Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Cold Spring Harb Mol Case Stud. 2021 Dec 9;7(6). doi: 10.1101/mcs.a006134. Print 2021 Dec.
Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical intervention. Inhibitors of AKT, originally designed as cancer therapeutics, are a rational, targeted pharmacologic strategy to mitigate the devastating morbidity of Proteus syndrome. We present the 5-yr follow-up of an 18-yr-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-wk phase 1 pharmacodynamic study, the individual derived sufficient benefit that the study was amended to permit continued use and assess the long-term safety of miransertib. The treatment has been well-tolerated with mild treatment-attributed side effects including headache, transient hyperglycemia, and transient elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin. The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. This case report supplements the data from our prior study extending those findings out to 5 years. It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. Although an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study.
先天性红细胞生成性卟啉病是一种罕见的过度生长障碍，由合子后激活变异引起。患者可能会出现一系列皮肤、骨骼和软组织过度生长，导致功能障碍和畸形。这种疾病的治疗仅限于支持性护理和手术干预。最初设计用于癌症治疗的 AKT 抑制剂是一种合理的、靶向的药物治疗策略，可以减轻先天性红细胞生成性卟啉病的毁灭性发病率。我们报告了一名 18 岁男性接受 miransertib（MK-7075）治疗的 5 年随访结果，miransertib 是一种口服 pan-AKT 抑制剂。在完成计划的 48 周 1 期药效学研究后，该患者受益显著，因此研究方案修改为允许继续使用，并评估 miransertib 的长期安全性。该治疗方案耐受性良好，仅有轻微的治疗相关副作用，包括头痛、短暂性高血糖和天门冬氨酸氨基转移酶、丙氨酸氨基转移酶和胆红素短暂升高。患者的疼痛得到持续缓解，双侧足底脑回状结缔组织痣的生长速度也减缓。本病例报告补充了我们之前研究的数据，将这些发现延长至 5 年。结果表明，在使用的剂量下，miransertib 具有良好的安全性和持久的疗效，可以改善先天性红细胞生成性卟啉病患者的疼痛症状，并减缓过度生长的进展。虽然一项未经对照的单例报告不能证明安全性或疗效，但这些数据支持我们之前的 1 期药效学研究的初步令人鼓舞的数据。
