更新于：2024-05-01

PIK3CA-related overgrowth syndrome

PIK3CA相关的过度生长现象

更新于：2024-05-01

基本信息

别名

PIK3CA related overgrowth spectrum、PIK3CA related overgrowth syndrome、PIK3CA-Related Overgrowth Spectrum

+ [8]

简介

A group of rare disorders that are usually caused by somatic mutations in the PIK3CA gene, but may rarely be caused by de novo germline mutations. These disorders are typically characterized by sporadic overgrowth of parts of the body, intellectual disability, low muscle tone, and vascular malformations with congenital or early childhood onset. Representative examples include: fibroadipose hyperplasia, CLOVES syndrome, megalencephaly-capillary malformation syndrome, hemihyperplasia-multiple lipomatosis syndrome, hemimegalencephaly, and facial infiltrating lipomatosis.

关联

项与 PIK3CA相关的过度生长现象相关的药物

Alpelisib

阿培利司

靶点

PI3Kα

作用机制

PI3Kα抑制剂

在研机构

Novartis Pharmaceuticals Corp. [+9]

原研机构

Novartis Pharma AG

在研适应症

PIK3CA相关的过度生长现象 [+28]

非在研适应症

急性髓性白血病 [+24]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2019-05-24

CYH33

靶点

PI3Kα

作用机制

PI3Kα抑制剂

在研机构

上海海和药物研究开发股份有限公司 [+1]

原研机构

上海海和药物研究开发股份有限公司

在研适应症

输卵管透明细胞腺癌 [+12]

非在研适应症

子宫内膜癌 [+2]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 PIK3CA相关的过度生长现象相关的临床试验

NCT05983159 / Not yet recruiting临床2期IIT

A Modular Open Label, Signal Seeking, Phase II Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations (TARGET-VM)

Recent studies have demonstrated that growth of vascular malformations can be driven by genetic variants in one of 2 signalling pathways. Targeted drugs specific to these pathways have been developed and shown to be effective in treating cancer. This study will describe the effectiveness of (i) 48 weeks of alpelisib therapy for participants with slow-flow vascular malformations and a gene mutation in one of these signalling pathways (module 1) and (ii) 48 weeks of mirdametinib therapy for participants with fast-flow vascular malformations and a gene mutations in the other signalling pathway (module 2).

开始日期2024-04-01

申办/合作机构

Murdoch Childrens Research Institute

[+2]

NCT05563831 / RecruitingN/A

Evaluation Nationale Des Enfants et Adultes Avec Syndromes d'Hypercroissance Dysharmonieuse National Evaluation of Patients With PIK3CA-Related Overgrowth Spectrum (PROS)

Overgrowth syndromes are rare genetic disorders defined by tissue hypertrophy that can be either localized or generalized, affecting both latitudinal and longitudinal growth. The genes involved in overgrowth syndromes are not well characterized but mostly concern the PIK3CA/AKT/mTOR pathway, a major actor of cell growth and proliferation. The mutations are not inherited but occurs during embryogenesis leading to somatic mosaicism. Owing to the variability of the clinical presentation, their exact prevalence is yet unknown. In order to answer this question, the investigators team create here the first French national registry on overgrowth syndromes.

开始日期2023-02-21

申办/合作机构

Institut National de la Santé et de la Recherche Médicale

CTR20213097 / Active, not recruiting临床2期

一项评估alpelisib（BYL719）在PIK3CA相关过度生长疾病谱系（PROS）儿科和成年患者中的疗效、安全性和药代动力学的II期双盲研究（包括一个前期的16周随机、安慰剂对照阶段）

本研究的目的是评价alpelisib在确诊PROS的不同年龄参加者中的疗效、安全性/耐受性和药代动力学（PK）

开始日期2022-07-01

申办/合作机构

诺华中国

[+2]

100 项与 PIK3CA相关的过度生长现象相关的临床结果

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100 项与 PIK3CA相关的过度生长现象相关的转化医学

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0 项与 PIK3CA相关的过度生长现象相关的专利（医药）

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112

项与 PIK3CA相关的过度生长现象相关的文献（医药）

2023-12-10·Journal of the European Academy of Dermatology and Venereology : JEADV

Alpelisib decreases nevocytes of congenital melanocytic nevi.

