Phase 1 Trial of Subcutaneous rAvPAL-PEG in Subjects with Phenylketonuria
Identifieur interne : 001B47 ( Main/Exploration ); précédent : 001B46; suivant : 001B48Phase 1 Trial of Subcutaneous rAvPAL-PEG in Subjects with Phenylketonuria
Auteurs : Nicola Longo [États-Unis] ; Cary O. Harding [États-Unis] ; Barbara K. Burton [États-Unis] ; Dorothy K. Grange [États-Unis] ; Jerry Vockley [États-Unis] ; Melissa Wasserstein [États-Unis] ; Gregory M. Rice [États-Unis] ; Donald G. Musson [États-Unis] ; Zhonghua Gu [États-Unis] ; Saba Sile [États-Unis]Source :
- Lancet [ 0140-6736 ] ; 2014.
Descripteurs français
- KwdFr :
- Adulte, Calendrier d'administration des médicaments, Facteurs temps, Femelle, Humains, Injections sous-cutanées, Mâle, Phenylalanine ammonia-lyase (administration et posologie), Phenylalanine ammonia-lyase (immunologie), Phenylalanine ammonia-lyase (pharmacologie), Phénylalanine (sang), Phénylcétonuries (sang), Phénylcétonuries (traitement médicamenteux), Polyéthylène glycols (administration et posologie), Résultat thérapeutique, États-Unis d'Amérique.
- MESH :
- administration et posologie : Phenylalanine ammonia-lyase, Polyéthylène glycols.
- immunologie : Phenylalanine ammonia-lyase.
- pharmacologie : Phenylalanine ammonia-lyase.
- sang : Phénylalanine, Phénylcétonuries.
- traitement médicamenteux : Phénylcétonuries.
- Adulte, Calendrier d'administration des médicaments, Facteurs temps, Femelle, Humains, Injections sous-cutanées, Mâle, Résultat thérapeutique, États-Unis d'Amérique.
- Wicri :
- geographic : États-Unis.
English descriptors
- KwdEn :
- Adult, Drug Administration Schedule, Female, Humans, Injections, Subcutaneous, Male, Phenylalanine (blood), Phenylalanine Ammonia-Lyase (administration & dosage), Phenylalanine Ammonia-Lyase (immunology), Phenylalanine Ammonia-Lyase (pharmacology), Phenylketonurias (blood), Phenylketonurias (drug therapy), Polyethylene Glycols (administration & dosage), Time Factors, Treatment Outcome, United States.
- MESH :
- chemical , administration & dosage : Phenylalanine Ammonia-Lyase, Polyethylene Glycols.
- chemical , blood : Phenylalanine.
- chemical , immunology : Phenylalanine Ammonia-Lyase.
- chemical , pharmacology : Phenylalanine Ammonia-Lyase.
- geographic : United States.
- blood : Phenylketonurias.
- drug therapy : Phenylketonurias.
- Adult, Drug Administration Schedule, Female, Humans, Injections, Subcutaneous, Male, Time Factors, Treatment Outcome.
Abstract
Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. A phenylalanine-restricted diet initiated early in life can ameliorate the toxic effects of phenylalanine. However, the diet is onerous and compliance is extremely difficult. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. This Phase 1, multicenter clinical trial evaluated the safety, tolerability, pharmacokinetics and efficacy of rAvPAL-PEG (recombinant
Single subcutaneous injections of rAvPAL-PEG in escalating doses (0·001, 0·003, 0·01, 0·03, and 0·1 mg/kg) were administered to 25 adults with phenylketonuria recruited from those attending metabolic clinics in North America whose blood phenylalanine concentrations were ≥600 μmol/L.
The most frequently reported adverse events were injection-site reactions and dizziness. Reactions were self-limited without sequelae. During the trial, two subjects had adverse reactions to intramuscular (IM) medroxyprogesterone acetate, a drug containing polyethylene glycol as an excipient. Three subjects developed a generalized skin rash at the highest rAvPAL-PEG dose (0·1 mg/kg). Drug levels peaked ∼5 days after the injection. Treatment was effective in reducing blood phenylalanine in all five subjects receiving the highest dose (0·1 mg/kg, mean percent change of -58 from baseline), with a nadir ∼6 days after injection and inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine concentrations returned to near-baseline levels ∼20 days after the single injection.
Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0·1 mg/kg is safe and well tolerated in subjects with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. (NCT00925054 in
Url:
DOI: 10.1016/S0140-6736(13)61841-3
PubMed: 24743000
PubMed Central: 4447208
Affiliations:
- États-Unis
- Californie, Illinois, Missouri (État), Oregon, Pennsylvanie, Utah, Wisconsin, État de New York
- Saint-Louis (Missouri)
- École de médecine (Université Washington de Saint-Louis)
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Le document en format XML
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<term>Male</term>
<term>Phenylalanine (blood)</term>
<term>Phenylalanine Ammonia-Lyase (administration & dosage)</term>
<term>Phenylalanine Ammonia-Lyase (immunology)</term>
<term>Phenylalanine Ammonia-Lyase (pharmacology)</term>
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<term>Phenylketonurias (drug therapy)</term>
<term>Polyethylene Glycols (administration & dosage)</term>
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<term>Treatment Outcome</term>
<term>United States</term>
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<term>Calendrier d'administration des médicaments</term>
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<term>Humains</term>
<term>Injections sous-cutanées</term>
<term>Mâle</term>
<term>Phenylalanine ammonia-lyase (administration et posologie)</term>
<term>Phenylalanine ammonia-lyase (immunologie)</term>
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<keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Phenylalanine Ammonia-Lyase</term>
<term>Polyethylene Glycols</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Phenylalanine Ammonia-Lyase</term>
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<term>Polyéthylène glycols</term>
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<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Phenylalanine ammonia-lyase</term>
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<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Phenylalanine ammonia-lyase</term>
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<keywords scheme="MESH" qualifier="sang" xml:lang="fr"><term>Phénylalanine</term>
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<term>Drug Administration Schedule</term>
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<term>Humans</term>
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<term>Calendrier d'administration des médicaments</term>
<term>Facteurs temps</term>
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<term>Humains</term>
<term>Injections sous-cutanées</term>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Objective</title>
<p id="P1">Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. A phenylalanine-restricted diet initiated early in life can ameliorate the toxic effects of phenylalanine. However, the diet is onerous and compliance is extremely difficult. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. This Phase 1, multicenter clinical trial evaluated the safety, tolerability, pharmacokinetics and efficacy of rAvPAL-PEG (recombinant <italic>Anabaena variabilis</italic>
PAL produced in <italic>E. coli</italic>
conjugated with polyethylene glycol [PEG] to reduce immunogenicity) in reducing phenylalanine levels in subjects with phenylketonuria.</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P2">Single subcutaneous injections of rAvPAL-PEG in escalating doses (0·001, 0·003, 0·01, 0·03, and 0·1 mg/kg) were administered to 25 adults with phenylketonuria recruited from those attending metabolic clinics in North America whose blood phenylalanine concentrations were ≥600 μmol/L.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">The most frequently reported adverse events were injection-site reactions and dizziness. Reactions were self-limited without sequelae. During the trial, two subjects had adverse reactions to intramuscular (IM) medroxyprogesterone acetate, a drug containing polyethylene glycol as an excipient. Three subjects developed a generalized skin rash at the highest rAvPAL-PEG dose (0·1 mg/kg). Drug levels peaked ∼5 days after the injection. Treatment was effective in reducing blood phenylalanine in all five subjects receiving the highest dose (0·1 mg/kg, mean percent change of -58 from baseline), with a nadir ∼6 days after injection and inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine concentrations returned to near-baseline levels ∼20 days after the single injection.</p>
</sec>
<sec id="S4"><title>Conclusions</title>
<p id="P4">Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0·1 mg/kg is safe and well tolerated in subjects with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. (NCT00925054 in <ext-link ext-link-type="uri" xlink:href="http://clinicaltrials.gov">clinicaltrials.gov</ext-link>
)</p>
</sec>
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<settlement><li>Saint-Louis (Missouri)</li>
</settlement>
<orgName><li>École de médecine (Université Washington de Saint-Louis)</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Utah"><name sortKey="Longo, Nicola" sort="Longo, Nicola" uniqKey="Longo N" first="Nicola" last="Longo">Nicola Longo</name>
</region>
<name sortKey="Burton, Barbara K" sort="Burton, Barbara K" uniqKey="Burton B" first="Barbara K." last="Burton">Barbara K. Burton</name>
<name sortKey="Grange, Dorothy K" sort="Grange, Dorothy K" uniqKey="Grange D" first="Dorothy K." last="Grange">Dorothy K. Grange</name>
<name sortKey="Gu, Zhonghua" sort="Gu, Zhonghua" uniqKey="Gu Z" first="Zhonghua" last="Gu">Zhonghua Gu</name>
<name sortKey="Harding, Cary O" sort="Harding, Cary O" uniqKey="Harding C" first="Cary O." last="Harding">Cary O. Harding</name>
<name sortKey="Musson, Donald G" sort="Musson, Donald G" uniqKey="Musson D" first="Donald G." last="Musson">Donald G. Musson</name>
<name sortKey="Rice, Gregory M" sort="Rice, Gregory M" uniqKey="Rice G" first="Gregory M." last="Rice">Gregory M. Rice</name>
<name sortKey="Sile, Saba" sort="Sile, Saba" uniqKey="Sile S" first="Saba" last="Sile">Saba Sile</name>
<name sortKey="Vockley, Jerry" sort="Vockley, Jerry" uniqKey="Vockley J" first="Jerry" last="Vockley">Jerry Vockley</name>
<name sortKey="Wasserstein, Melissa" sort="Wasserstein, Melissa" uniqKey="Wasserstein M" first="Melissa" last="Wasserstein">Melissa Wasserstein</name>
</country>
</tree>
</affiliations>
</record>
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