Compositions of prokaryotic phenylalanine ammonia-lyase and methods of treating adolescent subjects
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Publication Number
US-11918633-B2
Publication Date
2024-03-05
Expiration Date
Abstract
Phenylalanine ammonia-lyase (PAL) variants with a greater phenylalanine-converting activity and/or a reduced immunogenicity as compared to a wild-type PAL for therapeutic uses, including the treatment of adolescent subjects having PKU.
Core Innovation
The described invention relates to reducing blood phenylalanine concentration in a subject by administering a weekly dose of a formulation comprising an AvPAL variant. The subject is about 12 years old to about 17 years old, and the weekly dose is administered for more than 50 weeks. The formulation includes an AvPAL variant comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:4.
In the adolescent treatment context, the formulation can include a pegylated AvPAL variant and is described as comprising pharmaceutically acceptable carriers and stabilizers. The stabilizers include L-phenylalanine and/or structural analogs such as trans-cinnamic acid and benzoic acid. Additional components described include sodium chloride and tromethamine and tromethamine hydrochloride.
The document further describes rationale and clinical evaluation for adolescent dosing, including trial results and monitoring concepts. Example targets are described for blood Phe concentrations using thresholds such as <600 μM, <360 μM, and <120 μM, together with summarized safety and immunogenicity outcomes. The clinical evaluation also includes discussion of adolescent dosing and monitoring within defined adolescent cohorts.
Claims Coverage
The provided independent claim covers a method of reducing blood phenylalanine concentration in an adolescent by weekly administration of a formulation comprising an AvPAL variant with sequence identity to SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4, administered for more than 50 weeks; it also specifies the subject age range (about 12 to about 17 years old).
Weekly dose for more than 50 weeks to reduce blood phenylalanine in an adolescent
Administering to a subject about 12 years old to about 17 years old a weekly dose of a formulation, where the weekly dose is administered for more than 50 weeks to reduce blood phenylalanine concentration.
AvPAL variant with amino acid sequence SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:4
Using an AvPAL variant comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:4 in the weekly-dose formulation.
In combination, the independent claim requires adolescent subjects, weekly dosing for more than 50 weeks, and a formulation comprising an AvPAL variant limited to the amino acid sequences SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4.
Stated Advantages
Reduces blood phenylalanine concentration in a subject.
Documented Applications
Adolescent treatment for phenylketonuria (PKU), using weekly administration of pegylated AvPAL variant formulations with monitoring of blood phenylalanine concentration and summarized safety/immunogenicity outcomes.
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