Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Kuvan (Merck Serono)
100 mg soluble tablets
Approved indication: hyperphenylalaninaemia
Australian Medicines Handbook Appendix A

The amino acid phenylalanine is normally metabolised by phenylalanine hydroxylase to form tyrosine. This metabolism involves a co-enzyme called tetrahydrobiopterin (BH4). Inborn errors of metabolism or a deficiency of BH4 result in the accumulation of phenylalanine which leads to intellectual disability. There are many possible mutations. Phenylketonuria is the most common of the hyperphenylalaninaemias.

Patients with phenylketonuria have to follow a diet low in phenylalanine. The diet can be difficult to adhere to, so there has been research into other approaches. Supplementing BH4 may help to offset the abnormal metabolism. In a study of 31 patients with mild hyperphenylalaninaemia/phenylketonuria, giving BH4, after a loading dose of phenylalanine, reduced the concentration of phenylalanine in the blood.1

Sapropterin is a synthetic form of BH4. Although its bioavailability is probably low, it can be given by mouth. Taking the daily dose with food improves absorption.

An open-label trial of sapropterin treated 485 patients with phenylketonuria for eight days. The concentrations of phenylalanine in the blood fell by at least 30% in 96 of the patients.2 A group of these responders was later enrolled in a double-blind trial.

In the double-blind trial the 89 patients were randomised to take sapropterin or a placebo for six weeks. Both groups had similar blood concentrations of phenylalanine in the two weeks before drug treatment began. These concentrations then fell by at least 30% in 44% of the sapropterin group, but in only 9% of the placebo group. The mean change from the baseline concentration was a fall of 235.9 micromol/L in the treatment group and a rise of 2.9 micromol/L in the control group.3

Although the trial included a few children, another study looked specifically at children who were 4–12 years old. In the first part of the trial the children were given an eight-day course of sapropterin. Those who experienced at least a 30% reduction in phenylalanine concentrations, to below 300 micromol/L, were eligible for the next part of the study. Following a washout period of at least one week, 46 responders were randomised to take sapropterin or a placebo for 10 weeks. After three weeks there was a significant difference in the blood concentrations of phenylalanine in the treatment and control groups. The mean concentrations fell in the 33 children who took sapropterin, but were unchanged with placebo. From the third week of the study, depending on the blood concentrations, supplements of phenylalanine were added to the children's diet. The amount could be increased or decreased every two weeks. At the end of the study the children given sapropterin had been able to tolerate significantly more supplements than the placebo group.4

The placebo-controlled trials were short and few differences emerged in adverse events. The events which were more frequent with sapropterin than with placebo included rhinorrhoea, pharyngolaryngeal pain, diarrhoea and headache. Nobody withdrew from the trials because of adverse reactions.3,4 There were no studies of drug interactions, but sapropterin could interact with drugs such as methotrexate, which inhibit folate metabolism, and nitric oxide-mediated vasodilators such as sildenafil. There may be neurological adverse effects if the patient takes sapropterin and levodopa.

Only a minority of patients with phenylketonuria or BH4 deficiency will have a significant response to treatment with sapropterin. The only way to identify these patients is with a therapeutic trial. If there is no change in the blood concentration of phenylalanine after one month, treatment should be stopped. Sapropterin will not be effective enough to allow many patients to ease their dietary restrictions. A low phenylalanine diet should therefore continue during treatment with regular monitoring of blood concentrations.

Read about The Transparency Score manufacturer provided additional useful information

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (