Sapropterin Can Be Effective Long-Term in PKU

May 24, 2013

By Megan Brooks

(Reuters Health) - Sapropterin (Kuvan) can be an effective long-term treatment for people with phenylketonuria (PKU), leading to improved metabolic control, increased tolerance to dietary phenylalanine (Phe), and a better quality of life, a retrospective study from Europe suggests.

PKU, the most common autosomal-recessive inherited disorder of amino acid metabolism, is caused by Phe hydroxylase (PAH) deficiency in the liver. In patients with the disorder, Phe accumulates in the blood and brain, leading to mental retardation if left untreated.

The goal of PKU treatment is to maintain normal Phe blood concentrations, often through a low-Phe diet. However, compliance with dietary restriction is often poor, especially in adolescents.

An alternative option, available in the U.S. since 2007 and in Europe since 2008, is to lower blood Phe concentrations using sapropterin dihydrochloride (6R-tetrahydrobiopterin, BH4).

"Although as of today worldwide more than 3000 PKU patients receive sapropterin as an alternative pharmacological treatment, almost no information was available on the long-term metabolic control and outcome of these patients," Dr. Nenad Blau, senior consultant in biochemical genetics, division of inborn metabolic diseases, University Children's Hospital in Heidelberg, Germany, told Reuters Health.

In the June issue of Pediatrics, available online now, Dr. Blau and colleagues report long-term metabolic outcomes of 147 PKU patients treated with sapropterin at 16 medical centers in six European countries.

"The main take home message is that sapropterin treatment is safe and that in this study, about 64% of PKU patients received sapropterin alone and (were) thus able to discontinue the low-phenylalanine diet," Dr. Blau said.

The mean age of the patients was 14.4 years. Forty-two percent had mild hyperphenylalaninema, 51% had mild PKU, and 7% had classic PKU. All were followed for at least 12 years.

"A total of 85 different genotypes were reported," the researchers say. "With the exception of two splice variants, all of the most common mutations were reported to be associated with substantial residual Phe hydroxylase activity."

With sapropterin treatment, median tolerance to Phe increased fourfold compared with dietary treatment alone, and median Phe blood concentrations were within the therapeutic range in all patients.

Compared with diet alone, improvement in quality of life was reported in 49.6% of patients, improvement in adherence to diet was reported in 47% of patients, and improvement in adherence to treatment was reported in 63.3% of patients. No severe adverse events were reported.

Since the approval of sapropterin in the U.S. and Europe, the drug has become a part of the standard treatment of PKU patients who respond to it, the investigators note.

"Several placebo-controlled, double-blind studies have revealed that sapropterin administration reduces blood Phe concentrations, increases dietary tolerance for Phe, and is safe in PKU patients, with only few adverse events reported. Our retrospective study with 147 PKU patients adds to the available knowledge and documents the long-term efficiency (up to 12 years) of BH4/sapropterin."

Amy Cunningham, a metabolic nutritionist at Hayward Genetics Center, Tulane University School of Medicine in New Orleans, noted in an email to Reuters Health, "This paper is a retroactive compilation of data from several centers in Europe and the authors are very well known in the field of PKU treatment and research."

"Because Kuvan has only been available for prescriptive use for a few years, we are only beginning to see papers such as this that publish information regarding patients who have received Kuvan for long term treatment. They are valuable, to clinicians especially," said Cunningham, who wasn't involved in the research.

She said the value of Kuvan in PKU patients who are responsive is multifaceted. "A lowering of blood Phe levels is paramount, especially in patients who are unable to accomplish this with dietary treatment alone. But there is also great benefit to patients when Kuvan responsiveness allows them to increase the amount of dietary protein they can eat. The diet is very restrictive so being able to add a drug to treatment that allows a more normal diet has great quality of life impact."

An additional area of "great interest" is finding a genotype marker that will predict Kuvan responsiveness, Cunningham said. "Currently the only way to determine this is a trial with the drug and with dietary Phe intake challenges. This takes considerable time and resources. Unfortunately, genotype data is not universally available for most of the PKU population - especially in the U.S. Studies such as this that help to broaden that pool of data are valuable," Cunningham said.

She noted that Genetic Metabolic Dietitians International (GMDI), the professional organization for metabolic dietitians, is in the process of developing updated guidelines for treatment of PKU, and is working in partnership with ACMG (American College of Clinical Genetics) to contribute similar medical guidelines.

"As a member of both of these work groups, I find this article valuable," she said. "Contributions to our understanding of long term use of Kuvan is important as we move beyond clinical trials to practical knowledge of how using Kuvan affects our PKU patients and how we can best add it to management of their care."

Merck Serono SA, Geneva, Switzerland, provided support for the study. Dr. Blau has received research grants and honoraria for consulting and lecturing for the company. A complete list of investigator disclosures is listed with the original article.


Pediatrics 2013.


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