Long-term treatment with Palynziq (pegvaliase-pqpz) led to a sustained reduction of blood phenylalanine levels in adults with phenylketonuria (PKU) for more than two years, an analysis of three clinical trials has found.
While increased doses were used for the extended treatment regimen, the frequency of adverse events was shown to decrease and stabilize over time.
The study, “Pegvaliase for the treatment of phenylketonuria: Results of the phase 2 dose-finding studies with long-term follow-up,” was published in the journal Molecular Genetics and Metabolism.
PKU is characterized by reduced activity of the liver enzyme phenylalanine hydroxylase, which metabolizes the amino acid phenylalanine — one of the building blocks of proteins.
As a result, phenylalanine can build up to toxic levels in the blood of patients, who must rely on a low-phenylalanine diet and medical foods to help manage symptoms.
When standard approaches fail to achieve target blood phenylalanine concentrations — typically between 120 and 360 micromol (mcmol)/L — patients may be prescribed Palynziq, which is approved for adults with PKU who have blood phenylalanine levels greater than 600 mcmol/L.
Palynziq, developed by BioMarin Pharmaceutical, is a modified form of the enzyme phenylalanine ammonia lyase, which breaks down phenylalanine. The therapy is administered at home by subcutaneous (under-the-skin) injection.
Two dose-finding Phase 2 studies — PAL-002 (NCT00925054) and PAL-004 (NCT01212744) — assessed the effects of Palynziq in adults with PKU. Participants who completed these trials could join the long-term extension study PAL-003 (NCT00924703).
Data about the safety and blood phenylalanine-lowering effects of Palynziq from these three trials were analyzed in the new study by researchers at multiple sites across the U.S.
Participants in all three studies were instructed to maintain a diet that provided a consistent protein intake.
Patients who took part in PAL-002 received one of five fixed starting doses of Palynziq — 0.001, 0.003, 0.01, 0.03, or 0.1 mg/kg weekly for eight weeks. They continued treatment for eight more weeks with dose or frequency adjusted to achieve blood phenylalanine concentrations between 60 to 600 mcmol/L.
The mean average blood phenylalanine level at the beginning of PAL-002 was 1311 mcmol/L, which did not substantially decrease with treatment after 16 weeks. Four participants (10%) each achieved a phenylalanine level of up to 600 mcmol/L.
Participants in PAL-004, who were treatment-naive (not previously treated for PKU), received Palynziq doses of 0.001 to 0.4 mg/kg five days per week for 13 weeks, with dose modifications based on safety and efficacy, and then had a three-week period of follow-up.
The mean blood phenylalanine level decreased from 1482.1 to 1045.1 mcmol/L after 13 weeks. The lowest phenylalanine levels were found after two weeks, but were not sustained due to dose modifications and interruptions caused by hypersensitivity-related adverse events (AEs). As in PAL-002, four patients (25%) in PAL-004 reached a blood phenylalanine level of up to 600 mcmol/L.
A total of 33 patients from PAL-002 and 15 from PAL-004 joined the PAL-003 extension study, in which doses were adjusted to minimize AEs and to achieve or maintain a blood phenylalanine level in the range of 60 to 600 mcmol/L.
After joining PAL-003, the average Palynziq dose was increased to 142.2 mg and was stable by week 120 (2.3 years), remaining stable throughout the follow-up period.
With increased dose and duration, the mean blood phenylalanine levels steadily decreased over time. In patients who transferred from PAL-002, phenylalanine levels decreased to 428.2 mcmol/L at week 120, representing a 68.8% decrease from study start.
In patients from PAL-003, mean phenylalanine concentrations decreased to 350.4 mcmol/L at week 120, representing a 75.9% decrease from study start. A significant reduction had already been reported at week 48.
All participants in PAL-002 and PAL-004 reported one or more AEs, with most (about 87% in both trials) being mild or moderate (about 13%). The most common AEs in PAL-002 included injection site reaction, headache, nausea, and joint pain. In PAL-004, common AEs were joint pain, headache, dizziness, and injection site reaction.
In the PAL-003 study, the rate of hypersensitivity-related side effects decreased to 3.5 events per person-year as participants continued treatment.
“In two phase 2 dose-finding studies, pegvaliase [Palynziq] did not lead to substantial blood Phe [phenylalanine] reductions,” the investigators wrote. “With increased dose and duration of treatment in PAL-003, mean blood Phe reduction was substantial and sustained, and the frequency of hypersensitivity AEs decreased and stabilized.”
The findings have led to an approved regimen in which patients start at a low weekly dose of Palynziq that gradually increases in dose and frequency until they achieve a daily maintenance dose, the researchers said.
“This regimen has been tested in a third phase 2 study [NCT01560286], as well as in two successful phase 3 studies of pegvaliase [NCT01819727 and NCT01889862],” they added.
Of note, the researchers declared that they had financial ties with BioMarin or were company employees.