Long-term treatment with Kuvan (sapropterin dihydrochloride) helped to control blood levels of phenylalanine, and preserve normal intelligence and growth in infants and children with phenylketonuria (PKU), a Phase 3 trial that followed patients for up to seven years reports.
Trial findings were detailed in the study, “Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: A seven-year analysis,” published in the journal Molecular Genetics and Metabolism.
Marketed by BioMarin, Kuvan is approved in the U.S. and Europe to treat PKU patients of all ages, including infants and children, in combination with a phenylalanine (Phe)-restricted diet.
The therapy is an activator of phenylalanine hydroxylase (PAH), an enzyme that is needed to convert the amino acid phenylalanine into a different one, called tyrosine, and found at lower levels in people with PKU. (Amino acids are the building blocks of proteins.)
By mimicking tetrahydrobiopterin (BH4), an enzyme co-activator that helps PAH make this amino acid conversion, Kuvan is expected to help lower Phe levels in the blood, preventing the intellectual disabilities that can result from sustained high levels.
An open-label Phase 3b trial, called PKU-015 (NCT00838435), was launched to assess the long-term safety and efficacy of Kuvan in newborns through children up to age 6. The study, which opened in 2009 in the U.S. and Canada, also aimed to complement data from clinical trials in older PKU patients regarding Kuvan’s safety and efficacy.
PKU-015 was divided into two parts: an initial four-week phase to identify patients who responded to Kuvan, defined as a reduction of at least 30% in blood Phe levels; and a second phase, lasting up to seven years, to evaluate Kuvan’s long-term effects in responders.
Those moving to the trial’s second phase also needed an IQ of at least 80 on age-relevant testing. All enrolled were on a Phe-restricted diet.
Kuvan was given orally, once daily, at a dose of 20 mg/kg, dissolved in water or apple juice, or mixed with soft foods.
The study’s main goal was to assess the long-term effects of Kuvan on patients’ intellectual abilities, as measured by the Full-Scale Intelligence Quotient (FSIQ). This test’s composite score incorporates information from other scales used to evaluate intellectual abilities in infants and children in different age groups.
Secondary study goals included Kuvan’s long-term safety, as well as changes in blood phenylalanine levels and in children’s height, weight, and overall growth.
An interim analysis after two years of follow-up showed that children being treated Kuvan — in conjunction with a restricted diet — were growing normally and with age-relevant intelligence.
Newly published data cover the study’s entire seven years. Of the 95 children initially enrolled, 71 (74.7%) responded to treatment and were invited to its second phase. A total of 65 (91.5%) entered this long-term part, with 62 (95.4%) followed for at least one year and eligible to be included in FSIQ analyses; 27 stayed with the study for 84 months, or seven years.
At the study’s start (baseline), participants had a mean FSIQ score of 101.1, “which is not significantly different from the population norm of 100.” FSIQ scores remained stable through the study, and mostly above the 100 score threshold, confirming Kuvan’s long-term benefits at preserving intellectual functioning.
Mean blood levels of phenylalanine also remained within the target range (120–360 micromole per liter) defined by American College of Medical Genetics (ACMG) for the study’s entire duration. About 60% of children maintained levels within this range for the entirety of the study.
All growth measures, including height, weight, and head circumference, also remained within the normal range over the study’s seven years. Normal growth ranges were based on growth charts by the World Health Organization (WHO) for infants under age 2, and on charts by the Centers for Disease Control and Prevention (CDC) for children over 2.
In line with prior trials, all 65 children on long-term treatment experienced at least one side effect. In general, upper respiratory tract infections, abdominal pain, and vomiting were the most common side effects reported.
No side effects led a child to stop Kuvan’s use or withdraw from the study.
“In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years,” the investigators wrote.
These findings also support the use of treatment response tests early in life “and initiation of sapropterin in those infants and young children who are diagnosed with sapropterin-responsive PKU,” they added.