Only one study reliably reported outcomes of intelligence scores (n = 216) and found that these were significantly better for patients continued on the diet compared with those who stopped, with a difference of 5 points at 12 months. 2 The authors of the review concluded that a low-phe diet is effective at reducing Phe levels and improving intelligence and neuropsychological outcomes, although there is uncertainty about the precise level of Phe restriction and when, if ever, a low-phe diet can be relaxed or ceased. 1,2 3. Effectiveness 3.1 Expected benefits Possibly improved control of phenylalanine levels, particularly in patients who are non-compliant with a low-phe diet. There is some question however, over whether patients who are non-compliant with diet will be compliant with daily medication. 3.2 Side-effects/complications Safety data from relatively short-term studies do not indicate any important safety concerns with treatment. Most adverse effects consist of a mild gastrointestinal type, or headache. 1,3 3.3 Review of evidence (See Appendix 1. for Search Strategy and Summary of Results) Several reviews of sapropterin for PKU have been recently conducted: Cochrane Collaboration systematic review and meta-analysis: 3 Results: Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.this trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarinsponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference µmol/l (95% confidence interval to ); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference µmol/l (95% confidence interval to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval to 23.72) in the 20 mg/kg/day sapropterin group. 3 Authors' conclusions There is evidence of short-term benefit from using sapropterin in some patients with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term. 3

3 There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria North East Treatment Advisory Group (NETAG) (Full review attached) 1 Evidence validity: The evidence-base comes from studies that used an enriched patient selection process resulting in a potentially biased population. This will result in low external validity unless these scenarios can be replicated in practice. 1 Evidence effect: An important endpoint was arbitrarily selected as 30% reduction in Phenylalanine levels from baseline. In practice clinicians may be more interested in achieving a specific threshold as defined by relevant PKU guidelines. Additionally, in older patients the greatest effect of treatment was generally seen with lower baseline Phe levels. Reported outcomes relate to biochemical surrogate end points however a reduction in Phe levels has been shown to result in improvements in patientoriented outcomes such as neurocognitive performance. Sapropterin shows high levels of efficacy for a proportion of the patient population with PKU All Wales Medicines Strategy Group (AWMSG) The All Wales Medicines Strategy Group (AWMSG) has issued an appraisal notice (March 2009 stating that they do not recommend sapropterin (Kuvan ) for use within NHS Wales for the treatment of hyperphenylalaninaemia in patients with PKU. 4 The holder of the marketing authorisation does not have sufficient data to complete a submission to AWMSG for the appraisal of sapropterin for the above indication, and therefore the AWMSG is unable to provide advice to the Minister for Health and Social Services Scottish Medicines Consortium (SMC) May 2009 ADVICE: in the absence of a submission from the holder of the marketing authorisation. Sapropterin (Kuvan) is not recommended for use within NHSScotland for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients with phenylketonuria (PKU) and for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients with tetrahydrobiopterin (BH4) deficiency. 5 The holder of the marketing authorisation has not made a submission to SMC regarding this product in this indication. As a result we cannot recommend its use within NHS Scotland Summary of Key Points for Consideration 4.1 National guidance: No known guidance referring to the use of sapropterin in PKU in the NHS. 4.2 Efficacy There is evidence of short-term benefit from using sapropterin in some patients with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events

4 associated with using sapropterin in the short term. 3 There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria Potential Benefits over existing therapy Possibly improved control of phenylalanine levels, particularly in patients who are non-compliant with a low-phe diet. There is some question however, over whether patients who are non-compliant with diet will be compliant with daily medication. There are some special populations that may potentially gain greater benefits from treatment, for example in maternal PKU (where raised Phe can affect the developing fetus, and stricter control of Phe levels (and diet) are therefore required), or young patients with poor control despite dietary intervention. Studies in these groups specifically have not been conducted however Potential disadvantages Cost: Sapropterin is several times more expensive than usual management with special dietary foods and supplements. See section 4.5 below. 4.5 Budgetary Impact Cost: Sapropterin is designated an orphan drug. It is an expensive treatment, with typical annual costs in the range 20,000 to 50,000 depending on the actual dose. Sapropterin is unlikely to meet conventional criteria for cost-effectiveness in terms of cost per quality adjusted life year. 1 For details on cost, see the NETAG appraisal (attached) Precedent setting: PKU is the most common hereditary metabolic disorder in Europe, with prevalence in Caucasians of about 1 in 10,000. It has a lower prevalence in nonwhite populations. 1 Using this figure there is expected to be about 100 patients with PKU within NHS Surrey. All newborn children are screened for PKU at birth however the neonatal screening programme did not commence until after 1960 resulting in a pool of affected but undiagnosed patients. 1-6 Within NHS Surrey approximately 34% of the patient population is aged 50 years which leads to an estimate of a known patient population of about 66. The manufacturers of sapropterin (Merck Serono) estimate that 20% of patients with PKU may be suitable for treatment, leading to an estimated patient number in Surrey of 14. This would lead to estimated costs for NHS Surrey of between and Precedent setting: Kent and Medway Area Prescribing committee: Sapropterin should not be routinely funded for the management of phenylketonuria. In exceptional circumstances only funding may be considered for individual patients via IFR panels.

5 North East Treatment Advisory Group: Sapropterin (Kuvan ) is not recommended for the routine management of phenylketonuria. The case has yet to be made for any subgroups where there may be a compelling argument for treatment (for example maternal PKU syndrome). Situations in which there is a pressing clinical case for treatment should be considered via individual funding requests to the relevant PCT Conclusions and Recommendations Options for Consideration 1.Due to limited evidence of ongoing effectiveness and lack of cost-effectiveness, it is recommended that the routine funding of sapropterin for the management of phenylketonuria should not be supported. In patient specific exceptional circumstances only funding may be considered for individual patients via IFR panels. 2. Support sapropterin only in a very clearly defined subgroup of patients who are most likely to gain maximum benefit from treatment (further information awaited from consultants in paediatric metabolic medicine). Appendix 1. References 1.North East Treatment Advisory Group. Sapropterin (Kuvan) in the management of phenylketonuria. April Available from 2. Poustie VJ, Wildgoose J, Rutherford P. Dietary interventions for phenylketonuria. CochraneDatabase of Systematic Reviews 1999 (republished with edits 2009), Issue 3. Art. No.:CD DOI: / CD Somaraju UR, Merrin M. Sapropterin dihydrochloride for phenylketonuria. Cochrane Database of Systematic Reviews 2010, Issue 6. Art. No.: CD All Wales Medicines Strategy Group. March Appraisal notice to NHS Wales. Sapropterin (Kuvan). Available from Accessed 17/11/ Scottish Medicines Consortium. 05 th May Statement of Advice: Sapropterin (Kuvan). Available from Accessed 17/11/2010.