Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM).
Mol Genet Metab
; 124(1): 27-38, 2018 05.
Article
en En
| MEDLINE
| ID: mdl-29653686
ABSTRACT
BACKGROUND:
Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU.METHODS:
Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600⯵mol/L were randomized 11 to a maintenance dose of 20â¯mg/day or 40â¯mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5â¯mg/day to 60â¯mg/day.RESULTS:
Of 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12â¯months andâ¯≥â¯24â¯months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) µmol/L at baseline, 564.5 (531.2) µmol/L at 12â¯months, and 311.4 (427) µmol/L at 24â¯months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24â¯months, 68.4% of participants achieved blood Phe ≤600⯵mol/L, 60.7% of participants achieved blood Phe ≤360⯵mol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120⯵mol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6â¯months of exposure (early treatment phase) than after 6â¯months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae.CONCLUSION:
Results from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fenilanina Amoníaco-Liasa
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Fenilalanina
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Fenilcetonurias
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Proteínas Recombinantes
Tipo de estudio:
Clinical_trials
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Guideline
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Mol Genet Metab
Asunto de la revista:
BIOLOGIA MOLECULAR
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BIOQUIMICA
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METABOLISMO
Año:
2018
Tipo del documento:
Article