Article

作者: Alejandra Tomás-Velázquez ; Juan Carlos López-Gutiérrez ; Carlos de Andrea ; Miguel Reyes-Múgica ; Claudia M Salgado ; Pedro Redondo

BACKGROUND:

Multiple, large or giant congenital melanocytic nevi (CMN) are uncommon and affected patients can show progressive growth and thickening, associate neurocutaneous melanocytosis or develop melanoma. Current treatment modalities are mostly complex surgeries that frequently do not solve the disease and its risks completely. Thus, investigation on new treatment options for CMN and its complications must continue. MAPK pathway inhibitors are being investigated, also targeting PI3K-AKT. Omipalisib (PI3K inhibitor, with no indications approved yet) has been studied for CMN in vitro and in mice with promising results. However, alpelisib, a PI3K inhibitor approved with an adequate safety profile for patients with severe manifestations of PROS (PIK3CA-Related Overgrowth Spectrum), had not yet been tested for CMN.

OBJECTIVE:

To evaluate the effect of alpelisib in nevocytes of congenital melanocytic nevi.

METHODS:

Nevomelanocytic tissue samples of 10 patients were collected prospectively and, following a previously reported preclinical ex vivo model, explants were placed in organotypic culture for 5 days, with or without alpelisib. Consecutively, tissue sections were stained and using scanned images with Qupath and ImageJ softwares, representative regions from the dermis were analysed (using Wilcoxon test and Spearman's correlation).

RESULTS:

When comparing alpelisib-treated explants with respect to control explants, we found a decrease in cell density (p = 0.0273), in density of SOX10⁺ -cells (p = 0.0391) and also in the % of S-100⁺ area (p = 0.0078), in alpelisib samples. The three markers showed a positive correlation (p < 0.05).

CONCLUSIONS:

This study provides first-time evidence that alpelisib induces nevocyte reduction in CMN from patient-derived explants, probably inducted by autophagy. Alpelisib is an approved drug with an adequate safety profile used in another mosaicism affecting PI3K (PROS). Further studies are needed to evaluate its efficacy in treating CMN and potentially, their complications, either with local or systemic administration, alone or in combination.

2023-11-27·Genes

Work-Up and Treatment Strategies for Individuals with PIK3CA-Related Disorders: A Consensus of Experts from the Scientific Committee of the Italian Macrodactyly and PROS Association.

Article

作者: Andrea Gazzin ; Chiara Leoni ; Germana Viscogliosi ; Federica Borgini ; Lucrezia Perri ; Matteo Iacoviello ; Marilidia Piglionica ; Maurizio De Pellegrin ; Giovanni Battista Ferrero ; Andrea Bartuli ; Giuseppe Zampino ; Paola Sabrina Buonuomo ; Nicoletta Resta ; Alessandro Mussa ; Italian Macrodactyly and PROS Association

PIK3CA-related disorders encompass many rare and ultra-rare conditions caused by somatic genetic variants that hyperactivate the PI3K-AKT-mTOR signaling pathway, which is essential for cell cycle control. PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations and PIK3CA-related non-vascular lesions. Phenotypes are extremely heterogeneous and overlapping. Therefore, diagnosis and management frequently involve various health specialists. Given the rarity of these disorders and the limited number of centers offering optimal care, the Scientific Committee of the Italian Macrodactyly and PROS Association has proposed a revision of the most recent recommendations for the diagnosis, molecular testing, clinical management, follow-up, and treatment strategies. These recommendations give insight on molecular diagnosis, eligible samples, preferable sequencing, and validation methods and management of negative results. The purpose of this paper is to promote collaboration between health care centers and clinicians with a joint shared approach. Finally, we suggest the direction of present and future research studies, including new systemic target therapies, which are currently under evaluation in several clinical trials, such as specific inhibitors that can be employed to downregulate the signaling pathway.

2023-11-10·American journal of medical genetics. Part A

Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach.

Article

作者: Leanne de Kock ; Alexanne Cuillerier ; Meredith Gillespie ; Madeline Couse ; Taila Hartley ; Wendy Mears ; Francois P Bernier ; Albert E Chudley ; Patrick Frosk ; Sarah M Nikkel ; A Micheil Innes ; Julie Lauzon ; Maryann Thomas ; Andrea Guerin ; Christine M Armour ; Rosanna Weksberg ; James N Scott ; Debra Watkins ; Shirley Harvey ; Cheryl Cytrynbaum ; Care4Rare Canada Consortium ; Kristin D Kernohan ; Kym M Boycott

Activating variants in the PIK3CA gene cause a heterogeneous spectrum of disorders that involve congenital or early-onset segmental/focal overgrowth, now referred to as PIK3CA-related overgrowth spectrum (PROS). Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel-Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation-polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain-of-function variants in PIK3CA as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic PIK3CA variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low-level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population.

项与 PIK3CA相关的过度生长现象相关的新闻（医药）

2024-03-14

·Pharmaceutical Technology

EMA pins lack of long-term data as rationale for Novartis’ failed Vijoice bid

The European Medicines Agency (EMA) released a report detailing the reasons for the withdrawal of Novartis marketing authorisation application for Vijoice. Credit: Bloomberg via Getty Images. The European Medicines Agency (EMA) recently released its main concerns with Novartis ’ Vijoice (alpelisib) application which led to the company withdrawing its conditional authorisation application for a group of rare genetic disorders last autumn. In Europe, Novartis was pursuing a label for the treatment of adults and children aged two years and above with severe or life-threatening symptoms of PIK3CA-Related Overgrowth Spectrum (PROS) requiring systemic therapy. In an updated withdrawal assessment report that was released earlier today (14 March), the EMA explained that the long-term safety profile of Vijoice, especially its impact on growth and development in the paediatric population, is still unknown. Furthermore, it questioned whether the assessment of tumour size was an adequate measure of patient benefit in the group of patients with the target indication. The US Food and Drug Administration (FDA) approved Vijoice in April 2022 as the first and only treatment for select patients with PROS. In May 2019, the regulator also granted approval to alpelisib, under the brand name Piqray . The treatment was made available for postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-), PIK3CA-mutated advanced or metastatic breast cancer. PROS are a group of genetic disorders in which mutations occur in the PIK3CA gene, causing overgrowth of certain body parts. Vijoice treats the condition by inhibiting the PI3K/Akt signalling pathway. See Also: Novartis exercises option to acquire IFM Due for $835m Novartis files patent for combination therapy for b-cell lymphoma with CD19 car and BCL2 inhibitor In October 2023, Novartis withdrew its EU marketing authorisation application for Vijoice following an EMA evaluation. At the time of withdrawal, the agency reported concerns that the clinical data, provided from the EPIK-P2 study (NCT04589650), was not sufficient in demonstrating the exact effect of the medicine on tumour size and whether patients experienced significant reductions in tumour size. In a letter to the EMA released in the same month, Novartis had also expressed the need to acquire further data to support the drug’s benefit/risk assessment. Novartis submitted the initial application based on real-world evidence from a retrospective chart review study. However, the Swiss company was unable to answer all questions from the Committee for Medicinal Products for Human Use (CHMP) within the necessary timeframe. At the time, the Swiss company announced intentions to submit a new marketing authorisation application once it collects new data. The EMA designated the drug as an orphan medicine on 26 March 2021 for the treatment of PROS. In the EU, there are currently no disease-modifying treatments available for PROS.

上市批准孤儿药

2022-05-02

·医药观澜

诺华一季度财报：多款新药迎监管进展，2026年前预计有20+重磅新产品获批

近日，诺华（Novartis）发布2022年第一季度财报。报告显示，一季度诺华集团净销售额同比增长5%至125亿美元。其中，中国区净销售额同比增长16%至8.8亿美元。与此同时，诺华的创新药研发管线也取得了许多新进展。诺华集团首席执行官Vas Narasimhan先生在财报中提到，该公司“2026年前预计会有20多个重磅新产品获批”。本文中就让我们跟随诺华的财报看看，今年以来该公司的产品都取得了哪些重要监管和研发进展？ 1、多款新药获监管机构批准，3款新药在中国迎来新适应症根据诺华公司的报告，2022年以来，该公司有2款新药首次获得监管机构批准。其中，靶向放射性配体疗法Pluvicto（曾用名177Lu-PSMA-617）于今年3月获得美国FDA批准，用于治疗进展性前列腺特异性膜抗原（PSMA）阳性的转移性趋势抵抗性前列腺癌（mCRPC）患者。公开资料显示，Pluvicto将结合PSMA的小分子化合物与放射性同位素连接在一起，可与表达PSMA的前列腺癌细胞结合，放射性同位素释放的辐射能量会损害肿瘤细胞引发细胞死亡，这也是首款获FDA批准用于治疗这类mCRPC患者的靶向放射配体疗法今年4月，FDA基于真实世界研究数据加速批准诺华的PI3Kα抑制剂Vijoice（alpelisib）上市，用于治疗需要接受系统治疗的PIK3CA相关过度生长疾病谱系（PROS）成人和2岁及以上儿童患者。诺华新闻稿指出，Vijoice是FDA批准的首个用于治疗PROS的药物。此外，诺华还有多款药物在今年迎来了新适应症，其中有3款新药在中国获批新适应症： -Beovu（brolucizumab）：一种靶向抑制VEGF的人源化单链抗体片段，于今年3月获得欧盟委员会批准用于治疗糖尿病性黄斑水肿（DME）。此前，该药已在欧盟获批治疗湿性年龄相关性黄斑变性。 -奥马珠单抗：一种抗IgE人源化单克隆抗体，于今年4月获得中国国家药监局（NMPA）批准一项新适应症，用于治疗采用H1抗组胺药治疗后仍有症状的成人和青少年慢性自发性荨麻疹患者。此前，该药已在中国获批用于治疗成人及6岁以上儿童的中重度过敏性哮喘。 -甲磺酸达拉非尼联合曲美替尼：达拉非尼是一种选择性BRAF激酶活性抑制剂，曲美替尼是一种可逆的、高选择性MEK1和MEK2激酶活性的变构抑制剂。今年3月，这一双靶向联合疗法获得NMPA批准一项新适应症，用于治疗BRAF V600突变阳性转移性非小细胞肺癌。此前，该联合疗法已在中国获批用于治疗BRAF V600突变阳性的不可切除或转移性黑色素瘤、以及用于BRAF V600突变阳性的III期黑色素瘤患者完全切除后的辅助治疗。 -依维莫司：一种口服的mTOR选择性抑制剂，于今年2月获得NMPA批准一项新适应症，联合依西美坦用于治疗来曲唑或阿那曲唑治疗失败后的HR+/HER2-绝经后晚期女性乳腺癌患者。此前，该药已在中国获批用于治疗晚期肾细胞癌、结节性硬化症相关的肾血管平滑肌脂肪瘤、神经内分泌瘤等。除了上述药物，诺华还有多款新药取得新的监管进展，包括：欧洲药品管理局人用药品委员会（CHMP）支持批准JAK抑制剂ruxolitinib，用于治疗12岁及以上急性移植物抗宿主病或慢性移植物抗宿主病（GvHD）患者；CHMP支持批准CAR-T疗法Kymriah扩展适应症，用于治疗接受过两种以上全身性治疗的复发/难治性滤泡性淋巴瘤患者；从百济神州引进的抗PD-1抗体替雷利珠单抗上市申请获得欧洲药品管理局受理，申请的适应症包括晚期或转移性食管鳞状细胞癌患者和多种非小细胞肺癌。 2、CDK 4/6抑制剂、KRAS抑制剂等迎来新研究进展根据诺华公司报告，今年以来，该公司的KRAS抑制剂、CDK 4/6抑制剂、脊髓性肌萎缩症（SMA）基因疗法、抗CD20单抗也在临床研究中取得积极的研究数据，它们取得的进展分别如下。 