Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial

Harding, Cary O.; Amato, Roberto; Stuy, Mary; Longo, Nicola; Burton, Barbara K.; Posner, John; Weng, Haoling H.; Meriläinen, Markus; Gu, Zhonghua; Jiang, Joy; Vockley, Jerry; Prism., Investigators

doi:10.1016/j.ymgme.2018.03.003

Cited by 72 publications

(89 citation statements)

References 28 publications

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“…8 These abnormalities can include lower IQ, executive functioning deficits, and psychiatric disorders (anxiety and depression), with the incidence of deficits increasing with increased blood Phe concentration. [10][11][12] A recent US Food and Drug Administration (FDA)-approved enzyme substitution therapy (pegvaliase) for adults with uncontrolled hyperphenylalaninemia on a diet has revealed dramatic improvements in blood Phe management [13][14][15][16] but is associated with a significant incidence of immune-mediated hypersensitivity reactions against the foreign protein. Additionally, pegvaliase is not approved for use in individuals less than 18 years of age.…”

Section: Introductionmentioning

confidence: 99%

AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria

Richards

Winn

Dudley

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Phenylketonuria (PKU) due to recessively inherited phenylalanine hydroxylase (PAH) deficiency results in hyperphenylalaninemia, which is toxic to the central nervous system. Restriction of dietary phenylalanine intake remains the standard of PKU care and prevents the major neurologic manifestations of the disease, yet shortcomings of dietary therapy remain, including poor adherence to a difficult and unpalatable diet, an increased incidence of neuropsychiatric illness, and imperfect neurocognitive outcomes. Gene therapy for PKU is a promising novel approach to promote lifelong neurological protection while allowing unrestricted dietary phenylalanine intake. In this study, liver-tropic recombinant AAV2/8 vectors were used to deliver CRISPR/Cas9 machinery and facilitate correction of the Pah enu2 allele by homologous recombination. Additionally, a non-homologous end joining (NHEJ) inhibitor, vanillin, was co-administered with the viral drug to promote homologydirected repair (HDR) with the AAV-provided repair template. This combinatorial drug administration allowed for lifelong, permanent correction of the Pah enu2 allele in a portion of treated hepatocytes of mice with PKU, yielding partial restoration of liver PAH activity, substantial reduction of blood phenylalanine, and prevention of maternal PKU effects during breeding. This work reveals that CRISPR/Cas9 gene editing is a promising tool for permanent PKU gene editing.

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Section: Introductionmentioning

confidence: 99%

AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria

Richards

Winn

Dudley

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…Also pegvaliase (Palynziq®), the new enzyme substitution therapy [54][55][56], is estimated to cost approximately 190,000 CHF or USD per year and patient. Of note, neither sapropterin nor pegvaliase enabled clinically relevant significant improvement of cognitive outcome [22,24,57,58].…”

Section: Discussionmentioning

confidence: 98%

Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial

Trepp

Muri

Abgottspon

et al. 2020

Trials

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Background: The population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional, and neurometabolic parameters of the brain. Methods: The PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebocontrolled, crossover, noninferiority trial. Participants: Thirty adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex, and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are 18 years of age or older and had PKU diagnosed after a positive newborn screening and were treated with a Phe-restricted diet starting within the first 30 days of life. Intervention: The cross-over intervention consists of 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach. Objectives: The primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As a secondary objective, the PICO Study will elucidate the cerebral (fMRI, neural activation during a n-back task; rsfMRI, functional connectivity at rest; DTI, white matter integrity; and ASL, cerebral blood flow) and neurometabolic mechanisms (cerebral Phe level) that accompany changes in Phe concentration. Cognition, and structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland.

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“…Also pegvaliase (Palynziq ® ), the new enzyme substitution therapy (51)(52)(53), is estimated to cost about 190'000 CHF / USD per year and patient. Of note, neither saproprotein nor pegvaliase enabled clinically relevant significant improvement of cognitive outcome (19,22,54,55).…”

Section: Discussionmentioning

confidence: 98%

The PICO Study: Impact of Phenylalanine on Cognitive, Cerebral and Neurometabolic Parameters in Adult Patients with Phenylketonuria – a Randomized, Placebo-Controlled, Crossover, Non-inferiority Trial

Trepp¹,

Muri²,

Bošanská³

et al. 2019

Preprint

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Background The population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood Phe levels in adults outside pregnancy is discussed controversially. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional and neurometabolic parameters of the brain. Methods The PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week phenylalanine (Phe) load on cognition and cerebral parameters in 30 adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, non-inferiority trial. The primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance in adults with early-treated PKU. As secondary objective, the PICO Study will elucidate cerebral and neurometabolic mechanisms, which accompany changes in Phe concentration using advanced neuroimaging methods. In addition to the intervention study, cognition, structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls, who will be comparable with regard to age, gender and education level. Advanced MR-techniques will be used to investigate intensity of neural activation during the working memory task (fMRI), strength of functional connectivity between brain regions related to performance in working memory (rsfMRI), white matter integrity (DTI), cerebral blood flow (ASL) and brain Phe concentrations (MRS). Discussion Using a combination of neuropsychological and neuroimaging data, the PICO study will considerably contribute to improve the currently insufficient level of evidence on how adult patients with early-treated PKU should be managed.

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Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial

Cited by 72 publications

References 28 publications

AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria

AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria

Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial

The PICO Study: Impact of Phenylalanine on Cognitive, Cerebral and Neurometabolic Parameters in Adult Patients with Phenylketonuria – a Randomized, Placebo-Controlled, Crossover, Non-inferiority Trial

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