OBJECTIVE To provide recommendations for managing hypersensitivity adverse events (HAEs) to an injectable enzyme substitution therapy (pegvaliase, a PEGylated phenylalanine ammonia lyase enzyme) in adult patients with phenylketonuria (PKU). METHODS Eight European academic immunology experts with a broad range of experience in hypersensitivity, anaphylaxis, and/or drug reactions, and two geneticists from the USA with pegvaliase experience convened for two advisory board meetings. Efficacy, safety, and immunological profile of pegvaliase were discussed with the objective of developing recommendations for the clinical management of HAEs associated with pegvaliase treatment. RESULTS Based on available immunogenicity data, it was concluded that pegvaliase induces a Type III hypersensitivity reaction, causing HAEs with peak event rates during induction/titration and a decline over time during maintenance therapy. The decline in HAEs with longer duration of therapy was considered to likely be driven by anti-drug antibody affinity maturation, reduced immune complex formation, and decreased complement activation over time. Immunology and PKU experts unanimously supported that the use of an induction, titration, and maintenance dosing regimen and implementation of several risk mitigation strategies contributed to the improvement of tolerability over time. Key risk mitigation strategies utilized in the Phase 3 clinical trials such as premedication with H1-receptor antagonists, allowance for a longer titration period after an HAE, patient education, and requirement to carry auto-injectable adrenaline (epinephrine) should be continued in clinical practice. A tool for administration of auto-injectable adrenaline in patients using pegvaliase was suggested. It was added that after the occurrence of a severe HAE a temporary dose reduction is more likely to improve tolerability than treatment interruption. CONCLUSIONS Overall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable adrenaline is recommended. Because pegvaliase offers the possibility to normalize diet, while maintaining blood phenylalanine within the recommended therapeutic range, safe use of this medication in the clinical setting is important. Ongoing monitoring of long-term clinical safety of patients on pegvaliase treatment in the commercial setting was recommended.

中文翻译：

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Pegvaliase：使用该酶替代疗法治疗的苯丙酮尿​​症患者的超敏反应的免疫学分析和临床管理建议。

目的为成人苯丙酮尿症（PKU）患者的注射性酶替代疗法（pegvaliase，一种聚乙二醇化的苯丙氨酸氨裂合酶）的超敏反应不良事件（HAEs）提供管理建议。方法八位在超敏性，过敏性和/或药物反应方面具有丰富经验的欧洲免疫学专家，以及两名来自美国的具有聚乙二醇戊二酸酶的遗传学家参加了两次咨询委员会会议。讨论了聚乙二醇戊二酸酶的功效，安全性和免疫学特征，目的是为与聚乙二醇丙二酸酶治疗相关的HAE的临床管理提出建议。结果根据可用的免疫原性数据，得出的结论是聚乙二醇戊二糖酶可引起III型超敏反应，导致HAE的诱导/滴定期间事件发生率达到峰值，而维持治疗期间随时间而下降。随着治疗时间的延长，HAE的下降可能是由于抗药物抗体亲和力成熟，免疫复合物形成减少以及随着时间的推移补体激活减少而引起的。免疫学和PKU专家一致支持使用诱导，滴定和维持剂量方案以及几种风险缓解策略的实施有助于随着时间的流逝提高耐受性。在3期临床试验中使用的关键风险缓解策略，例如H1受体拮抗剂的预用药，HAE后允许更长的滴定时间，患者教育，在临床实践中应继续要求携带自动注射的肾上腺素（肾上腺素）。建议使用pegvaliase在患者中使用自动注射肾上腺素的工具。补充说，发生严重的HAE后，暂时减少剂量比中断治疗更有可能提高耐受性。结论总体而言，已达成共识的是，在患有PKU的成人中，pegvaliase具有普遍可耐受的安全性。重要的是，考虑将临床试验中使用的降低风险的策略支持在商业环境中继续使用关键的管理策略，例如缓慢的诱导/滴定剂量范例以及使用H1受体拮抗剂进行预用药。但是，医生和患者需要意识到与聚乙二醇戊二酸酶相关的HAE的风险。在某些情况下，训练有素的观察员在早期治疗中的出现可能是有益的，因此建议携带自动注射的肾上腺素。由于pegvaliase可以使饮食正常化，同时将血液中的苯丙氨酸维持在推荐的治疗范围内，因此在临床环境中安全使用该药物非常重要。建议在商业环境中持续监测患者接受pegvaliase治疗的长期临床安全性。在临床环境中安全使用该药物很重要。建议在商业环境中持续监测患者接受pegvaliase治疗的长期临床安全性。在临床环境中安全使用该药物很重要。建议在商业环境中持续监测患者接受pegvaliase治疗的长期临床安全性。