JDQ443是一款口服选择性KRAS G12C共价抑制剂，它能够不可逆地将KRAS G12C锁定在失活状态，在临床前研究中表现出良好的抗癌活性。在2022年4月举行的美国癌症研究协会（AACR）上，诺华公布了该候选药治疗晚期非小细胞肺癌患者的1/2期临床试验初步结果。数据显示，在接受推荐剂量治疗的患者中，患者的客观缓解率（ORR）为57%。利柏西利（ribociclib）是一种选择性CDK 4/6抑制剂，此前已在多个国家和地区获批用于治疗多种乳腺癌适应症，并已在中国申报上市。来自3期临床MONALEESA-2的最新数据显示，HR+/HER2-晚期或转移性乳腺癌绝经后妇女接受利柏西利治疗后，总生存期增加超过12个月，具有统计学意义。其它分析还显示，与单独接受来曲唑治疗的患者相比，接受利柏西利+来曲唑作为一线治疗的患者死亡风险降低了24%。 Zolgensma（onasemnogene abeparvovec）是首款被批准用于治疗SMA的基因疗法。今年3月，诺华公布了一项3期临床试验的最新数据，该研究旨在评估具有2或3个SMN2拷贝的SMA患者在出现症状前一次性静脉输注Zolgensma的安全性和疗效，患者年龄≤6周。试验结果显示，具有3个SMN2基因拷贝并在出现症状前接受治疗的儿童达到了符合年龄的运动里程碑，包括站立和行走、不需要通气或饲管支持，且无严重、治疗相关不良事件。此外，1型SMA患儿在接受Zolgensma治疗后实现或维持了重要的延髓功能指标，包括说话能力、吞咽和满足营养需求、以及维持气道保护。值得一提的是，近期该药也在中国启动了3期临床试验。 Kesimpta（ofatumumab）是一款靶向CD20的单克隆抗体药物，已获FDA批准治疗复发型成人多发性硬化（RMS）患者。今年4月，诺华公布的来自ASCLEPIOS和ALITHIOS研究的最新数据显示，Kesimpta治疗复发型多发性硬化患者具有长期的疗效和安全性，能将患者的残疾恶化风险降低长达4年，且IgG 水平稳定。此外，KYRIOS研究表明接受Kesimpta治疗的患者可以对COVID-19 mRNA疫苗产生免疫反应。此外，诺华还在第一季度与其它公司就创新疗法开发达成合作。今年1月，诺华宣布与Alnylam公司达成合作，利用后者专有的小干扰核糖核酸（siRNA）技术开发一种旨在恢复终末期肝病（ESLD）患者功能性肝细胞再生的创新疗法，为肝衰竭患者提供肝脏移植的替代方法。今年3月，诺华和Voyager Therapeutics公司达成许可和研发协议，利用后者的创新AVV衣壳开发针对神经系统的下一代基因疗法。诺华在财报中表示，未来该公司将继续深入五个核心治疗领域（心肾、免疫学、神经科学、实体瘤和血液学）的研究，并加强公司在基因治疗、细胞治疗、放射配体治疗、靶向蛋白降解和xRNA技术平台方面的实力。诺华集团首席执行官Vas Narasimhan先生在财报中表示，该公司的中期在研产品线进展良好，2026年前预计会有20多个重磅新产品获批。参考资料： [1] First quarter 2022 results. Retrieved Apr 26, 2022, from https://www.novartis.com/investors/event-calenda [2] 诺华财报 | 2022年第一季度集团净销售额同比增长5%，创新药物同比增长4%. Retrieved Apr 27, 2022, from https://mp.weixin.qq.com/s/TOIQhyTkOZzMUAUJ1zE7uw [3] 诺华公司官网. From https://www.novartis.com.cn/xin-wen-zhong-xin/xin-wen-fa-bu 内容来源于网络，如有侵权，请联系删除，谢谢。

