Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial.
Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial.
复制标题
DOI：
10.1016/s0140-6736(13)61841-3
复制
发表时间：
2014-07-05
期刊：
影响因子：
168.9
通讯作者：
Sile, Saba
中科院分区：
文献类型：
--
作者：
Longo, Nicola;Harding, Cary O.;Burton, Barbara K.;Grange, Dorothy K.;Vockley, Jerry;Wasserstein, Melissa;Rice, Gregory M.;Dorenbaum, Alejandro;Neuenburg, Jutta K.;Musson, Donald G.;Gu, Zhonghua;Sile, Saba
苯丙酮尿症是一种由苯丙氨酸羟化酶（将苯丙氨酸转化为酪氨酸的酶）活性受损引起的遗传性疾病，导致苯丙氨酸积累和随后的神经认知功能障碍。在生命早期开始限制苯丙氨酸饮食可以减轻苯丙氨酸的毒性作用。然而，饮食是繁重的，遵守是非常困难的。苯丙氨酸解氨酶（PAL）是一种原核生物酶，可将苯丙氨酸转化为氨和反式肉桂酸。这项1期多中心临床试验评价了rAvPAL-PEG（在大肠杆菌中生产的重组变异鱼腥藻PAL）的安全性、耐受性、药代动力学和疗效。与聚乙二醇[PEG]缀合以降低免疫原性的大肠杆菌）在降低苯丙酮尿症受试者中的苯丙氨酸水平中的作用。对从北美代谢诊所招募的25名苯丙酮尿症成人（血苯丙氨酸浓度≥600 μmol/L）单次皮下注射递增剂量（0·001、0·003、0·01、0·03和0·1 mg/kg）的rAvPAL-PEG。最常报告的不良事件是注射部位反应和头晕。反应为自限性，无后遗症。在试验期间，两名受试者对肌肉注射（IM）醋酸甲羟孕酮（一种含有聚乙二醇作为赋形剂的药物）发生不良反应。3名受试者在最高rAvPAL-PEG剂量（0·1 mg/kg）下发生全身性皮疹。药物水平在注射后35天达到峰值。在接受最高剂量（0·1 mg/kg，相对于基线的平均百分比变化为-58）的所有5名受试者中，治疗有效降低了血液苯丙氨酸，注射后约6天达到最低点，血浆中药物和苯丙氨酸浓度呈负相关。单次注射后20天，苯丙氨酸浓度恢复到接近基线水平。在苯丙酮尿症受试者中，rAvPAL-PEG以高达0·1 mg/kg的单次剂量皮下给药是安全的且耐受性良好。在测试的最高剂量下，rAvPAL-PEG降低了血液苯丙氨酸浓度。（clinicaltrials.gov中的NCT 00925054）
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 Anabaena variabilis PAL produced in E. coli conjugated with polyethylene glycol [PEG] to reduce immunogenicity) in reducing phenylalanine levels in subjects with phenylketonuria. 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 clinicaltrials.gov)