BioMarin Announces that Kuvan Significantly Increases Phe Tolerance in BH4-Responsive PKU
By Alexander Porter, M.D. Medical Services, BioMarin Pharmaceutical Inc.
From the Spring/Summer 2007 issue of National PKU News.
Kuvan (sapropterin dihydrochloride) is the new name for our investigational oral drug
for the treatment of PKU. You may remember the name Phenoptin;
it turns out that Phenoptin was confused for another drug when we tested the name,
and we had to retire that name. So remember KUVAN.
Positive Results from Clinical Study
BioMarin Pharmaceutical Inc. announced last month positive results from the Phase 3 diet study of KuvanTM , the drug formerly known as Phenoptin, in combination with diet in 4-12 year old patients with PKU.Kuvan (sapropterin dihydrochloride) is an investigational oral drug in clinical trials for the treatment of patients with phenylketonuria (PKU) who have elevated phenylalanine (Phe) levels. The active ingredient in Kuvan, sapropterin dihydrochloride, is a form of 6R-BH4 (tetrahydrobiopterin), a naturally occurring enzyme cofactor that targets the phenylalanine hydroxylase (PAH) enzyme to break down phenylalanine.
The results of the diet study show that in patients who responded to Kuvan, the drug caused a significant increase in Phe tolerance, as well as a reduction in blood phe levels. In addition, the data showed that Kuvan was well tolerated in younger PKU patients who were under dietary control.
About the Clinical Study
The goal of the diet study was to understand whether patients taking Kuvan could increase Phe tolerance. This study was a Phase 3 study that lasted 11 weeks and enrolled 90 patients. It was a double-blind, placebo-controlled study; placebo-controlled means that a portion of the patients take the active drug, while the remainder take a placebo pill (which looks exactly like the active drug, but doesn’t have any active drug). Double-blind means that neither the patients nor the doctors know which patient is on placebo and which patient is on drug. The drug was taken once per day.Patients in the trial were 4 to 12 years old, following a phe-restricted diet, and had blood phe levels below 480 µmol/L (8 mg/dl). Patients were screened for responsiveness to Kuvan with a one-week treatment at a dose of 20 mg/kg body weight/day (Part 1). Of the 89 patients who completed Part 1, 50 subjects demonstrated a blood phe reduction of at least 30%, and 45 of the 50 were randomized to Kuvan (20 mg/kg/day) or placebo, and enrolled in the 10-week double-blind, placebo-controlled portion of the study (Part 2).
For the first three weeks, patients maintained their pre-existing restricted diet with no extra phe. Thereafter, every other week, specific amounts of phe were added (or removed) to the restricted diet of each patient according to pre-defined blood phe levels. The maximum amount of phe that could be added to a patient’s diet during the study was 50 mg/kg/day.
Key Findings from the Study
At the end of the study, patients on Kuvan were able to significantly increase their daily phe supplement by an average of 20.9 mg/kg ersus an average of 2.9 mg/kg for placebo patients (p<0.001). Patients treated with Kuvan were able to, on average, double their baseline intake of phe. At week 10, they were able to take a mean total phe intake of approximately 43.8 mg/kg/day, while maintaining controlled blood phe levels. The mean phe tolerance represents approximately half the amount of phe in a normal diet.
As an example and according to the average results above, a 6-year-old girl who weighs 50 pounds (22.7 kg), would have increased her daily phe consumption from 474 mg to 993 mg.
Kuvan provided a mean reduction of 148.5 µmol/L (2.5 mg/dl), from a starting mean of 275.7 µmol/L (4.6 mg/dl) in blood phe level from baseline to week 3 (prior to phe supplementation) (p<0.001).
The frequency and type of side effects were similar in both the placebo and Kuvan groups and all reported side effects were mild or moderate in severity. There were two serious adverse events: a case of strep throat in the Kuvan group and a case of appendicitis in the Placebo group; neither event was considered drug-related. The most frequently reported side effects were headache, stomach pain, fatigue, and diarrhea.
The results of the clinical trials of Kuvan carried out over the past several years show that it is not possible to predict response to Kuvan based on the patient’s blood phe levels. This is likely due to the genetic variability of PKU patients. Based on our trials, while generally mild and moderate patients are more likely to respond, some of the classic patients have responded. In addition, while some patients will look for a reduction in blood phe levels, others would prefer an increase in phe consumption.
Last update: February 2008
National PKU News: www.pkunews.org
E-mail: schuett@pkunews.org