Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria.
Mol Genet Metab
; 125(3): 217-227, 2018 11.
Article
em En
| MEDLINE
| ID: mdl-30146451
ABSTRACT
BACKGROUND:
Phenylketonuria (PKU) is caused by a deficiency in phenylalanine hydroxylase enzyme activity that leads to phenylalanine (Phe) accumulation in the blood and brain. Elevated blood Phe levels are associated with complications in adults, including neurological, psychiatric, and cognitive issues. Even with nutrition and pharmacological management, the majority of adults with PKU do not maintain blood Phe levels at or below guideline recommended levels. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is an investigational enzyme substitution therapy to lower blood Phe in adults with PKU.METHODS:
Pegvaliase was administered using an induction, titration, and maintenance dosing regimen in adults with PKU naïve to pegvaliase treatment. Doses were gradually increased until blood Pheâ¯≤â¯600⯵mol/L was achieved. The maintenance dose was the dose at which participants achieved and sustained blood Pheâ¯≤â¯600⯵mol/L for at least 4â¯weeks without dose modification. Analyses were performed for participants who achieved (Group A, nâ¯=â¯11) and did not achieve (Group B, nâ¯=â¯13) maintenance dose during the first 24â¯weeks of study treatment.RESULTS:
Baseline mean blood Phe for Group A and Group B were 1135⯵mol/L and 1198⯵mol/L, respectively. Mean blood Pheâ¯≤â¯600⯵mol/L was achieved for Group A by Week 11 (mean blood Phe of 508⯱â¯483⯵mol/L) and for Group B by Week 48 (mean blood Phe of 557⯱â¯389⯵mol/L). The most common adverse events involved hypersensitivity reactions, which were mostly mild to moderate in severity and decreased over time. One participant in Group B had four acute systemic hypersensitivity events of anaphylaxis consistent with clinical National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria; all events were non-IgE mediated and resolved without sequelae, with pegvaliase dosing discontinued after the fourth event. The incidence and titers of anti-drug antibodies were generally lower in Group A compared to Group B.CONCLUSIONS:
Pegvaliase administered with an induction, titration, and maintenance dosing regimen demonstrated substantial efficacy at reducing blood Phe in both Group A and Group B by Week 48, with a manageable safety profile in most participants. Blood Phe reduction due to pegvaliase appears to be related to dose, treatment duration, and individual immune response; given additional time on treatment and dose titration, later Phe responders (Group B) achieved benefit similar to early Phe responders (Group A), with similar long-term safety profiles.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenilalanina Amônia-Liase
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Fenilalanina
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Fenilcetonúrias
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Proteínas Recombinantes
Tipo de estudo:
Guideline
Limite:
Adolescent
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Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Mol Genet Metab
Assunto da revista:
BIOLOGIA MOLECULAR
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BIOQUIMICA
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METABOLISMO
Ano de publicação:
2018
Tipo de documento:
Article