Kuvan - sapropterin dihydrochloride

What is Kuvan?

Kuvan is a medicine that contains the active substance sapropterin dihydrochloride. It is available as light yellow soluble tablets (100 mg).

What is Kuvan used for?

Kuvan is used to treat hyperphenylalaninemia (HPA, high levels of phenylalanine in the blood) in patients with genetic phenylketonuria (PKU) disorders or tetrahydrobiopterin (BH4) deficiency. Patients suffering from these disorders fail to convert the amino acid phenylalanine (found in dietary proteins) into tyrosine (another amino acid). This causes an accumulation of phenylalanine in the blood which can cause brain and nervous system problems.

Kuvan can be used in adults and children. Kuvan is indicated for use in children with HPA due to PKU who are at least four years old. The medicine has not been studied in children with HPA due to PKU under the age of four years. Kuvan can be used in children of all ages with HPA due to BH4 deficiency.

Treatment with Kuvan should only be continued in patients who adequately respond to the medicine.

Because the number of patients with HPA is low, the disease is considered 'rare' and Kuvan was designated an 'orphan medicine' (a medicine used for rare diseases) on 8 June 2004.

The medicine can only be obtained with a prescription.

How is Kuvan used?

Kuvan therapy should be started and supervised by a doctor experienced in the treatment of PKU and BH4 deficiency. It is necessary to monitor the amount of phenylalanine and protein in the patient's diet to ensure that levels of phenylalanine in the blood and nutritional balance are controlled. Kuvan is indicated for long-term use.

The dose of Kuvan depends on the patient's weight. Patients with PKU must start with 10 mg per kilogram body weight once a day and those with BH4 deficiency must start with 2 - 5 mg / kg once a day. After one week, the dose can be adjusted up to 20 mg / kg once a day if the patient has not responded to treatment. A satisfactory answer is a reduction in the levels of phenylalanine in the blood by at least 30% or to a level established by the doctor. If this response is obtained after one month, the patient is classified as 'responsive' and can continue to take Kuvan.

Kuvan is taken together with a meal every day at the same time, preferably in the morning. The tablets dissolve in a glass of water before the patient drinks the solution. For some patients with BH4 deficiency, sometimes the dose should be divided into two or three doses throughout the day to get the best effect. Kuvan should be used with caution in patients over the age of 65 and in patients with liver or kidney problems.

How does Kuvan work?

The high levels of phenylalanine in the blood depend on a problem of conversion of phenylalanine to tyrosine by the enzyme 'phenylalanine hydroxylase'. Patients with PKU have a defective version of the enzyme and patients with BH4 deficiency have low levels of BH4, a 'cofactor' that serves the enzyme to function properly. The active substance in Kuvan, sapropterin dihydrochloride, is a synthetic copy of BH4. In PKU, it acts by enhancing the activity of the defective enzyme, and in the BH4 deficiency it replaces the missing cofactor. This helps to restore the enzyme's ability to convert phenylalanine to tyrosine, reducing the levels of phenylalanine in the blood.

How has Kuvan been studied?

The effects of Kuvan were first tested in experimental models before being studied in humans.

For the treatment of patients with PKU, Kuvan was studied in two main studies that compared Kuvan with placebo. All patients participating in the studies had shown a response to a first eight-day Kuvan cycle but had spent at least a week without the medicine before the studies began.

The first study included 89 patients aged eight years and over who did not follow a strict diet. The main measure of effectiveness was the reduction of blood phenylalanine levels in six weeks.

The second study included 46 children aged between four and 12 who were on a diet with a controlled level of phenylalanine. From the third week of therapy, the diet was adapted every two weeks based on the levels of phenylalanine in the blood. The main measure of effectiveness was the change in the amount of phenylalanine that children could take through feeding by keeping the phenylalanine in the blood at the desired levels. The study lasted 10 weeks.

For the treatment of patients with BH4 deficiency, the company presented the results of three studies available in the published literature on sapropterin dihydrochloride. One of these studies included 16 patients treated for an average of 15.5 months.

What benefit has Kuvan shown during the studies?

For the treatment of PKU, Kuvan was more effective than placebo. In the first study, the levels of phenylalanine in the blood were around 867 'micromoles per liter' at the beginning of the study. Normal levels are around 60 micromoles per liter in people without PKU. After six weeks, phenylalanine levels had decreased by 236 micromoles per liter in patients taking Kuvan and had increased by 3 micromoles per liter in patients taking placebo. In the second study, children taking Kuvan could take an average of 17.5 mg more phenylalanine per pound of body weight every day after 10 weeks, compared to 3.3 mg more than children taking placebo .

In studies of patients with BH4 deficiency, patients showed an improvement in levels of phenylalanine in the blood and other indicators of the disease when they took sapropterin dihydrochloride.

What is the risk associated with Kuvan?

The most common side effects with Kuvan (seen in more than 1 patient in 10) are headache and runny nose (runny nose). For the full list of all side effects reported with Kuvan, see the Package Leaflet.

Kuvan should not be used in people who may be hypersensitive (allergic) to sapropterin dihydrochloride or any of the other substances.

Why has Kuvan been approved?

The Committee for Medicinal Products for Human Use (CHMP) has determined that Kuvan's benefits are greater than its risks for the treatment of HPA in adult and pediatric patients with PKU and with BH4 deficiency, which have been shown to be responsive to this therapy . The Committee recommended that Kuvan be given marketing authorization.