财报免疫疗法抗体放射疗法基因疗法

2022-04-07

·新浪医药新闻

基于真实世界证据 FDA批准诺华PI3K抑制剂

4月6日，诺华（Novartis）宣布，美国FDA加速批准Vijoice（alpelisib）上市，用于治疗需要接受系统治疗的PIK3CA相关过度生长疾病谱系（PROS）成人和2岁及以上儿童患者。他们表现出严重的症状。新闻稿指出，Vijoice是美国FDA批准的首个PROS治疗药物，针对特定患者的PROS疾病根本原因。 PROS泛指因PIK3CA基因突变所致病谱系，特征为血管、淋巴系统和其他组织非典型过度生长和异常，估计影响14人/100万人。与PROS相关的特异性疾病包括CLOVES综合征（丁香综合征）、巨指症、肌肉性HH和表皮痣、良性苔藓样角化病或脂溢性角化病等。PROS疾病可影响生活质量，并对患者及其家庭构成一系列身体、情绪和社会挑战，范围从功能影响和发育迟缓至慢性疼痛、运动问题和孤独感。PROS管理可能具有挑战性，需要多学科团队的合作，患者和医生只能获得专注于症状管理的干预措施。美国FDA的批准基于EPIK-P1的真实世界证据，EPIK-P1是一项回顾性、非干预性病历研究，研究显示接受Vijoice治疗的患者出现了靶病灶体积减小和PROS相关症状的改善。在第24周进行的主要终点分析显示，27%的患者（10/37）达到确认的治疗缓解，定义为PROS靶病灶体积总和减少20%以上。在基线和第24周进行影像学检查的患者中，近四分之三（74%，23/31）患者显示靶病灶体积有所缩小，平均缩小13.7%，在主要分析时无患者发生疾病进展。此外，在第24周，研究者观察到患者的疼痛（90%，20/22）、疲乏（76%，32/42）、血管畸形（79%，30/38）、肢体不对称（69%，20/29）和弥散性血管内凝血（55%，16/29）较基线获得改善。患者组织CLOVES综合征社区（CLOVES Syndrom Community）执行主任Kristen Davis女士表示：“今天PROS的首个治疗药物获批，为受这些罕见病症影响的患者和家庭提供了更好生活质量的希望。PROS状况可能使人衰弱和致残，并可能导致日常活动中断。直到今天，患者的唯一治疗选择往往是手术或介入放射学手术。” 诺华美国创新药部门总裁Victor Bulto先生表示：“Vijoice的获批标志着患者的一个转折点，直到现在，这些患者还没有一种获批的疗法来专门解决他们的疾病，我们感谢参与EPIK-P1试验的医生、患者和家属。我们正在继续投资研究，以推进对PROS状况的科学理解，并了解Vijoice的全部潜力。” 参考来源： [1] FDA approves Novartis Vijoice® (alpelisib) as first and only treatment for select patients with PIK3CA-Related Overgrowth Spectrum (PROS). Retrieved 2022-04-06, from https://www.globenewswire.com/news-release/2022/04/06/2417163/0/en/FDA-approves-Novartis-Vijoice-alpelisib-as-first-and-only-treatment-for-select-patients-with-PIK3CA-Related-Overgrowth-Spectrum-PROS.html 内容来源于网络，如有侵权，请联系删除，谢谢。

免疫疗法加速审批放射疗法