Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria

Zori, Roberto T.; Thomas, Janet A.; Shur, Natasha; Rizzo, William B.; Decker, Celeste; Rosen, Orli; Li, Mingjin; Schweighardt, Becky; Ly, Kévin; Longo, Nicola

doi:10.1016/j.ymgme.2018.06.010

Cited by 24 publications

(63 citation statements)

References 25 publications

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“…Pegvaliase doses were similar to those previously tested in the parent studies [ 13 , 14 ], between 2.5 mg/week and 375 mg/week or between 0.001 mg/kg/week and 5 mg/kg/week, administered up to 7 days/week; weight-based dosing allowed participants > 75 kg to receive a dose higher than 375 mg/week, but a protocol change in October 2014 clarified an absolute maximum dose of 375 mg/week.…”

Section: Methodssupporting

confidence: 70%

“…In the third phase 2 study, 165–205, pegvaliase was started at a low dose (2.5 mg/week) that was gradually increased (to a maximum of 375 mg/week) to minimize hypersensitivity events. This pegvaliase dosing regimen with an induction, titration, and maintenance period led to substantial reductions in mean plasma Phe concentration during the 24-week study [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Here we report on the longest duration of pegvaliase treatment to date. Long-term efficacy, safety, and immunogenicity of pegvaliase was assessed in participants who initiated treatment in PAL-002 (NCT00925054) [ 13 ], PAL-004 (NCT01212744) [ 13 ], or 165–205 (NCT01560286) [ 14 ] and then continued on in the PAL-003 extension study reported here.…”

Section: Introductionmentioning

confidence: 99%

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Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study

Longo

Zori

Wasserstein

et al. 2018

Orphanet J Rare Dis

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BackgroundDeficiency of phenylalanine hydroxylase causes phenylketonuria (PKU) with elevated phenylalanine (Phe) levels and associated neuropsychiatric and neurocognitive symptoms. Pegvaliase (PEGylated phenylalanine ammonia lyase) is an investigational agent to lower plasma Phe in adults with PKU. This study aimed to characterize the long-term efficacy, safety, and immunogenicity of pegvaliase in adults with PKU.MethodsPAL-003 is an ongoing, open-label, long-term extension study of the pegvaliase dose-finding parent phase 2 studies. Participants continued the dose of pegvaliase from one of three parent studies, with dose adjustments to achieve a plasma Phe concentration between 60 and 600 μmol/L.ResultsMean (standard deviation [SD]) plasma Phe at treatment-naïve baseline for 80 participants in the parent studies was 1302.4 (351.5) μmol/L. In the 68 participants who entered the extension study, plasma Phe decreased 58.9 (39)% from baseline, to 541.6 (515.5) μmol/L at Week 48 of treatment. Plasma Phe concentrations ≤120 μmol/L, ≤360 μmol/L, and ≤ 600 μmol/L were achieved by 78.7, 80.0, and 82.5% of participants, respectively. Mean (SD) protein intake at baseline was 69.4 (40.4) g/day (similar to the recommended intake for the unaffected population) and remained stable throughout the study. All participants experienced adverse events (AEs), which were limited to mild or moderate severity in most (88.8%); the most common AEs were injection-site reaction (72.5%), injection-site erythema (67.5%), headache (67.5%), and arthralgia (65.0%). The AE rate decreased from 58.3 events per person-year in the parent studies to 18.6 events per person-year in the extension study.ConclusionsPegvaliase treatment in adults with PKU produced meaningful and persistent reductions in mean plasma Phe concentration with a manageable safety profile for most subjects that continued with long-term treatment.Trial registrationClinicalTrials.gov, NCT00924703. Registered June 18, 2009, https://clinicaltrials.gov/ct2/show/NCT00924703Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0858-7) contains supplementary material, which is available to authorized users.

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Section: Methodssupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study

Longo

Zori

Wasserstein

et al. 2018

Orphanet J Rare Dis

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“…A Phase 1 clinical study demonstrated a single dose of pegvaliase treatment reduced blood Phe concentrations [17]. Phase 2 clinical studies of pegvaliase demonstrated that treatment leads to meaningful and sustained reductions in blood Phe concentrations [18][19][20].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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

Harding

Amato

Stuy

et al. 2018

Molecular Genetics and Metabolism

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“…For this reason, Phe supplementation is sometimes recommended in TT1 in case of persistently low Phe levels [4,5,7]. Furthermore, especially this lower range might be important with the upcoming new treatment for PKU patients, pegvaliase [22,23]. Patients treated with pegvaliase often have low Phe concentrations, which can drop below the detection limit.…”

Section: Discussionmentioning

confidence: 99%

Dried blood spot versus venous blood sampling for phenylalanine and tyrosine

Vliet

Ginkel

Dam

et al. 2020

Orphanet J Rare Dis

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Background: This study investigated the agreement between various dried blood spot (DBS) and venous blood sample measurements of phenylalanine and tyrosine concentrations in Phenylketonuria (PKU) and Tyrosinemia type 1 (TT1) patients. Study design: Phenylalanine and tyrosine concentrations were studied in 45 PKU/TT1 patients in plasma from venous blood in lithium heparin (LH) and EDTA tubes; venous blood from LH and EDTA tubes on a DBS card; venous blood directly on a DBS card; and capillary blood on a DBS card. Plasma was analyzed with an amino acid analyzer and DBS were analyzed with liquid chromatography-mass spectrometry. Agreement between different methods was assessed using Passing and Bablok fit and Bland Altman analyses. Results: In general, phenylalanine concentrations in LH plasma were comparable to capillary DBS, whereas tyrosine concentrations were slightly higher in LH plasma (constant bias of 6.4 μmol/L). However, in the low phenylalanine range, most samples had higher phenylalanine concentrations in DBS compared to LH plasma. Remarkably, phenylalanine and tyrosine in EDTA plasma were higher compared to all other samples (slopes ranging from 7 to 12%). No differences were observed when comparing capillary DBS to other DBS. Conclusions: Overall agreement between plasma and DBS is good. However, bias is specimen-(LH vs EDTA), and possibly concentration-(low phenylalanine) dependent. Because of the overall good agreement, we recommend the use of a DBS-plasma correction factor for DBS measurement. Each laboratory should determine their own factor dependent on filter card type, extraction and calibration protocols taking the LH plasma values as gold standard.

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Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria

Cited by 24 publications

References 25 publications

Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study

Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study

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

Dried blood spot versus venous blood sampling for phenylalanine and tyrosine

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